PATHOLOGY PAO 2101

REVIEW SUMMARY

Uniformed Services University

School of Medicine

A Vocabulary Based Approach to Pathology:

From Robbins Pathologic Basis of Disease

Block 1 & Quiz Chapters

Page

1. Diseases of Immunity

.5

2. Environmental Diseases

21

3. Infectious Diseases

31

4. Blood Vessels

37

Block 2

Page

1. Blood RBC

50

2. Blood WBC

60

3. Blood Bleeding Disorders

72

4. Pulmonary System

76

5. Gastrointestinal System

96

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A Vocabulary Based Approach to Pathology:

From Robbins Pathologic Basis of Disease
Block 3

Page

1. Liver and Biliary Tract

114

2. Pancreas

130

3. Kidney

142

4. Male Genital System

...158

5. Endocrine

170

6. Female Genital System and Breast

188

7. Skin

204

Block 4

Page

1. Musculoskeletal

215

2. The Nervous System

229

3. Genetic Diseases

245

4. Pediatric Diseases

255

5. Multisystem Review

263

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PATHOLOGY PAO 2101

BLOCK I

Uniformed Services University

School of Medicine

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CHAPTER 5
DISEASES OF IMMUNITY
There are two interrelated components of the immune system designed to protect against extracellular and
intracellular pathogens:

Humoral immunity: is mediated by Blymphocyte produced antibodies which can

directly neutralize extracellular microbes or by
activating the complement cascade and
neutrophils and macrophages.
Cellular immunity: is mediated by Tlymphocytes after antigen is presented to them
in two ways: (1) direct lysis of target cells
(cytotoxic T-cells), or (2) controlling the
immune response by producing cytokines (Thelper cells).

CELLS OF THE IMMUNE SYSTEM

Pg 104 107
B-lymphocyte
B-lymphocytes are the source of antibodies, which participate in immunity either by
directly neutralizing extracellular microbes or by activating complement and certain
effector cells to kill microorganisms.
B-cell receptor (BCR): is a monomeric surface IgM that allows B-cells to
recognize antigen.
Plasma cell: After stimulation, B cells for
plasma cells that secrete immunoglobulins,
which in turn are the mediators of humoral
immunity.
There are five types of
immunoglobulins (IgG, IgA, IgM, IgE, and IgD)
each with a unique function in activating
compliment or recruiting inflammatory cells.

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T-lymphocyte
T-lymphocytes can either directly lyse targets (cytotoxic T cells; CD8 T cells), or
orchestrate the antimicrobial immune response of other cells by producing soluble protein
mediators called cytokines (made by Helper T cells; CD4 T cells which are further
divided into TH1 and TH2 cells). Cytokines can be further divided into interleukins (IL)
and interferons (IFN).
Major histocompatibility complex (MHC): T cells can only see
antigen that has been processed and presented by other cells in
the context of MHC. There are
two classes of MHC
molecules: CD4 T cells recognize MHC class II molecules
which are found on antigen presenting cells, while CD8
T cells recognize MHC class I molecules (which are found on
all nucleated cells).
Antigen-presenting cell (APC): include macrophages and
dendritic cells, process and display antigen in their MHC
molecules to activate T cells.
T-cell receptor (TCR): are found on all T cells and allows each
T cell to recognize a unique processed peptide fragment in the
context of an MHC molecule.
Macrophage
Macrophages express MHC II molecules and are critical antigen processing cells that
can activate CD4 T cells, produce cytokines which play a role in certain types of
hypersensitivity reactions, and can phagocytose and kill opsonized microbes.
Dendritic cells
There are two types of dendritic cells, interdigitating and follicular dendritic cells.
Interdigitating dendritic cells are the most potent APCs for nave T cells, express high
levels of MHC class II and costimulatory molecules, and are widely distributed
throughout the body. Follicular dendritic cells are localized to germinal centers of
lymphoid organs, express Fc receptors for IgG which trap antigen bound antibodies in the
lymph tissue, and facilitate the maintenance of immunologic memory.
Langerhans cells: are interdigitating dendritic cells that exist in the epidermis.
Natural killer (NK) cells
NK cells comprise 10-15% of blood lymphocytes and are able to lyse a variety of tumor
cells, virally infected cells, and some normal cells without previous sensitization. As
such, they are classified as part of the innate immune system (immunity you are born
with).

HISTOCOMPATIBILITY MOLECULES & CYTOKINES

Pg 107 110
Human leukocyte antigen (HLA)
The principle role of histocompatibility
molecules is to bind peptide fragments of
foreign proteins for presentation to
appropriate antigen-specific T-cells. A
cluster of genes on chromosome 6, known
as the MHC complex, codes for these
molecules. Class I molecules are coded
by the loci HLA-A, B, and C loci, and
Class II molecules are coded by HLA-D,
Q, and R. Each person inherits one HLA
allele from each parent; therefore, heterozygous individuals can express 6 different class I
and II molecules. A person will recognize and mount an immune response against a
given antigen only if they inherit those MHC molecules that can bind the antigenic
peptide. Many diseases are associated with HLA types (summarized in the table), and
seems to be the source of several questions on Q-bank!
Autocrine effect
Refers to the effect induced by a cytokine when they act on the same cell that produces
them.
Paracrine effect
Refers to the effect induced by a cytokine when they affect other cells in their vicinity.
Endocrine effect
Refers to the effect induced by a cytokine when they affect cells systemically.
Colony-stimulating factors (CSF)
These cytokines, which are produced by lymphocytes and bone marrow stromal cells,
stimulate hematopoiesis.
Superantigens
Superantigens are a class of microbial proteins that bind to class II MHC molecules
outside the antigen binding cleft and activate a large number of CD4 T cells in an
antigen-nonspecific manner. This results in widespread cytokine mediated pathology
analogous to shock induced by LPS.

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HYPERSENSITIVITY REACTIONS
Pg 111 121

Summary of the mechanisms of hypersensitivity reactions. The vocabulary below

summarizes additional key points about each type.

Type I hypersensitivity
Susceptibility to localized type I reactions appears to be genetically controlled, and the
term atopy is used to imply familial predisposition to such localized reactions. Within
minutes of exposure in a sensitized host, itching, urticaria (hives), and skin erythema
appears. Without immediate intervention, there may be systemic vasodilation
(anaphylactic shock), and the patient may progress to circulatory collapse and death
within minutes.
Type II hypersensitivity
The hypersensitivity response results from abtibody binding followed by one of three
different mechanisms:
Complement: mediates type II hypersensitivity through direct lysis and
opsonization. Direct lysis occurs when antibody bound to a cell surface antigen
causes fixation of complement to the cell surface with subsequent lysis via the
membrane attack complex. Cells coated with antibodies and C3b (opsonized) are
also susceptible to phagocytosis.
Antibody-dependent cell-mediated cytotoxicity (ADCC): involves killing via cell
types that bear receptors for the Fc portion of IgG; targets coated by antibody are
lysed without phagocytsosis or complement fixation.
Antibody-mediated cellular dysfunction: antibodies directed against cell surface
receptors impair or dysregulate function without causing cell injury or
inflammation (as in Graves disease or myasthenia gravis).

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Type III hypersensitivity

Acute serum sickness was first described in humans when large amount of foreignserum
were administered for passive immunization. Approximately 5 days after foreign protein
is injected, specific antibodies are produced which react with the antigen still present in
the circulation to form complexes. These complexes deposit in tissue beds and cause an
inflammatory reaction leading to fever, urticaria, arthralgias, node enlargement, and
proteinuria.
Fibrinoid necrosis: is the descriptive term applied to the appearance of necrotic
vessel walls which take on a smudgy eosinophilic appearance due to protein
deposition.
Arthus reaction: is defined as a localized area of tissue necrosis resulting from
acute immune complex vasculitis. It is seen experimentally when antigen is
injected into the skin of a sensitized person and manifests as a few hours later as
visible edema and hemorrhage.
Type IV hypersensitivity (DTH)
A classic example of DTH is the tuberculin reaction, elicited in an individual already
sensitized to the tubercle bacillus by a previous infection. Eight-twelve hours after
intracutaneous injection with tuberculin, a local area of erythema and induration appears.
It is used to screen the population for tuberculosis.
Granuloma: is a special form of DTH occurring in the setting of persistent
antigens. Accumulated, activated macrophages become large, flat, and
eosinophilic (now termed epithelioid cells). These epitheliod cells occasionally
fuse together to form multinucleated giant cell.
T-cell mediated cytotoxicity: is another form of type IV hypersensitivity where
CD8 T-cells kill antigen-bearing cells. This is done through two mechanisms: (1)
through the release of perforin (which punches holes in cells walls) and
granzymes (which enter target cells activate apoptosis), and (2) expression of Fas
ligand, a molecule that binds Fas on target cells activating apoptosis.

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TRANSPLANT REJECTION
Pg 121 125
Generally Speaking
In general terms, humoral rejection is associated with a vasculitis and damage to the
blood vessels. T-cell mediated rejection is associated with parenchymal damage and
edema. There are three types of rejection based on the time that they occur:
(1) Hyperacute Rejection (minutes hours)
This type of rejection occurs when pre-formed anti-donor antibodies are present in the
host before transplant causing damage by the following mechanisms: complement
activation, immune complex formation, and ADCC-mediated pathways. Damage mainly
targets the vascular endothelium leading to thrombosis and ischemic injury to graft.
(2) Acute Rejection (10-14 days)
Acute rejection results from activation of the hosts (donor recipient) immune system
against the graft (donor parts). It is mainly a T-cell reaction though antibodies are also
involved. The immune system is activated in two ways: (1) donor dendritic cells (found
in the graft) present antigen to host CD4+ T-cells, and (2) host APCs destroy some of the
graft, process the peptides, and present it via MHC II to CD4+ T-cells. Both of these
mechanisms lead to parenchymal damage and edema, and perhaps most importantly,
endothelial cell death resulting in thrombosis and graft ischemia.
(3) Chronic Rejection (months years)
Chronic rejection mostly works by a slowly progressive destruction of the vascular
endothelium.
Graft-versus-host disease (GVHD)
GVHD can be acute or chronic. Acute GVHD causes epithelial cell necrosis in the liver,
skin, and gut leading to jaundice, GI ulceration and bloody diarrhea, and a generalized
rash. Chronic GVHD may follow acute GVHD and causes skin lesions resembling
systemic sclerosis and symptoms resembling an autoimmune disorder. GVHD can be
minimized by depleting the recipients T-cells prior to bone marrow transplant, or HLA
matching.

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AUTOIMMUNE DISEASES
Pg 125 144
Autoimmunity
An immune reaction to self-antigens.
Immunologic tolerance
Is a state in which an individual is incapable
of developing an immune response against a
specific antigen. Self-tolerance specifically
refers to a lack of immune responsiveness to
ones own tissue antigens.
Anergy
Refers to prolonged or irreversible
inactivation (rather than apoptosis) of
lymphocytes induced by encounter with
antigens under certain conditions.
Mechanisms involved in central
and peripheral tolerance.

Molecular mimicry
Some infectious agents share epitopes with self-antigens, and an immune response
against such microbes will elicit similar responses to the cross-reacting self-antigen.
Example: rheumatic heart disease following streptococcal infection because antibodies to
streptococcal M protein cross-react with cardiac glycoproteins.

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Systemic lupus erythematosus (SLE)

SLE is an autoimmune, multisystem disease that principally affects the skin, kidneys,
serosal membranes, joints, and heart. It is a disease of multifactoral origin, resulting in a
T-cell and B-cell activation that culminates in the production of several species of
autoantibodies. It affects women more than men and black women more than anyone
else.
Antinuclear antibodies (ANA): are directed against
several nuclear antigens and
can be grouped into
four categories, those against DNA, histones, non-histone
protein bound to RNA, and antibodies to nucleolar antigens.
They are present in nearly all patients with SLE, but may
be found in other immune diseases.
Smith (Sm) antigen: the presence of antibodies to doublestranded DNA, or to the so-called Smith (Sm) antigen, is
virtually diagnostic of SLE.

Lupus anticoagulant: phospholipids are required for clotting and patients with
anti-phospholipid antibodies may display prolongation of in-vitro clotting tests,
such as the PT time; therefore, these antibodies are referred to as lupus
anticoagulants.
Antiphospholipid antibody syndrome: refers to the fact that SLE patients are
actually in a prothrombotic state despite the prolonged PT time. They tend to
have venous and areterial thromboses, thrombocytopenia, and recurrent
spontaneous miscarriages.
LE cell: a phagocytic cell that has engulfed the denatured nucleus of another
injured cell. When blood is withdrawn and agitated, a number of WBC are
damage to expose their nuclei to ANAs, with secondary compliment activation;
these nuclei are then phagocytized. This LE test is present in 70% of SLE
patients but is not used any longer.
Acute necrotizing vasculitis: is characterized by necrosis and by fibrinoid deposits
within vessel walls containing antibody, DNA, complement, and fibrinogen. In
chronic states, this can lead to thickening and luminal narrowing.
Photosensitivity: the skin is involved in the majority of patients and classically
manifests as a characteristic eryhtematous or maculopapular rash over the malar
eminences and bridge of the nose (butterfly pattern). Exposure to sunlight makes
the rash worse and the development of a new rash over other exposed areas.

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Libman-Sacks endocarditis: are valvular, non-bacterial lesions that take the form
of 1 to 3-mm warty deposits, distinctively on either surface of the leaflets and at
the margins.
Glomerulonephritis: involves deposition of DNA/anti-DNA complexes within the
glomeruli. These evoke an inflammatory response that may cause proliferation of
the endothelial, mesangial, and/or epithelial cells, and in severe cases, necrosis of
the glomeruli.

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Rheumatoid arthritis (RA)

RA is a systemic, chronic inflammatory disease affecting multiple tissues but principally
attacking the joints. The arthritis typically presents as a symmetric arthritis, mainly
affecting the small joints (excluding the DIP joints), may be accompanied by
constitutional symptoms, and causes joint pain and stiffness that is worse in the morning.
The joint inflammation is immunologically mediated; however, the initiating antigen is
not known.
Rheumatoid factor (RF): is circulating IgM autoantibodies
directed against the Fc portion of IgG and are present in 80% of
patients. RFs and IgG form immune complexes that fix
complement, attract neutrophils, and lead to tissue injury by a
type III hypersensitivity reaction.
Synovitis: in the affected joints is characterized by synovial cell
hyperplasia, perivascular infiltrates of CD4 T-cells, plasma cells,
and macrophages, angiogenesis, organizing fibrin on the
synovial surface in the joint space, and increased osteoclast
activity.

Pannus: is proliferating tissue composed of synovial and inflammatory cells,

granulation tissue and fibrous connective that it causes the usually smooth
synovial membrane to become thickened into edematous, villous projections.
Rheumatoid subcutaneous nodule: are firm, nontender, masses up to 2-cm in
diameter that occur along the extensor surface of the forearm or other areas
subjected to pressure. They have a central focus of fibrinoid necrosis surrounded
by a palisade of macrophages, which is rimmed by granulation tissue.
Juvenile rheumatoid arthritis (JRA)
JRA refers to a group of disorders that cause chronic, idiopathic arthritis in children. RF
is usually absent, as are rheumatoid nodules. Some variants involve relatively few larger
joints such as knees, elbows, and ankles and are thus called pauciarticular.
Seronegative spondyloarthropathy
A group of disorders characterized by: (1) pathologic changes that begin in the
ligamentous attachments to bone, (2) involvement of the sacroiliac joints, (3) absence of
RFs, and (4) association with HLA-B27. Ankylosing spondylitis is the prototype for this
group of diseases.

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Sjogren syndrome
Is a clinicopathologic entity characterized by dry eyes (keratoconjunctivitis) and dry
mouth (xerostomia) resulting from immune-mediated destruction of the lacrimal and
salivary glands. I can exist alone, but usually accompanies another immune disorder
(most commonly RA). leading to inflammation and ulceration,
Ribonucleoprotein (RNP) antigens (SS-a (Ro) and SS-B (La)): autoantibodies to
these antigens are found in most patients with primary Sjogren syndrome though
they are not specific for the disease.
Systemic sclerosis (SS; Scleroderma)
SS is characterized by excessive fibrosis throughout the body to include the skin (hence
scleroderma) and internal organs. It occurs most frequently in females and has a peak
incidence between 30 50 years of age. It is divided into two groups based on it clinical
course:
Diffuse sclerodema: is characterized by initial
widespread skin involvement, with rapid
progression and early visceral involvement.
DNA topoisomerase I (anti-Scl-70): is a
marker for patients likely to develop
more aggressive SS with pulmonary
fibrosis
and
peripheral
vascular
pathology.
Possible mechanisms
leading to systemic sclerosis.

Limited: is characterized by minimal skin involvement with visceral involvement

late. This is also called the CREST syndrome because of its frequent features of
Calcinosis, Raynaud phenomenon, Esophageal dysmotility, Sclerodactyly, and
Telangiectasia.
Raynaud phenomenon: is a vascular disorder characterized by reversible
vasospasm of the arteries. Exposing the hands to the cold produces a
series of color changes (from white, to blue, and then red) as the arterioles
constrict and then relax again.
Anticentromere antibody: is found in 90% of patients with limited
scleroderma and indicates a relatively benign course.

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Inflammatory myopathy
A group of disorders that are characterized by immune-mediated muscle injury and
inflammation causing symmetric weakness in the large muscles of the trunk, neck, and
limbs. Histologically, a lymphocytic infiltrate is mixed in with degenerating and
regenerating muscle fibers. There are three distinct disorders: (1) polymyositis, (2)
dermatomyositis is associated with a rash described as a lilac (heliotrope) discoloration
affecting the periorbital area, and (3) inclusion body myositis.
Jo-1 antibody: is an antinuclear antibody specific for this group of disorders
directed against tRNA synthetase.
Creatine Kinase: is elevated in these patients due to increased muscle breakdown.
Mixed connective tissue disease (MCTD)
Is used to denote the presence of features consistent with SLE, polymyositis, and
systemic sclerosis in the same patient. These patients have elevated levels of antibodies
to an RNP antigen called U1RNP and show an excellent response to corticosteroids.
Polyarteritis nodosa
PAN belongs to a group of diseases characterized by necrotizing inflammation of the
walls of blood vessels, most likely of an immune pathogenesis.
IMMUNODEFICIENCY DISEASES
Pg 144 158

Scheme of lymphocyte development and sites of

block in primary immunodeficiency diseases.
The affected genes are indicated in parentheses
for some of the disorders. ADA, adenosine
deaminase; CD40L, CD40 ligand; SCID, severe
combined immunodeficiency.

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X-linked agammaglobulinemia (Bruton disease)

Results from a mutation in the tyrosine kinase involved in pre-B cell transduction
causing failure of pre-B cells to differentiate into B-cells. Patients have an absence of Bcells and gamma globulin, and small germinal centers. Presentation with Brutons
disease occurs mainly in males after six months of age with recurrent bacterial
infections (mostly) and to a lesser extent, recurrent viral and protozoal infections.
Common variable immunodeficiency
A heterogenous group of disorders characterized by hypogammaglobulinemia, impaired
antibody responses to infection (vaccination), and increased numbers of infections.
Patients have a normal number of B-cells; however there is a lack of plasma cells.
Males and females are affected equally and present in the 2-3rd decade of life.
IgA deficiency
Affects 1/700 white people and is characterized by a low level of IgA due to a block in
the terminal differentiation of IgA-secreting B cells to plasma cells. These patients are
usually asymptomatic, though they have an increased risk for sinopulmonary and GI
infection (diarhhea).
Hyper-IgM syndrome
Patients with Hyper-IgM syndrome can produce IgM antibodies in response to antigen
but lack the ability to produce IgG, IgA, or IgE due to a failure of T-cells (mutated
CD40L) to induce isotype switching in B cells. There is an increased frequency of
pyogenic infections, a suppressed DTH response, and an increased risk of autoimmune
hemolytic anemia and pancytopenia due to IgMs ability to react with the blood elements.
Thymic hypoplasia (DiGeorge syndrome)
As a consequence of a malformation affecting the third and fourth pharyngeal arches, the
thymus fails to develop properly and there is a subsequent lack of maturation of T-cells.
Infants with this defect are vulnerable to viral, fungal, and protozoal infections, have
absent thymic shadows on x-ray, and may have tetany resulting from hypocalcemia (due
to absence of parathyroid glands).
Severe combined immunodeficiency (SCID)
Diseases with defects in both humoral and cell-mediated immunity are termed SCID.
The result is a severely increased susceptibility of affected infants to a wide range of
pathogens. In 40-50% of cases, this is an autosomal recessive disease, with half of those
having a mutation in adenosine deaminase (ADA), an enzyme involved in purine
metabolism. Patients have a hypoplastic thymus, the lymph tissues are atrophic and lack
germinal centers, and may have marked lymphopenia.
Wiscott-Aldrich syndrome
This is an X-linked disease characterized by thrombocytopenia, eczema, and a marked
vulnerability to recurrent infection, ending in early death. In these patients, there is
progressive depletion of T-cells with loss of cell mediated immunity.

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C1 esterase inhibitor deficiency

A lack of C1 esterase inhibitor allows unfettered C1 esterase activation with the
generation of downstream vasoactive complement mediators; the result is hereditary
angioedema, characterized by recurrent episodes of localized edema affecting skin and/or
mucous membranes.
Acquired immunodeficiency syndrome (AIDS)
AIDS is a retroviral disease caused by the Human immunodeficiency virus (HIV) and is
characterized by profound immunosuppression leading to opportunistic infections,
secondary neoplasms, and neurologic manifestations.
Pneumocytis carinii: is an opportunistic fungus that causes pneumonia and is the
presenting feature in many cases. The risk for this increased dramatically when
the CD4 count falls below 200 cells/uL.
Mycobacterium avium-intracellulare: is another disease that is seen more
frequently among the AIDS population.
Kaposi sarcoma/human herpes virus 8 (HHV8): infection leads to the
development of Kaposi sarcoma, a vascular tumor that is the most common
neoplasm in AIDS patients. It is characterized by multicentric, aggressive,
violaceous lesions that affect the skin, mucous membranes, GI tract, lymph nodes,
and lungs.

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AMYLOIDOSIS
Pg 158 164
Amyloidosis
This is a group of diseases that share in common the deposition of similar appearing
proteins. Amyloidosis affects many organs causing a wide-range of symptoms: renal
disease leading to nephrotic snydrome, hepatosplenomegaly may be a presenting clinical
finding though is often asymptomatic, or cardiac abnormalities which may present as
conduction abnormalities and arrhythmias. Cardiac and renal involvement are important
causes of death in amyloidosis.
Amyloid
Amyloid is the generic term for a variety of proteinaceous materials that are abnormally
deposited in tissue interstitium in a spectrum of clinical disorders. It appears as an
eosinophilic, extracellular substance that is constructed of non-branching fibrils arranged
in a -pleated sheet. This architecture allows it to be visualized with Congo red staining,
an important diagnostic tool. There are three major forms of amyloid:
(1) AL (Amyloid light chain): is derived from plasma cells, contains
immunoglobulin light chains, and is associated with some form of monoclonal Bcell proliferation.
(2) AA (Amyloid-associated): is a unique non-immunoglobulin protein
synthesized by the liver and is typically deposited in the setting of chronic
inflammatory states.
(3) A amyloid: is found in the cerebral lesions of Alzeihmer disease, as well as
the blood vessels. The A is derived from the larger transmembrane glycoprotein,
called amyloid precursor protein (APP).
Transthyretin (TTR): is a normal serum protein that binds and transports
thyroxine and retinal. A mutant form of TTR is deposited in a group of genetic
disorders called familial amyloid polyneuropathies. Normal TTR is responsible
for senile amyloidosis affecting the heart.
2-microglobulin: is a normal serum protein and component of MHC I molecules
that is responsible for amyloidosis in patients on long-term hemodialysis (it
deposits in the synovium, joints, and tendon sheaths).

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Primary amyloidosis
This term is applied to amyloidosis when it is associated with some immunocyte
dyscaria. It is usually systemic in distribution and the amyloid is of the AL type.
Multiple myeloma: is a malignant neoplasm of B-cells that characteristically
synthesize abnormal amounts of a single specific immunoglobulin, producing an
M (myeloma) protein spike on serum electrophoresis.
Bence-Jones protein: are or light chains secreted by the malignant B-cells of
multiple myeloma. Nearly all patients with myeloma who develop amyloidosis
have these proteins in their blood and/or urine.
Secondary amyloidosis
This is the term applied to amyloidosis when it occurs as a complication of an underlying
chronic inflammatory or tissue destructive process. It is seen most often in the setting of
chronic inflammation caused by autoimmune states (rheumatoid arthritis, ankylosing
spondylitis, and inflammatory bowel disease). It may also occur with non-immunocytederived tumors, as in renal cell carcinoma and Hodgkin disease.
Familial Mediterranean Fever
Is an autosomal recessive condition characterized by attacks of fever accompanied by
inflammation of serosal surfaces, including peritoneum, pleura, and synovial membrane.
It is associated with systemic amyloidosis composed of AA proteins.

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CHAPTER 8
ENVIRONMENTAL DISEASES
Environmental disease
Injuries and illnesses that result from exposure to exogenous chemical or physical agents,
to include those in the workplace, as well as personal habits (alcohol, cigarette smoking,
and drug use), and nutritional status.
Ozone
Ozone arises from interactions of oxygen with various pollutants such as oxide of
nitrogen, sulfur, and hydrocarbons. It is highly reactive and oxidizes polyunsaturated
lipids that become irritants and induce release of inflammatory mediators affecting all
airways down to bronchoalveolar junctions. After exposures, healthy subjects experience
mild respiratory symptoms (decreased lung function and pain), but those with asthma or
emphysema or harmed even more.
Mucociliary escalator
This is the name referring to the action of the pseudostratified ciliated columnar
epithelium that lines the respiratory tract. When particles are inhaled, they are trapped in
the cilia of these cells. The cilia moves the material up the trachea and tosses it into the
esophagus.
Radon
Radon is a radioactive gas derived from uranium, and is widely present in soil. It can
seep into homes (especially those near nuclear power plantslike the Simpsons).
Exposure to low levels of radon over time has been suspected in the etiology of lung
cancer.
Bioaerosol
These range from microbiologic agents capable of causing infectious diseases such as
legionnaires disease, viral pneumonia, and the common cold, and also else threatening
but nonetheless distressing allergens derived from pet dander, dust mites, and
fungi/molds responsible for rhinitis, eye irritation, and even asthma.
Pneumoconiosis
This is a term to describe the non-neoplastic lung reaction/diseases to inhalation of
organic as well as inorganic particulates, and even chemical fume and vapor induced lung
diseases. The four most common pneumoconiosis are mineral dusts: coal dust, silica,
asbestos, and beryllium (almost all occur in the workplace). Particles that are 1-5
micrometers are the most dangerous because they impact on the bifurcation of the distal
airways.

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Pulmonary Alveolar Macrophages

These are the key players that lead to the initiation and perpetuation of lung injury and
fibrosis. They release free radicals, chemotactic factors, and fibrogenic cytokines that
cause the damage to the lung followed by fibrosis via collagen deposit.
Anthracosis
Usually asymptomatic accumulation of carbon pigment in the lungs without a perceptible
cellular reaction. This is seen in coal miners, urban dwellers, and tobacco smokers.
Inhaled carbon pigment is engulfed by alveolar or interstitial macrophages, which then
accumulate in the connective tissue along the lymphatics.
Coal workers pneumoconiosis (CWP)
Disease in which cellular accumulations of macrophages occur with little to no
pulmonary dysfunction. This is characterized by coal macules (dust-laden macrophges)
and somewhat larger coal nodules (macules + collagen fibers). Again, usually
asymptomatic to mild symptoms, but can develop into PMF.
Progressive massive fibrosis (PMF)
This disease is also called complicated CWP. There is extensive fibrosis and lung
function is compromised. Worsening of CWP with coalescence of coal nodules and
intensely blackened scars 2-10 centimeters in diameter. These scars contain dense
collagen and pigment.
Emphysema
Centralobular emphysema can be a complication of CWP. Type of emphysema where
the pattern of involvement targets the central/proximal part of the acinus, which is formed
by the respiratory bronchioles. Seen most often in people who smoke cigarettes. Affects
the upper lobes more severely.
Caplan syndrome
This syndrome is defined as the coexistence of rheumatoid arthritis with a
pneumoconiosis, leading to the development of distinctive nodular pulmonary lesions
that develop fairly rapidly. These nodules exhibit central necrosis surrounded by
fibroblasts, plasma cells, macrophages, and collagen. This also occurs in asbestosis and
silicosis.
Silicosis (crystalline/amorphous)
Silicosis is caused by inhalation of crystalline silica, mostly in the occupational settings.
Silica exists in two forms: crystalline (more dangerous) and amorphous forms. Quartz is
most frequently implicated in the cause of silicosis. Silicosis is associated with an
increased susceptibility to tuberculosis. Silicotic nodules have a distinctive whorled
appearance. Sometimes lymph nodes develop eggshell calcification in silicosis.

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Acute: Results from high level exposure to silica shortly after the incident.
Histologically, there is interstitial inflammation and the accumulation of
proteinaceous fluid rich in surfactants within the alveolar spacs.
Chronic: Results from inhaling silica over long periods of time with formation of
fibrotic nodules of silicosis. Primarily affects upper lobes and subpleural spaces.
Radiologically appear as well demarcated rounded opacities.
Complicated: Results from progression of chronic silicosis, with expansion and
coalescence of individual silicotic nodules and destruction of lung parenchyma.
This is exactly the same as PMF!
Asbestosis/serpentine/amphibole/chrysotile
Asbestosis is diffuse parenchymal interstitial fibrosis. There are two types of asbestos
based on their geometry: serpentine (curly and flexible) and amphibole (straight and
more dangerous). A crystal of asbestos is called a chrysotile. Asbestosis is linked to
increased risk of bronchiogenic carcinoma, fibrous plaques, and mesotheliomas. In
contrast to silicosis and CWP, asbestosis begins in the lower lobes.
Asbestos body
In asbestosis, you will see golden brown, fusiform or beaded rods with a translucent
center. They consist of asbestos fibers coated with an iron-containing protenaceous
material.
Berylliosis
Heavy exposure to beryllium may cause acute pneumonitis, while more protracted lowdose exposure may cause pulmonary and systemic granulomatous lesions that closely
mimic those of sarcoidosis. Berylliosis is caused by induction of T-cell-mediated
immunity in susceptible individuals. Beryllium acts as a hapten that binds to proteins.
This leads to the formation of non-caseating granulomas in the lungs and hilar nodes
that become fibrotic. Hilar adenopathy is present in about half of the cases.
Adverse drug reaction (ADR)
Adverse drug reactions refer to untoward effects of drugs that are given in conventional
therapeutic settings, or injury by therapeutic agents. Affect 7-8% of patients admitted to
hospitals.
Oral contraceptive (OC)
OCs contain synthetic estrogens and progestrin to help counteract some of the potential
risks associated with giving estrogen alone (see below).

- 23 -

Estrogen/progestin/Hormone replacement therapy

Estrogens are used to prevent or slow the progression of osteoporosis and to reduce the
likelihood of a heart attach. Such therapy is referred to as Hormone Replacement
Therapy. There are increased risks for the following with HRT: endometrial carcinoma
and probably breast carcinoma. When estrogen is combined with progestrin (as is the
case in birth control) the risks for developing adverse side effects significantly decreases.
Acetaminophen
When taken in large doses (15-25 g), this widely used nonprescription analgesic and
antipyretic causes hepatic necrosis. Toxicity begins with nausea, vomiting, diarrhea, and
sometimes shock, and possibly jaundice. Liver failure can ensue with centrilobular
necrosis.
Acetylsalicylic acid/Salicylism
May overdose by ingesting large quantities of 325-mg tablets; can be suicidal (if take 1030g) in adults. Metabolic effects ensue; respiratory alkalosis, then acidosis that often
proves fatal. Chronic aspirin toxicity can develop in those taking 3g or more/day.
Tinnitus: ringing in the ears. A sign of aspirin toxicity.
Analgesic nephropathy
Proprietary analgesic mixtures of aspirin and phenacetin or its active metabolite,
acetapminophen, when taken over a span of years, have caused renal papillary necrosis,
referred to as analgesic nephropathy.
Lead lines
In children, excess lead interferes with the normal remodeling of calcified cartilage and
primary bone trabeculae in the epiphyses, leading to increased bone density, which is
detected as radiodense lead lines on radiographs.
Zinc-protoporphyrin
Lead interferes with normal heme synthesis, as a consequence zinc-protoporphyrin is
formed instead of heme. Thus, the elevated blood level of zinc-protoporphyrin or its
product, free erythrocyte protoporphyrin, is an important indicator of lead poisoning.
Basophilic stippling
Even more distinctive is a punctuate basophilic stippling of the erythrocytes.
Wristdrop/footdrop
At the severe end of lead toxicity manifestations a peripheral demyelinating neuropathy
appears, typically involving the motor innervations of the most commonly used muscles.
Thus, the extensor muscles of the wrist and fingers are often the first to be affected,
followed by paralysis of the peroneal muscles (this is called wrist-drop and foot-drop).

- 24 -

Lead colic
This is another possible (gastrointestinal) manifestation of lead toxicity and is
characterized by extremely severe, poorly localized abdominal pain.
Carbon monoxide
This nonirritating, colorless, tasteless, odorless gas produced by the imperfect oxidation
of carbonaceous materials continues to be a cause of accidental and suicidal death. CO
acts as a systemic asphyxiant. Hemoglobin binds CO with 200x greater affinity than it
binds to O2.
Carboxyhemoglobin
This is the term applied to the complex formed when CO binds to hemoglobin and
displaces oxygen; it is thus rendered incapable of carrying oxygen. In light skinned
patients, acute poisoning is marked by a characteristic generalized cherry-red color of the
skin and mucous membranes, resulting from carboxyhemaglobin.

- 25 -

Cytochrome P-450 (enzyme system)

With rising blood alcohol levels, cytochrome P450 (in the liver) biotransforms alcohol to
acetaldehyde (causes widespread tissue damage). The acetaldehyde is then converted to
acetic acid. Chronic alcoholics have an increased number of P450 in their livers leading
to an increased tolerance for alcohol. Increased P450 can increase the metabolism of
other drugs as well, such as cocaine and acetaminophen.
Cocaine
Cocaine produces an intense euphoria with so-called reinforcing qualities, making it one
of the most addictive of all drugs. The most serious effects of cocaine relate to its effect
on the cardiovascular system, where it behaves as a sympathomimetic.
Sympathomimetic
This means it mimics the sympathetic nervous system. The next effect is the
accumulation of these two neurotransmitters (epi and norepi) in the synapses, resulting in
excess stimulation, manifested by tachycardia and hypertension, dilated pupils and
vasoconstriction. Cocaine also induces myocardial ischemia and lethal arrythmias.
Hyperpyrexia
The most common CNS finding in cocaine use is hyperpyrexia (extremely elevated body
temperature) and seizures.
Rhabdomyolysis
This is a fatal disease that entails the breakdown of skeletal muscle.
Heroin
The effects of Heroin are varied and can include euphoria, somnolence, and sedation.
The possible negative of using heroin are sudden death due to overdose, pulmonary
complications infections complications due to IV drug use, cutaneous lesions due to
inserting needles, and kidney disease.
Marijuana/tetrahydrocannabinol (THC)
When it is smoked, 5-10% of the THC (active ingredient) is absorbed. The use of pot
distorts sensory perception and impairs motor coordination. There are a series of
smoking related illness: laryngitis, bronchitis, pharyngitis. Pot also increases the heart
rate and sometimes blood pressure.
Abrasion
An abrasion is a wound produced by scraping or rubbing, resulting in removal of the
superficial layer.
Contusion
A contusion, or bruise, is a wound usually produced by a blunt object and is characterized
by damage to blood vessels and extravasation of blood into tissues.

- 26 -

Laceration
A laceration is a tear or disruptive stretching of tissue caused by the application of force
by a blunt object. Most lacerations have intact bridging blood vessels and jagged,
irregular edges.
Incised wound
An incised wound is one inflected by a sharp instrument. The bridging blood vessels are
severed.
Puncture wound/penetrating/perforating
A puncture wound is caused by a long narrow instrument and is termed penetrating when
it pierces the tissue and perforating when it traverses a tissue to also create an exit wound.
Hyperthermia
Heat Cramps loss of electrolytes through sweat; cramping of voluntary muscle
with vigorous exertion; body is able to maintain normal core body temperature.
Heat Exhaustion most common; sudden onset, results from failure of the CV
system to compensate for hypovolemia, secondary to water depletion.
Heat Stroke associated with high ambient temps and humidity; thermoregulation
fails and body temp rises; over 106F is grave; peripheral vasodilation with
peripheral pooling and decrease circulating blood volume;
Hypothermia
Results from prolonged exposure to low ambient temperature. At 90F, loss of
consciousness occurs, followed by bradycardia and a fib at lower temps. Chilling and
freezing of cells causes injury in two ways: (1) crystallization of intracellular water and
(2) vasoconstriction and increased permeability which can cause edema and ischemia..
Protein-energy malnutrition
A serious and often lethal disease, PEM is characterized by a dietary intake of protein and
calories inadequate to meet the bodys needs. The two ends of the spectrum are known
as marasmus and kwashiorkor. The central anatomic changes in PEM are growth failure.
Marasmus
A marasmus child is usually 60% of normal weight and suffers growth retardation and
loss of somatic protein (skeletal muscle). The visceral protein compartment is depleted
only marginally, and hence serum albumin levels are either normal or only slightly
reduced. The extremities are emaciated and the head appears too large for the body.
Kwashiorkor
Kwashiorkor occurs when there is protein deprivation with little or no depletion in the
total intake of calories. This is a more severe form of PEM than marasmus and affects
the visceral protein (liver stores) leading to fatty liver change and hypoalbuminemia.
Flaky paint appearance, hairchanges showing alternating bands of pale and darker color.

- 27 -

Cachexia
A severe form of secdonary PEM seen with advanced cancer characterized by a severe
wasting away. Possibly caused by an increasing resting metabolic rate and the
production of catabolic cytokines by the tumor (IL-1/6 and TNF).
Anorexia nervosa/Bulimia
Anorexia nervosa is self-induced starvation resulting in marked weight loss. Bulimia is a
condition in which the patient binges on food and then induces vomiting. There are
similar findings here as there was in PEM.
Amenorrhea
This is failure of menstrual bleeding resulting from decreased secretion of GnRH and
LH/FSH. It is a diagnostic feature of anorexia nervosa. Other characteristics of aneroxia
are: cold intolerance, bradycardia, constipation, dry/scaly skin, and body hair (lanugo).
Fat soluble/water soluble vitamins
Four vitamins are fat soluble: D, A, K, and E. The remaining vitamins are water soluble.
The fat soluble vitamins are more likely to be deficient in patients who have GI problems
that interfere with fat absorption (and thus Fat soluble vitamins).
Vitamin A/retinal/-carotene
Vitamin A is a fat soluble vitamin and is actually a group of related hormones in the
body. Retinol is perhaps the most important. It is oxidized in vivo to the aldehyde
retinal (the form used for visual pigment). The body can obtain B-carotene from green,
leafy vegetables which is then metabolized to active Vitamin A. Deficieny of Vitamin A
can lead to night blindness (impaired vision) and squamous cell metaplasia. Vitamin A
toxicity presents as headache, vomiting, stupor, and papilledema.
Xerophthalmia
Collectively, the ocular changes that occur with Vitamin A deficiency are called
Xerophthalmia (dry eye). First, there is dryness of the conjunctiva followed by the buildup of keratin debris in small opaque plaques (Bitot spots), and eventually erosion of the
roughened corneal surface with softening and destruction of the cornea (keratomalacia),
ultimately ending in night blindness.
Tetany
Characterized by muscular cramps and twitching. Vitamin D maintains the correct
concentration of ionized calcium in the extracellular fluid compartment required for
normal neural excitation and relation of muscle. Vitamin D deficiency leads to
decreased amount of extracellular calcium resulting in continuous muscle excitement.

- 28 -

Rickets/Osteomalacia
Rickets and Osteomalacia is the disease that occurs in children and adults respectively
due to Vitamin D deficiency. This can result from a deficient diet, but more usually from
lack of exposure to sunlight. A deficiency in Vitamin D causes hypocalcemia. The
compensatory mechanisms of PTH are then put into effect to correct this (breakdown of
bone releasing calcium into blood and phosphate into urine). In children causes bowing
of the legs. In adults, this leads to osteopenia (loss of bone mass).
Intramembraneous
Process of the development of flat bones. Mesenchymal cells differentiate directly into
osteoblasts, which synthesize the collagenous osteoid matrix on which calcium is
deposited.
Enchondral calcification
Process by which long bones are formed. Growing cartilage at the epiphyseal plates is
provisionally mineralized and then progressively resorbed and replaced by osteiod matrix
which undergoes mineralization to create bone.
Scurvy
A deficiency of water-soluble vitamin C leads to the development of scurvy,
characterized principally by bone disease in growing children and by hemorrhages and
healing defects in both children and adults. Ascorbic acid functions ina variety of
biosynthetic pathways by accelerating hydroxylation and amidation reactions; most
importantly, it functions in the hydroxylation of procollagen. Inadequately hydroxylated
procollagen cannot acquire a stable helical configuration and cannot be adequately crosslinked, so it is poorly secreted from the fibroblast. This leads to weak blood vessels
causing frequent and easy bleeding (purpura) and possibly anemia.
BeriBeri
This is a deficiency in Vitamin B1 (Thiamine). There is wet-beriberi with cardiac failure
and edema, as well as dry beriberi with peripheral neuropathy.
Pellegra
This is a deficiency of Niacin. Dont forget the three Ds of Pellagra: Diarrhea, dementia,
and dermatitis.
Vitamin B6 deficiency
Think angular cheilitis, stomatitis, and glossitis.
Obesity
Obesity is defined as a state of increased body weight, due to adipose tissue acculmation,
that is of sufficient magnitude to produce adverse health effects.

- 29 -

Body mass index (BMI)

This is a low-tech way to estimate fat accumulation. The BMI expresses weight in
relation to height. BMI = (weight in kilograms)/(height in meters)^2.
A BMI of:
20 = associated with increased mortality
25 = normal
27< = 20% excess body weight and imparts health risk
There is a greater risk of disease with central, or visceral, obesity than there is with
diffuse fat in subcutaneous tissue. These diseases include: diabetes, hypertension,
hypertriglyceridemia, low HDL and CAD.
Simply put, obesity is a disorder of energy balance.
Leptin
This is a member of the cytokine family that is secreted by adipocytes and is coded for by
the Ob gene. It regulates food intake and energy expenditure. It exerts its effects on two
classes of neurons in the hypothalamus. The abundance of leptin (therefore an abundance
of adipose cells) increases physical activity, production of heat, and energy expenditure.

- 30 -

CHAPTER 9
CATEGORIES OF INFECTIOUS AGENTS
Pg 309 312
Prion
Prions are only composed of modified host protein (no genetic material). Infectious prion
proteins (PrP) combine with normal host proteins on the surface of neurons and induce a
conformational change that forms abnormal, non-degradable complexes. These
complexes are then internalized by the neuron leading to cell damage and spongiform
encephalopathies (kuru and CJ disease).
Creutzfeldt-Jakob (CJ) disease
A spongiform encephalopathy that is associated with corneal transplants in
people. There is an atypical CJD that causes prion-associated bovine spongiform
encephalopathy (mad cow disease).
Virus
Viruses are obligate, intracellular agents composed of a protein coat (capsid) that
surrounds genetic material (DNA or RNA).
Herpes zoster (VZV): Some viruses have a latent period and can be reactivated
later in life. Herpes zoster causes chickenpox, and then persists in the body by
hiding in the dorsal root ganglia. It can reactivate later in life to cause the painful
skin condition called shingles.
Inclusion body
Some viruses aggregate within the cells they infect and form characteristic inclusion
bodies, which may be diagnostic with the light microscope. Inclusion bodies can be
found within the cytoplasm (rabies and smallpox), or nucleus (herpes viruses except for
EBV).
Cytomegalovirus(CMV): CMV infected cells are enlarged and show a large
eosinophilic nuclear inclusion and smaller basophilic cytoplasmic inclusions.
Bacteriophage/plasmid/transposon
These are mobile genetic elements that infect bacteria and indirectly cause human
diseases by encoding bacterial virulence factors, including adhesions, toxins, and
enzymes, that confer drug resistance.
Bacteria
Bacteria are prokaryotes (lack
nuclei), have cells walls composed
of
two
phospholipid-bilayer
membranes
separated
by
a
peptidoglycan layer (G-), or an
inner membrane surrounded by a
peptidoglycan layer (G+).

- 31 -

Skin bacteria
A normal, healthy persons skin is colonized by as many as 1012 of the following
bacteria: S. epidermidis, Corynebacterium, Propionibacterium acnes.
Facultative intracellular organism
Facultative intracellular organisms, like Mycobacterium spp., can survive and replicated
either outside or within host cells.
Chlamydiae
Chlamydiae cannot synthesize ATP and is an obligate intracellular agent. It is the
leading infectious cause of female sterility and blindess.
Trachoma: a chronic inflammation of the conjuctiva, caused by Chlamydia
trachomatis, that eventually scars and opacifies the cornea.
Rickettsias
Also an obligate intracellular agent that is transmitted by arthropod vectors, including lice
(epidemic typhus), ticks (Q Fever, RMSF), and mites (scrub typhus). They damage
endothelial cells and cause a rash.
Mycoplasmas
Mycoplasma organisms do not have a rigid cell wall and are the tiniest living freeorganisms. They are spread via aerosol and cause an atypical pneumonia.
Fungi
Fungi possess thick, ergosterol-containing cell walls and grow as perfect, sexually
reproducing forms in vitro and imperfect forms in vivo: the latter include budding yeast
cells and slender tubes (hyphae) which may produce fruiting bodies called conidia.
Tinea: Fungal species that is confined to the superficial layers of the skin, or may
infect hair shafts or nails (dermatophytes).
Protozoal parasites
Protozoal parasites are motile, single-celled eukaryotes that are among the foremost
causes of disease and death in developing countries.
Plasmodium falciparum: spread by mosquitoes and causes malaria
Thrichomonas vaginalis: STD and colonize vagina and male urethra
E. histolytica: trophozoites attach to the intestinal wall and invade
G. lamblia: trophozoites attach to the intestinal wall (purple burp flatulence)
Helminths
Parasitic worms with complex life cycles that become resident in the host and generate
eggs or larvae. Disease is often caused by inflammatory reaction to the eggs and the
severity of disease is proportional to the number of worms in the host. There are three
classes of parasitic worms:

- 32 -

(1) Roundworm (nematode): have a tegument and non-segmented structure and

include Ascaris, hookworms, and Stongyloides (intestinal), and filariae and
Trichinella (tissue).
(2) Flatworm (cestode): gutless worms, whose head (scolex) sprouts a ribbon of
flat segments (proglottids) covered by an absorptive tegument. Tapeworms.
(3) Fluke (trematode): primitive leaf-like worms with a synctial integument, and
includes Asian liver/lung flukes and blood-dwelling schistosomes.
Ectoparasite
Insects (lice, bedbugs, fleas) or arachnids (mites and ticks) that attach to, and live on or in
the skin.
BARRIERS TO INFECTION AND HOW THEY BREAK DOWN
Pg 312 316
Skin
Human papillomavirus (HPV)/ Treponema pallidum
Both can penetrate warm, moist skin during sexual intercourse. HPV causes venereal
warts and T. pallidum causes syphilis.
S. aureus
Superficial infections of the stratum corneum of the epidermis by S. aureus (impetigo) is
aggravated by heat and humidity.
Urogenital Tract
Urinary tract infection (UTI)
The urinary tract is normally sterile because it is flushed several times per day. When
UTI ascends from the bladder to the kidney, it causes pyelonephritis. Most urinary tract
infections are caused by E. coli.
Respiratory Tract
Mucociliary blanket/defense
Large microbes are trapped in the mucociliary blanket. Organisms are trapped in the
mucus secreted by goblet cells and transported by ciliary action back to the throat to be
tossed down the esophagus.
Intestinal Tract
IgA antibodies/mucosa-associated lymphoid tissue (MALT)
Normal defenses against enteric pathogens include IgA antibodies that are made by B
cells located in mucosa-associated lymphoid tissue (MALT). MALT is covered by a
single layer of M cells that transport antigen to MALT. Most enveloped organisms are
killed by digestive juices, while non-enveloped ones may be resistant.

- 33 -

Enterotoxin/exotoxin/invasive organism
Bacteria cause gastrointestinal disease by many mechanisms: Staphylococcus grows on
contaminated food and releases enterotoxins into the food causing food-poisoning,
Cholera and ETEC live inside the gut and secrete exotoxins causing secretory diarrhea,
and Shigella, Salmonella, and Campylobacter are invasive organisms that damage the
intestinal mucosa and lamina propria causing ulceration, inflammation, and hemorrhage.
Thrush/esophagitis
Mostly in immunosuppressed patients, Candida can overgrow causing thrush and
esophagitis.
Hookworm/iron deficiency anemia
Hookworms attach to the intestinal mucosa and may cause iron deficiency anemia by
chronic blood loss, sucked from intestinal villi.
Diphyllobothrium/vitamin B12 deficiency
Diphyllobotrium is an intestinal protozoan that competes with and can deplete its host of
vitamin B12, giving rise to an illness resembling pernicious anemia.
Spread of Microbes throughout the body
Furuncle
Staphylococci cause a locally expanding skin abscess (furuncle), followed by a regional
lymphadenitis that sometimes leads to bacteremia (bacteria in the blood) and
colonization of distant organs.
Carried by WBC
Once some organisms enter the blood, they are transported by WBC: Herpes, HIV, CMV,
Myocobacterium, Leishmania, and Toxoplasma.
Carried by RBC
Once in the blood, some organisms are carried within RBC: Plasmodium and Babesia.
Congenital Rubella infection/Syphilis infection
Severe damage to the developing fetus occurs when infectious organisms circulate in the
mothers blood. Rubella infection in the first trimester can cause heart disease, mental
retardation, cataracts, or deafness in the infant. Syphilis can cause a severe
osteochondritis and periostitis that leads to multiple bony lesions.
HOW INFECTIOUS AGENTS CAUSE DISEASE
Pg 316 319
Ligands/receptors
Viruses damage host cells by entering the cell and replicating at the hosts expense. They
have specific viral surface proteins (ligands) that bind host proteins (receptors) and
allow entry.

- 34 -

Viral tropism
The presence or absence of host cell proteins that allow the virus to attach is one reason
for viral tropism, or the tendency of certain viruses to infect specific cells but not others.
Adhesin
Bacterial adhesions are molecules that bind bacteria to host cells.
Fimbriae (pili)
Fibriae, or pili, are surface proteins. Sex pili are used to exchange genes carried on
plasmids or transposons from one bacterium to another, but most pili mediate adherence
of bacteria to host cells.
Endotoxin/lipopolysaccharide (LPS)
Bacterial endotoxin is an LPS that is a structural component of the outer cell wall of Gbacteria. LPS is composed of a long fatty chain (lipid A), connected to a core sugar
which is attached to a variable carbohydrate chain (O antigen). Causes: fever, septic
shock, DIC, and ARDS.
Superantigen
Bacterial superantigens (Staphylococcus enterotoxins and toxic shock syndrome toxin)
bind to MHC II molecules on the surface of many APCs, without the usual internal
processing or discrimination. The result is indiscriminate activation of T cells which
secrete lots of IL2 and TNF.
Exotoxin
Bacterial exotoxins are secreted proteins that directly cause cellular injury and determine
disease manifestations. For example, B. anthracis produces the exotoxin lethal factor.
Diphtheria toxin: composed of A-B subunits held together by a disulfide bond.
The B fragment binds to target cells and facilitates uptake of the toxin. Inside the
cell the disulfide bond breaks, the A fragment ADP-ribosylates EF-2, and the
cells dies.
V. cholerae, E. coli: cholera and heat labile toxin also have A-B subunits. They
ADP-ribosylate G-protein and cause an increase in cAMP, causing intestinal
epithelial cells to secrete isoosmotic fluid (secretory diarrhea).
Clostridium perfringens: causes gas gangrene by digesting tissue with its alphatoxin which acts as a lecithinase. The toxin disrupts plasma membranes.
Clostridium tetani: this is a wound contaminant that produces tetanospasmin.
This is a neurotoxin that inhibits the release of GABA (an inhibitory
neurotransmitter) causing violent muscle contractions.

- 35 -

IMMUNE EVASION, DIAGNOSIS, AND INFLAMMATORY RESPONSES

Pg 319 322
Leukotoxin
Pseudomonas bacteria secrete a leukotoxin that kills neutrophils.
K antigen
Certain E. coli have K antigens that prevent activation of compliment by the alternative
pathway and lysis of the cells.
Long polysaccharide O antigen
Some G- bacteria have very long polysaccharide O antigens that bind host antibody and
activate complement at such a distance from the bacterial cell that the organism fails to
lyse.
Protein A
Staphylococci are covered by Protein A molecules that bind the Fc portion of the
antibody and inhibit phagocytosis.
Five histologic patterns of tissue reaction:
(1) Suppurative polymorphonuclear inflammation: Reaction to acute tissue damage
marked by increased vascular permeability and neutrophilic exudation. The rapidly
dividing pyogenic bacteria that cause this response are mostly extracellular G+ cocci
and G- rods.
(2) Mononuclear inflammation: Diffuse, predominantly mononuclear interstitial
infiltrates are common in chronic inflammatory processes, but when they occur acutely
they are often a response to viruses, intracellular bacteria, or intracellular parasites.
Granulomatous inflammation: a distinctive form of mononuclear inflammation
usually evoked by relatively slowly dividing infectious agents and almost always
reflects a cell-mediated immune reaction.
(3) Cytopathic-cytoproliferative inflammation: Usually produced by viruses, it is
characterized by damage to individual host cells, with little or no host inflammatory
response. It includes: inclusion bodies, cell-cell fusion, and blisters.
(4) Necrotizing inflammation: C. perfringens and other organisms that secrete very strong
toxins act so quickly that there is no immune response and cell death is the dominant
feature. The lesions resemble infarcts.
(5) Chronic inflammation: the final common pathway of many infections, it may lead to
scarring or cirrhosis (HCV).

- 36 -

CHAPTER 10
BLOOD VESSELS
NORMAL VESSELS
Pg 326 327
This is a brief review of the structure and function of the basic elements of the
cardiovascular systems vessels.
Elastic arteries: are the large arteries (aorta, its
larger branches, and iliac) and are characterized
by a thick media containing elastin (necessary
for elastic rebound to handle high pressures).

Intima: is the innermost concentric layer of

vessel walls composed of a single layer of
endothelial cells. It thickens (smooth muscle
cells migrate into it and multiply) in response to
vascular injury
Internal elastic lamina: is a dense elastic
membrane separating the tunica intima and
media.
Media: is the middle layer of vessel walls
composed of smooth muscle cells. It is supplied
with O2 and nutrients by diffusion from the
lumen and by vaso vasorum.
External elastic lamina: is at the outer limit of the
tunica media, separating it from adventitia.
Adventitia: is the outer layer of vessels,
consisting of connective tissue and the vaso
vasorum.
Vasa vasorum: are small vessels outside medium
and large vessels and act to provide nutrients to
the media.
Internal elastic lamina: is a dense elastic
membrane separating the tunica intima and
media.

Muscular arteries: are medium-sized, comprise

other branches of the aorta (coronary and renal),
and are characterized by thick media containing
mostly smooth muscle, which allows them to
regulate blood flow to organs
Arterioles: which are the smallest, found within
tissues, are characterized by media only 1-2
smooth muscle cells thick, and function to
regulate blood flow to capillary beds acting as
principle points of physiologic resistance to
blood flow.
Capillaries: are the smallest vessels with an
endothelial lining only one cell thick and no
media. They provide the largest total cross
sectional area in the vasculature and are sites of
nutrient exchange in tissues.
Veins: and the venous system, have the largest
capacity and the lowest pressure of the vascular
system. Compared to arteries, they have large
diameters and thin walls, less organized walls.
They can be subject to irregular dilation,
compression, degeneration, and penetration by
tumors or inflammation.
Lymphatics: are thin-walled, endothelium-lined
channels that drain interstitial fluid and
lymphocytes from tissue, returning it to the
circulating blood. They are an important path for
disease dissemination through transport of
bacteria and tumor cells to distant sites.

- 37 -

VASCULAR WALL RESPONSE TO INJURY

Pg 327 328
Endothelium
Endothelial cells (EC) form a semipermeable, monolayer that lines the entire vascular
system. The endothelium acts to control the transfer of molecules into the vascular wall.
It also plays a role in blood clotting and contains Weibel-Palade bodies, which are
storage organelles for von Willebrand factor.

Schematic diagram of
the mechanism of
intimal
thickening,
emphasizing smooth
muscle cell migration
to, and proliferation
and
extracellular
matrix elaboration in,
the intima.

Vascular Injury
Constitutes acute EC loss or chronic endothelial injury/dysfunction. Vascular injury
stimulates smooth muscle cell growth by disrupting the physiologic balance between
inhibition and stimulation. Reconstruction of the vascular wall represents a physiologic
healing response with the formation of a neointima (see illustration above).
VASCULAR DISEASE AND ARTERIOSCLEROSIS
Pg 328 Arteriovenous fistula
AV fistulas are small abnormal communications between arteries and veins. They can
arise from development defects, vascular injuries, or can be made intentionally to allow
vascular access for chronic hemodialysis. Pathology can occur if the arterial-venous
shunt causes the heart to pump too much extra blood leading to high-output cardiac
failure.
Arteriosclerosis
Is the generic term for thickening and loss of elasticity of the arterial walls. There are
three main patterns: (1) Atherosclerosis, which is the most frequent and important
pattern, (2) Monckeberg medial calcific sclerosis which is calcific deposits in muscular
arteries in people over age 50, and (3) Arteriolosclerosis, which affects small arteries and
arterioles and is associated with hypertension and diabetes.

Atherosclerosis
Atherosclerosis refers to the deposition of fatty material in
vessel walls. Over time, this fatty material accumulates,
hardens, and can eventually occlude the lumen. One theory to
explain why this happens is called the response to injury
hypothesis, the proposed sequence of which is pictured in
the illustration below. These areas of fat accumulation,
termed atheromas, can also weaken the vessels, leading to
serious complications and death.
Some of these
complications include: focal rupture, ulceration, or erosion,
which can induce thrombus formation or produce emboli
(increasing the risk of stroke and MI), hemorrhage into the
plaque can occlude vessels or induce thrombosis, and the
weakened vessel walls can make aneurysm (particularly
aortic aneurysm) formation easier.
There are several risk factors, both modifiable and nonmodifiable, to keep in mind when thinking about
atherosclerosis: increasing age, gender (males), family
history, genetics, low levels of physical activity, obesity, high
stress levels, diabetes, cigarette smoking, alcohol, and
saturated fat intake.
Evolution of arterial wall changes in the response to injury hypothesis. 1,
Normal. 2, Endothelial injury with adhesion of monocytes and platelets (the latter to denuded endothelium).
3, Migration of monocytes (from the lumen) and smooth muscle cells (from the media) into the intima. 4,
Smooth muscle cell proliferation in the intima. 5, Well-developed plaque

Atheroma (atheromatous plaque)

These characteristic lesions of atherosclerosis are intimal lesions that protrude into and
obstruct vascular lumens and weaken the underlying media. They begin as a fatty streak
(and can be seen in children), developing primarily in elastic and large-to-medium-sized
muscular arteries; with the abdominal aorta more involved than the thoracic and the ostia
(origins) of major branches off the abdominal aorta favorite sites due to the turbulent
flow. The lesions are composed of a necrotic, soft yellow core of lipid (mainly
cholesterol) covered by a firm, white fibrous cap.

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Neovascularization: (the proliferation of new blood vessels) occurs around the periphery
of the lesion and the plaques, which often calcify.
LDL and HDL (see illustration below)
Hyperlipidemia and other risk factors are thought to cause endothelial injury, resulting in
adhesion of platelets and monocytes and release of growth factors, leading to smooth
muscle cell migration and proliferation. Foam cells of atheromatous plaques are derived
from both macrophages and smooth muscle cellsfrom macrophages via the very-lowdensity lipoprotein (VLDL) receptor and low-density lipoprotein (LDL) modifications
recognized by scavenger receptors (oxidized LDL). Extracellular lipid is derived from
insudation from the vessel lumen, particularly in the presence of hypercholesterolemia,
and from degenerating foam cells. Cholesterol accumulation in the plaque reflects an
imbalance between influx and efflux, and high-density lipoprotein (HDL) likely helps
clear cholesterol from these accumulations. Smooth muscle cells migrate to the intima,
proliferate, and produce extracellular matrix, including collagen and proteoglycans.

Hyperhomocystinemia
Increased levels of homocysteine in the blood is a potential risk factor for atherosclerosis.
Hyperhomocystinemia is caused by low folate and vitamin B intake, thus supplements
may reduce the risk.

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Monckeberg medial calcific sclerosis

Is a form of arteriosclerosis that affects people over the age of 50 and is characterized by
calcific deposits in the media of muscular arteries that do not encroach on the lumen.
This calcification can be seen on x-rays and may be palpable.
Arteriolosclerosis
Is another form of arteriosclerosis that affects small arteries and arterioles, is most often
associated with hypertension and diabetes mellitus, and causes downstream ischemic
injury due to narrowed vessel lumens.

HYPERTENSIVE VASCULAR DISEASE

Pg 338 341
Hypertension
Hypertension is simply elevated blood pressure, defined clinically as a diastolic blood
pressure over 90 mmHg and/or a systolic pressure over 140 mmHg. Several changes
occur in the cardiovascular system during long standing hypertension. There is left
ventricular hypertrophy of the heart which can eventually outgrow its oxygen supply and
die, larger arteries have thickened media and disrupted elastic tissue, smaller arteries and
arterioles have thickened intima which are prone to rupture (stroke) or form
atherosclerotic plaques. These changes can culminate in hypertensive heart disease,
aortic dissection, or renal failure. Epidemiologically, the elderly and African Americans
are at greater risk of developing hypertension as are those with major risk factors for
atherosclerosis and coronary artery disease.
Essential Hypertension: accounts for 95% of hypertension and is due to idiopathic
(unknown) causes. It is controllable and generally asymptomatic unless a
complication intervenes.
Secondary Hypertension: is hypertension secondary to an identifiable underlying
cause like: renal disease, primary aldosteronism, Cushing syndrome., renal artery
stenosis, eclampsia, etc.
Malignant Hypertension: is a form of hypertension characterized by a rapidly
increasing blood pressure (BP greater than 200 mmHg) leading to death within 2
years if untreated. The small arteries become thickened and occluded, causing
distal tissue ischemia, renal failure, retinal hemorrhages, and sometimes
papilledema.

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Renin-angiotensin system
This is the major endocrine regulatory system controlling normal blood pressure.
Dysfunction due to genetic or environmental factors can result in hypertension. It acts
through the kidneys primarily by controlling peripheral resistance and sodium
homeostasis: Decreased renal blood flow causes increased secretion of renin which
cleaves plasma angiotensinogen to angiotensin I. Angiotensin I is converted to
angiotensin II by the enzyme ACE. Angiotensin II increases aldosterone which acts to
increased distal Na+ reabsorption by the kidneys. Water follows the Na+, leading to
increased body fluid volume, and an increase in blood pressure.
Renovascular hypertension
Renovascular hypertension is a form of secondary hypertension characterized by renal
artery stenosis which decreases glomerular blood flow and pressure. The decreased
pressure activates RAAS system leading to increased blood pressure.
Hyaline arteriolosclerosis
Hyaline arteriolosclerosis describes vascular lesions characteristic of benign
nephrosclerosis and is associated with diabetes mellitus. The arterioles appear pink due
to hyaline thickening of the arteriole walls with loss of underlying structure and
narrowing of the lumen. These changes reflect leakage of plasma components and
excessive ECM production by smooth muscle cells.
Benign nephrosclerosis: is one of 2 small blood vessel diseases associated with
hypertension common affecting elderly patients, and is most pronounced with
diabetes. Arteriolar narrowing impairs renal blood supply, causes
loss
of
nephrons, and contraction of the kidneys.
Hyperplastic arteriolosclerosis
This is the second small blood vessel disease seen with hypertension and is associated
with more acute or severe elevations of blood pressure (as in malignant hypertension).
The small blood vessels are described as having onion skin, concentric, laminated
thickening of the arteriolar walls with progressive lumen narrowing. In malignant
hypertension, it includes necrotic deposits in vessel walls (necrotizing arteriolitis).
ANEURYSMS AND DISSECTIONS
Pg 341 345
Aneurysm
An aneurysm is an abnormal, localized dilation of a blood vessel or even the wall of the
heart. A true aneurysm is an aneurysm bounded by all arterial wall components or
attenuated wall of the heart, while a false (pseudo) aneurysm is simply a breach of
vascular wall causing an extravascular hematoma that communicates with the
intravascular space (contained only by extravascular connective tissue).

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Abdominal aortic aneurysm (AAA)

AAA is the most common form of aneurysm and typically affects men over 50 years of
age with atherosclerosis (cystic medial degeneration is also a common cause). AAA is
also of concern in patients with Marfan syndrome, or other connective tissue disorders.
The aneurysm is usually positioned below the renal arteries and above the bifurcation of
the aorta. These aneurysms can become large and are filled with blood leading to many
clinical consequences, including stroke, myocardial infarction, rupture with subsequent
loss of massive amounts of blood into the peritoneal cavity, obstruction or compression
of other structures, release of emboli, and presentation of an abdominal mass mimicking
a tumor.
Inflammatory AAA: is an aneurysm caused by an inflammatory process of
uncertain cause that weakens the wall of the aorta. It involves dense periaortic
fibrosis containing abundant inflammatory cell infiltrate.
Mycotic AAA: is an aneurysm caused by infection that weakens wall of
abdominal aorta; due to complication of infective endocarditis releasing septic
emboli that arrest in the vessel wall, adjacent suppurative processes spreading to
the aorta, or circulating organisms directly infecting the arterial wall.
Syphilitic (leutic) Aneurysm
Is an aneurysm caused by tertiary-stage syphilis. Inflammation begins with the vaso
vasorum of the aorta causing narrowing of their lumina leading to ischemic injury of the
aortic media. The destruction of media causes the aorta to lose its elastic recoil and it
begins to dilates (syphilitic aneurysm).
Obliterative endarteritis: is the destructive inflammatory process of syphilitic
aneurysms that destroy the vaso vasorum of aorta, leading to ischemic injury.
Aortic dissection
Dissection refers to the formation of a blood-filled channel within the aortic wall. The
pathologic sequence of aortic dissection begins with tearing of the aortic intima due to
cystic medial necrosis of the vessel the wall. The tear allows high-pressure blood to push
into the wall space and create a pocket that expands down the aorta. In response, the
aorta balloons out, trapping the blood in the wall. This trapped blood can subsequently
rupture and cause hypovolemic shock (the major cause of death in aortic dissection).
Ninety-percent of affected patients have hypertension, so aortic dissection should always
be a concern in these patients. Aortic dissection can also be seen in connection with
Marfan syndrome, Ehler-Danlos syndrome, penetrating trauma, and pregnancy. There
are three types of aortic dissection based on portion of the aorta affected:

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Type I : affects the ascending and

descending aorta (stem to stern, incl.
arch vessels),
Type II: involves only the ascending
aorta ending before the aortic arch
vessels.
Type III: only affects the descending
aorta, starting after the aortic arch
vessels.

Types I and II both affect the ascending aorta, they may be referred to as Type A while
Type III is referred to as Type B. The reason for this is that involvement of the ascending
aorta carries a higher risk of lethal complications and requires different treatment.
The symptoms of aortic dissection can be defined according to their Type. Type II aortic
dissection presents with severe pain radiating to the back, widened mediastinum, aortic
regurgitation, and cardiac tamponade. Type III also presents with severe pain and
widened mediastinum, but can also cause loss of pulses, bowel ischemia, and paraplegia.
Since type I is a combination of the previous two types, it can cause all of the mentioned
symptoms, as well as, syncope, hemiplegia, and hemianesthesia.
Cystic medial degeneration
Involves elastic tissue fragmentation and separation in the aortic media that then fills
with amorphous connective tissue, ultimately leading to large-scale loss of the elastic
lamina enabling blood to breach the aortic wall. It is a common cause of both aortic
dissections and aneurysms, and is especially common with Marfan syndrome.

- 44 -

Vasculitis
Simply means inflammation of vessel walls caused by any of the following mechanisms:
(1) direct invasion of vascular walls by infectious pathogens, (2) immune-mediated
mechanisms, (3) non-infectious, systemic immune-mediated (hypersensitivity or crossreactivity), or (4) physical or chemical injury (irradiation, trauma, toxins).
Antineutrophil
cytoplasmic
antibodies
(ANCA): are auto-antibodies directed
against enzymes within neutrophils,
monocytes, and endothelial cells. They are
diagnostic for certain disorders and their
levels reflect the degree of inflammatory
activity.
c-ANCA: cytoplasmic staining pattern
indicating neutrophil granules and is its
presence is diagnostic for Wegener
granulomatosis.
p-ANCA: perinuclear staining pattern
usually specific for myeloperoxidase (MPO)
and its presence is diagnostic for
polyangiitis and Churg-Strauss syndrome.
Vasculature involved by the major forms of vasculitis
(width of the trapezoid indicates frequencies of involvement)

Giant cell (temporal) arteritis

Is characterized by acute and chronic, granulomatous inflammation of the large and
small arteries. It most commonly causes systemic vasculitis in adults over age 50 and
primarily affects the arteries of the head (also vertebral, ophthalmic, and aorta)
presenting with vague symptoms of fever, headache, and fatigue. Histologically, affected
segments of arteries develop nodular thickenings with constricted lumens, granulomatous
inflammation of inner media, a mononuclear infiltrate with multinucleate giant cells, and
fragmentation of internal elastic lamina.

- 45 -

Takayasu arteritis
Another granulomatous vasculitis of medium and larger arteries; however, it is the most
common form of systemic vasculitis in adults under age 50 with a female
preponderance. It can involves ocular disturbances and marked weakening of the pulses
in the upper extremities leading to coldness or numbness in the fingers, ocular
disturbances, hypertension, neurological deficits.
Polyarteritis nodosa (PAN)
PAN is a systemic vasculitis of small and medium-sized muscular arteries (does not
involve the arterioles, capillaries, or veins) affecting the renal and visceral (heart, liver,
GI) vessels most, but typically sparing the pulmonary circuit. Histologically, there is
transmural inflammation of the arterial wall with neutrophils, eosinophils, and
mononuclear cells. Fibrinoid necrosis develops leading to thickening of the vessel wall.
PAN frequently follows an episodic course with bewildering symptoms of: fever,
malaise, weight loss, hypertension, abdominal pain, bloody stool, diffuse muscle aches.
Kawasaki disease
Kawasaki disease is an arteritis involving the coronary arteries, usually occuring in
children and infants. This disease is the leading cause of acquired heart disease in
children of North America and Japan, and is associated with mucocutaneous lymph node
syndrome. The vasculitis is PAN-like with necrosis and inflammation affecting the entire
vessel wall.
Microscopic polyangiitis
Is a necrotizing vasculitis affecting arterioles, capillaries, and venules (these vessels are
smaller than those associated with PAN) where p-ANCA is present in 70% of patients.
All lesions tend to be of same age (in PAN, all stages of development exist at once). The
lesions involve necrotizing glomerulonephritis and pulmonary capillaries (unlike PAN)
without granulomatous inflammation (unlike Wegeners granulomatosis). This typically
presents as palpable purpura involving the skin, mucous membranes, lungs, brain, heart,
GI tract, kidneys, and even muscle leading to symptoms of arthralgia, abdominal pain,
hematuria, proteinuria, hemorrhage, and muscle pain.
Allergic granulomatosis and angiitis (Churgg-Strauss syndrome): is a vasculitis of
small vessels accompanied by granulomas and eosinophilic necrosis typically
affecting vessels of the respiratory tract. There is a strong association with
asthma, eosinophilia, and p-ANCA may be present (~50%).
Wegener granulomatosis
Is a necrotizing vasculitis affecting small and medium-size vessels characterized by a
triad of symptoms: (1) acute necrotizing granulomas of the upper and/or lower
respiratory tract, (2) necrotizing granulomatous vasculitis affecting capillaries, venules,
arterioles, and arteries, and (3) renal disease in the form of focal necrotizing glomerulitis
(often crescentic). c-ANCA is present in 95% of patients.

- 46 -

Thrombangiitis obliterans (Buerger disease)

Buerger disease is a segmental, thrombosing inflammation of medium and small-size
arteries of the extremities (tibial and radial arteries). The inflammation can extend to
adjacent veins and nerves leading to ulcerations of digits and gangrene. It has been
associated with heavy cigarette smoking, adults younger than 35, and is more common in
Israel, Japan, and India.
Instep claudication: is a symptom of Buerger disease and is characterized by pain
in the instep of the foot induced by exercise.
Raynaud disease
Raynaud disease is cyanosis of digits (paroxysmal pallor) and sometimes tips of the nose
or ears. This phenomenon is due to cold-induced vasoconstriction of the digital arteries,
pre-capillary arterioles, and cutaneous shunts. The vasoconstriction causes a sequence of
color changes in the fingers: first, the fingers turn white from lack of blood flow, then
blue as cyanosis appears, and finally red as blood flow returns. There are no structural
changes in the arterial walls until late, when intimal thickening may appear.

Secondary Raynaud disease: is caused by

arterial insufficiency in the extremities caused
by another disease (SLE, scleroderma,
atherosclerosis, or Buerger disease). It oftens
affected older people and is more severe.

VEINS AND LYMPHATICS

Pg 353 355
Varicose veins
Varicose veins are caused by increased intraluminal pressure with loss of vessels wall
support and deformed valves, and appear as abnormally dilated and tortuous veins
usually in the lower extremities. They typically occur in people who spend a lot of time
on their feet, or in long car or plane rides. Other people affected include those with a
family history, obese people, pregnant women, and older people.
Esophageal varices: are due to cirrhosis of the liver. Rupture of these veins leads
to massive upper GI hemorrhage.
Hemorrhoids: are varicose dilations of veins at the anorectal junction.
- 47 -

Migratory thrombophlebitis
Also called Trousseau Sign, migratory thrombophlebitis occurs as a paraneoplastic
syndrome in cancer patients (lung, pancreas, colon). The hypercoaguability results in
venous thromboses appearing at one site, disappearing, and then reappearing in other
veins.
Homan sign: is pain elicited upon forced dorsiflexion of the foot; due to thrombi
in the legs. Bedridden patients often show no other signs of deep venous thrombi.
Phlegmasia alba dolens: literally means painful white leg. It is a variant of
primary phlebothrombosis where an iliofemoral venous thrombosis occurrs in
pregnant women prior to or after delivery.
Superior vena cava syndrome
The superior vena cava syndrome is caused by neoplasms that compress or invade the
superior vena cava leading to impaired drainage of the vessels above the level of the
block. Primary bronchogenic carcinoma or mediastinal lymphomas are usually the
culprits. The symptoms include a dusky cyanosis, dilation of veins in head, neck, and
arms often accompanied by respiratory distress because the pulmonary veins will also be
compressed.
Inferior vena cava syndrome
The inferior vena cava syndrome is caused by neoplasms (hepatocellular and renal cell
carcinomas) that compress or invade the inferior vena cava, or by thrombi from the
femoral or iliac veins. Obstruction of the inferior vena cava causes edema in the legs,
distention of the superficial veins of the lower abdomen, and, if renal veins involved,
patients will have massive proteinuria.
Lymphangitis
Acute inflammation of the lymphatic channels due to systemic bacterial infection. The
Lymphatics become dilated and filled with an exudate that extends through the wall
causing cellulitis and abscess formation. Externally, there is the appearance of painful,
subcutaneous red streaks (inflammation of the vessels) with an accompanying painful
enlargement of lymph nodes (in an acute process).
Lymphedema
Is obstruction of lymphatic drainage causing an accumulation of interstitial fluid and
dilation of the lymphatics up to the point of obstruction, edema, and a peau dorange
appearance of the skin. It can occur secondary to a wide-range of problems. Subsequent
rupture of the obstructed vessel can produce:
Chylous ascites: is rupture into peritoneum.
Chylothorax: is rupture into pleural cavity.
Chylopericardium: is rupture into pericardium.
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PATHOLOGY PAO 2101

BLOCK II

Uniformed Services University

School of Medicine
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Robbins Pathology Vocabulary Review

CHAPTER 12
BLOOD - RBC
RED CELL DISORDERS
Pg 397 415
Anemia
Reduction in the oxygen-transporting capacity of blood, usually because of a reduction of
the total circulating RBC mass to below-normal levels. This is usually reflected in the
following lab values:
Hematocrit: Represents the percentage of whole blood volume composed of
erythrocytes and is calculated as: Hct = RBC x MCV
Hemoglobin: Major protein of RBC and transports oxygen from the lung to
peripheral tissues.
Erythropoietin (EPO)
Protein produced by kidney cells that stimulates bone marrow to produce RBCs. In
excess, this can trigger a hyperplasia of erythroid precursors in the bone marrow.
Extramedullary hematopoiesis
RBC production in the secondary hematopoietic organs (spleen, liver, and lymph nodes).
Can occur in prolonged exposure to high levels of erythropoietin.
Hemolysis
Destruction of red blood cells; increased amount can cause anemia.
hemolysis can be seen in an increased reticulocyte count.

Evidence of

Reticulocytosis: newly formed RBCs in the perphiral blood. The number of

reticulocytes in the peripheral blood increases when the bone marrow is trying to
produce large numbers of RBC very quickly (as in hemolysis).
Normocytic/microcytic/macrocytic
All of these refer to the size of the RBC: normocytic refers to a normal sized RBC;
microcytic is a small RBC, and macrocytic is a large RBC. Some types of anemia
characteristically present as one of these (i.e. macrocytic = B12 or folate deficiency).
Mean cell volume (MCV): The average volume of an RBC. A normal value is
between 80 -100. Over 100 would be a macrocytic anemia while under 80 would
be microcytic.
Normochromic/hypochromic
These terms refer to the color of RBC which is a sign of the amount of Hb in the RBC.
Normochromic is normal and hypochromic is pale color (which correlates to low Hb).

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USUHS Pathology PAO 2101

Mean cell hemoglobin concentration (MCHC): The average concentration of Hb

in a given volume of packed RBC. The MCHC is low if the RBCs are
hypochromic.
Mean cell hemoglobin (MCH)
The average content of Hb per RBC.
RBC distribution width (RDW)
The coefficient of variation of RBC volume. An increased RDW means that the RBCs
are extremely variable in size.
Hemorrhage
An escape of blood from the intravascular space (to bleed).
Hemodilution
Increase in the volume of plasma in relation to RBCs; reduced concentration of RBC of
RBCs in the circulation.
Erythropoiesis
The formation of RBCs.
THE HEMOLYTIC ANEMIAS
Pg 398 409
Hemolytic Anemia
Anemias associated with a decreased lifespan of RBCs (normal 120 days). There is
marked hyperplasia in the bone marrow and increased reticulocytes in the blood. Usually
accompanied by splenomegaly due to hyperplasia of the mononuclear system. Hemolytic
anemia can be described or categorized with the following terms:
Hemolysis (intravascular): Occurs when RBCs are subjected to mechanical
trauma or damaged by a variety of biochemical or physical agents (compliment
binding, exposure to toxins, or heat).
Results in hemoglobiinemia,
hemoglobinuria, and hemosiderinuria. May lead to jaundice
Hemolysis (extravascular): The more common mode of RBC destruction, takes
place largely within the phagocytic cells of the spleen and liver. Does not result
in hemoglobinemia or hemoglobinuria, but may result in bilirubin-rich gall stones.
Intracorpuscular/extrcorpuscular: Shortened survival of the RBC due to inherited
defects pertaining of the RBC/shortened survival of the RBC due to acquired
defects outside of the RBC.

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Robbins Pathology Vocabulary Review

Hemoglobinemia/hemoglobinuria/hemosiderinuria
Refers to excess hemoglobin in the blood/hemoglobin in the urine/and presence of
hemosiderin the urine.
Haptoglobin
A protein that binds free Hb in the serum. It is decreased in hemolytic anemias.
Pigment gallstones
Extravascular hemolysis may result in jaundice and if of long standing in the formation of
bilirubin-rich gallstones called pigment stones.
Hemosiderosis/secondary hemochromatosis
Iron excretion by the body is limited and hemolytic anemia results in accumulation of
iron (hemosiderin). This excess accumulation is termed hemosiderosis.
Unconjugated bilirubinemia
A severe hemolytic anemia will release increasing amounts of heme into the bloodstream.
This will be converted to bilirubin, and may give rise to unconjugated bilirubinemia.
Hereditary spherocytosis
Inherited defect in the RBC membrane that renders the RBCs spheroidal, less
deformable, and vulnerable to splenic sequestration and desctruction. (autosomal
dominant inheritance; 25% more severe autusomal recessive inheritance).
Spectrin/ankyrin: Protein components of
the RBC membrane. They form a meshlike
network on the intracellular face of the cell
membrane. The major
protein is spectrin
(long, heterodimer) and connects to the cell
membrane via anotherprotein, ankyrin.
Osmotic fragility: Because the RBCs of HS
are spheroidal, they have little margin for
expansion of volume when they are exposed
to hypotonic solution. As a result, increased
osmotic fragility is a characteristic finding
of HS.

Aplastic crisis: RBC production is shut-off. Since hemolytic anemias produce

RBCs with shortened life spans, this is bad. Aplastic crisis is usually triggered by
parvovirus infection of developing erythroblasts in the marrow.
Hemoglobinopathy
A group of hereditary disorders characterized by the presence of a structurally abnormal
Hb.

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USUHS Pathology PAO 2101

Sickle cell anemia and Sickle cell trait

Sickle cell anemia results from a mutation (single AA substitution) in the gene coding for
the -chain of Hb. With Sickle cell anemia (disease), both -chains are mutated, in sickle
cell trait, only one chain is affected. (heterozygous and homozygous).
Plasmodium falciparum: parasite responsible for causing malaria.
Polymerization (gelation/crystallization): on deoxygenation, HbS molecules
undergo polymerization. This change causes the RBC to assume a sickle shape.
HbSC disease: HbC has a greater tendency than HbA to aggregate with HbS
when it assumes the sickle shape. Those individuals with HbS/C are at a greater
risk for aggregation and are said to have HbSC disease.
Microvascular obstruction: this
occurs when the HbS RBC become
deoxygenated, fall out of the blood,
and begin to aggregate in the
microvasculature. This aggregation
eventually leads to obstruction of
the vessel.
Autosplenectomy: Chronic
microvasculature obstruction of the
spleen causes repeated infarcts of
the spleen. Eventually, the spleen
is so damaged that it becomes
shrunken and fibrotic.

Priapism: constant erection (the pyramid of power, per CMS); may lead to
erectile dysfunction and fibrosis.
Vaso-occlusive/pain crisis: occlusion of the microvasculature due to HbS
aggregation causing infarcts in the muscles and causing the patient pain.
Acute chest syndrome: vaso-occlusion of the marrow can lead to fat embolism
that travels to the lung. Causes the blood flow in the lung to become sluggish
leading to increased sickling which leads to more occlusion.
Salmonella osteomyelitis: patients with sickle cell disease are particularly prone
to this.
Hydroxyurea: a drug that affects eryhtropoietic stem cells in a manner that
results in increased levels of HbF in the newly formed cells. Also is an antiinflammatory drug that may limit the amount of blood stasis resulting from
infection.

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Robbins Pathology Vocabulary Review

Thalassemias
This is a heterogeneous group of genetic disorders, transmitted in an autosomal codominant fashion, affecting the synthesis of hemoglobin. They are characterized by a
lack or decrease in synthesis of the - or -globin chains.
Hypochromic: in any condition affecting hemoglobin synthesis (as in iron
deficiency or thalassmeias), the RBC appears pale, because hemoglobin gives the
color to the RBC cytoplasm.
Ineffective erythropoiesis: is intra-medullary destruction of erythroblasts caused
by membrane damage resulting from the accumulation of unpaired -chain
aggregation (in -thalassemia, -chain production is low, but -chain production
is normal leading to the relative excess of -chains). Ineffective erythropoiesis is
associated with an increased absorption of dietary Fe leading to iron overload.
Poikilocytosis: Abnormal shape of RBCs
Anisocytosis: Abnormal size variation among RBCs.
Normoblast: A nucleated RBC; the immediate precursor of the mature red blood
cell. If in peripheral blood, reflects marked hyperplasia of erythroid progenitors.
(1) -thalassemia/-globin
The -chain of Hb is absent (0) or drastically reduced (+). Most -Thalassemias result
from single base change mutations in the -globin genes.
Target cell: Microcytic/hypochromic RBCs of -thalassemia that tend to puddle
together when placed on a glass slide.
-Thalassemia major: Homozygous form of thalassemia associated with severe
hemolytic anemia. Can produce skull deformities due to increased marrow
hyperplasia.
-Thalassemia minor: Heterozygous form of thalassemia which may be
asymptomatic or mildly symptomatic. Usually only a mild
microcytic/hypochromic anemia.
Hb electrophoresis: Diagnostic method of identifying -thalassemia minor
(2) -thalassemia/-globin
Most of the -thalassemias are caused by deletions of an -globin gene loci. Since there
are four -globin genes, there are four different degrees of -thalassemia based on the
loss of 1-4 -globin genes. Silent carrier: only one gene missing, HbH excess betaglobin chains form stable tetramers, H Bart excess delta-globin chains form stable
tetramers, and Fetal Death all four are missing.

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USUHS Pathology PAO 2101

Glucose-6-phosphate dehydrogenase (G6PD) deficiency

Normally, intracellular GSH inactivates reactive oxygen species. Abnormalities of
enzymes that participate in the hexose monophosphate shunt/glutathione metabolism
reduce the ability of the RBC to protect themselves from oxidative injury and lead to
hemolytic anemias. Most prevelatn is G6PD.

Oxidant stress: Continuous insult to the

RBC by reactive oxygen species.
A

Heinz body (A): denatured Hb precipitates

within the RBC; results because
regeneration of GSH is impaired in G6PD
deficient cells thus, hydrogen peroxide
accumulates and denatures globin chains by
oxidation of the sulfhydryl groups.

Bite cell (B): Heinz bodies can cause membrane damage in RBCs and make them
less flexible. This causes them to be trapped in the spleen and the splenic
phagocytes try to bite out the inclusions.
Unfavorable lyonization: results when the random inactivation of X
chromosomes in females favors a defective gene (as in G6PD).
Paroxysmal nocturnal hemoglobinuria
Idiopathic; only form of hemolytic amemia that results from an acquired membrane
defect due to a mutation that affects myeloid stem cells.
PIGA: The mutated gene in paroxysmal nocturnal hemoglobinuria. It is required
for the synthesis of an intramembrane glycolipid anchor (PIG). PIG proteins limit
the activation of complement on the cell membrane. Those cells that do not
express PIG (due to faulty PIGA) are more susceptible to complement mediated
lysis.
Immunohemolytic anemia
Hemolytic anemia caused by antibodies that react against normal or altered RBC
membranes. To diagnose, you must be able to show that there are anti-RBC antibodies in
the patients serum.
Coombs antiglobulin test/direct/indirect: test to determine if the RBC is coated
with RBC. Take the patients RBC and react them with anti-antibodies. If the

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Robbins Pathology Vocabulary Review

RBC agglutinate, then you have a positive Coombs Test and the person has
immunohemolytic anemia.
Warm antibody immunohemolytic anemia
Characterized by the presence of IgG antibodes that are active at 37 C. Can be associated
with SLE.
Spherocyte
Similar to the spherical RBCs produced in HS. Here, the phagocytes take bites out of the
RBCs and the resulting RBC takes on the form of a sphere.
Cold antibody immunohemolytic anemia
Characterized by low-affinity IgM antibodies, which bind to RBC membranes at
temperatures below 30C. Hemolysis is extravascular. Raynaud phenomenon may occur
in these patients.
Mycoplasma
pneumonia/infectious
mononucleosis:
cold
antibody
immunohemolytic anemia can result as a consequence of these conditions.
Traumatic hemolytic anemia
Clinically important hemolytic anemias that are caused by cardiac valve prostheses or by
narrowing and partial obstruction of the vasculature. Physical trauma to the RBC.
Microangiopathic hemolytic anemia
Characterized by mechanical damage to the RBC as they squeeze through abnormally
narrowed vessels.
Disseminated intravascular coagulation: microangiopathic hemolytic anemia is
seen in association with DIC.
Schistocyte: injured RBCs
Burr cell and Helmet cells: are types of cell shapes seen in microangiopathic
hemolytic anemia.
Malaria
P. malariae, ovale, or falcipirum (most deadly) infect RBCs. Transmitted by Anopheles
mosquito. The parasites destroy large numbers of RBCs and thus cause hemolytic
anemia. Also accompanied with splenomegaly.
Blackwater fever: caused by P. falcipirum and is associated with massive
hemolysis, leading to jaundice, hemoglobinemia, and hemoglobinuria.

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ANEMIAS OF DIMINISHED ERYTHROPOESIS

Pg 409 415
Iron deficiency anemia
The most common form of nutritional deficiency. Negative iron balance may result from
low dietary intake, malabsorption, excessive demand (pregnancy and infancy), and
chronic blood loss (ulcers). Decrease in serum iron and increase in TIBC. Leads to
hypochromic and microcytic (low MCV) RBCs due to hemoglobin synthesis deficiency.
Ferritin: Serum ferritin is a good indicator of the adequacy of bone iron stores.
Stainable bone marrow iron: staining for iron-containing macrophages is another
useful and simple method for estimating body iron content.
Transferrin: iron is transported in the blood by transferring (protein).
Total iron-binding capacity (TIBC):
Atrophic glossitis: the tongue has a smooth, glazed appearance.
Plummer-Vinson syndrome: occurs in iron deficiency anemia when atrophic
glossitis co-exists with dysphagia and esophageal webs.
Pica: eating of unusual substances or odd cravings. Desire to eat dirt, clay, or
chew ice.
Anemia of chronic disease
Most common form of anemia in hospitalized patients. Caused by inflammation induced
sequestering of iron within the cells of the reticuloendothelial system. Increased storage
iron in marrow macrophages, high serum ferritin, and reduced total iron-binding capacity.
Diseases associated with anemia of chronic disease all produce a prolonged state of
systemic inflammation.
Megaloblastic anemia
Caused by either folate deficiency or B12 deficiency. Both of these affect DNA
synthesis. Hallmark of megaloblastic anemia is enlargement of erythroid precursors
which give rise to large RBCs. Bone marrow is hypercellular
Megaloblasts: Enlarged erythroid precursors.
Macrocytes: Abnormally large RBCs.
Giant metameylocytes: Granulocyte precursors are enlarged.
Hypersegmented neutrophils: these are produced by the giant metamyelocytes.

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Nuclear-cytoplasmic ascynchrony: since DNA development is affected, it doesnt

continue at the same pace as RNA and cytoplasmic protein synthesis does.
Therefore, there is a disjunct between the two processes.
Pancytopenia
Anemia, thrombocytopenia, and granulocytopenia together as a result of the precursors of
each lineage being affected in the bone marrow.
Folate deficiency
Uncommon disorder associated with poor diet and increased metabolic needs. Can be
caused by malabsorption which usually takes place in the upper third of the small
intestine (celiac disease and sprue affect this part of GI tract). Unlike B12 deficiency,
there is no neurologic abnormalities.
Cheliosis: disorder around mouth/lips characterized by fissures and scales.
Vitamin B12 (cobalamin) deficiency: causes a megaloblastic anemia (pernicious
anemia) and causes a demyelination of the peripheral nerves and ultimately spinal
cord.
Pernicious anemia
Describes Vit B12 deficiency resulting from inadequate
defective function of IF necessary to absorb B12.

gastric

production

or

Intrinsic factor: secreted by parietal cells of the stomach. Binds to B12 and
travels to terminal ileum where IF attaches to the epithelium and B12 is absorbed.
Parietal canalicular antibody: causes deranged synthesis of IF by binding to
mucosal parietal cells of the stomach, leading to pernicious anemia.
Blocking antibody: block binding of B12 to IF leading to pernicious anemia.
Binding antibody: react with IF-B12 complex and prevent it from binding to
ileal receptors.
Gastrectomy: removal of part of the stomach which takes with it the parietal
cells that synthesize IF, leading to pernicious anemia.
Demyelination of posterior and lateral columns of the spinal cord: these are the
principal neurologic lesions associated with B12 deficiency.
Aplastic anemia
Characterized by the suppression of multipotent myeloid stem cells, with resultant
anemia, thrombocytopenia, and neutropenia (pancytopenia). Hypocellular bone marrow
filled with fat and splenomegaly is characteristically absent. Reticulocytosis is absent.

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Idiopathic: term applied to diseases of unknown cause.

Idiosyncratic: unusual reaction to a particular drug or food.
Thrombocytopenia: presents as appearance of petechiae an ecchymoses due to
low platelet count.
Granulocytopenia: low white blood cells manifested by frequent or persistent
minor infections or the sudden onset of chills, fever, and prostration.
Myelophthisic anemia
Marrow failure caused by extensive replacement of the marrow by tumor or other lesions.
Associated with metastatic cancer arising from a primary lesion in the breast, lung,
prostate, or thyroid. Presents with anemia and thrombocytopenia.
Teardrop cell: misshapen RBCs that resemble teardrops seen in the peripheral
blood that are characteristic of myelophthisic anemia (occurs with slightly
elevated white cell count).
POLYCYTHEMIA
Pg 415
Polycythemia
Denotes increased concentration of RBCs with corresponding increase in Hb level.
Relative PV: hemoconcentration caused by decreased plasma volume
Absolute PV: increase in the RBC mass.

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CHAPTER 12
BLOOD - WBC
NON-NEOPLASTIC DISORDERS
Pg 416 419
Leukopenia
Leukopenia is a decrease in the peripheral white cell count that may occur because of
decreased numbers of any of the specific types of leukocytes, but most often it involves
the neutrophils.
Neutropenia/agranulocytosis
A reduction in the number of granulocytes in blood is known as neutropenia or
sometimes, when severe, as agranulocytosis. The total white cell count is below
1000/microliter. This may occur due to inadequate granulopoiesis (marrow failure,
chemotherapy) or accelerated removal of neutrophils (immune-mediated injury due to
drugs).
Lymphopenia
This is a deficiency of the production of lymphocytes that is much less common than the
other leukopenias. It is usually associated with congenital immunodeficiency diseases or
acquired deficiencies such as HIV.
Erythropoiesis
The formation of red blood cells.
Megakaryopoiesis
A megakaryocyte is a very large cell in the bone marrow that gives rise to platelets.
Granulocyte colony stimulating factor (GCSF)
This is a hematopoietic growth factor that stimulates the production of neutrophils in the
bone marrow.
Leukocytosis
An increase in the number of white cells is a common reaction in a variety of
inflammatory states caused by microbial and non-microbial stimuli. Leukocytoses are
relatively nonspecific and can be classified on the basis of the particular white blood cell
series affected.
Leukemoid reaction: in some cases, reactive leukocytosis may mimic leukemia
(especially chronic myelogenous leukemia (CML)); these reactions are termed
Leukemoid reactions. CML and leukemoid reactions differ in that, in CML the
leukocyte alkaline phosphatase (LAP: another lab test that can be ordered) is very
low and in leukemoid reactions is elevated.

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Infectious mononucleosis
This is an acute, self-limited disease of adolescents and young adults that is caused by B
lymphcytotrophic EBV, a member of the herpesvirus family. The infection is
characterized by fever, sore throat, and generalized lymphadenitis, increase in
lymphocytes (with atypical morphology), and humoral antibody against EBV.
Epstein-Barr virus (EBV): the virus initially infects oropharyngeal epithelial cells
and then spreads to the underlying lymphoid tissue (tonsils and adenoids) where B
lymphcytes, which have receptors for EBV, are infected. B cells that are latently
infected with EBV undergo polyclonal activation and proliferation, owing to the
action of several EBV-encoded polypeptides.
Atypical lymphocyte: Virus specific cytotoxic T-cells appear as atypical
lymphocytes in the circulation (the lab will report these along with the CBC
differential), which is characteristic of the disease. These cells are 12-16
micrometers in diameter, possess abundant cytoplasm containing multiple clear
vacuolations, and have an oval, indented, or folded over nucleus.
Lymphocytosis: the peripheral blood shows absolute lymphocytosis (increase in
the number of lymphocytes) with a total white cell count between 12,00018,000/microliter.
Paracortical area of lymph node: the area that surrounds the germinal centers of
lymph nodes and is usually filled with T-cells. In IM, the abundant atypical
lymphocytes begin to intrude into this area.
Heterophil reaction: a diagnostic test to confirm infectious mononucleosis. The
test is a qualitative enzyme immunoassay (EIA) that detects IgM antibodies to
Paul-Bunnell heterophil, Epstein-Barr virus capsid antigen (EBV-VCA), and
Cytomegalovirus (CMV).
Lymphadenitis/lymphadenopathy
Lymphadenitis (acute and chronic forms) is inflammation of a lymph node or nodes,
while lymphadenopathy is any disease process affecting a lymph node or lymph nodes
(usually leading to lymph node enlargement). Chronic lymphadenitis takes on three
forms: follicular hyperplasia, paracortical lymphoid hyperplasia, or sinus histiocytosis:
(1) Follicular hyperplasia: associated with infections or inflammatory processes
that activate B cells. Proliferating B cells accumulate within large, round or
oblong germinal centers (secondary follicle). There is preservation of lymph
node architecture and marked variation in the shape and size of cells.
Tingible body macrophage: nodular aggregates also feature scattered
phagocytic macrophages containing nuclear debris (these are the tingible
body macrophages).

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(2) Paracortical lymphoid hyperplasia: characterized by reactive changes within

the T-cell regions of the lymph node. Parafollicular T-cells undergo proliferation
and transformation to immunoblasts that may efface the germinal follicles
(Usually indicated Viral infections).
(3) Sinus histiocytosis: characterized by distention and prominence of the
lymphatic sinusoids, owing to marked hypertrophy of lining endothelial cells and
infiltration with histiocytes (drainage of cancers).
Cat-scratch disease
This is a self-limited lymphadenitis caused by Bartonella henselae. It takes the form of
lymphadenopathy mainly in the axilla and neck. A raised inflammatory nodule, vesicle,
or eschar (a thick, coagulated crust or slough) may or may not be visible at the site of
skin injury.
Stellate necrotizing granuloma: the anatomic changes in the lymph node are
quite characteristic for this disease, and initially look like sarcoid-like granulomas
that develop central necrosis with accumulation of neutrophils.
NEOPLASTIC PROLIFERATIONS OF WHITE CELLS
Pg 419 443
Before you begin looking at specifics, keep in mind that the neoplastic proliferation of
white cells is a dense area. This section starts with some general considerations and then
goes into more specifics.
CATEGORIES OF WHITE CELL NEOPLASMS
Lymphoid

Myeloid

Histiocytic

Tumors are composed of cells that appear to be blocked at particular stages of

differentiation resembling normal stages of lymphocyte differentiation
Tumors arise from stem cells that normally give rise to the formed elements of
the blood: granulocytes, RBCs, and platelets. There are three categories:
(1) Acute myelogenous leukemias (immature progenitors accumulate in
the marrow),
(2) Chronic myeloproliferative disorders (inappropriate production of
WBCs leads to elevated WBC count), and
(3) Myelodisplastic
syndromes
characterized
by
ineffective
hematopoiesis and cytopenias.
Proliferative lesions of histiocytes (i.e., Langerhans Cells)

Leukemia and Lymphoma

Leukemias arise in the bone marrow and present as an increase in WBC counts in the
peripheral blood. Lymphoma appear as tumor masses within either lymph nodes or
organs.

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Cell Markers
Determining which cells are neoplastic is an important task that can be accomplished by
looking at the types of cell markers that are expressed on the neoplastic cells surface:
these markers are like their fingerprints!
IMPORTANT CELL MARKERS
Cell Type
T-Cell

Maker
CD2, CD3, CD4, CD7, CD8

B-Cell

CD10, CD19, CD20, sIG

NK Cell

CD16, CD56

Myeloid Cell

CD13, CD14, CD15, CD64

Pluripotent
Stem Cell

CD34

Immature
Lymphoblasts

Terminal deoxytransferase (TdT)

Use
To identify T cells and their tumors
Most lymphoid neoplasms in Western
countries are of B-cell origin
(85%). These markers are used to
identify B cells and their tumors
To identify NK cells and their tumors.
Used to distinguish between myeloid
neoplasms and lymphoid neoplasms
This marker is retained on the earliest
lymphoid and myeloid progenitor cells
Immature T and B cells (lymphoblasts)
express the enzyme TdT. It is useful in
distinguishing lymphobasts from
immature myeloid cells.

Monoclonal/polyclonal
If a tumor arises from a single cell, it is a monoclonal tumor (all the cells are the same).
If the tumor arises from more than one cell, it is termed polyclonal.
MORE SPECIFICS
PLASMA CELL DYSCRASIAS
This is a group of B-cell neoplasms that have in common the expansion of a single clone
of immunoglobin-secreting cells and a resultant increase in serum levels of a single
homogeneous Ig or its fragments. There are six major variants of plasma cell dyscrasia.
M component: this is the term applied to the homologous Ig in the blood.
Monoclonal gammopathy: due to the increase in monoclonal Ig, these diseases
have also been called monoclonal gammopathy.
(1) Multiple myeloma
This is the most common plasma cell dyscrasias and is a clonal proliferation of
neoplastic plasma cells in the bone marrow that is usually associated with multifocal
lytic lesions throughout the skeletal system.
IL-6: this interleukin maintains the proliferation of the myeloma cells.
and light chains: Most myloma cells produced IgG (60%) or IgA (25%), but
sometimes they only secrete light chains, which are excreted in urine.
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Robbins Pathology Vocabulary Review

Bence Jones protein: Light chains that are secreted in the urine are then termed
Bence-Jones proteins.
Light chain disease: A patient with Bence-Jones proteins in the urine without an
M component in the serum is said to have light chain disease.
Pathologic fracture: Plasma cell lesions often cause pathologic fractures by
eroding and destroying the cortical substances. Most commonly, the lesions
appear radiographically as punched-out defects usually 1-4 cm in diameter.
Diagnostic of multiple myeloma.
Myeloma nephrosis: this is a distinctive feature of multiple myeloma.
Protenaceous casts are prominent in the distal convoluted tubules and collecting
ducts. Most casts are made of Bence Jones proteins. Some casts have tinctorial
properties of amyloid. The cells that line tubules containing casts become
necrotic or atrophic.
(2) Localized plasmacytoma
This referes to the presence of a single lesion in the skeleton or in the soft tissues
(extraosseous). The extraosseous lesions typically present in the upper respiratory
tract.
(3) Lympoplasmacytic lymphoma
This tumor is composed of a mixed proliferation of B-cells. It is associated with a
translocation of IgH (14) with PAX5 (9). There is an M component but
predominantly with IgM. Neoplastic B-lymphocytes invade the marrow, nodes, and
liver. Lytic bone lesions are not seen, but the B-cells produce large amount of IgM
leading to hyperviscosity Waldenstrom macroglobulinemia: visual impairment,
neural problems, bleeding, and cold symptoms (Raynauds).
(4) Heavy-chain disease
A disease where only heavy chains are produced (usually of IgG, A, or M class).
(5) Primary amyloidosis
Monoclonal proliferation of plasma cells, with extensive production of light chains
causes amyloid deposits (AL type) which consist of partially degraded light chains.
(6) Monoclonal gammopathy of undetermined significance (MGUS)
An M component is present in 1-3% of patients over 50 years old who are
asymptomatic, (MGUS).

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Cryoglobulinemia
Lymphoplasmacytic lymphoma is characterized by Waldenstrom macroglobulinemia,
visual impairments, neural sequelae, bleeding, and cryoglobulinemia (this is related to the
preceipitation of macroglobulins at low temperatures and producing symptoms such as
Raynauds and cold urticaria.
HODGKIN LYMPHOMA
Lymphoma characterized by lesions of the distinctive neoplasticReed-Sternberg giant
cells and by the presence of non-neoplastic inflammatory cells greatly outnumbering the
tumor cells in the affected nodes. This often presents at a single site and spreads
methodically to contiguous lymph node groups, therefore it can be treated with local
therapy (excision/local radiation). There are four subtypes of Hodgkin lymphoma.
Reed-Sternberg cell: Diagnostic of HL. They have two mirror-image nuclei or
nuclear lobes, each containing a large (inclusion-like) acidophilic nucleolus
surrounded by a distinctive clear zone.
(1) Nodular sclerosis HL: Most common histologic form. Two main features:
Lacunar cells, large and has a single hyperlobate nucleus with multiple small
nucleoli and an abundant, pale staining cytoplasm, and the presence of collagen
bands that divide the lymphoid tissue into nodules.
(2) Mixed cellularity Common in patients older than 50. Contains typical RS
cells within a distinctive heterogenous cellular infiltrate. These patients usually
have systemic manifestations.
(3) Lymphocyte predominance This is characterized by a large number of small,
mature looking reactive lymphocytes. Diagnostic of this type are L&H cell
(popcorn cell) which have a delicate multilobed, puffy nucleus that has been
likened in appearance to popcorn.
(4) Lymphocyte depletion very rare.
NON-HODGKIN LYMPHOMAS
Non-hodgkin lymphomas usually affect several of the peripheral lymph nodes and are
usually composed of B-cells. There is no hypergaamaglobulinemia and the peak
incidence is between 20-40 years of age. These have usually metastasized by the time of
diagnosis, and thus need to be treated with systemic therapies.
(1) Small lymphocytic lymphoma (SLL)/Chronic lymphocytic leukemia (CLL)
SLL and CLL are virtually identical tumors that differ only in the extent of peripheral
blood involvement; those with large numbers of circulating cells are called CLL, while
those without large numbers are called SLL.

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Prolymphocyte/Proliferation center: Sheets of small round lymphocytes and

scattered ill foci of larger cells (prolymphocytes) diffusely efface involved lymph
nodes. The foci of mitotically active prolymphocytes are called proliferation
centers.
Smudge cell: The neoplastic lymphocytes are fragile and frequently disrupted
during smear preparation, producing these characteristic smudge cells.
CD5: SLL/CLL neoplastic B-cells express all B-cell markers (CD 19,20,23) but
also express CD5 (normally a T-Cell marker).
Hypogammaglobulinemia: The neoplastic B-cells do not respond to antigen and
actually suppress the action of non-neoplastic B-cells, leading to
hypogammaglobinemia.
Autoimmune hemolytic anemia: Some patients with SLL/CLL also produce Ig
against their own RBC, leading to autoimmune hemolytic anemia.
(2) Follicular lymphoma
These tumors are extremely common in the US. (40% of adult NHL). The lymph nodes
are effaced by proliferations that usually have a distinctly nodular appearance under low
power. The tumor cells resemble normal germinal centers.
Centrocyte-like: These cells are slightly larger than resting lymphocytes, with an
angular cleaved nuclear contour characterized by prominent indentations and
linear infoldings.
Centroblast-like: These cells are three to four times larger than normal
lymphocytes with vesicular chromatin, several nucleoli, and modest cytoplasm.
BCL2: These neoplastic cells express BCL2 protein, a feature that distinguishes it
from normal germinal centers. This is an antiapoptosis protein that is
overexpressed due to the translocation (t(14;18)).
(3) Mantle cell lymphoma
These lymphomas are composed of B cells that resemble the mantle zone of normal
lymphoid follicles. In most cases the tumor cells are slightly larger than normal
lymphocytes and have an irregular cleaved nucleus. A characteristic tendency of this
lymphoma is frequent involvement of the GI tract causing lymphomatoid polyposis.
Cyclin D1: This is distinguished from SLL/CLL by the absence of proliferation
centers and the presence of abnormally high levels of cyclin D1.
t(11;14): These tumors have a t(11;14) translocation that causes the disregulation
of cyclin D1 and lead to its overexpression.
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(4) Diffuse large B-cell lymphoma

This is a category of lymphoma that shares certain features: B-Cell phenotype, a diffuse
growth pattern, and an aggressive clinical history. Accounts for more than 50% of all
adult NHL. The B-Cells are large and take a variety of forms: resembling centroblasts or
immunoblasts.
(5) Primary effusion lymphoma/human herpes virus 8 (HHV-8)
This is a rare group of tumors that present as malignant effusions. Tumor cells are
infected with HHV-8, which encodes proteins homologous to several known
oncoproteins, including cyclin D1 (this is considered a primary effusion lymphoma.
Associated with Karposi sarcoma of AIDS patients.
(6) Burkitt lymphoma
Tumor cells are monotomous, are intermediate in size, and have round or oval nuclei
containing two to five prominent nucleoli. There is a moderate amount of cytoplasm
which often contains lipid vacuoles. A high mitotic rate is present. It rarely arises in
lymph nodes, and is most common as an abdominal tumor (bowel, ovary, etc.). This is a
very high grade tumor (possibly the most aggressive in humans), but can be cured.
Starry sky pattern: The rate of cell death is also high in this type of lymphoma.
As such, there are many macrophages present filled with debris. These
macrophages are surrounded by a clear space, creating a starry sky pattern.
MYC gene: Burkitt lymphoma is strongly associated with translocations involving
the MYC gene on chromosome 8 with IgH on chromosome 14. This leads to an
overexpression of the MYC gene which has protein transforming potential.
PRECURSOR B- AND T- CELL LYMPHOBLASTIC LEUKEMIA/LYMPHOMA
These tumors are composed of immature lymphocytes (lymphoblasts) and occur
predominately in children and young adults. Pre-B lymphoblastic tumors present as
leukemias with extensive bone marrow/peripheral blood involvement.
Pre-T
lymphoblastic tumors present as mediastinal masses involving the thymus. Both pre-B
and pre-T tumors usually have the clinical appearance of Acute Lymphoblastic
Leukemia.
Acute Luekemias
There is a block in differentiation and that the neoplastic blasts have a prolonged rather
than shortened generation time. Thus, there is accumulation of lymphoblasts. The major
clinical consequences are that there is suppression of RBC, WBC, and platelets, and
therapeutically, the aim is to suppress leukemic clonal expansion to allow the other blood
cells to grow. There are two types of acute leukemia:
Acute lymphoblastic leukemia (ALL): ALL is characterized by lymphoblasts
whose nuclei have somewhat coarse and clumped chromatin with one or two
nucleoli. The blood smear will be full of lymphoblasts (pre-B or pre-T)
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Robbins Pathology Vocabulary Review

Acute myeloblastic leukemia (AML): AML tend to have finer chromatin and
more cytoplasm, which may contain granules. The blood smear will be full of
myeloblasts (more below).
Thrombocytopenia/pancytopenia: this is the condition that results during acute
leukemias from suppression of bone marrow by lymphoblasts: thrombocytopenia
(lowered platelet count) and pancytopenia (lowered count of all cells).
Hyperdiploidy: Hyperdiploidy (over 50 chromosomes per cell) is a nonrandom
karyotypic abnormality most common in pre-B cell tumors. This abnormality is
associated with a t(12:21) chromosome translocation involving the TEL1 and
AML1 genes. These aberrations are associated with a good outcome.
Philadelphia (Ph) chromosome: poor prognoses are associated with translocations
involving the ML1 gene on chromosome 11q23 (the Philadelphia chromosome).
Acute myeloblastic leukemia (AML)
These are tumors marked by a blockage in the differentiation of early myeloid cells.
Immature myeloid cells (myeloblasts: delicate nuclear chromatin, 3-5 nucleoli, and fine
azurophili granuoles) accumulate in the marrow, replacing normal elements, and
frequently circulate in the peripheral blood.
Auer rod: These are distinctive red-staining rod-like structures present in the
promyelocytic variant. They are found only in neoplastic myeloblasts.
French-American-British (FAB) classification: divides AML into eight groups
that has little prognostic value.
Granulocytic sarcoma: A discrete tissue mass associated with AML.
t(8;21)/inv[16]: AML tumors with these karyotypic aberrations are more likely to
have a good prognosis.
AML M3 (acute promyelocytic leukemia (APL))
Hypergranular promyelocytes, often with many Auer rods per cell, and may have
reniform or bilobed nuclei. The presence of t(15;17) translocation is characteristic and
this AML responds well to retinoic acid therapy.
t(15;17)/retinoic acid receptor gene (RARA)/ retinoic acid: results in the
fusion of the retinoic acid receptor alpha gene (RARA) with the PML
gene. This mutant gene blocks the differentiation of myeloid cells by
inhibiting the function of normal RARA. Giving high doses of retinoic
acid overcomes this block causing the cells to differentiate and die.

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USUHS Pathology PAO 2101

Extranodal marginal zone lymphoma (MALT lymphoma)

Special category of low-grade B-cell tumors that arise most commonly in mucosalassociated lymphatic tissue (MALT), such as salivary glands, small and large bowel, and
lungs, and some nonmucosal sites such as the orbit and breast. Associated with SS,
Hashimoto thyroiditis, or Helicobacter pylori.
Helicobacter pylori: When MALT lymphoma occurs in the setting of H. pylori
nfection, treatment with antibiotics and eradication of the organism usually causes
egression of the tumor.
Hairy cell leukemia
Uncommon leukemia distinguished by the presence of leukemic cells that have fine,
hairlike cytoplasmic projections. These cells express CD19/20 and surface Ig, as well as
CD11c/103 (this is abnormal). The hairy cells can usually be seen in the peripheral blood
smear.
Mycosis fungoides/Sezary syndrome
Tumors of peripheral CD4+ T Cells characterized by involvement of the skin and
therefore belong to the group of cutaneuous T-cell lymphomas. Sezary syndrome is a
related condition in which skin involvement is manifested clinically as a generalized
exfoliative erythorderma along with an associated leukemia of Sezary cells.
Adult T-cell leukemia/lymphoma
This is a T-cell neoplasm caused by infection with a retrovirus (Human T-cell leukemia
virus type 1 (HTLV-1). In addition to causing lymphoid malignancies, HTLV-1
infection can give rise to a progressive demyelinating disease that affects the CNS. This
disease is characterized by skin lesions, generalized lymphadenopathy,
hepatospleenomegaly, hypercalcemia, and an elevated leukocyte count with multilobed
CD4 lymphocytes.
MYELODYSPLASTIC SYNDROME
This term refers to a group of clonal stem cell disorders characterized by maturation
defects resulting in ineffective hematopoiesis and an increased risk of transformation to
acute myeloblastic leukemias.
Chronic myelogenous leukemia (CML)
The neoplastic clone retains the capacity to undergo terminal differentiation but exhibits
increased or dysregulated growth. There is an increase in one or more of the formed
elements of the peripheral blood.
BCR-ABL fusion gene: This fusion gene is found in all cases of CML. It encodes
a protein consisting of portions of BCR and the tyrosine kinase domain of ABL.
This fusion protein possesses an increased, dysregulated tyrosine kinase activity
that plays a critical role in the pathophysiology of CML.
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Robbins Pathology Vocabulary Review

Thrombocytosis: As many as 50% of patients with CML have thrombocytosis.

This is an increase in the number of platelets leading to an increased tendency of
clot formation.
Alkaline phosphatase STI-571 (Gllevec): This is an adenosine triphosphate
analogue that specifically inhibits a subset of tyrosine kinases, including the BCRABL fusion protein. This can be used to treat CML.
Polycythemia vera
This is associated with excessive proliferation of erythroid, granulocytic, and
megakaryocytic elements, all derived from a single neoplastic stem cell. Obvious clinical
symptoms are associated with the absolute increase in RBC mass. This causes an
increase in viscosity and vascular stasis, thromboses, and infarctions are common; affects
the heart, spleen, and kidneys most often.
Erythropoietin: PV is associated with low levels of erythropoietin (reflects the
fact that the neoplastic progenitors are erythropoietin independent).
Plethoric: excess of blood or any other fluid.
Hematemesis/melena: These are both symptoms scene with PV. Hematemesis is
vomiting of blood. Melena is abnormal dark, tarry stool, containing blood, usually
from GI bleeding.
Myeloid metaplasia with myelofibrosis
This is the spent phase of PV. As fibroblasts begin to invade and populate the bone
marrow, hematopoiesis shifts from the BM to the liver and spleen. This leads to anemia
and thrombocytopenia.
Extramedullary hematopoiesis: formation of blood in locations other than the
bone marrow. Production of blood in these cites tends to be disordered and
inefficient.
Leukoerythrocytosis: In the peripheral blood, the presence of nucleated RBC
precursors and immature white cells is referred to as leukoerythrocytosis.
LANGERHANS CELL HISTIOCYTOSIS
This is a small cluster of relatively rare conditions that are characterized by the clonal
proliferation of a special type of cell, Langerhans cells. These are dendritic antigenpresenting cells that are normally distributed in many organs, most prominently the skin.
Birbeck granule: Proliferating Langerhans cells have HX bodies (Birbeck
granules) in their cytoplasm. Under EM, these are seen to have a pentalaminar,
rod-like tubular structure, with characteristic periodicity and sometimes a dilated
terminal end (tennis racket appearance).
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USUHS Pathology PAO 2101

Letterer-Siwe disease: This is also called Acute disseminated Langerhans cell

histiocytosis. Occurs before two years of age. The dominant clinical feature is
the development of skin eruptions, secondary to infiltrations of Langerhans
histiocytes.
Eosinophilic granuloma: This can be unifocal (usually the skeleton) or multifocal
(affects children and presents with fever), and is characterized by expanding,
erosive accumulations of Langerhans cells, usually within the medullary cavities
of bones. Histiocytes are mixed with eosinophils, lymphocytes, plasma cells, and
neutrophils.
Multifocal langerhans cell histiocytosis: There are diffuse eruptions that
particularly target the scalp and ear canals (with frequent bouts of otitis media,
mastoiditis, and URT infections. This can affect the pituitary stalk and cause
diabetes insipidus.
Hand-Schuller-Christian triad: The combination of calvarial bone defects,
diabetes insipidus, and exophthalmos is referred to as HSC triad.

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CHPATER 12
BLEEDING DISORDERS
BLEEDING DISORDERS
Pg 443 452
Tests used for the initial evaluation of patients with bleeding disorders:
Bleeding time (tests platelet function)
This is the time (min) taken for a standardized skin puncture to stop bleeding. Standard
depends on test used (2-9 minutes). It is abnormal when there is a defect in platelet
numbers/function.

Prothrombin time (PT)

EXTRINSIC (if prolonged,
deficient in factors V, VII,
or X; prothrombin;
fibroinogen)
Measured in seconds, this
procedure tests the adequacy
of the extrinsic and common
coagulation pathways. It is
the time needed for plasma to
clot in the presence of an
exogenously added source of
tissue thromboplastin and Ca
2+.

Partial thromboplastin time

(PTT)
INTRINSIC (if prolonged,
same as above as well as
possibility of acquired
inhibitor (antibody))
The time (s) needed for the
plasma to clot in the presence
of kaolin (activates factor
XII), cephalin (substitutes for
platelet phospholipids), and
calcium is measured.

Coagulation pathway/coagulation factors

This is the series of events, or pathway, that occurs to prevent bleeding. The players in
the pathway are the coagulation factors.

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Disseminated intravascular coagulation (DIC)/consumptive coagulopathy

It is characterized by activation of the coagulation sequence, leading to formation of
thrombi throughout the microcirculation. As a consequence of the widespread
thromboses, there is consumption of platelets and coagulation factors and, secondarily,
activation of fibrinolysis. DIC can be caused by release of tissue factor or thromboplastic
substances into the blood or by widespread endothelial damage.
Microangiopathic hemolytic anemia: DIC leads to fibrin deposition within the
microcirculation causing hemolysis as the RBCs are traumatized while passing
through the fibrin strands.
Bleeding diathesis: DIC also causes a bleeding diathesis (bleeding disorder).
Fibrin split products: These are increased in the blood during DIC.
Thrombocytopenia
This is characterized by spontaneous bleeding (occurs when platelet count is below
20,000), a prolonged bleeding time, and normal PT/PTT tests.
Idiopathic thrombocytopenic purpura (ITP)
This is a disorder of autoimmune origin. ITP most often occurs as an apparently isolated
derangement but sometimes as a first manifestation of SLE. Most patients are adult
females between 20 and 40, in whom the condition is designated chronic. This can occur
with an underlying condition of lymphoma.
Antiplatelet immunoglobulin: These are directed against platelet membrane
glycoproteins IIb/IIIa or Ib/IX complexes can be identified in many patients.
Heparin-induced thrombocytopenia (HIT)
This is a drug-induced thrombocytopenia. Patients (2-5%) treated with unfractionated
heparin become moderately to severely thrombocytopenic after 1 to 2 weeks of therapy.
This is caused by acquisition of IgG antibodies that recognize 4/heparin complexes on the
platelet surface. Stopping heparin therapy stops the process.
Thrombotic thrombocytopenic purpura (TTP)
TTP has been characterized by its occurrence in adult females and the pentad of fever,
thrombocytopenia, microangiopathic hemolytic anemia, transient neurological deficits,
and renal failure. Recently, however, it has been found that symptomatic patients are
deficient in an enzyme that normally degrades very high molecular weight multimers of
vWF.

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Hemolytic-uremic syndrome (HUS)

HUS is also associated with microangiopathic hemolytic anemia and thrombocytopenia
but is distinguished from it by the absence of neurological symptoms, the dominance of
acute renal failure, and onset in childhood.
Vitamin K deficiency
This is an acquired coagulation disorder. Vitamin K is associated with a severe
coagulation defect, because this nutrient is essential for the synthesis of prothrombin and
clotting factors VII, IX, and X.
von Willebrand factor/glycoprotein 1b
When endothelial cells are stripped away by trauma or injury, subendothelial vWF
becomes exposed and binds to platelets through the receptors glycoprotein 1b and
IIb/IIIa. The most important function of vWF in vivo is to facilitate the adhesion of
platelets to damaged blood vessel walls.
von Willebrand disease
von Willebrand disease is characterized clinically by spontaneous bleeding from mucous
membranes, excessive bleeding from wounds, menorrhagia, and a prolonged bleeding
time in the presence of normal platelet count. Most commonly these is reduced
quantity of vWF.
Factor VIII deficiency (hemophilia A)
This is the most common hereditary disease associated with serious bleeding. It is caused
by a reduced amount or reduced activity of factor VIII. As an X-linked trait, it occurs
mostly in males. Approximately 30% are caused by a new mutation and there is no
family history. There are degrees of hemophilia depending on the type of mutation
present. Patients have a normal bleeding time, platelet count, and PT, with a prolonged
PTT.
Hemarthrosis: Spontaneous hemorrhages into the joints.
Factor IX deficiency (hemophilia B/Christmas disease)
Severe factor IX deficiency is a disorder that is clinically indistinguishable from
hemophilia A. It is X-linked. The PTT is prolonged and bleeding time is normal.
Extremely rare and you must assay factor levels to find the deficiency.

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DISORDERS THAT AFFECT THE SPLEEN AND THYMUS

Pg 450-452
Hypersplenism
This is the state that exists when the spleen removes excessive amounts of one or more of
the formed blood elements resulting in anemia, leucopenia, or thrombocytopenia.
Thymic hyperplasia
The normal thymus is devoid of lymphoid follicles. Hyperplasia of the thymus is
characterized by the appearance of lymphoid follicles within the medulla. It is usually
present in myasthenia gravis and possibly SLE or RA.
Thymoma
A thyomoma is a term applied to tumors in which epithelial cells constitute the neoplastic
element. Thymomas are lobulated, firm, gray-white masses up to 15-20 cm in longest
dimension. It is composed of various neoplastic epithelial cells and some non-neoplastic
lymphocytes.
Benign Thymoma: cytologically and biologically benign
Malignant Thymoma (Type I): cytologically benign but biologically aggressive
Malignant Thymoma (Type II): cytologically aggressive with all characteristics of
cancer
Thymic carcinoma
This is better described as Malignant Thymoma Type II. They are usually cleshy,
obviously invasive masses sometimes accompanied by metastases to such sites as the
lungs. Most are squamous cell carcinomas.
Pure red cell aplasia
This is associated with thymomas. The failure to produce only red blood cells?

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CHAPTER 13
THE RESPIRATORY TRACT
ATELECTASIS (COLLAPSE)
Pg 454
Atelectasis (Four types)
Also known as collapse, is loss of lung volume caused by inadequate expansion of the
airspaces. This process is usually reversible and should be treated quickly to prevent
hypoxemia and superimposed infection of the collapsed lung.
Ventilation-perfusion imbalance: Shunting of inadequately oxygenated blood
from pulmonary arteries into veins, thus giving rise to a ventilation-perfusion
imbalance and hypoxia.

(1) Resorption atelectasis

Occurs when an obstruction prevents air from
reaching distal airways. The air already
present gradually becomes absorbed, and
alveolar collapse follows.
Compression atelectasis
(2) Compression atelectasis
Usually associated with accumulations of
fluid, blood, or air within the pleural cavity,
which mechanically collapse the adjacent
lung. A frequent cause of pleural effusions is
congestive heart failure. Pneumothorax also
causes compression of the lung.
(3) Microatelectasis
This is a generalized loss of lung expansion
caused by a complex set of events, the most
important of which is loss of surfactant.
(4) Contraction atelectasis
This occurs when either local or generalized
fibrotic changes in the lung or pleura hamper
expansion and increase elastic recoil during
inspiration.

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OBSTRUCTIVE LUNG DISEASES

Pg 455 465
Obstructive lung disease
This is characterized by limitation of airflow usually resulting from partial or complete
obstruction at any level. Major disorders include asthma, emphysema, chronic
bronchitis, bronchiectasis, CF, and bronchiolitis. The hallmark of obstructive disease is a
decreased expiratory flow rate, usually measured by FEV1. Thus the FEV1/FVC ratio is
decreased.
Forced vital capacity (FVC): This is the volume that can be forcibly expired after
a maximal inspiration.
Forced expiratory volume at 1 second (FEV1): This is the amount of air that can
be expired in the first second following a maximal inspiration. It is normally 80%
of the FVC.
Asthma
This is characterized by episodic, reversible bronchospasms resulting from an
exaggerated bronchoconstrictor response to various stimuli (namely, persistent bronchial
inflammation).
Extrinsic asthma: an asthmatic episode is triggered by a Type 1
hypersensitivity reaction induced by exposure to an extrinsic agent. Atopic
asthma is a type of extrinsic asthma.
Atopic asthma: develops during the first decades of life and is believed to be
driven by the TH2 subset of CD4 T cells. Serum IgE is also present at higher
levels. It has an early phase and a late phase to an attack. Early phase starts
shortly after expose to antigen and quickly stops (this is mediated by leukotrienes,
prostaglandins, histamine). This is followed by a late phase reaction 4-8 hours
later that is more prolonged (this is mediated by recruitment of more eosinophils
and mast cells).
Intrinsic asthma: The triggering mechanism for this type of asthma is not
immune mediated. External factors trigger bronchospasm: such as aspirin,
pulmonary infections, cold, psychological stress, exercise, and inhaled irritants
such as ozone and sulfur dioxide. Serum IgE is normal. Usually develops later in
life.
Airway hyperresponsiveness: This is the term used to describe the exaggerated
bronchoconstrictor response to a variety of stimuli. This is the underlying
problem in all forms of asthma.

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Asthma (Cont.)
Type I hypersensitivity: This is the immune mechanism that explains bronchial
inflammation in extrinsic asthma. CD4 T cells of TH2 line drive this response.
They release IL-4, 5, and 13 which favor the formation of IgE, increased growth
of mast cells, and activation of eosinophils. Eosinophils eventually sustain the
inflammatory response without additional exposure to the triggering antigen.
Status asthmaticus: Prolonged severe asthma attack in which bronchospasm does
not respond to traditional treatments.
Curschmann spiral: Occlusion of bronchi/bronchioles can occur is asthmatics by
formation of mucus plugs that contain sheds of epithelium arranged in a swirl
pattern (Curshmann spirals).
Charcot-Leyden crystal: The mucus plugs also contain collections of crystalloids
made up of eosinophil proteins.

Comparison of a normal bronchiole with that

in a patient with asthma. Note the
accumulation of mucus in the bronchial lumen
resulting from an increase in the number of
mucus-secreting goblet cells in the mucosa and
hypertrophy of submucosal mucus glands. In
addition, there is intense chronic inflammation
due to recruitment of eosinophils, macrophages,
and other inflammatory cells. Basement
membrane underlying the mucosal epithelium is
thickened, and there is hypertrophy and
hyperplasia of smooth muscle cells.

Chronic obstructive pulmonary disease (COPD)

Primarily irreversible airflow obstruction (distinguishes this from asthma where airflow
obstruction is reversible). Some people use this term to include two common conditions:
(1) emphysema and (2) chronic bronchitis. With severe COPD, the patient will
develop hypercapnia, hypoxia, and possibly cyanosis. Eventually, the patient will
develop pulmonary hypertension and ultimately, cardiac failure.

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(1) Emphysema
This is characterized by permanent enlargement of the airspaces distal to the terminal
bronchioles accompanied by destruction of their walls. The definition of emphysema is
a morphologic one, whereas chronic bronchitis is defined based on clinical features.
Acinus: The structure distal to the terminal bronchioes and includes the
respiratory bronchiole, alveolar ducts, and alveoli. Three to five acinus are
termed a lobule.
Centriacinar emphysema: Type of emphysema where the pattern of involvement
targets the central or proximal part of the acinus, which is formed by the
respiratory bronchioles. Seen most often in people who smoke cigarettes.
Affects the upper lobes more severely.
Panacinar (panlobular) emphysema: Type of emphysema where the acini are
uniformly enlarged from the level of the respiratory bronchiole to the terminal
blind alveoli. Seen most often in people with alpha 1-antitrypsin deficiency.
Affects the lower lobes more severely.
Distal acinar (paraseptal) emphysema: Type of emphysema that principally
involves the distal part of the acinus. Affects the lungs at the margins (adjacent
to the pleurae) and occurs adjacent to areas of fibrosis, scarring, or atelectasis
and is usually more severe in the upper half of the lungs. Probably cause for
spontaneous pneumothorax in younger patients.

A, Diagram of normal structures within the acinus,

the fundamental unit of the lung. A terminal
bronchiole (not shown) is immediately proximal to
the respiratory bronchiole. B, Centriacinar
emphysema with dilation that initially affects the
respiratory bronchioles. C, Panacinar emphysema
with initial distention of the peripheral structures (i.e.,
the alveolus and alveolar duct); the disease later
extends to affect the respiratory bronchioles.

Bullae: Multiple, contiguous, enlarged airspaces that range in diameter from less
than 0.5 mm to more than 2.0 cm, sometimes forming cystlike structures that with
progressive enlargement are referred to as bullae.

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Protease-antiprotease
imbalance: One explanation
for emphysema where
emphysema is seen from the
destructive effect of high
protease activity in subjects
with low anitprotease activity.
1-antitrypsin deficiency:
Patients with this type of
deficiency have a markedly
enhanced tendency to develop
emphysema due to decreased
anti-protease activity.

Elastase/metalloproteinase: Produced by macrophages and neutrophils during

inflammation; they are proteases and cause tissue damage.
Oxidant-Antioxidant Imbalance: Tobacco smoke contains an abdundance of
reactive oxygen species which use up all of the lungs antioxidants, thereby
causing tissue damage in the lung.
Dyspnea: Shortness of breath or labored, difficult breathing.
Pink puffer
Refers to a patient who is barrel-chested and dyspneic, with obviously prolonged
expiration, sitting forward in a hunched over position, attempting to squeeze the air out of
the lungs with each expiratory effort. They have prominent dyspnea and adequate
oxygenation of hemoglobin.
Blue bloater
Refers to patients with emphysema who also have a history of pronounced chronic
bronchitis and a history of recurrent infections with purulent sputum. They usually have
less prominent dyspnea and respiratory drive, so they retain CO2, become hypoxic, and
are often cyanotic.
Conditions related to Emphysema
Compensatory emphysema: Term used to refer to the compensatory dilation of
alveoli in response to loss of lung substance elsewhere, such as occurs I residual
lung parenchyma after surgical removal of a diseased lung or lobe.
Senile emphysema: Term used to refer to overdistended lungs of elders, resulting
from age-related alterations of the internal geometry of the lung.
Obstructive overinflation: Condition where the lung expands because air is
trapped in it. A common cause is subtotal obstruction by a tumor or foreign
object.
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Mediastinal emphysema: Designates the entrance of air into the connective tissue
stroma of the lung, mediastinum, and subcutaneous tissue. Results from a sudden
increase in intra-alveolar pressure that causes a sudden tear, with air dissecting
into the interstitium.
(2) Chronic bronchitis
The diagnosis of chronic bronchitis is made on clinical grounds: it is defined as a
persistent cough for at least 3 consecutive moths in at least 2 consecutive years. Occurs
as simple, mucopurulent, asthmatic, and obstructive chronic bronchitis.
Lacks
eosinophils.
Mucus hypersecretion: This is the defining feature of chronic bronchitis and
begins in the large airways. Irritants induce hypersecretion of mucous glands and
cause hypertrophy of the glands.
Reid index: The magnitude of the increase in size of the mucous secreting glands
is assessed by the ratio of the thickness of the submucosal gland layer to that of
the bronchial wall.
Squamous metaplasia: This frequently develops in chronic bronchitis, followed by
dysplastic changes in the lining epithelial cells, a sequence of events that can lead
to bronchogenic carcinoma.
Chronic bronchiolitis: This is similar to chronic bronchitis except it affects the small
airways. It is characterized by goblet cell metaplasia, inflammation, fibrosis in the walls,
and smooth muscle hyperplasia. It is the peribronchiolar fibrosis that results in airway
obstruction.
Hypercapnia: Increased CO2 in the blood. This results with development of
severe COPD.
Hypoxemia: Decrease O2 in the blood. This results with development of severe
COPD.
Bronchiectasis
The permanent dilation of bronchi and bronchioles caused by destruction of the muscle
and elastic supporting tissue, resulting from or associated with chronic necrotizing
infections. Secondary affliction due to persistent infection or obstruction. Two processes
are critical and intertwined in the pathogenesis of bronchiectasis: obstruction and chronic
persistent infection.
Cystic fibrosis: Widespread, severe bronchiectasis results from obstruction and
infection caused by the secretion of abnormally viscid mucus.

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Kartagener syndrome: This is an autosomal recessive disorder, that predisposes to

bronchiectasis, and is associated with sterility in males. There is a structural
abnormality of the cilia and impairs the mucociliary ladder.
Fetid: Bronchiectasis can cause the production of mucopurulent, sometimes fetid
sputum. Fetid means that it has a nasty smell!
RESTRICTIVE LUNG DISEASES
Pg 465 475
Restrictive lung disease
This is characterized by reduced expansion of lung parenchyma accompanied by
decreased total lung capacity. FVC is reduced and the expiratory flow rate is normal or
reduced proportionately. Therefore, the ratio of FEV1/FVC is near normal. Divided
into two categories: extrapulmonary (obesity, GBS) and interstitial lung diseases (ARDS,
indiopathic pulmonary fibrosis).
Interstitial lung disease
Initiating injuries in Restrictive lung diseases usually affect Type I or II epithelial cells.
Because of the changes in the interstitium, these disorders are often referred to as
interstitial lung disease.
Acute lung injury (ALI)/Acute respiratory distress syndrome (ARDS)
ALI (less severe) and ARDS (more severe) are a continuum of progressive respiratory
failure defined by (1) acute onset of dyspnea, (2) hypoxemia, (3) bilateral pulmonary
infiltrates, and (4) absence of clinical evidence of left sided heart failure. In ALI/ARDS
the microvascular endothelium/alveolar epithelium is damaged, leading to an
inflammatory response dominated by neutrophils (they cause the tissue damage).
Exudative phase: (0-7 days),
demonstrates capillary congestion,
necrosis of alveolar epithelial cells,
interstitial and intra-alveolar
edema/hemorrhage, and possibly
collections of neutrophils in the
capillaries. The most characteristic
finding is hyaline membranes lining
the distended alveolar ducts.
Proliferative phase: (1-3 weeks), is
marked by proliferation of type II
pneumocytes and by phagocytosis of
remnant hyaline membranes by
pulmonary macrophages.

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ALI/ARDS (Cont)
Hyaline membrane: This is the characteristic sign of the exudative phase.
Type II pneumocyte: characteristic of the proliferative phase where it undergoes
hyperplasia. This is thought to be part of the reparative process. Type II cells
replace type I cells and then differentiate into Type I cells.
Honeycomb lung: After the reparative process following injury in ARDS, the
outcome results in marked distortion of lung parenchyma, usually leading to
diffuse interstitial fibrosis interspersed with dilated and distorted airspaces (this is
called Honeycomb lung).
Idiopathic pulmonary fibrosis
Refers to a pulmonary disorder of unknown etiology characterized histologically by
diffuse interstitial fibrosis, which in advanced cases results in severe hypoxemia and
cyanosis. Known causes (asbestos, etc.) must be ruled out before applying this term.
It is believed that this is initiated by an immune response that subsequently heals by
fibrosis.
Usual interstitial pneumonia: All IPF is associated with some form of interstitial
pneumonia. Usual interstitial pneumonia has a heterogeneous appearance with
areas of normal lung, interstitial inflammation, and fibrosis.

A possible schema of the

pathogenesis of idiopathic
pulmonary fibrosis.

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Sarcoidosis
This is a multisystemic disease of unknown etiology characterized by noncaseating
granulomas in many tissues and organs. Primary manifestation is bilateral, hilar
adenopathy.
Schaumann body
These are found inside the granulomas that characterize sarcoidosis. They are
laminated concretions composed of calcium and proteins.
Asteroid body: These are found inside the granulomas that characterize
sarcoidosis. They are stellate inclusions enclosed within giant cells.
Lymphangitic distribution: The granulomas of sarcoidosis predominantly involve
the lung intersititium rather than air spaces, with some tendency to localize in the
connective tissue around bronchioles and pulmonary venules and in the pleura
(lympangitic distribution).
Erythema nodosum: This is the hallmark of sarcoidosis. It is characterized by
raised, red, tender nodules on the anterior aspects of the legs.
Lupus pernio: This is another characteristic skin lesion of sarcoidosis that consists
of indurated plaques associated with violaceous discoloration in the region of the
nose, cheeks, and lips.
Iritis: Inflammation of the Iris.
Sicca syndrome: Occular lesions that affect the lacrimal glands, with suppression
of lacrimation is called sicca syndrome.
Mikulicz syndrome: Comined uveoparotid involvement is designated Mikulicz
syndrome.
Hypersensitivity pneumonitis
This is an immunologically mediated response to an extrinsic antigen that involves both
type III and type IV hypersentivity reactions. Unlike bronchiolar asthma that targets the
bronchi, hypersensitivity pneumonitis affects the alveoli: therefore, it presents as a
restrictive lung disease.
Goodpasture syndrome
This is the prototype disorder for the diffuse alveolar hemorrhage syndromes which are
characterized by anemia, hemoptysis, and diffuse pulmonary infiltrates. Goodpasture
syndrome is an uncommon disorder characterized by a crescentic, usually rapidly
progressive, glomerulonephritis and hemorrhagic institial pneumonitis. It is a type II
hypersensitivity reaction.

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Idiopathic pulmonary hemosiderosis

This is similar to Goodpastures syndrome, however there is no renal involvement and no
circulating antibodies against basement membrane.
Wegener granulomatosis
Is a vasculitide that can have an impact on the lung. The lung lesions in WG are
characterized by a combination of necrotizing vasculitis (angiitis) and parenchymal
necrotizing graulomnatous inflammation.
Caplan syndrome
This is a form of accelerated pneumoconiosis seen in patients with rheumatoid arthritis
who are exposed to coal, silica, or asbestos.

VASCULAR LUNG DISEASES

Pg 475 478
Pulmonary thromboembolism
The emobolization of venous and right-sided cardiac thrombi to the lungs. Most emboli
arise from DVT, typically originating in the popliteal vein and larger veins above it.
Saddle embolus: Large emboli that lodge astride the bifurcation of the major
vessels in the lung.
Pulmonary hypertension
Can be primary or secondary to another disease. Is the increase in blood pressure in the
pulmonary circulation. Primary pulmonary hypertension is believed to be caused by
chronic vasoconstriction resulting from vascular hyperreactivity.
Pulmonary vascular sclerosis
This is a narrowing of the vessels within the lung that leads to pulmonary hypertension or
can be a result of pulmonary hypertension.

PULMONARY INFECTIONS
Pg 479 498
Pneumonia
This can be broadly defined as any infection of the lung. Acute bacterial pneumonia can
present as one of two anatomic and radiographic patterns, referred to as bronchopneumonia and lobar pneumonia. The best way to classify pneumonias is by the clinical
setting in which infection occurs.

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Bronchopneumonia
This implies a patchy distribution of
inflammation that generally involves more
than one lobe. This results from an initial
infection of the bronchi and bronchioles with
extension into the adjacent alveoli.
Lobar pneumonia
In lobar pneumonia, the contiguous airspaces
of part or all of a lobe are homogenously filled
with an exudates that can be visualized on
radiographs as a lobar or segmental
consolidation.

Community-acquired pneumonia
These are bacterial in origin and the infection usually follows a viral upper respiratory
tract infection. The onset is usually abrupt, with high fever, shaking chills, pleuritic chest
pain, and a productive mucopurulent cough. The lower lobe of the right lung is most
commonly involved.
Streptococcus pneumoniae: responsible for more than 90% of lobar pneumonias
and is also the most commonly cause of community-acquired acute pneumonia. It
is also be referred to as a pneumococcus and can present as bronchopneumonia or
lobar pneumonia. This bacteria is usually cleared from the blood by the spleen.
Four Stages of pneumonia:
(1) Congestion affected lobes are heavy, red, and boggy; vascular congestion
can be seen, with proteinaceous fluid, scattered neutrophils, and many bacteria in
the alveoli.
(2) Red hepatization within a few days of congestion, the lung lobe has a liverlike consistency; the alveolar spaces are packed with neutrophils, red cells, and
fibrin; the pleura usually demonstrates a fibrinous exudates.
(3) Gray hepatization the lung is dry, gray, and firm, because the red cells get
lysed, while the fibrinous exudates persists within the alveoli.
(4) Resolution follows in uncomplicated cases, as exudates within the alveoli
are enzymatically digested and either resobred or expectorated leaving the lung
architecture intact.
Empyema: Suppurative material accumulation in the pleural cavity.

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Other Bacteria Causing Pneumonia

Haemophilus influenzae
Another organism implicated in community-acquired pneumonia. This is the most
common bacterial cause of acute exacerbation of COPD.
Moraxella catarrhalis
Another organism implicated in community-acquired pneumonia. Contributes to
pneumonia in the elderly (primarily), COPD, and one of the three most common causes
of otitis media in children.
Staphylococcus aureus
Another organism implicated in community-acquired pneumonia. Important cause of
secondary pneumonia in children and healthy adults following viral respiratory illness.
Klebsiella pneumoniae
Another organism implicated in community-acquired pneumonia. This is the most
frequent cause of gram-negative bacterial pneumonia.
Afflicts debilitated and
malnourished persons, particularly chronic alcoholics.
Pseudomonas aeruginosa
Another organism implicated in community-acquired pneumonia. Most frequently seen
in hospital settings. Has a propensity to affect those who are neutropenic (decrease in the
number of neutrophils) and to invade vessels at the site of infection.
Legionella pneumophila
Another organism implicated in community-acquired pneumonia.
Community-acquired atypical pneumonia
Sputum production was modest, there were no physical findings of consolidation, the
white cell count was only moderately elevated, and bacteria and influenza A viruses
could not be isolated.
Mycoplasma pneumoniae: This is the most common cause of communityacquired atypical pneumonia.
Chlamydia pneumoniae: This is increasing recognized as a cause of communityacquired atypical pneumonia.
Coryza: Both of the above bacteria cause coryza inflammation with diffuse
discharge from the nasal mucosa.

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Nosocomial pneumonia
These are pneumonias defined as pulmonary infections acquired in the course of a
hospital stay.
Enterobacteriaceae: These gram-negative rods are the most common isolates of
nosocomial pneumonias.
Aspiration pneumonia
Occurs in people who aspirate gastric contents either while unconscious or during
repeated vomiting. This pneumonia is due in part to chemical irritation and partly
bacterial. Complications of this pneumonia include abscess formation.
TUBERCULOSIS
Mycobacterium tuberculosis
This is the causative agent of tuberculosis (a communicable chronic granulomatous
disease) that usually involves the lungs, but may affect any organ or tissue. The centers
of tubercular granulomas undergo caseous necrosis.
Acid fast: Mycoplasmas are acid-fast bacteria which means that they have a high
content of complex lipids that readily bind the Ziehl-Neelsen stain and
subsequently stubbornly resist decolorization.
Tuberculin (Mantoux) test
Infection with M. tuberculosis leads to the development of delayed hypersensitivity,
which can be detected by tuberculin (Mantoux) test. After 2-4 weeks following infection,
intracutaneous injection of Purified protein derivative (PPD) induces a palpable
induration that peaks in 48-72 hours. It is well recognized that false-negative reaction (or
skin test anergy) may be produced by other conditions (viral infections, sarcoidosis, or
malnutrition).
Primary tuberculosis
This is the form of tuberculosis that develops in a previously unexposed person, and
therefore unsensitized person. The source of the organism is exogenous.
Ghon focus: M. tuberculosis bacteria typically affect the
lower portions of the
upper lobe or the upper portions
of the lower lobe. As sensitization develops against
this
bacteria, areas of gray-white inflammatory consolidation
emerges, this is the Ghon focus.
Ghon complex: The combination of parenchymal lesion and
nodal involvement is referred to as the Ghon complex.
Ranke complex: When the Ghon complex undergoes
progressive fibrosis, often followed
by
radiologically
detectable calcification this is the Ranke complex.

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Reactivation
The implications of primary tuberculosis are that it induces hypersensitivity and
increased resistance and the foci of scarring may harbor viable bacilli for years, and thus
be the nidus for reactivation.
Progressive primary tuberculosis
If the disease continues without interruption (it is not contained) then progressive primary
tuberculosis develops. This occurs in individuals who are immunocompromised.
Milliary tuberculosis: Occurs
when organisms drain from the
lung via lymphatics and spread to
and infect other parts of the lung.
It can also refer to the systemic
spread when bacteria infect the
pulmonary veins returning to the
heart that is then pumped to the
rest of the body.
Secondary (reactivation)
tuberculosis: is the pattern of
disease arsing in a previously
sensitized host from reactivation
of dormant primary lesions. It is
classically located in the apex of
the lungs.

Pott disease
When there is systemic milliary spread of tuberculosis that affects the vertebrae, this is
referred to as Pott diease.
Scrofula
Lymphadenitis is the most frequent form of extrapulmonary tuberculosis, usually
occurring in the cervical region (scrofula).
Hemoptysis
Coughing up blood.
NON-TB MYCOBACTERIA
Mycobacterium avium-intracellulare (M. avium complex)
Chronic pulmonary disease in immunocompetent persons is the most common localized
clinical disease caused by nontuberculosis myobacteria. Mimics M. tuberculosis as it
affects the upper lobes (and cause cavitation).

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FUNGAL INFECTIONS
Candida albicans
This is the most frequent disease-causing fungusIt is a normal part of the flora in the GI,
mouth, and vagina. Therefore, clinically, it can affect the mucous membranes, skin, and
deep organs (invasive candidiasis).
Pseudohyphae: This is an important diagnostic structure of C. albicans and
represent budding yeast cells joined end to end at constrictions, thus simulating
true fungal hyphae.
Thrush: This is the most common clinical manifestation of Candidiasis. It takes
the form of a superificial infection on mucosal surfaces of the oral cavity.
Candida pneumonia: This is a type of invasive Candidiasis that usually presents as
bilateral nodular infiltrates, resembling Pneumocystis pneumonia.
Cryptococcus neoformans
This bacteria causes Cryptococcosis. It almost exclusively presents as an opportunistic
infection in immunocompromised persons. The capsule of this bacteria is critical to
diagnosis; it replicates through budding This fungus usually localizes in the lungs and
then disseminates to other sites, particularly the meninges.
Aspergillus species
This is an opportunistic mold species whose hyphae are septate and branch at more acute
angles. Tends to invade blood vessels and can potentially enter the blood stream and
travel to the head with fatal consequences.
Invasive aspergillosis: Occurs almost exclusively in immunocompromised
patients and tends to localize In the lungs, presenting with necrotizing pneumonia.
Allergic bronchopulmonary aspergillosis: Occurs in patients with asthma who
develop IgE antibodies against the asperigillus.
Aspergilloma: This means fungus ball. Occurs by colonization of preexisting
pulmonary cavities.
Mucormycosis
This is an opportunistic mold that is caused by the class of fungi known as Zygomycetes.
Hyphae are nonseptate and branch at right angles.
Rhinocerebral/pulmonary mucormycosis: Caused by Zygomycetes and have a
propensity to colonize the nasal cavity or sinuses and then spread by direct
extension into the brain, orbit, and other head and neck structures.

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Deep-seated mycosis
Usually caused by one of the three dimorphic fungi listed below. In immunocompetent
persons, the disease is usually localized to the lung, whereas in immunosuppressed
persons, the disease disseminates.
Histoplasma capsulatum: Round to oval in shape and 2-5 micrometers in size.
Found in warm, rich soil that contains the feces of birds and bats.
Coccidiodes immitis: Non-budding spherules and 20-60 micrometers in size. This
is known as valley fever in the southwest and far west.
Blastomyces dermatitidis Round to oval and larger than Histoplasma (5-25
micrometers in size). Found in overlapping areas of Histoplasma.
Lung abscess
This refers to a localized area of suppurative necrosis within the pulmonary parenchyma,
resulting in the formation of one or more large cavities.
Necrotizing pneumonia: This term has been used to describe a similar process
resulting in multiple small cavitations; this condition often coexists with lung
abscess.
Anaerobic bacteria: These are present in almost all lung abscesses.
Air-fluid level: As the focus of suppuration (of the lung abscess) enlarges, it lmost
inevitably ruptures into airways. Thus, the contained exudates may be partially
drained, producing an air-fluid level on radiographic examination.
Pneumothorax: Occasionally abscesses rupture into the pleural cavity and produce
bronchopleural fistulas, the consequence of which is pneumothorax or empyma.
Cytomegalovirus (CMV)
CMV is a member of the herpes virus. Cells infected by the virus exhibit gigantism of
both the entire cell and its nucleus. The nucleus takes on an Owls Eye appearance.
CMV typically affects the lungs, GI, and retina. CMV can be transferred from mother to
fetus (congenital), from mother to baby via breast milk (perinatal), if acquired in
childhood/adolescence it is usually asymptomatic, or from transplants or blood
transfusions (Iatropic).
Microcephaly: This is a possible fatal outcome of congenitally acquired CMV.
Pneumocystits carinii
This is an opportunistic infectious agent. This is an extremely common cause of
infection in patients with AIDS. It is predominantly confined to the lung where it caused
pneumonia.

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LUNG TUMORS
Pg 498 504
Bronchogenic carcinoma
This represents 95% of the primary lung tumors and arise from the bronchial epithelium.
It is also the number one cause of death due to cancer in the US. It is now the number
one cancer in women and has a strong association with cigarette smoking. There are four
major types of bronchogenic carcinoma: squamous cell carcinoma, adenocarcinoma
(most common), large cell undifferentiated carcinoma, and small cell carcinoma.
Bronchogenic carcinoma is also divided into two broad groups for therapeutic reasons:
Small cell lung cancer: By the time these types of cancer present, they have
metastasized. Therefore, surgery will not help, but chemotherapy with/without
radiation is useful.
Non-small cell lung cancer: Includes squamous cell carcinoma, adenocarcinoma,
and large cell undifferentiated carcinoma. These tumors are best treated with
surgery as they usually have not metastasized.
Squamous cell carcinoma
There are more common in men than women and show a strong correlation with
smoking. They tend to arise centrally in major bronchi and eventually spread to local
hilar nodes. They are often preceded for years by metaplasia which then turns into
carcinoma in situ. Tumors may have keratin pearls.
Adenocarcinoma
These are more peripherally located lesions, many arising in relation to peripheral lung
scars (scar carcinoma). They tend to metastasize at an early stage. The precursor of
peripheral adenocarcinomas has been described as:
(1) Atypical adenomatous hyperplasia (AAH). This is recognized as welldemarcated focus of epitheial proliferation composed of cuboidal to lowcolumnar cells, which demonstrate various degrees of cytologic atypia.
(2) Bronchioloalveolar carcinoma (BAC)
The key feature of BAC is their growth along preexisting structures and
preservation of alveolar architecture. This is like an in situ carcinoma.
Lepidic: Describes the situation that occurs when tumor cells grow in a
monolayer on top of the alveolar septa, which serves as a scaffold.
(3) Finally, the basement membrane is broken and invasive adenocarcinoma is
formed.

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Large cell carcinoma/giant cell carcinoma/spindle-cell carcinoma

A group of neoplasms that lack cytologic differentiation and probably represent
squamous cell or glandular neoplasms that are too undifferentiated to permit
categorization. Tend to spread early in their development.
Small Cell Carcinoma
Usually appear as pale gray, centrally located masses with extension into the lung
parenchyma and early involvement of the hilar and mediastinal nodes.
Parathyroid hormone-related peptide: Small cell carcinomas can secrete this and
cause hypercalcemia.
Cushing syndrome: Small cell carcinomas can secrete ACTH causing increased
secretion of corticosteroid from the adrenals resulting in Cushing syndrome.
Crush artifact: The tumor cells of small cell carcinoma are fragile and often show
fragmentation in small biopsy specimens.
Nuclear molding: Another feature of small cell carcinoma is nuclear molding
resulting from close apposition of the tumor cells that have scant cytoplasm.
Neuroendocrine cell: Small cell carcinomas are derived from neuroendocrine cells
of the lung, and they express a variety of neuroendocrine markers and a host of
polypeptide hormones that may result in paraneoplastic syndrome.
Virchow node
This is another name for the supraclavicular node. Its involvement in cancer could call
attention to an occult primary tumor.
Vena cava syndrome
Cancers may compress or infiltrate the superior vena cava to cause either venous
congestion or the full blown vena caval syndrome.
Pancoast tumor
Apical neoplasms that invade the brachial or cervical sympathetic plexus to cause severe
pain in the distribution of the ulnar nerve or to produce Horner Syndrome.
Horner syndrome: Ipsilateral enophthalmos, ptosis, meiosis, and anhidrosis.
Syndrome of inappropriate secretion of ADH (SIADH)
A paraneoplastic syndrome associated with lung cancers.
Bronchial carcinoid
Thought to arise from neuroendocrine cells that line the bronchial mucosa. They appear
at an early age and can be respectable and curable. Usually presents with findings related
to their intraluminal growth (cough, hemoptysis, and recurrent infection).
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PLEURAL LESIONS
Pg 504 506
Malignant mesothelioma
Rare cancer of meosthelial cells, usually arising in the parietal or visceral pleura. It is
associated with occupational exposure to asbestos in the air. The latent period of this
cancer is between 25-40 years. The combination of cigarette smoking with asbestos
exposure greatly increases the risk of malignant mesothelioma.
Asbestos/amphibole/chrysotile: Asbestos occurs in two forms: amphibole or
chrysotile. The amphibole asbestos, which has long, straight fibers are related to
nearly all cases of malignant mesothelioma.
Hydrothorax
A pleural effusion that is a transudate. This occurs mainly as a result of CHF.
Pleuritis
An exudates is characterized by a specific gravity greater than 1.020. Often,
inflammatory cells are present if there is pleuritis.
Pneumothorax/Hemothorax/Chylothorax
This refers to air/gas in the pleural sac/blood in the pleural sac/lymphatic fluid in the
pleural sac.
LESIONS OF THE UPPER RESPIRATORY TRACT
Pg 506 508
Pharyngitis
This manifests as a sore throat and may be caused by a host of agents.
Epiglottitis
This is a syndrome of predominantly young children who have an infection of the
epiglottis by H. influenzae, in which pain and airway obstruction are the major findings.
Laryngitis/croup
This can result from the inhalation of irritants or maybe caused by allergic reactions. In
children, parainfluenza virus is the most common cause of laryngotracheobronchitis,
more commonly known as croup.
Nasopharyngeal carcinoma
Has a strong link to EBV and has a high frequency in the Chinese. EBV infects the host
by first replicating in the nasopharyngeal epithelium and then infecting nearby tonsillar B
lymphocytes.

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Vocal cord nodule/laryngeal papilloma/juvenile laryngeal papillomatosis

These are the sufficiently cause common laryngeal tumors. There most common clinical
presentations are hoarseness.
Vocal cord nodules: smooth hemispherical protrusions located on the true vocal
cords. These occur chiefly in heavy smokers and singers.
Laryngeal papilloma: is a bening neoplasm usually on the true vocal cords, that
forms a soft, raspberry like excrescence rarely more than 1cm in diameter.
Juvenile laryngeal papillomas: though papillomas are usually singular in adults,
they occurs as multiple papillomas in children. These lesions are caused by
human pappilomovirus 6-11.
Carcinoma of the larynx
Only 2% of all cancers; usually presents in patients over the age of 40 and more often in
men than women. There is a strong correlation between this and smoking, drinking, and
asbestos exposure. Manifests as persistent hoarseness. The location of the carcinoma is
designated as:
Glottic tumors: directly on the vocal cords, usually keratinizing
Supraglottic tumors: above the vocal cords, 1/3 of these metastasize due to rich
lymphatics in the suprglottic region.
Subglottic tumors: below the vocal cords

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CHAPTER 15
GI TRACT
THE ORAL CAVITY
Pg 543 549
Apthous ulcer
Extremely common (<20 years old) painful shallow ulcers of the soft tissue in the mouth
(buccal mucosa, soft palate). They are characterized as rounded, superficial erosions,
often covered with gray-white exudates surrounded with an erythematous rim. They are
self-limited, but may recur.
Trigger: stress, foods, fever and inflammatory bowel disease.
Cause: autoimmune
Herpetic stomatitis
Solitary or multiple small vesicles containing clear fluid that ultimately rupture and form
ulcers before healing. Most commonly affects the lips or nasal orifices. They are also
called cold sores and are caused by herpes simplex virus (HSV) type I. HSV type I is
transmitted from person to person by kissing and most people have been infected but
remain asymptomatic. The sores are triggered by sun, fever, hot/cold exposure.
Intranuclear inclusion: infected cells become ballooned and develop
intranuclear acidophilic viral inclusions.
Tzanck test: is used to identity the inclusion-bearing cells or polykaryons in
smears of blister fluid.
Herpetic gingivostomatitis/encephalitis: herpetic gingivostomatitis is marked by
multiple vesicles throughout the oral cavity, including the pharynx. In the worst
case, viremia may seed to the brain (encephalitis).
Keratoconjunctivitis: HSV-1 may localize to the conjunctivae.
Oral candidiasis
This is a common fungal infection in immunocompromised (i.e., AIDS, diabetes mellitus,
anemia, antibiotic therapy). It takes the form of an adherent white, curdlike
circumscribed plaque anywhere within the oral cavity. This pseudomembrane
(composed of fungi in box-car like chains) can be scrapped away to reveal an
erythramatous base.
Kaposi sarcoma
This is a multifocal systemic disease that eventually evolves into highly vascular tumor
nodules. This can cause oral lesions characterized by purpuric discolorations or raised
nodular masses. Is associated with HHV-8.

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Hairy leukoplakia
Seen almost exclusively in HIV patients. These are white patches anywhere on the oral
mucosa that have a corrugated surface. They are caused by Epstein-Barr virus
infection of epithelial cells.
Leukoplakia
This term refers to a whitish, well-defined mucosal patch or plaque caused by epidermal
thickening or hyperkeratosis. Microscopically, it varies from hyperkertanosis to
dysplasia and near carcinoma in situ (which can lead to squamous cell carcinoma). They
are more common in older mens lower lips and buccal mucosa. There is a strong
association with tobacco use (particularly smokeless tobacco).
Erythroplasia
Refers to red, velvety, often granular, circumscribed areas that may or may not be
elevated, having poorly defined and irregular boundaries. This has a high rate (50%) of
malignant transformation.
Oral squamous cell carcinoma
The overwhelming preponderance of oral cavity cancers are squamous cell carcinomas
(moderately well differentiated with keratinizing pearls). Usually occur >40 years old
and about 50% result in death within 5 years. Clinically, these lesions are painless and
often go long periods before presenting to the doctor. By this time, the cancer has spread
and is beyond cure.
Early lesion: appear as pearly white to gray, circumscribed thickenings of the
mucosa closely resembling leukoplakia. Early lesions proceed to form palpable
nodular lesions or a cancerous ulcer.
Sialadenitis/viral/bacterial/chronic/autoimmune
This is the inflammation of a salivary gland and can be viral, bacterial, or autoimmune in
origin.
Mumps: viral infection producing enlargement of the salivary glands and
predominantly the PAROTID gland. The mumps virus belongs to the
Paramyxovirus family. It is an RNA virus related to the influenza and is the
dominant cause of mumps.
Bacterial Sialadenitis: usually occurs secondary to duct obstruction resulting from
stone formation (sialolithisasis). Dehydration increases risk for bacterial
sialadenitis.
Chronic Sialadenitis: arises from decreased production of saliva with subsequent
inflammation. The dominant cause is autoimmune sailadenitis. This is seen in
Sjogrens syndrome (clinically presents as dry mouth and dry eyes).
Xerostomia/Keratoconjunctivitis sicca
This is dry mouth and dry eyes respectively.
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Mikulicz syndrome
Salivary gland and lacrimal gland inflammation and xerostomia is sometimes referred to
by this name.
Pleomorphic adenoma (Mixed tumor)
This tumor accounts for 90% of benign tumors of the salivary glands. Usually this tumor
is well-differentiated, encapsulated, and arises in the superficial parotid gland.
Histologically, this tumor consists of a mix of epithelial and mesenchyme-like elements.
Malignant mixed salivary gland tumor
When primary or recurrent benign tumors are present for many years, malignant
transformation may occur, they are then referred to as a malignant mixed salivary
gland tumors. Malignancy is more common in the submaxillary gland than in the
parotid gland.
Warthin tumor (Papillary cystadenoma lymphomatosum)
Occurs virtually only in the region of the parotid gland. Histologically, these tumors are
cystic spaces lined by double-layered eosinophilic epithelium, all embedded in lymphoid
stroma.
Dysphagia
Difficulty in swallowing due to deranged motor function of esophagus or
narrowing/blockage of the lumen.
Heartburn
Retrosternal burning pain due to reflux of gastric contents into esophagus.
Hematemesis
Vomiting of blood. This can signal eruption of esophageal veins.
Melena
Blood in the stool.

ESOPHAGUS
Pg 549 554
Hiatal hernia/sliding/paraesophageal
Separation of the diaphragmatic crura and widening of the space between the muscular
crura and the esophageal wall permits a dilated segement of stomach to protrude above
the diaphragm. Associated conditions are: ulceration, bleeding, and perforation.

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Sliding hernia (95%)

Protrusion of the stomach
above the diaphragm creating a
bell-shaped dilation.
Paraesophageal hernia
Part of the greater curvature
protrudes through the
esophageal hiatus.

Major conditions associated

with esophageal motor
dysfunction.

Achalasia
This term means failure to relax. As applied to the esophagus, it denotes incomplete
relaxation of the lower esophageal sphincter in response to swallowing. Three forms: (1)
aperistaltic, (2) imcomplete relaxation of the LES, and (3) increased tone of LES.
Inflammation in the location of the esophageal myenteric plexus is pathogomonic. This
can lead to squamous cell carcinoma of the esophagus.
Primary achalasia: loss of innervation of LES or smooth muscle.
Secondary achalasia: pathologic process that impairs esophageal motility
Chagas disease/trypanosoma cruzi
This parasite causes Chagas disease; Chagas disease includes the destruction of the
myenteric plexus of the esophagus, duodenum, colon, and ureter.
Mallory-Weiss Tear
Longitudinal tears in the esophagus at the esophagogastric junction. Associated with
alcoholics after severe vomiting spell. This accounts for 5 10% of upper GI bleeds.
Esophageal varices
Esophageal veins (within the submucosa of the stomach and esophagus) are sites of
communication between portal veins and systemic veins. When portal venous flow is
obstructed to a cirrhotic liver, the resultant portal hypertension shunts blood to these
veins and cause dilation of the vessels. This is most often associated with alcoholic
cirrhosis.
Variceal rupture: this leaks massive amount of blood into the lumen and into the
esophageal wall.
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Reflux esophagitis/gastroesophageal reflux disease (GERD)

Injury to the esophagus with subsequent inflammation. In the US, mostly attributed to
gastroesophageal reflux. Clinically presents as heartburn and can occasionally mimic a
heart attack. Reflux can predispose to Barretts esophagus. Three histologic feature are
characteristic of reflux esophagitis:
(1) Eosinophils (if more serious, neutrophils as well)
(2) Basal zone hyperplasia
(3) Elongation of the lamina propria papillae.
Barrett esophagus/metaplastic columnar epithelium
This is a complication of long standing gastroesophageal reflux. It is defined as the
replacement of the normal stratified squamous mucosa by metaplastic columnar
epithelium containing goblet cells. This is most common in white males. This can lead
to the development of adenocarcinoma. Macroscopically, Barretts esophagus looks like
a salmon pink tissue in the distal esophagus (normally pale pink).
Barrett esophagus. A, B, Gross
view of distal esophagus (top) and
proximal stomach (bottom),
showing A, the normal
gastroesophageal junction (arrow)
and B, the granular zone of Barrett
esophagus (arrow). C, Endoscopic
view of Barrett esophagus showing
red velvety gastrointestinal mucosa
extending from the
gastroesophageal orifice. Note the
paler squamous esophageal
mucosa.

Esophageal carcinoma
Esophageal carcinoma is insidious in onset and presents with dysphagia and obstruction.
This is followed by pain related to swallowing. There are two main forms of esophageal
carcinoma:
SCC
These are more common in blacks than whites. Predisposing factors include slow transit
of food through the esophagus and smoking/drinking. This usually follows the
dysplasia, carcinoma in situ, invasive cancer histologic sequence. The initially look
like gray-white plaques with turn into: (1) polypoid exophytic masses that protrude into
the lumen (2) cancerous ulcerations, or (3) infiltrative neoplasms that obstruct the lumen
of the esophagus. Half of the carcinomas arise in the middle esophagus.
Tylosis: This is a rare genetic disease causing hyperkeratosis of the palms and
soles and is associated with the development of squamous cell carcinoma.

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Adenocarcinoma (primary in US)

This is linked to Barretts esophagus and Barretts esophagus is the only known precursor
to adenocarcinoma. These are usually in the distal 1/3 of the esophagus and can invade
the gastric cardia. The tumors are usually mucin producing glandular tumors.

Transition from Barrett esophagus to adenocarcinoma.

STOMACH
Pg 554 563

Anatomy of the stomach

Helicobacter pylori
H. pylori cause gastritis owing to the combined influence of bacterial enzymes and toxins
and release of noxious chemicals by the recruited neutrophils. They can be seen in the
mucus layer overlying the mucosal epithelium. H. pylori infection causes an increased
risk of developing peptic and duodenal ulcer. H. pylori-induced proliferation of the
lymphoid tissue has been associated with an increased risk of gastric carcinoma.

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Gastritis
Simply defined as inflammation of the gastric mucosa. There are acute and chronic
forms with the chronic form being the most prevalent. Clinically, patients may be
asymptomatic. There is a characteristic hypochlorhydria (low level of gastric HCl) and
hypergastrinemia.
Acute gastritis: Acute gastritis is an acute mucosal inflammatory process, usually
of a transient nature. This is frequently associated with NSAIDs/chemical
ingestion, excessive alcohol/smoking, trauma. Acute gastritis is one of the
major causes of hematemesis, particularly in alcoholics. Histologically, this is
characterized by marked mucosal edema and an inflammatory infiltrate of
neutrophils.
Acute erosive gastritis: this is concurrent erosion and hemorrhage of the mucosa.
Chronic gastritis: The presence of chronic mucosal inflammatory changes leading
to mucosal atrophy and epithelial metaplasia. Histologically, this is characterized
by lymphocytic and plasma cell infiltrates in the lamina propria (possibly with
gland loss and mucosal atrophy).
Autoimmune gastritis: This results from autoantibodies to the gastric gland
parietal cells, in particular to the acid-producing enzyme H,K-ATPase. This
ultimately leads to deficiency in intrinsic factor (IF) and pernicious anemia.
Intestinal metaplasia
Refers to the replacement of gastric epithelium with columnar and goblet cells of
intestinal variety. The metaplastic cells can become displastic, which can lead to gastrointestinal carcinomas.
Hypochlorhydria/achlorhydria
Decreased HCl production and no HCl production respectively.
Peptic ulcer
Round, sharply punched-out craters 2 to 4 cm in diameter usually found along the lesser
curvature or anterior/posterior walls of the duodenum. They are chronic, usually solitary
lesions that can occur in any portion of the GI tract exposed to acid-peptic juices. Usually
diagnosed in middle-age or older adults. 2 key factors must occur to cause a peptic ulcer:
(1) mucosal exposure to gastric acid/pepsin and (2) H. pylori.
Unlike ulcerated cancers there is no significant elevation or beading of the edges. If
the ulcer perforates, there may be an associated peritonitis.
Most peptic ulcers present with burning pain that is worse at night and after a meal: is
relieved by antacids.

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Zollinger-Ellison syndrome
This syndrome is associated with multiple peptic ulcerations in the stomach, duodenum,
and jejunum due to excess gastrin secretion by a tumor leading to excess gastric acid
production.
Curling ulcer/Cushing ulcer
Curling ulcers are ulcers that present in the context of severe burns, while Cushing ulcers
present in the context of CNS injury.
Gastric polyp/hyperplastic/fundic gland/adenomatous
A polyp is any nodule or mass that projects above the level of the surrounding mucosa.
In the GI tract, this term is generally restricted to mass lesions arising in the mucosa.
These are uncommon lesions. There are three types found in the stomach and all are
associated with chronic gastritis: (1) hyperplastic (excess response to damage), (2) fundic
gland (harmatomas), and (3) adenomatous (true neoplasms).
Gastric carcinoma/intestinal/diffuse
This is the most common malignant tumor of the stomach. They occur most often along
the lesser curvature and more often in the pylorus and antrum region. Clinical outcome is
most related to depth of invasion. There are two morphological types:
Intestinal: malignant cells forming neoplastic intestinal glands resembling those
of colonic adenocarcinoma.
Diffuse: composed of gastric-type mucous cells that generally do not form glands
but rather permeate the mucosa and wall as scattered signet-ring cells. Has
red, mucin containing tumor cells.
Linitis plastica (leather bottle stomach)
Term applied to a stomach whose gastric wall is extensively infiltrated by malignancy.
Krukenberg tumor
Metastatic spread to both ovaries.
In early gastric carcinoma (A),
the tumor is confined to the
mucosa and submucosa and
may exhibit an exophytic, flat
or depressed, or excavated
conformation. Advanced
gastric carcinoma (B) extends
into the muscularis propria and
beyond. Linitis plastica is an
extreme form of flat or
depressed advanced gastric
carcinoma.

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SMALL AND LARGE INTESTINES

Pg 563 588
Small intestinal atresia/stenosis
Atresia is the complete failure of development of the intestinal lumen and stenosis is a
narrowing of the lumen.
Small intestinal duplication
This takes the form of a well-formed saccular or tubular cystic structure which may or
may not communicate with the lumen.
Meckel diverticulum (Small intestine)
This is the most common anomaly. It results from failure of involution of the
omphalomesenteric duct, leaving a persistent blind-ended tubular protrusion 5-6cm long.
Omphalocele (Small intestine)
A congenital defect of the periumbilical abdominal wall leaves behind a membranous
sac, into which the intestines herniated.
Malrotation (Large intestine)
This abnormality in development causes the intestines to take a different position in the
abdomen than is usual. The large intestine is predisposed to volvulus.
Hirschsprung disease (congenital megacolon)
This disease results when the caudad migration of neural crest-derived cells along the
alimentary tract arrests at some point before reaching the anus leading to an aganglionic
segment that lacks the Meissner submucosal and Auerback myenteric plexuses:
fucntional obstruction and progressive distention of the colon proximal to the segment is
the result.
Meissner plexus/Auerbach plexus
The submucosal plexus (Meissners Plexus) primarily controls the secretion and blood
flow. The myenteric plexus (Auerbachs Plexus) primarily controls the motility of the GI
smooth muscle.
Acquired megacolon
This can result from (1) Chagas disease (parasites destroy the plexuses), (2) mechanical
obstruction, (3) toxic megacolon or Crohns disease, (4) psychosomatic disorder.
Ischemic bowel disease
Impaired blood flow to the intestines usually results from the occlusion of an artery as
compared to the obstruction of a vein. The main arteries are: celiac and superior/inferior
mesenterics. The extent of the disease is associated with which artery and which branch
of that artery is affected. The severity ranges from transmural infarction (all layers), to
mural infarction (mucosa and submucosa), and mucosal infarction.

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Angiodysplasia
Tortuous dilations of submucosal and mucosal blood vessels are seen most often in the
cecum or right colon, usually only after the sixth decade of life. These lesions account
for 20% of lower GI bleeding.
Hemorrhoids
Variceal dilations of the anal and perianal submucosal venous plexuses.
Internal: varicosities in the superior and middle hemorrhoidal veins appear in
above the anorectal line and are covered by rectal mucosa.
External: varicosities that appear below the anorectal line are dilations of the
inferior hemorrhoidal plexus and are covered by anal mucosa.
Dysentery
This is low volume, painful, bloody diarrhea. Go micro.
Secretory diarrhea
Net intestinal fluid secretion that is isotonic with plasma and persists during fasting.
Osmotic diarrhea
Excessive osmotic forces exerted by luminal solutes that abate with fasting.
Malabsorption
Output of voluminous, bulky stools with increased osmolarity owing to unabsorbed
nutrients and excess fat (steatorrhea).
Typhoid fever
Salmonella typhi is the responsible agent for typhoid fever. Typhoid fever is a protracted
disease featuring bacteremia, widespread retculoendothelial involvement with
splenomegaly and foci of necrosis in the liver, and ulceration of Peyer patches wth
intestinal bleeding and ulceration. It can also colonize the Gallbladder.
Pseudomembranous colitis/clostridium difficile
C. difficile is a part of the normal flora. Cyto-toxin producing strains overgrow after
systemic antibiotic use. A distinctive pseudomembranous colitis is produced.
Flask-shaped ulcer/entamoeba histolytica
E. histolytica is a dysentery causing protozoan parasite. Amebae invade the crypts of
colonic glands and burrow down into the submucosa. The organisms fan out laterally
creating flask shaped ulcers.
Amebic abscess: E. histolytica can penetrate the portal veinous system and spread
to locations outside the intestine. When it arrives at the target tissue (usually
liver) it forms abscesses.

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Giardia lamblia
G. lamblia is an intestinal protozoan that attaches to the small intestinal mucosa but do
not appear to invade. It causes a malabsorptive diarrhea that appears to result from
mucosal cell injury.
Cryptosporidia
Cryptospridiosis leads to diarrhea and is a potentially fatal complication of AIDS.
Lactose intolerance
Lactose intolerance can be inherited (deficiency of disaccharidase: rare) or acquired. In
infants, the disease can lead to diarrhea, eight loss, and failure to thrive.
Abetalipoproteinemia
This is a rare autosomal deficiency of apolipoprotein B. It renders the mucosal epithelial
cell unable to export lipid, because this protein is synthesized by these cells for assembly
of dietary lipids into chylomicrons for export to intestinal lymphatics.
Gluten-sensitive enteropathy (celiac disease)
Noninfectious cause of malabsorption resulting from a reduction in small intestinal
absorptive surface area. The basic disorder in celiac disease is sensitivity to gluten, the
component of wheat and related grains that contains the water-insoluble protein gliadin.
Gliadin: Gliadin peptides are efficiently presented by celiac disease-specific
APCs in the lamina propria of the small intestine to CD4+ T Cells, creating an
immune response to gluten. In addition to filling the lamina propria, the
lymphocytes also cross into the epithelial space, damaging the surface
enterocytes.
Tropical sprue
This is an infectious disease that resembles celiac disease symptoms.
Whipple disease/PAS-positive macrophage
Whipple disease is a rare, systemic infection (T. whippelii) that may involve any organ of
the body but principally affects the intestine, CNS, and joints. The hallmark of Whipple
disease is PAS positive macrophages in the lamina propria. The affects of this disease
are felt as a malabsorptive syndrome occasionally accompanied by lymphadenopathy.
Idiopathic Inflammatory Bowel Disease
Crohns disease and ulcerative colitis are chronic relapsing disorders of unknown
origin that share many common features and are collectively known as IBD. IBD is a
heterogeneous group of diseases characterized by an exaggerated and destructive mucosal
immune response. The tissue injury in IBD is likely to be initiated by diverse genetic and
immunologic pathways that are modified by environmental influences, including
microbes and their products.

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Crohn disease (CD)

CD must be viewed as a systemic inflammatory disease with predominant GI
involvement (mainly small intestine and colon). When fully developed, CD is
characterized by (1) sharply delimited and typically transmural involvement of the bowel
by an inflammartory process with mucosal damage, (2) the presence of noncaseating
granulomas (40-60%), and (3) fissuring with formation of fistulae.
Creeping fat: mesenteric fat wraps around diseased segments of intestine.
String sign: radiological evidence of CD and is visualized as a thin stream of
barium passing through the diseased segment.
Skip lesion: classic feature of CD is the sharp demarcation of diseased bowel
segements from adjacent uninvolved bowel. When multiple bowel segments are
involved, the intervening bowel is essentially normal.
Fistula: abnormal opening or channel connecting two internal organs or leading
from an internal organ to outside the body. In CD, begins as an ulceration.
Crypt abscess: inflammation with neutrophilic infiltration into the epithelial layer
and accumulation within crypts to form crypt abscesses.
Granulomas: can be present in CD.

Comparison of the
distribution patterns of
Crohn disease and
ulcerative colitis, as well as
the different conformations
of the ulcers and wall
thickenings.

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Ulcerative colitis (UC)

UC is an ulceroinflammatory disease affecting the colon but limited to the muosa and
submucosa except in the most severe cases. UC begins in the rectum and extends
proximally in a continuous fashion, sometimes involving the entire colon. UC does not
involve granulomas, skip lesions (its continuous), or mural thickening. It is associated
with an increased risk of carcinoma. Clinically, UC presents as recurrent bouts of
bloody, mucoid diarrhea. The attacks are marked by an insidious onset with cramps,
tenesmus, and colicky lower abdominal pain.
Pseudopolyp: UC is an ongoing inflammatory disease: isolated islands of
regenerating mucosa bulge upward to created pseudopolyps.
Toxic megacolon: Rarely, the ulcers may compromise the muscularis propria.
Exposure of the muscularis propria and neural plexus to fecal material also may
lead to complete shutdown of neuromuscular function. This causes the colon to
progressively swell and become gangrenous.
Tenesmus: This is one of the presenting symptoms of IBD. There is spasm of the
rectum and desire to defecate without the production of significant amounts of
feces.
Migratory polyarthritis: This is an extraintestinal manifestation that is more
common with UC than with CD.

Colonic Diverticulosis
A diverticulum is a blind pouch leading off the alimentary tract, lined by mucosa, that
communicates with the lumen of the gut. The most common congenital diverticulum is
Meckels diverticulum. Virtually all others are acquired and occurs most commonly in
the colon. Two factors leading to diverticulosis genesis: (1) exaggerated peristaltic
contractions with abnormal elevation of intraluminal pressure, and (2) focal defects
peculiar to the normal muscular colonic wall.
Hernia/incarceration/strangulation
A weakness/defect in the wall of the peritoneal cavity may permit protrusion of a
pouchlike, serosa-lined sac of peritoneum, called a hernial sac. Pressure at the neck of
the pouch may impair venous drainage of the trapped viscus. Stasis and edema ensue
leading to permanent entrapment of the herniated loop (incarceration). Further
compromise of blood supply leads to infarction (strangulation).
Adhesion
Adhesions may occur between bowel segments and the abdominal wall. They are fibrous
bridges that that can create closed loops through which intestines may slide and become
trapped (causing internal herniations).

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Intussusception
This denotes telescoping of a proximal segment of bowel into the immediately distal
segment. In adults, such telescoping often points to an intraluminal mass (tumor).
Volvulus
Twisting of a loop of bowel or other structure about is base of attachment, constricting
the venous outflow and sometimes the arterial supply as well.

Schematic depicting the

four major causes of
intestinal obstruction:
(1) Herniation of a
segment in the umbilical
or inguinal regions; (2)
adhesion between loops
of intestine; (3)
intussusception; (4)
volvulus formation.

Hyperplastic polyp
These are small nipple-like, hemispherical, smooth protrusions of the mucosa. They can
occur singly but usually occur multiply. A vast majority have no malignant potential.
They are formed as the result of abnormal mucosal maturation, inflammation, or
architecture.
Juvenile polyp
These are harmatomatous proliferations, mainly of the lamina propria, enclosing widely
spaced, dilated cystic glands. Usually in children less than 5 years old.
Adenomas
Neoplastic polyps that range from small, often pedunculated tumors to large lesions that
are usually sessile. There are three subtypes:
Tubular adenoma: are the most common and usually arise in the rectosigmoid part
of the colon. Histologically, the stalk is covered by normal colonic mucosa, but
the head is composed of neoplastic epithelium.
Intramucosal carcinoma: this is cancer confined to the mucosa.
Villous adenoma: are generally sessile, up to 10cm in diameter, velvety or
cauliflower masses projecting 1-3cm above the normal mucosa.
Tubulovillous adenoma: are composed of a mix of tubular and villous areas.

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Familial adenomatous polyposis

Patients typically develop 500-2500 colonic adenomas that carpet the mucosal surface.
Most of the polyps are tubular adenomas. With this disease, there is a 100% risk of
colonic cancer by midlife.
APC gene: the underlying defect in FAP is in the APC gene on 5q21.
Gardner syndrome/Turcot syndrome
Both of these syndromes share the same APC genetic defect as FAP but differ in the
following regard: these two syndromes have extraintestinal tumors whereas FAP does
not.
Peutz-Jeghers syndrome
Peutz-Jeghers polyps are uncommon hartomatous polyps that occur as part of the rare
autosomal dominant Peutz-Jeghers syndrome, characterized in addition by melanotic
mucosal and cutaneous pigmentation.
Cowden syndrome
This syndrome is also characterized by hartomatous polyps in the GI tract, and by an
increased risk of neoplasms of the thyroid, breast, uterus, and skin.
Colorectal carcinoma
98% of all cancers in the large intestine are adenocarcinomas. The peak incidence is 6070 years of age. When found in a young person, one must think of UC or another
polyposis syndrome. Adenomas are the presumed precursor lesion.

Adenoma-carcinoma
sequence
The development of
carcinoma from
adenomatous lesions is
referred to as the
adenoma-carcinoma
sequence:

K-RAS gene
The K-RAS gene encodes a signal transduction molecule that oscillates between an
activated GTP and an inactivated GDP. Mutated RAS is stuck in the activated state and
delvers mitotic signals and prevents apoptosis.
Carcinoembryonic antigen (CEA)
This is a serum marker for disease, but is of little diagnostic value for colon cancer since
it is elevated in other conditions.

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Gastrointestinal stromal tumor (GIST)

This is a neoplasm of the small intestine and they have a mutation that affects KIT, a
tyrosine kinase receptor. Because of this, they can be treated with the tyrosine kinase
receptor inhibitor (STI-571 (Gleevec)), which was originally developed for treatment of
chronic myeloid leukemia.
Carcinoid tumor
Small, slow-growing neoplasms composed of islands of rounded, oxyphilic, or spindleshaped cells of medium size, with moderately small vesicular nuclei, and covered by
intact mucosa with a yellow cut surface. They can arise from neuroendocrine cells along
the GI tract and secrete hormones creating a carcinoid syndrome.
MALT lymphoma
A lymphoma that arises from the B-cells of the mucosa-associated lympoid tissue. This
usually affects adults and may arise anywhere in the gut (mostly the stomach and small
intestine). Most MALT lymphomas are sporadic, however those in the stomach have
been linked to H. pylori.
T-cell lymphoma
Celiac disease is associated with a higher than normal risk of T-cell lymphoma.

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APPENDIX
Pg 588 589
Acute appendicitis
Appendiceal inflammation is associated with obstruction by a fecalith (50-80%). After
obstruction, mucous cells of the appendix continue to secrete mucous leading to
increased intraluminal pressure. The increased pressure causes collapse of draining
vessels, leading to ischemic injury, and bacterial proliferation.
Oxyuriasis vermicularis: ball of worms that can obstruct the appendix.
Early Acute Appendicitis
Inflammatory reaction that causes changes in the appendix: congested vessels
neutrophilic infiltrate, and the serosa turns from shiny to dull and red.
Acute suppurative appendicitis
Increased neutrophilic infiltrate that generates a fibropurulent exudates which coats the
serosa. Later there is abscess formation and ulceration.
Acute gangrenous appendicitis
Hemorrhagic, green ulceration of the mucosa, and green-black gangrenous necrosis
through the wall of the appendix extending to the serosa. This is quickly followed by
rupture of the appendix.
Clinical Appendicitis Presentation
(1) Mild periumbilical discomfort
(2) Anorexia, nausea, and vomiting
(3) Right, lower quadrant tenderness
(4) Deep constant ache or pain
Tumors of the Appendix
Most commonly are carcinoids.
Mucocele
Dilation of the lumen of the appendix by mucinous secretion.
Mucinous neoplasms range from the benign mucinous cystadenoma, to mucinous
cystadenocarcinoma (malignant mucin-secreting neoplasm), which invades the wall, to
form a disseminated intraperitoneal cancer called pseudomyxoma peritonei.

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PATHOLOGY PAO 2101

BLOCK III

Uniformed Services University

School of Medicine

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Robbins Pathology Vocabulary Review

CHAPTER 16
LIVER AND BILIARY TRACT
GENERAL PRINCIPLES
Pg 592 597
Hepatitis
Injury to hepatocytes associated with an influx of acute or chronic inflammatory cells
into the liver is termed hepatitis.
Ballooning degeneration
Hepatocytes take on a swollen, edematous appearance with irregularly clumped
cytoplasm and large, clear spaces.
Foamy degeneration
Retained biliary material may impart a diffuse, foamy, swollen appearance to hepatocytes
Steatosis/microvesicular/macrovesicular
Accumulation of fat droplets within hepatocytes.
Microvesicular steatosis multiple droplets that do not displace nucleus.
Macrovesicular steatosis single large droplet that displaces nucleus.
Reye syndrome
This is a rare disease characterized by fatty change in the liver and encephalopathy. It
primarily affects children under 4 years old, typically following a viral infection. The
onset is heralded by pernicious vomiting and is accompanied by irritability or lethargy
and hepatomegaly. It has been associated with giving children aspirin during a viral
infection (that is bad).
Hydropic degeneration
Hepatocytes may osmotically swell and rupture, so called hydropic degeneration or lytic
necrosis.
Centrilobular necrosis
Term applied when necrosis is distributed immediately around the central vein.
Interface hepatitis
In immunologically mediated hepatocyte death, apoptosis may be limited to scattered
cells within the hepatic parenchyma or to the interface between the periportal
parenchyma and inflamed portal tracts.
Bridging necrosis
Continuous hepatocytes may span adjacent lobules in a portal-to-portal, portal-to-central,
or central-to-central fashion.

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Submassive/massive necrosis
Destruction of entire lobules of the liver and destruction of most of the liver, usually
accompanied by liver failure, respectively.
Bridging fibrosis
Fibrous strands link regions of the liver together (portal-to-portal, portal-to-central, or
central-to-central) together.
Cirrhosis
Generally irreversible fibrosis of the liver most commonly caused by alcoholism, but
also by chronic hepatitis, biliary disease, and Fe overload. Defined by three
characteristics:
1. Bridging fibrous septa scarring affecting adjacent lobules
2. Parenchymal nodules created by regeneration of encircled hepatocytes
3. Disruption of the architecture of the entire liver.
The three major pathologic mechanisms that lead to cirrhosis are hepatocellular death,
regeneration, and progressive fibrosis (Types I and III collagen).
Jaundice
A yellow discoloration of skin and sclerae (icterus) occurs when systemic retention of
bilirubin leads to elevated serum levels above 2.0 mg/dl. Most frequently caused by
hemolytic anemias, hepatitis, and obstruction to the flow of bile.
Bilirubin
Bilirubin is the end product of heme degradation.
Unconjugated bilirubin
Tightly complexed to serum albumin and is insoluble in water
at physiological pH. It cannot be excreted and can diffuse into
tissue causing toxic injury.
Conjugated bilirubin
Only weakly associated with albumin and can be excreted.

Bilirubin metabolism and elimination. 1, Normal bilirubin production

from heme (0.2 to 0.3 gm/day) is derived primarily from the breakdown of
senescent circulating erythrocytes, with a minor contribution from
degradation of tissue heme-containing proteins. 2, Extrahepatic bilirubin is
bound to serum albumin and delivered to the liver. 3, Hepatocellular uptake
and (4) glucuronidation in the endoplasmic reticulum generate bilirubin
monoglucuronides and diglucuronides, which are water soluble and readily
excreted into bile. 5, Gut bacteria deconjugate the bilirubin and degrade it to
colorless urobilinogens. The urobilinogens and the residue of intact
pigments are excreted in the feces, with some reabsorption and excretion
into urine.

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Urobilinogen
Bilirubin glucuronides are deconjugated by gut bacterial glucuronidases and degraded to
colorless urobilinogens (this is excreted in the feces).
Bile acids
Steroid molecules derived from cholesterol conjugated with taurine or glycine, and
function to solubilize phospholipids and cholesterol in bile and dietary lipids in the gut
lumen.
Enterohepatic circulation
The bodies mechanism for maintaining large endogenous pools of bile acids for secretory
and digestive purposes. The bile acids are constantly secreted into the gut lumen and
recycled back to the liver.
Crigler-Najjar syndrome
Type 1 (Fatal) - Rare, autosomal recessive condition with a complete lack of the enzyme
responsible for conjugating glucuronic acid to bilirubin.
Kernicterus: diffusion of unconjugated bilirubin into tissue (namely the brain)
resulting in toxic damage.
Type 2 (Non-fatal): Only partial defect in conjugating enzyme.
Gilbert syndrome
Present in up to 7% of population. Syndrome is caused by decreased levels of
glucuronosyl-transferase causing mild, fluctuating unconjugated hyperbilirubinemia.
Dubin-Johnson syndrome
Results from autosomal recessive defect in the transport protein responsible for
hepatocellular excretion of bilirubin glucuronides across the canalicular membrane. The
liver is pigmented, there is hepatomegaly, but there are no functional problems.
Rotor syndrome: This is a variant of Dubin-Johnson syndrome in which the liver
is not pigmented.
Cholestasis
System retention of not only bilirubin (still presents with jaundice) but also other solutes
eliminated in bile (bile salts and cholesterol) due to hepatic dysfunction or biliary
obstruction (either intrahepatic or extrahepatic). Can be caused by chlorpromazine.
Pruritis: itching.
Skin xanthomas: focal accumulations of cholesterol.
Serum Alkaline Phosphatase: enzyme elevated in obstructive hepatobiliary
disease.

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In the parenchyma (upper panel), cholestatic hepatocytes (1)

are enlarged with dilated canalicular spaces (2). Apoptotic
cells (3) may be seen, and Kupffer cells (4) frequently
contain regurgitated bile pigments. In the portal tracts of
obstructed liver (lower panel), there is also bile ductular
proliferation (5), edema, bile pigment retention (6), and
eventually neutrophilic inflammation (not shown).
Surrounding hepatocytes (7) are swollen and undergoing
degeneration.

Kupffer cell
Rupture of canaliculi leads to extravasation of bile into the sinusoid, which is quickly
phagocytosed by Kupffer cells.
Bile ductular proliferation
The bile stasis and back pressure induce proliferation of epithelial cells and looping and
reduplication of the ductules connecting bile ducts to the parenchyma.
Portal tract fibrosis
Unrelieved obstruction leads to portal tract fibrosis, which initially extends into and
subdivides the parenchyma with relative preservation of hepatic architecture.
HEPATIC FAILURE
Pg 597 598
Massive hepatic necrosis
The entire liver may be involved or only random areas. There is massive loss of hepatic
substance causing the liver to shrink to 500-700 grams and become transformed into a
limp, red organ covered by a wrinkled, too-large capsule. On transection, the liver
appears mushy with blotchy areas of bile staining.
Fetor hepaticus
Musty body odor
Palmar erythema
On a longer-term bases, impaired estrogen metabolism due to liver failure, and
consequent hyperestrogenemia are the putative causes of:
Palmar erythema: reflection of local vasodilation
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Robbins Pathology Vocabulary Review

Spider angiomas: dilation of superficial capillaries with an elevated red dot from
which blood vessels radiate.
Hypogonadism: testicular atrophy.
Gynecomastia: enlargement of the male breasts.
Hepatic encephalopathy
Complication of acute and chronic liver failure. It is a metabolic disorder of the CNS.
asterixis (nonrhythmic, rapid extension-flexion movements of head and extremities, best
seen when the arms are held in extension with dorsiflexed wrists) is characteristic.
Hepatorenal syndrome
Refers to the appearance of renal failure in patients with severe liver disease, in whom
there are no intrinsic morphologic or functional causes for the renal failure. Kidney
function promptly improves if hepatic failure is reversed. Mechanism is believed to be
decreased blood flow to the kidney and the syndrome is marked by a reduction in urine
output with an increase in BUN and creatinine.
CIRRHOSIS
Pg 598 600
Cirrhosis is the end stage of chronic liver disease, and is defined by three characteristics:
1) Bridging fibrous septa - Delicate bands or broad scars replace multiple adjacent
lobules.
2) Parenchymal nodules created by regeneration of encircled hepatocytes, vary from
small to large.
3) Disruption of the entire liver architecture.

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Portal hypertension
The dominant intrahepatic cause of portal hypertension is cirrhosis of the liver. There are
four major clinical consequences of portal hypertension:
1. Ascites collection of excess fluid in the
peritoneal cavity.
2. Portosystemic venous shunts resistance to flow
caused by the cirrhotic liver forces blood to move
into the systemic circulation. Three places of
anastasmosis: esophagus, umbilical (caput
medusae), hemorrhoidal veins.
3. Congestive splenomegaly
4. Hepatic encephalopathy

The major clinical consequences of portal hypertension in

the setting of cirrhosis, shown for the male. In women,
oligomenorrhea, amenorrhea, and sterility are frequent,
owing to hypogonadism.

INFLAMMATORY DISORDERS
Pg 600 610
Viral Hepatitis
Term usually reserved for infection of the liver caused by a small group of viruses having
a particular affinity for the liver (Hepatitis A-E, and G). Elevated ALT is a sign of viral
hepatitis.
Hepatitis A
HAV is a benign, self limited disease that can present with jaundice. It does not cause
chronic hepatitis or a carrier state and only rarely causes fulminant hepatitis. HAV is
shed in the stool for 2-3 weeks before and 1 week after the onset of jaundice. It is found
in the blood only transiently. HAV is spread by ingestion of contaminated water/food, or
raw/steamed shellfish. The injury to the liver in HAV results from immunologically
mediated damage of infected hepatocytes.

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Hepatitis B (major cause of liver disease)

HBV can produce acute hepatitis, progressive and non-progressive chronic hepatitis,
fulminant hepatitis with massive liver necrosis, and an asymptomatic carrier state. The
virus is found in all body fluids except the stool. In endemic areas, it is spread from
mother to child, in the States, it can be spread by needle sticks or as an STD.
1) Proliferative phase HBV DNA is present in episomal form with formation of
complete virions and CD8+ T cells are activated against infection.
2) Integrative phase viral DNA may be incorporated into the host genome.
Damage to hepatocytes is believed to be caused by CD8+ T cells and not the virus itself.
Ground-glass hepatocytes a finely granular, eosinophilic cytoplasm shown by
EM to contain massive quantities of HBsAg.
Sanded Nuclei abundant intranuclear HBcAg.
Hepatitis C (major cause of liver disease)
The major routes of transmission are inoculations and blood transfusions with IV drug
use. Occupational exposure to health care workers accounts for 4% of cases in US. HCV
has a higher rate of progression to chronic disease and eventual cirrhosis, estimated at
20%. There are multiple types and subtypes of HCV making vaccine development
difficult. Persistent infection is the hallmark of HCV, occurring in more than 75% of
individuals with subclinical or asymptomatic infection.
- In HCV chronic hepatitis, lymphiod aggregates often seen in portal tracts.
- Concurrent HCV infection with alcoholic liver disease accelerates the course of
alcoholic liver disease.
Hepatitis D
HDV needs to be encapsulated in HBsAg (HBV envelope glycoprotein) to be infective,
thus HDV is absolutely dependent on HBV coinfection for multiplication. In the US,
HDV infection is mostly restricted to drug addicts. IgM anti-HDV is the most reliable
indicator of recent HDV exposure.
Hepatitis E
HEV is an enterically transmitted, waterborne infection. It is seen mainly in travelers and
accounts for over 50% of cases of sporadic acute viral hepatitis in India. A characteristic
feature of HEV is the high mortality rate among pregnant women (~20%). The virus can
be detected in the stool.
Hepatitis G
HGV has similarities to HCV and is transmitted by contaminated blood and blood
products, and possibly, as an STD. The site of HGV replication is most likely in
mononuclear cells, not hepatocytes; therefore, there is no elevation in ALT.

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Clinical Syndromes of Hepatitis Infection

There are five clinical syndromes that can develop after exposure to hepatitis viruses:
(1)Carrier State
An individual without manifest symptoms who harbors and can transmit the virus.
Carrier state is more common if you acquire the virus very young. (B,C,D,G)
(2)Asymptomatic infection
Patients identified incidentally.
(3)Acute hepatitis
There are four phases: (1) incubation period, (2) symptomatic preicteric phase
(malaise, nausea, loss of appetite), (3) symptomatic icteric phase (jaundice, scleral
icterus, and dark colored urine), and (4) convalescence.
Ballooning
degeneration hepatic
injury takes the form of
diffuse swelling.
Cholestasis bile plugs
in canaliculi and brown
pigmentation of
hepatocytes.
Kupffer Cells undergo
hypertrophy and
hyperplasia and are
often laden with
lipfuscin pigment.
(4)Chronic hepatitis
Continuing or relapsing hepatic disease for more than 6 months and histologically
documented inflammation and necrosis. The most common overt symptom is
fatigue, and less commonly malaise, loss of appetite, and bouts of mild jaundice.
(B, C, D)
The hallmark of irreversible liver damage is the deposition of fibrous tissue.
(5)Fulminant hepatitis
Fulminant hepatic failure denotes clinical hepatic insufficiency that progresses
from onset to hepatic encephalopathy within 2-3 weeks. It may present as
jaundice, encephalopathy, and fetor hepaticus. The histological correlate of
fulminant hepatic failure is massive hepatic necrosis.

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Lobular disarray
Hepatocyte swelling, necrosis, and regeneration produce compression of the vascular
sinusoids and loss of the normal, more or less radial array of the parenchyma.
Interface hepatitis
The inflammartory infiltrate may spill over into the parenchyma to cause necrosis of
periportal hepatocytes.
Periportal fibrosis/bridging fibrosis
At first, only portal tracts exhibit increased fibrosis, but with time periportal fibrosis
occurs, followed by linking of fibrous septa between lobules.
Autoimmune hepatitis
This is a syndrome of chronic hepatitis in patients with a set of immunologic
abnormalities. Salient features are: female preponderance, presence of other autoimmune
diseases, and an increase in serum IgG. There are three types of autoimmune hepatitis
grouped according to the target of the auto-antibodies.
Liver abscess
Most common in developing countries due to parasitic (amebic) infections. In
developing countries, the cause is more often bacterial or fungal representing a
complication of an infection elsewhere. Liver abscesses are associated with fever, and
often right upper quadrant pain and tender hepatomegaly.
DRUG AND TOXIN INDUCED LIVER DISEASE
Pg 610 615

Alcoholic Liver Disease

Alcohol is the leading
cause of liver disease in
most Western countries.
There are three
components to alcoholic
liver disease: hepatic
steatosis, alcoholic
hepatitis, and cirrhosis.

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1) Hepatic steatosis (fatty liver)

Lipid droplets accumulate in hepatocytes (micro, or marcovesicular). Macroscopically,
this gives the liver a soft, yellow, greasy appearance. Up to the time that fibrosis
appears, the fatty change is completely reversible if there is abstention from alcohol.
2) Alcoholic hepatitis
This is characterized by hepatocyte swelling and necrosis, Mallory bodies (eosinophilic
cytoplasmic inclusions in degenerating hepatocytes), neutrophilic reaction, and fibrosis.
3) Cirrhosis
This is the final and irreversible form. The liver begins large and fatty, but insidiously
develops into a brown, shrunken organ. In time, micronodules form from regenerating
hepatocytes trapped between the fibrotic strands. Eventually, the nodules predominate
and vary in size, creating a hobnail appearance.
The stigmata of cirrhosis is a grossly distended abdomen with ascites, wasted
extremities, and caput medusae.
Micronodular cirrhosis regenerative activity of entrapped hepatocytes generates
small nodules less than 0.3 cm in diameter and is more often associated with
alcoholic liver cirrhosis.
Macronodular cirrhosis nodules formed are more than 0.3 cm in diameter and
happens more often in cirrhosis caused by viral hepatitis.
Alanine aminotransferase (ALT)
Intracellular enzyme involved in amino acid metabolism. Present in large amounts in
liver and kidney. It is released with tissue damage, particularly liver injury.
Aspartate aminotransferase (AST)
Intracellular enzyme involved in amino acid metabolism. Present in large amounts in
liver and kidney. It is released with tissue damage, particularly liver injury.
Nonalcoholic fatty liver (NAFL)
This is fatty liver occurring in patients who do not drink alcohol. The single most
consistent association for NAFL is obesity. Another key association is type 2 diabetes.
NAFL is diagnosed on liver biopsy and is often underrecognized.
Nonalcoholic steatohepatitis (NASH)
The presence of parenchymal mixed inflammation with neutrophils and mononuclear
cells, hepatocytes containing Mallory hyaline, and hepatocyte destruction earns the
monker NASH.

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INBORN ERRORS OF METABOLISM

Pg 615 622
Hereditary hemochromatosis
This is the excessive accumulation of body iron, most of which is deposited in the
parenchymal organs such as the liver and pancreas. It exists as a hereditary and as an
acquired disease.
Normal level of body iron = 2-6g
Hemochromatosis = > 50g or higher
Clinically, hemochromatosis affects males more than females and rarely presents before
the age of 40. The principal manifestations are hepatosplenomegaly, abdominal pain,
skin pigmentation, diabetes mellitus from destruction of pancreatic isles, cardiac
dysrythmia, and atypical arthritis.
This may also predispose to hepatocellular carcinoma.
HFE gene/C282Y
The hemochromatosis gene is HFE. An intact HFE is necessary in regulatin iron uptake
by the intestinal enterocyte. In hereditary hemochromatosis, there is a mutation at
nucleotide 845 in which adenine is substituted for guanine, resulting in a tyrosine
substitution for cysteine at amino acid 282 (C282Y). This disrupts a critical disulfide
bond.
Wilson disease/hepatolenticular degeneration
This is an autosomal recessive disorder of copper metabolism that is marked by the
accumulation of toxic levels of copper in many tissues and organs, principally the liver,
brain, and eye.
There is a defective transporter that fails to secrete copper from the liver into the bile,
which is the primary means to excrete copper from the body.
Kayser-Fleischer rings eye lesions that are green to brown deposits of copper in
the Descement membrane in the limbus of the cornea.
Ceruloplasmin hepatocellular uptake of Copper followed by incorporation of
alpha-globulin forms ceruloplasmin (this is then secreted into the blood).
Clinically, it rarely appears prior to 6 years old. The most common presentation is acute
or chronic liver disease. There are also neurological symptoms: behavioral changes,
frank psychosis, or a Parkinsons like syndrome. Elevated hepatic copper levels with low
serum ceruloplasmin levels strongly favor the diagnosis.

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1-Antitrypsin deficiency (AAT)

AAT is an autosomal recessive disorder marked by abnormally low serum levels of the
protease inhibitor, 1-Antitrypsin (inhibits neutrophil elastase). The normal allele is
PiMM, those with AAT deficiency are PiZZ. AAT is synthesized in the liver. Those
with the deficient allele form a mutant AAT that is not released by the liver. Therefore,
there is an accumulation of AAT which stains with PAS, and appears as red, cytoplasmic
granules in hepatocytes.
10-20 % of newborns with AAT deficiency exhibit cholestasis. In older people,
presenting symptoms may be related to chronic hepatitis, cirrhosis, or pulmonary
disease.
Neonatal hepatitis
A mixed group of disorders that cause neonatal cholestasis. Clinical presentation of a
newborn with cholestasis is fairly stereotypical, with jaundice, dark urine, light or acholic
stools, and hepatomegaly.
Idiopathic neonatal hepatitis represents 50-60% of cases and about 20% are caused by
extrahepatic biliary atresia (EHBA).
Reye syndrome
This is a rare disease characterized by fatty change in the liver and encephalopathy. It
primarily affects children under 4 years old, typically following a viral infection. The
onset is heralded by pernicious vomiting and is accompanied by irritability or lethargy
and hepatomegaly. It has been associated with giving children aspirin during a viral
infection (that is bad).
Primary biliary cirrhosis
This is a chronic, progressive, and often fatal cholestatic liver disease, characterized by
the destruction of intrahepatic bile ducts, portal inflammation and scarring, and liver
failure over years to decades. The primary characteristic is nonsuppurative,
granulomatous destruction of medium-sized intrahepatic vessels.
Antimitochondrial antibody these are present in over 90% of patients.
This usually affects women between the ages of 40-50, and can have an accompanying
autoimmune disease (ie, Sjogrens Syndrome, scleroderma, Raynauds, etc).
Primary sclerosing cholangitis
Characterized by inflammation, obliterative fibrosis, and segmental dilation (there are
irregular strictures and dilations) of the obstructed intrahepatic and extrahepatic bile
ducts. This is commonly seen in conjunction with inflammatory bowel disease,
especially chronic ulcerative colitis.

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LIVER CIRCULATORY DISORDERS

Liver infarct
This is a rare event due to the dual blood supply to the liver. The one exception is
hepatic artery thrombosis in the transplanted liver. Thrombosis or compression of an
intrahepatic branch of the hepatic artery by polyarteritis nodosa, embolism, neoplasia, or
sepsis may result in a localized parenchymal infarct.
Portal vein obstruction
This blocks blood flow into the liver and typically produces abdominal pain, ascites, and
other esophageal varices. Acute impairment of the portal vein can cause congestion and
bowel infarction.
Cardiac cirrhosis
The combination of left-sided and right-sided cardiac decomposition acts synergistically
to generate a distinctive lesion, centrilobular hemorrhagic necrosis (nutmeg liver). An
uncommon complication of sustained chronic severe congestive heart failure is so called
cardiac sclerosis. The pattern of liver fibrosis is distinctive, in as much as it is mostly
centrilobular.
Peliosis hepatic
Sinusoidal dilation occurs in any condition in which efflux of hepatic blood is impeded.
Peliosis hepatis is a rare condition in which the dilation is primary, and is usually
associated with anabolic steroids.
Hepatic vein thrombosis (Budd-Chiari syndrome)
Acute, subacute, or chronic occlusive syndromes, characterized by hepatomegaly, weight
gain, ascites, and abdominal pain. Thrombosis is most often associated with states that
produce sluggish blood flow (PV, pregnancy, etc). In this syndrome, the liver is often
swollen, red-purple, and has a tense capsule.

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TUMORS AND TUMOR-LIKE CONDITIONS

Pg 625 627
Focal nodular hyperplasia (FNH)
Solitary or multiple benign hepatocellular nodules may develop in the liver in the absence
of cirrhosis. Focal nodular hyperplasia appears as a well-demarcated but poorly
encapsulated nodule with a central fibrous scar, ranging up to many centimeters in
diameter.
Liver cell adenoma
Liver cell adenoma is a benign neoplasm of hepatocytes most commonly occurring in
women of child-bearing age who have used oral contraceptives. The tumor regresses
with stopping oral contraceptives. The tumors themselves are pale, yellow-tan or bilestained, well demarcated nodules anywhere in the hepatic substance. Subcapsular
adenomas are at risk for rupture. Thats bad.
Hepatocellular carcinoma (HCC)
Primary carcinomas of the liver that most commonly arise from hepatocytes. This is rare
in the US but represents 20-40% of cancers in other countries (incidence linked to HBV
and HCV). Most liver cancers in the US are actually cancers that have metastasized to
the liver, not of liver in origin. All HCC have a propensity to invade vascular channels
(AKA they can metastasize). The tumors generally have bile globules within the
cytoplasm.
Aflatoxin: high exposure to dietary aflatoxins derived from the fungus Aspergillus
flavus is linked to HCC. These are found in moldy grains and peanuts. Aflatoxin
can bind with cellular DNA and suppress tP53.
Cholangiocarcinoma
Carcinomas of bile duct origin. The only known causal influences of
cholangiocarcinoma are primary sclerosing cholangitis, chornic infection of the biliary
tract by the liver fluke, Opisthorchis sinensis, and previous exposure to Thorotrast,
formerly used in radiography of the biliary tract. It usually appears as a welldifferentiated adenocarcinoma.
Fibrolamellar hepatocellular carcinoma
A variant of HCC is fibrolamellar HCC, which occurs in young male and female adults
(20-40), has no association with cirrhosis, and has a better prognosis than just HCC. It
usually consists of a single large, hard scirrhous tumor with fibrous bands coursing
through it, vaguely resembling focal nodular hyperplasia.
-fetoprotein (AFP)
Approximately 90% of patients have elevated serum levels of AFP. This marker,
however, lack sensitivity as it occurs in other condition. Levels greater than 1000 ng/ml
are rare outside of HCC.

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THE BILIARY TRACT

Pg 628 633
Cholelithiasis
These are gallstones. They most commonly affect middle-aged white women who are
obese (also associated with oral contraceptives). Most gallstones are asymptomatic,
though they have the potential to cause constant or colicky abdominal pain and
cholecystitis. There are two varieties:
Cholesterol stones these are composed of crystalline cholesterol monohydrate.
Pigment stones these are composed of bilirubin calcium salts (hemolytic
anemias).
Cholecystitis
Inflammation of the gallbladder that is almost always associated with gallstones.
Acute gallbladder is usually enlarged and tense with a bright red, or blotchy
green-black appearance (due to hemorrhage). The serosa may be layered by
fibrin with or without exudates. Stones are usually present and the bile contained
is often a mix of fibrin, hemorrhage, and pus.
Empyema When the contained exudates is virtually pure pus, the condition is
referred to as empyema of the gallbladder.
Gangrenous In severe cases, the gallbladder is transformed into a green-black
necrotic organ.
Chronic morphologically extremely variable with often only a mural
lymphocytic infiltrate present.
Acute calculous cholecystitis
Acute inflammation of a gallbladder that contains stones is termed acute calculous
cholecystitis and is precipitated by obstruction of the gallbladder neck or cystic duct. It is
initially the result of chemical irritation and inflammation of the gallbladder wall in the
setting of obstruction to bile outflow.
Acute acalculous cholecystitis
Cholecystitis without the presence of gallstones. This usually occurs in the setting of
trauma, burns, a post-operative state, or sepsis. Multiple states precipitate this including
dehydration and gallbladder stasis.
Choledocholithiasis
This is the presence of gallstones within the biliary tree. Symptoms may develop due to
biliary obstruction, pancreatitis, cholangitis, hepatic abscess, chronic liver disease, or
acute calculous cholecystitis.
Cholangitis
Acute inflammation of the wall of the bile ducts, almost always caused by bacterial
infection of the normally sterile lumen. Commonly occurs with choledocholithiasis.

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Ascending cholangitis
This refers to the fact that bacteria that enter the biliary tract, usually through the
Sphincter of Odi, tend to ascend and infect intrahepatic biliary radicals. The most
common organisms found are E. coli, Klebsiella, Costridium, Bacteriodes, or
Enterobacter.
Biliary atresia
Defined as a complete obstruction of bile flow caused by destruction or absence of all or
part of the extrahepatic bile ducts. It is not true atresia but is an acquired inflammatory
disorder of unknown cause. This is a major cause of neonatal cholestasis.
Gallbladder carcinoma
Tumors of the gallbladder are much more common than those arising in the bile ducts.
Women are at a slightly higher risk, they occur most commonly in the seventh decade of
life, and the five-year survival is 1%! Gallstones are present in 60-90% of cases. Most
carcinomas of the gallbladder are adenocarcinomas and most have invaded the liver by
the time they are discovered.
Extrahepatic bile duct carcinoma
Cancers arising in the extrahepatic ducts are extremely insidious and generally produce
painless, progressively deepening jaundice. They occur in older people and slightly more
in men. Because partial or complete obstruction of bile ducts rapidly leads to jaundice,
extrahepatic biliary tumors tend to be relatively small at the time of diagnosis. Again,
most bile duct tumors are adenocarcinomas.
Klatskin tumor carcinomas arising at the bifurcation of the right and left hepatic
ducts are called Klatskin tumors.
Whipple procedure These tumors are treated with the Whipple procedure.
As a note: The Whipple procedure is also called a pancreatico-duoden-ectomy,
which is generally the removal of the gallbladder, common bile duct, part of the
duodenum, and the head of the pancreas. This operation was first described by
.Dr. Alan O. Whipple of New York Memorial Hospital (now called Memorial
Sloan-Kettering).

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CHAPTER 17
PANCREAS
EXOCRINE PANCREAS
Pg 636 641
Exocrine Pancreas
Approximately 80-90% of the pancreas is an exocrine gland that secretes enzymes for the
digestion of food. This section talks about: (1) Acute Pancreatits, (2) Chronic
Pancreatitis, and (3) Carcinoma of the Pancreas.
Pancreatitis
Inflammation of the pancreas, almost always associated with acinar cell injury, is term
pancreatitis.
(1) Acute Pancreatitis
Characterized by acute onset of abdominal pain resulting for enzyme necrosis and
inflammation of the pancreas with an accompanying elevation of pancreatic enzymes
(lipase and amylase) in the blood and urine. There are two main events in pancreatitis:
(1) autodigestion and (2) cell injury due to inflammation.
Alcoholism and Gallstones these are the two most common causes of acute
pancreatitis in the US.
Trypsin proenzymes are released by the pancreas during pancreatitis in their
zymogen (inactive) form. Trypsin is believed to be the enzyme responsible for
the proenzymes activation and subsequent autodigestion of the pancreas.
Released lipase metabolizes fat cells releasing fatty acids. These fatty acids
combine with calcium to form insoluble salts that precipitate out.

Clinical Presentation
1. Abdominal Pain (located in
epigastrum and radiates to back)
2. Increased Lipase (7-10 days)
3. Increase Amylase (first 12 hours)
4. Hypocalcemia

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Bile Duct Obstruction

Gallstones or intrapancreatic stones (caused by alcoholism) cause mechanical obstruction
of the distal biliary tree and appears to be sufficient to produce acinar cell injury. First,
obstruction causes edema and increase in pancreatic secretion. The edema inhibits blood
flow, which results in ischemic injury to the pancreas. Somehow (no one knows) this
causes the activation of proenzymes within the pancreas and thenpancreatitis.
Acute hemorrhagic pancreatitis
In this most severe form of pancreatitis, there is damage to the vasculature with resulting
hemorrhage into the parenchyma of the pancreas. Grossly, the pancreas has areas of
blue-black hemorrhage with foci of yellow-white chalky fat necrosis.
Pancreatic Pseudocyst
This is a common sequela of acute pancreatitis and is defined as a liquefied area of
necrotic pancreatic tissue that is walled off by fibrous tissue to form a cystic space, which
does not contain an epithelial lining.
(2) Chronic Pancreatitis
Characterized by repeated bouts of mild to moderate pancreatic inflammation, with
continued loss of pancreatic parenchyma and replacement by fibrous tissue. This most
frequently occurs in middle-aged alcoholic men: biliary tract obstruction plays less of a
role.
CFTR Gene approximately 1/3 of people with chronic pancreatitis have a
mutation in this gene. This gene mediates the secretion of bicarbonate-rich
alkaline pancreatic juice. As in CF, the CFTR mutation cuase the pancrease to
secrete more viscous fluids, leading to the precipitation of proteins and the
formation of mucus plugs within the pancreatic ducts.
Chronic pancreatitis can present as silent to severe abdominal pain with only a
slight increase in pancreatic enzymes. Eventually, it can lead to the development
of diabetes mellitus and severe chronic pain.
(3) Carcinoma of the Pancreas
This implies a carcinoma arising from the exocrine portion of the pancreas. It is the 5th
most common cause of cancer deaths and less than 5% of people with pancreatic cancer
will live beyond five years. They are almost always adenocarcinomas (growing in poorly
formed glands), they metastasize, are usually painless until they become severe, and
usually (60-70%) arise in the head of the pancreas (causing biliary obstruction leading to
biliary jaundice).
K-RAS and CDKN2A these are two of the most common mutations (90%) found
in cases of pancreatic carcinoma. It is not common in other cancers and is
considered a molecular fingerprint for pancreatic cancer.

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(3) Carcinoma of the Pancreas (Cont)

Trousseau Sign spontaneously appearing phlebothrombosis (also called
migratory thrombophlebitis, is sometimes seen.
CA19-9 This is a serum antigen that has been found to be elevated when there is
a carcinoma of the pancreas.
EDOCRINE PANCREAS
Pg 641 655
Endocrine Pancreas
About 10-15% of the pancreas is acts as an endocrine gland, consisting of the islets of
Langerhans (clusteres of neuroendocrine cells), which secrete insulin, glucagon, and
other hormones. There are four main cell types within the islets:
Alpha cells Synthesize glucagon (stimulates conversion of glycogen in the liver
to glucose and accelerates fatty acids oxidation) (5-20% of islet)
Beta cells Synthesize insulin (70% of the islet)
Delta cells Synthesize somatostatin (suppresses the release of glucagon and
insulin)
PP cells Synthesize a polypeptide that affects the GI secretions and motility.
This section speaks mainly about: Diabetes Type I and II and its complications.
Diabetes Mellitus
This is a chronic disorder of carbohydrate, fat, and protein metabolism with a relative or
absolute decrease in insulin secretion and subsequent hyperglycemia. The different types
of diabetes vary in their pathogenic mechanisms, but the long term complications occur
in both types.
Type 1 diabetes is characterized by an absolute deficiency of insulin caused by
pancreatic -cell destruction. It accounts for approximately 10% of all cases.
Juvenile onset.
Type 2 diabetes is caused by a combination of peripheral resistance to insulin
action and an inadequate secretory response by the pancreatic -cells ("relative
insulin deficiency"). Approximately 80% to 90% of patients have type 2 diabetes.
Adult onset.
Insulin
Insulin is a major anabolic hormone and is produced by
beta-cells and stored in beta-cell granuoles. A rise in
blood glucose causes secretion of insulin from these
granuoles and the synthesis of new insulin.
Metabolic actions of insulin in striated muscle, adipose tissue, and
liver.

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Glucose Tolerance Test

Insulin Receptor
Insulin causes changes in target cells by interacting with the insulin receptor. The
receptor is a tyrosine kinase that triggers a number of intracellular pathways. A key
effect of insulin is to increase the number of GLUT on the surface of the cell.

Figure 24-28 Insulin synthesis and

secretion. Intracellular transport of
glucose is mediated by GLUT-2, an
insulin-independent glucose transporter
in cells. Glucose undergoes oxidative
metabolism in the cell to yield ATP.
ATP inhibits an inward rectifying
potassium channel receptor on the -cell
surface; the receptor itself is a dimeric
complex of the sulfonylurea receptor and
a K+ -channel protein. Inhibition of this
receptor leads to membrane
depolarization, influx of Ca2+ ions, and
release of stored insulin from cells.

Type IA
An autoimmune destruction of Beta-cells usually presenting in children who are insulin
dependent to survive. There are three interlocking mechanisms responsible for islet cell
destruction: genetic susceptibility, autoimmunity, and an environmental insult. Though
there is little doubt that environmental factors are essential for the development of
autoimmune diabetes, their mode of action is not clear. In some undefined manner, they
contribute to the immunologically mediated erosion of beta cells in individuals whose
genetic background, particularly involving MHC class II antigens, is conducive to the
development of autoimmunity.

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Type IA (Cont)
Latent Autoimmune Diabetes in Adults (LADA)
This is type 1A diabetes that presents in adulthood as a milder, non-insulin
dependent diabetes.
Insulitis
A lymphocyte rich inflammatory infiltrate frequently observed in the islets of
patients early in the course of clinically manifest disease. Mostly CD8+ T-cells.
Type II diabetes
There is no evidence that autoimmune mechanisms are involved in this type of diabetes.
Lifestyle (obesity!) does seem to be important, as do genetic factors (even more so that in
Type I diabetes). The two metabolic defects that characterize type II diabetes are a
derangement in beta-cell secretion of insulin and an inability of peripheral tissues to
respond to insulin.
Uncoupling Protein 2 (UCP2)
It is believed that increased levels of this protein within the mitochondia of betacells of people with Type II diabetes causes the characteristic loss of the glucose
signal.
Obesity and Pregnancy
Insulin resistance may be found in both of these situations.
Insulin Resistance
Insulin resistance could occur at the level of the insulin receptors or in any one of
the multiple signaling pathways that are activated by the binding of insulin to its
receptor. However, most resistance is believed to occur at the level of cellular
signaling.
Resistin
This is a cell signaling molecule that increases insulin resistance. It is produced
by fat cells, and its levels are increased in a variety of rodent models for obesity.

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Figure 24-33 Obesity and insulin

resistance: the missing links?
Adipocytes release a variety of
factors (free fatty acids and
adipokines) that may play a role
in modulating insulin resistance
in peripheral tissues (illustrated
here is striated muscle). Excess
free fatty acids (FFAs) and
resistin are associated with
insulin resistance; in contrast,
adiponectin, whose levels are
decreased in obesity, is an
insulin-sensitizing adipokine.
Leptin is also an insulinsensitizing agent, but it acts via
central receptors (in the
hypothalamus). The peroxisome
proliferator-activated receptor
gamma (PPAR) is an adipocyte
nuclear receptor that is activated
by a class of insulin-sensitizing
drugs called thiazolidinediones
(TZDs). The mechanism of
action of TZDs may eventually
be mediated through modulation
of adipokine and FFA levels that
favor a state of insulin
sensitivity.

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LONG TERM COMPLIATIONS OF DIABETES

Pg 647 654
Long term complications
These include microangiopathy, retinopathy, nephropathy, neuropathy, and accelerated
atherosclerosis. Most of these complications result from hyperglycemia and coexistent
hypertension (which contributes to atherosclerosis). There are two mechanisms by which
hyperglycemia is believed to contribute to long term complications:
(1) Non-enzymatic glycosylation
This is the process by which the excess glucose in the blood chemically attaches to free
amino groups of proteins without the aid of enzymes.
HbA1c
A clinical tool: this can be measured to determine the average blood glucose level
over the last 120 days (AKA test a diabetic patients compliance with treatment).
Advanced glycosylation end products (AGE)
AGEs are formed by the irreversible glycosylation of collagen and long-lived
proteins. Gylcosylation of vessel collagen can lead to cross-linking that can trap
non-glycosylated proteins (ie, LDL) within the vessel wall. This can accelerate
atherogenesis. This can also affect the basement membranes of the renal
glomeruli making the kidneys leaky.

Long term complications of

Diabetes. In most patients, after
10-15 years, morphologic
changes are likely to be found in
arteries (atherosclerosis), the
basement membranes of small
vessels (microangiopathy),
kidneys (diabetic nephropathy),
retina (retinopathy), nerves
(neuropathy), and other tissues.
These changes are seen in both
types of diabetes.

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HDL
Type II diabetics have a low level of HDL. Because HDL is a protective molecule
against atherosclerosis, low levels could contribute to increased susceptibility to
atherosclerosis.
(2) Intracellular hyperglycemia
Some cells (like nerves and the lens) do not use a transporter to take up glucose,
therefore, an increase in blood glucose leads to an increase in intracellular glucose. This
extra glucose is then metabolized to sorbitol and eventually fructose (this is not good
and it is bad).
(1) Sorbitol and fructose cause an osmotic influx of water leading to cell injury.
This influx of water causes clouding of the lens.
(2) Sorbitol inhibits ion pumps; this causes injury to Schwann cells and
ultimately leads to a peripheral neuropathy.

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MORPHOLOGIC CHANGES WITH DIABETES

Pg 648 654
(1) Pancreas
Type 1 reduction in the number and size of islets
Type 1A insulitis (WBC infiltrate in islets), and beta-cell degranulation
(reflecting depleted stores of insulin).
Type 2 amyloid replacement of islets (pink amorphous material beginning in
and around capillaries and between cells).
An increase in the number and size of islets is especially characteristic of
newborns with diabetic mothers!
(2) Vascular System
There is advanced development of atherosclerosis in the medium and large vessels,
including the coronary arteries. MI secondary to occlusion of the coronary arteries is the
most common cause of death in diabetics. Vascular disease also leads to gangrene of
the lower extremities, and hyaline arteriolosclerosis (amorphous, hyaline thickening of
the wall of arterioles) associated with hypertension.
(3) Diabetic Microangiopathy
This is a diffuse thickening of basement membranes (increased Type IV collagen) to
include those of the capillaries of the retinas and renal glomeruli, as well as some nonvascular structures, such as the renal tubules and Bowmans capsule. Even with this
thickening, basement membranes are more leaky to plasma proteins.
(4) Diabetic Nephropathy
This is the second most common cause of death for diabetics. There are three important
lesions encountered: glomerular lesions, renal vascular lesions (arteriolosclerosis), and
pyelonephritis.
a) Glomerular lesions: basement membrane thickening, diffuse
glomerulosclerosis, nodular glomerulosclerosis.
Diffuse Glomerulosclerosis
Consists of a diffuse increase in mesangial matrix along with mesangial cell
proliferation and is always associated with basement membrane thickening.
Nephrotic Syndrome
Characterized by proteinuria, hypoalbuminemia, and edema after diffuse
glomerulosclerosis becomes serious.
Nodular Glomerulosclerosis (Kimmelstiel-wilson lesion)
This describes the glomerular lesion made distinctive by ball-like deposits of a
laminated matrix within the mesangial core of the lobule. These lesions push
the glomerular capillary loops even more to the periphery creating halos about
the nodule.
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(4) Diabetic Nephropathy (Cont)

b) Renal Vascular Lesions: Hyaline ateriolosclerosis affects not only the afferent
but also the efferent arteriole (arteriolosclerosis affecting the efferent
arteriole is rarely encountered in persons other than diabetics).
c) Pyelonephritis: actue or chronic inflammation of the kidneys that usually
begins in the interstitial tissue and then spreads to affect the tubules and even
the glomeruli.
Necrotizing papillitis
This is a special pattern of acute pyelonephritis with acute necrosis of the
renal papillae.
(5) Diabetic Ocular Complications
This may take the form of: retinopathy, cataract formation, or glaucoma:
Retinopathy proliferative and non-proliferative:
Non-proliferative: includes intraretinal and preretinal hemorrhages, retinal
exudates, microanuerysms, venous dilations, edema, and thickening of retinal
capillaries.
Proliferative: a process of neovascularization and fibrosis. Vitreous hemorrhage
can result, with reorganization of the hemorrhage, leading to the retina being
pulled off its substratutm (retinal detachment).
(6) Diabetic Neuropathy
This most frequently a peripheral, systemic neuropathy of the lower extremities that
affects the sensory (mostly) and the motor function. There can also be Autonomic
neuropathy which produces a wide range of problems to include sexual impotence and
mononeuropathy, which may manifest as sudden footdrop and wristdrop.

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CLINICAL FEATURES OF DIABETES

Pg 652 653
Figure 24-40 Sequence of metabolic
derangements leading to diabetic coma in
type 1 diabetes mellitus. An absolute
insulin deficiency leads to a catabolic
state, eventuating in ketoacidosis and
severe volume depletion. These cause
sufficient central nervous system
compromise to lead to coma and eventual
death if left untreated.
Polyuria frequent urination due to
glucose in the urine exerting an osmotic
force, causing an increased fluid
secretion.
Polydipsia intense thirst due to
increased loss of water and
hyperosmolarity due to increased levels
of glucose in the blood.
Weight loss catabolism of proteins and
fats due to loss of insulin (insulin is
anabolic, remove this factor and
catabolism takes over)
Polyphagia increased appetite due to
weight loss
Ketoacidosis most frequently seen in
Type IA diabetes and is the result of
severe insulin deficiency coupled with
absolute or relative increases in
glucagon.

Ketone Bodies
Insulin deficiency causes excessive breakdown of adipose stores, resulting in an
increased level of free fatty acids. Oxidation of free fatty acids by the liver produces
ketone bodies. Glucagon accelerates fatty acid oxidation. An increased level of ketone
bodies beyond that which that body can excrete causes metabolic ketoacidosis.
Type II diabetes presentation
Present with polyuria and polydispia but are often asymptomatic. They are frequently
older than 40 however if obesity is present, can be any age. Most frequently discovered
with routine urinalysis: may develop hyperosmolar nonketotic coma, a syndrome of
severe dehydration from hyperglycemic diuresis in patients who dont drink enough
water.

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ISLET CELL TUMORS

Pg 654 655
Islet Cell Tumors
They originate in neuroendocrine cells (and thus resemble carcinoids) and have a
propensity to elaborate pancreatic hormones. There are three distinct clinical syndrome
associated with islet cell tumors:
(1) Hyperinsulinism
Certain islet cell tumors produce insulin and cause hypoglycemia. Hypoglycemic attacks
can be precipitated by fasting or exercise and cause nervousness, confusion, or stupor.
They are relived by glucose. Tumors giving rise to these symptoms are called
insulinomas.
Insulinomas most often benign tumors (90%) within the pancreas, as compared
to in the peripancreatic tissue. Histologically they look like giant islets, and
immunocytologically they contain neoplastic beta-cells that contain distinctive
round granules with dense crystals.
Factitious hypoglycemia this results from self-injection of too much insulin.
(2) Zollinger-Ellison Syndrome (Hypergastrinemia)
Marked hypersecretion of gastrin: usually has its origin in gastrin-producing tumors
(gastrinomas) which are locally invasive tumors that have usually metastasized by the
time of diagnosis. They arise not only in the pancreas, but also the duodenum and
peripancreatic tissue as well. Ulcers present 90-95%: duodenal>gastric. These ulcers
look like usual ulcers but fail to respond to traditional therapy and can occur in odd
spots (jejunum). 50% of patients have diarrhea.
(3) Multiple Endocrine Neoplasia

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CHAPTER 14
KIDNEY
THE KIDNEY & ITS COLLECTING SYSTEM
Pg 509 542
Glomerular filtration rate
The speed at which plasma is filtered through capillaries of the kidney (at the
glomerulus), removing waste products, conserving water, and forming urine. In a typical
day, normal kidneys will reabsorb more than 99% of the material filtered.
Azotemia
A biochemical abnormality that refers to an elevation of blood urea nitrogen (BUN) and
creatinine levels and is largely related to a decreased glomerular filtration rate (GFR).
Pre-renal Azotemia: azotemia caused by hypo-perfusion of the kidneys, which
impairs renal function in the absence of parenchymal damage.
Post-renal Azotemia: azotemia caused by urine flow obstruction below the level
of the kidney.
Uremia
Azotemia associated with a constellation of clinical signs and symptoms and biochemical
abnormalities. It is characterized by failure of renal excretory function and various
metabolic and endocrine alterations incident to renal damage.
Acute nephritic syndrome
Classic presentation of acute post-streptococcal glomerulonephritis: acute onset of
hematuria (blood in the urine), proteinuria (protein in the urine) azotemia, edema, and
hypertension.
Rapidly progressive glomerulonephritis
Loss of renal function within days-weeks and is manifested by active urine sediment
(hematuria, dysmorphic RBCs, and RBC casts).
Acute renal failure
Dominated by oliguria (abnormally little pee) or anuria (no pee), with recent onset of
azotemia.
Chornic renal failure
Prolonged symptoms and signs of uremia and is the end result of all chronic renal
diseases.
Urinary tract infection
Bacteriuria and pyuria (bacteria and WBC in urine). If the bladder is infected it is called
cystitis, and if the kidney is infected it is called pyelonephritis.

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Nephrolithiasis
Renal stones: may cause hematuria or renal colic (acute pain from smooth muscle
spasm).
RENAL DISEASES
Pg 511 542
Diseases of the kidney can be divided into those that affect one of the four basic
morphologic components: (1) glomeruli, (2) tubules, (3) interstitium, and (4) blood
vessels.
(1) Glomerular Disease (Pg 511 526)
First, a quick review of glomerular structure:
Glomerular Capillary Wall
This is the filtering membrane and
consists of the following structures:
(1) Fenestrated endothelial cells
(2) Glomerular basement membrane
(GBM): lamina rare interna, lamina
densa, and lamina externa (from
Bowmans capsule out)
(3) Podocytes visceral epithelial cell
with foot processes (pedicles) touching
the lamina rare externa.
(4) Filtration slits separate adjacent
pedicles and are covered by a filtration slit
membrane composed of nephrin.

Bowmans space
Also called the Urinary Space, this is the cavity in which plasma ultrafiltrate first collects.
Mesangial cell
These cells are support cells for the glomerulus. They are contractile and are capable of
proliferation, of laying down matrix and collagen, and secreting biologically active
mediators.
Glomerular Barrier Function
The glomerulus functions as a filter: it doesnt let large, anionic things, like proteins,
through (doesnt let them into the urine). The barrier function, in large part, is
maintained by the podocyte: its filtration slit diaphragm presents a distal resistance to the
flow of water and a diffusion barrier to the filtration of proteins.

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AUTOIMMUNE GLOMERULAR DISEASE

Pg 513
Immune complex disease (type III hypersensitivity)
Injury resulting from deposition of soluble circulating antigen-antibody complexes in the
glomerulus (Type III hypersensitivity). Complexes are formed in the body (like during
SLE) and become trapped in the glomerulus, where they produce injury mainly through
the binding of complement. The lesion may resolve if the source of the complexes is
removed, or this could become a chronic process if the source of the complexes is
continuous.
Electron-dense deposit: EM reveals the complexes as electron-dense deposits or
clumps that lie in the mesangium or one of two other spots:
(1) Subendothelial deposit: between the endothelial cells and the GBM.
(2) Subepithelial deposit: between the outer surface of the GBM and the
podocytes.
Granular deposit: When flourescinated anti-immunoglobulin or anti-complement
antibodies are used, the immune complexes are seen as granular desposits in the
glomerulus.
Immune complex nephritis in-situ
Results from antibodies reacting within the glomerulus, either with glomerular antigens
(intrinsic) or antigens planted within the glomerulus (extrinsic).

Anti-glomerular Basement Membrane

Disease
auto-antibodies called anti-GBM anitbodies
target the basement membrane causing a
linear pattern on immunoflourescense.
Goodpasture Syndrome
Anti-GBM antibodies cross-react with the
basement membrane of lung alveoli, causing
lung and kidney lesions. The basement
membrane antigen is a component of the
alpha-3 chain of Type IV collagen.
Figure 20-10 Antibody-mediated
glomerular injury can result either from the
deposition of circulating immune complexes
(A) or, more commonly, from in situ
formation of complexes exemplified by antiGBM disease (B) or Heymann nephritis
(C).

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Heymann Nephritis
This is characterized on immunoflourescense microscropy by diffuse deposition of
immunoglobulins and complement in a granular pattern along the GBM. Heymann
nephritis results from the reaction of auto-antibodies to an antigen complex located in the
coated pits of visceral epithelial cells of the glomerulus in a discontinuous fashion. These
auto-antibodies are also cross-reactive with a brush border antigen.
Immunoflourescense, add
glowing anti-antibodies to an
affected portion of a renal
biopsy. Left, granular pattern;
Right, linear pattern.

Mediators of Immune Injury

Once the immune complexes are lodged in the glomerulus or attached to the GBM, they
proceed to cause damage by a couple mechanisms: (1) activation of compliment and the
compliment cascade causes recruitment of neutrophils (C5a) which release proteases
causing destruction of the GBM, (2) formation of the membrane attack complex (C5-C9)
which causes epithelial cell detachment and up-regulation of TGF-R leading to increased
synthesis of ECM (GBM thickening), and (3) antibodies themselves may cause direct
damage.
End-stage renal failure
End-stage kidney disease occurs when the kidneys are no longer able to function at a level that is necessary
for day to day life. It usually occurs as chronic renal failure progresses to the point where kidney function is
less than 10% of baseline. At this point, kidney function is so low that without dialysis or kidney
transplantation, complications are multiple and severe, and death will occur from accumulation of fluids
and waste products in the body.

Glomerulosclerosis
Hyaline deposits or scarring within the renal glomeruli, a degenerative process occurring
in association with renal arteriolosclerosis or diabetes.

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GLOMERULAR SYNDROMES AND DISORDERS

Pg 517 526
Nephrotic Syndrome
This is a clinical syndrome characterized by increased basement membrane permeability
leading to massive proteinuria (>3.5 g/day) hypoalbuminemia, generalized edema, and
hyperlipidemia and lipiduria. Notice there is no hematuria.
The storyline of nephrotic syndrome goes like this: first there is damage to the capillary
walls of the glomeruli, resulting in increased permeability to plasma proteins, leading to
proteinuria. With long-standing proteinuria, serum albumin levels drop with a
consequent drop in osmotic pressure leading to severe edema (anasarca). Fluid
continues to escape from the vasculature causing the kidney to become hypoperfused
making the kidney think that the body is hypovolemic. The kidneys activate the RAAS
causing an increased retention of salt and water worsening the whole situation.
Somehow, there is also increased permeability to lipids.
There are 4 main diseases that cause Nephrotic Syndrome:
(1) Minimal Change disease (Lipoid Nephrosis)
This is the most frequent cause of the nephrotic syndrome in children (most common
between ages 2-3 years). It is characterized by normal appearance of glomeruli under the
light microscope, but show loss of visceral epithelial foot processes when viewed with
EM. The proximal tubules are often heavily laden with lipids secondary to reabsorption
of lipids passing through the diseased glomeruli (hence the old name Lipoid Nephrosis).
Foot process effacement: The disorder is believed to be caused by T cells
elaborating a factor that causes loss of epithelial foot processes and proteinuria.
Selective proteinuria: protein loss confined to smaller serum proteins (albumin).
(2) Membranous Glomerulonephritis (Membranous Nephropathy)
Most common between 30-50 year olds, this is characterized morphologically by the
presence of sub-epithelial immunoglobulin-containing deposits along the GBM. The
basic change in this disease appears to be diffuse thickening of GBM. The thickening is
caused, in part, by the sub-epithelial deposits that nestle against the GBM and are
separated by small, spike-like protrusions of GBM matrix (spike and dome pattern).
Nonselective proteinuria: in contrast to minimal change disease, globulins are lost
in the urine as well as albumin.

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(3) Focal Segmental Glomerulosclerosis (FSG)

FSG is characterized by sclerosis affecting some, but not all glomeruli and involving only
segments of each glomerulus. The injury to the visceral epithelial cells and the resultant
disruption of visceral epithelial cells is thought to represent the hallmark of FSG.
Hyalinosis: the focal lesions of FSG exhibit deposition of hyaline masses
* NOTE: In children, it is important to distinguish this from minimal change disease:
unlike the case with minimal change disease, patients with this lesion have a higher
incidence of hematuria and hypertension, their proteinuria is non-selective, and their
response to corticosteroid therapy is good.
(4) Membranoproliferative Glomerulonephritis
This is manifested histologically by alterations in the basement membrane and
mesangium and by proliferation of glomerular cells. Two types are recognized:
Type I: characterized by sub-endothelial electron-dense deposits. Accounts for 2/3
of the cases.
Type II: the lamina densa and the subendothelial space of the GBM are
transformed into an irregular, ribbon-like, extremely electron-dense structure due
to the deposition of some unknown material (dense deposit disease).
C3 nephritic factor: Patients with Type II MPGN have this factor which
can activate the alternative compliment pathway resulting in the
elaboration of biologically active complement fragments.
Double contour (tram track)/splitting: The GBM is thickened and the glomerular
capillary wall often shows a double contour or tram track appearance, caused by
splitting of the GBM due to the inclusion within it of processes of mesangial and
inflammatory cells extending into the peripheral capillary loops.

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Nephritic Syndrome
This is a clinical syndrome characterized by (1) hematuria with dysmorphic RBCs and
RBC casts in the urine, (2) some degree of oliguria and azotemia, and (3) hypertension.
The diseases that cause this syndrome are characterized by an inflammatory reaction that
injures the capillary walls, permitting escape of RBCs into the urine, and induces
hemodynamic changes that lead to a reduction in the GFR.
(1) Acute Proliferative (Poststreptococcal, Postinfectious) Glumerulonephritis
Typically caused by immune complexes depositing in the glumerulus and is characterized
by an intense inflammatory reaction involving nearly all glomeruli of both kidneys. The
antigen of the antigen-antibody complexes is usually from post-strept infection; however,
other infections can cause a similar effect. Clinically, the urine has a smoky brown
color, there is hypo-complimentemia, and a granular deposit of IgG on the GBM.
Sub-epithelial hump: EM often shows immune complexes as sub-epithelial humps
nestled against the GBM. These humps are composed of IgG and compliment.
(2) Rapidly progressive (crescentic) glomerulonephritis
This is defined clinically as the nephritic syndrome progressing rapidly to renal failure
within weeks or months. Histologically, it is characterized by the formation of crescents
(proliferations of parietal cells and the migration of monocytes) between Bowmans
capsule and the glomerular tuft. In most cases, the glomerular injury is immunologically
mediated, so there are three types:
Type I: anti-GBM disease characterized by linear deposits of IgG along the
GBM. If the IgG also binds to capillary basement membranes of the lung, it is
termed Goodpasture syndrome.
Type II: immune complex-mediated disorder and can be a complication of any
immune complex nephritide. In all cases, IF reveals the characteristic granular
(lumpy bumpy staining) pattern of staining.
Type III: also called pauci-immune type, is defined by lack of anti-GBM
antibodies or immune complexes. Most patients do have antineutrophil
cytoplasm antibodies (ANCA) in the serum. In some patients, this is a component
of PAN or Wegener granulomatosis.

Figure 20-17 Crescentic glomerulonephritis (PAS

stain). Note the collapsed glomerular tufts and the
crescent-shaped mass of proliferating cells and
leukocytes internal to Bowman capsule.

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(3) IgA Nephropathy (Berger Disease)

A disease characterized by deposition of IgA (due to abnormal production and clearance)
in the mesangium. It usually affects young children and clinically manifests as gross,
recurrent hematuria following an upper respiratory infection. It can exist alone, or as a
component of Henoch-Schonlein disease.
Henoch-Schonlein purpura: also characterized by deposition of IgA in the
mesangium, but this is a systemic syndrome involving the skin (purpuric rash), GI
tract (abdominal pain), joints (arthritis), as well as the kidneys.
(4) Hereditary Nephritis
Refers to a group of hereditary familial renal diseases associated with glomerular injury.
The best studied hereditary nephritis is Alport Syndrome:
Alport syndrome: most commonly affects males, presenting between 20-50 years
old, it is a nephritis accompanied by nerve deafness and various eye disorders
(lens dislocation, posterior cataracts, corneal dystrophy).
Basket-weave lamina densa: the basement membrane of glomeruli and tubules
shows irregular foci of thickening or attenuation with pronounced splitting and
lamination of the lamina densa, yielding a basket-weave appearance.
Chronic Glomerulonephritis
Chronic glomerulonephritis is the advanced stage of a group of kidney disorders (mentioned above),
resulting in inflammation and gradual, progressive destruction of the glomeruli. It is caused when

there is slow progressive destruction (thus has an insidious onset) of the glomeruli, with
progressive loss of kidney function.
End-stage kidney: marked interstitial fibrosis, associated with atrophy and
replacement of many of the tubules, arteries with thickened wall and narrowed
lumens (secondary to hypertension), and lymphocytic infiltrates; such markedly
damaged kidneys are called end-stage kidneys.

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DISEASES AFFECTING TUBULES AND INTERSTITIUM

Pg 526 533
Tubulointerstitial Nephritis (TIN)
TIN refers to a group of inflammatory diseases of the kidneys that primarily involve the
interstitium and tubules. TIN can be divided into chronic and acute categories:
Acute pyelonephritis
Acute Pyelonephritis is a bacterial infection of the kidney that mainly targets the renal
pelvis (pyelo=pelvis). It almost always involves infection of the lower urinary tract and
is an important manifestation of urinary tract infections (UTI).
Enteric Gram negative rods: These are the most common agents that cause UTIs.
Leading the pack is E. coli, but Proteus, Klebsiella, Enterobacter, and
Pseudomanas are also important.
Vesicoureteral reflux
An incompetent vesicoureteral orifice allows the reflux of bladder urine into the
ureters. This is present in 35-45% of young children with UTI and it is usually a
congenital defect that results in the incompetence of the ureterovesical valve
(vesico=bladder, and ureter=ureter). VUR affords a ready mechanism by which
the infected bladder urine can be propelled up to the renal pelves.
Pyonephrosis:
Suppurative exudates from pyelonephritis may be unable to drain and thus fills
the renal pelvis, calyces, and ureter, producing pyonephrosis.
Necrotizing papillitis/papillary necrosis
A second form of pyelonephritis is necrosis of the renal papillae (more
common among diabetics and with analgesic abuse). It consists of
ischemic and suppurative necrosis of the tips of the renal pyramids. The
pathognomonic feature of this is sharply defined gray-white to yellow
necrosis of the apical two-thirds of the pyramids.
Pyuria/bacteriuria
When acute pyelonephritis is clinically apparent, pyuria (WBC in the
urine) and bacteruria (bacteria in the urine) may be present.
Dysuria/frequency/urgency
These are also associated with acute pyelonephritis and are indications of
bladder and urethral irritation.

Figure 20-35 Schematic representation of pathways of renal infection.

Hematogenous infection results from bacteremic spread. More common is
ascending infection, which results from a combination of urinary bladder
infection, vesicoureteral reflux, and intrarenal reflux.

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Chronic Pyelonephritis
Defined as a morphologic entity in which predominantly interstitial inflammation and
scarring of the renal parenchyma is associated with grossly visible scarring and deformity
of the pelvicalyceal system. There are two forms:
Figure 20-42 Typical coarse scars of chronic pyelonephritis associated with
vesicoureteral reflux. The scars are usually polar and are associated with
underlying blunted calyces.

(1) Chronic Obstructive Pyelonephritis

Recurrent infections, superimposed on diffuse or localized
obstructive lesions lead to recurrent bouts of remal inflammation
and scarring, eventuating in chronic pyelonephritis.
(2) Chronic Reflux-Associated Pyelonephritis (Reflux Nephropathy)
This is the more common form of chronic pyelonephritic scarring and results from
superimposition of a UTI on congenital vesicoureteral reflux and intra-renal reflux. This
can lead to chornic renal insufficiency. Patients with this disease present late due its slow
evolution, most commonly with hypertension and renal insufficiency.
Acute drug-induced interstitial nephritis
An adverse reaction to a wide range of drugs that begins about 15 days after exposure to
the drug. The disease is characterized by fever, eosinophilia, rash, and renal
abnormalities (oliguria, leukocyturia, rising serum creatinine, and acute renal failure).
Removing the drug usually causes the disease to go away.
Analgesic nephropathy
Occurs in patients who consume large quantities of analgesics and is often associated
with renal papillary necrosis. Aspirin and acetaminophen are the major culprits.
Common clinical features include chronic renal failure, hypertension, and anemia. There
is also an increased incidence of transitional cell carcinoma.
Acute tubular necrosis
A clinicopathologic entity characterized
morphologically by destruction of tubular
epithelial cells and clinically by acute
suppression of renal function. It is the most
common cause of acute renal failure (signified
by oliguira). The most frequent cause is renal
ischemia due to shock, trauma, or G- bacterial
sepsis, or exposure to nephrotoxic agents. With
proper medical treatment, full recovery can be
achieved.
Figure 20-32 Possible pathogenetic mechanisms
in ischemic acute renal failure (see text).

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DISEASES INVOLVING BLOOD VESSELS

Pg 533 - 535
Benign Nephrosclerosis
Describes renal changes that occur in benign hypertension. Microscopically, it is always
associated with hyaline arteriolosclerosis (hyaline thickening of the walls of the small
arteries and arterioles). The result of the vessel wall thickening is decreased blood to the
kidney, with subsequent ischemic atrophy. This results in the kidneys being
symmetrically atrophic with a surface of diffuse, fine granularity that resembles grain
leather.
Clinically, there is some decreased kidney function and often some protein in the urine.
However, this is usually a result of systemic hypertension and people more likely will die
of hypertensive heart disease before any renal problems.
Malignant hypertension
This is much less common than benign hypertension and may arise in people who were
with or without preexisting hypertension. Purposed etiology: a self-perpetuating cycle in
which angiotensin II causes intra-renal vasoconstriction (increased BP and decreased
kidney perfusion), and the attendant renal ischemia perpetuates renin secretion (increased
fluid volume and increased BP).
Clinically, this is characterized by diastolic pressures greater than 120 and ultimately
renal failure. The major presenting symptom is that of headache, nausea, and visual
impairment due to increased intracranial pressure.
The consequences of markedly elevated BP on the blood vessels throughout the body are
known as malignant arteriolosclerosis, and the renal disorder is referred to as
malignant nephrosclerosis.
Damage to the vessel walls leads to increased permeability to fibrin, which is manifested
as fibrinoid necrosis. Inflammatory cells are also present due to the vascular damage
and this is termed necrotizing arteriolitis.
Smaller interlobular arteries and larger arterioles, where the proliferation of intimal cells
produces an onion-skin appearance is termed hyperplastic arteriolosclerosis. This
causes narrowing of the arterioles to the point of obliteration. Necrotizing arteriolitis
may extend to involve the glomeruli (necrotizing glomerulitis).

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Thrombotic microangiopathy
This is a group of clinical syndromes characterized by widespread thrombosis in the
microcirculation, and clinically by microangiopahtic hemolytic anemia,
thrombocytopenia, and sometimes renal failure. These disease include childhood and
adult HUS and TTP.
Hemolytic-Uremic syndrome (HUS) usually follows intestinal infection with
E.coli and infections with verocytotoxin/shiga toxin producing bacteria (shiga
toxin ultimately causes endothelial lysis/damage which enhances
thrombosis/vasoconstriction most prominently in the interlobular and afferent
arterioles of the kidney resulting in the characteristic microangiopathy).
It is one of the main causes of acute renal failure in children and clinically
manifests as sudden onset of GI/flulike symptoms, followed by bleeding problems
(melena, hematemesis, hematuria, etc).
Thrombocytopenic purpura (TTP): caused by an acquired defect in proteolytic
cleavage of vWF multimers.

CYSTIC DISEASES OF THE KIDNEY

Pg 535 536
Simple Cysts
Innocuous 1-5cm lesions, lined by a gray membrane, filled with clear fluid, and usually
confined to the cortex of the kidney. These must be differentiated from kidney tumors:
in contrast to tumors, cysts have smooth contours, are avascular, and give fluid signals on
ultrasonography.
Dialysis-associated acquired cysts: occurs in patients undergoing prolonged
dialysis with end-stage renal disease. The cysts occur in both the medulla and
the cortex and may bleed (causing hematuria). Renal adenomas may form in the
walls of these cysts.
Autosomal dominant (adult) polycystic kidney disease (APKD)
APKD is characterized by multiple expanding cysts of both kidneys that ultimately
destroy the intervening parenchyma. It accounts for 10% of chronic renal failure.
Patients usually present in their 40s with flank pain or a dragging sensation, and
intermittent hematuria (sometimes). The most important complications are hard to
control hypertension and urinary infection. If not treated with a transplant, this causes
end-stage renal disease at age ~50.

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APKD (Cont)
PKD1: 90% of the time, this is the defective gene. It codes for a cell membraneprotein, called polycystin-1. It may function in a cell-cell adhesion role. A cell
must be homozygous for the gene to develop cysts.
PKD2: occurs in 10% of cases and encodes polycystin-2. It has the same function
and forms a heterodimer with polycystin-1. A defect in either gene causes cysts.
Aneurysm of Circle of Willis: saccular aneurysms of the circle of Willis are
present in 10-30% of these patients which means that they have a high incidence
of sub-arachnoid hemorrhage.
Autosomal recessive (childhood) polycystic kidney disease
Rare, autosomal recessive, developmental disease subgrouped into: perinatal, neonatal,
infantile, and juvenile. All result from mutations on chromosome 6p. Serious illness
present at birth and death may follow due to renal or pulmonary failure. Grossly, the
kidneys are affected bilaterally and take on a sponge-like appearance. Patients who
survive develop cysts in the liver and ultimately develop congenital hepatic cirrhosis.
Figure 20-8 A and B, Autosomaldominant adult polycystic kidney disease
(ADPKD) viewed from the external
surface and bisected. The kidney is
markedly enlarged with numerous dilated
cysts. C, Autosomal-recessive childhood
polycystic kidney disease, showing
smaller cysts and dilated channels at right
angles to the cortical surface. D, Liver
with cysts in adult PKD.

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URINARY OUTFLOW OBSTRUCTION

Pg 536 539
Renal Stones (Urolithiasis)
This is calculus formation at any level in the urinary system (most often in the kidney).
Most of them are composed of calcium oxalate with or without calcium phosphate. The
most important cause is increased urine concentration of whatever the stone is made of
(supersaturation). Larger stones can be asymptomatic, but when smaller stones enter the
ureter, they present as flank pain radiating to the groin (renal colic) and possibly
hematuria.
Magnesium ammonium phosphate (struvite) stone: almost always occur in
patients with persistently alkaline urine due to UTIs. In particular, with:
Proteus vulgaris: renal stones can predispose to bacterial infection, or
bacteria, such as P. vulgaris can cause renal stone formation (theyre
urease+)!
Uric Acid Stones: gout and disease leading to rapid cell turnover lead to high uric
acid levels in the urine with the possibility of uric acid stone formation.
Cystine Stones: associated with a genetically determined defect in the renal
transport of amino acids (cysteine).
Staghorn calculi: accretion of salts leads to the development of these branching
structures which create a cast of the renal pelvis and calyx system.
Hydronephrosis
This refers to the dilation of the renal pelvis and calyces, with accompanying atrophy of
the parenchyma, caused by obstruction to the outflow of urine. Mechanism: block in
outflow of urine> increased back pressure on kidney> dilation of calyces which cause
compression of the blood vessels > atrophy of the parenchyma. It can be congenital or
acquired, unilateral or bilateral depending on the level of the obstruction:
Hydroureter: depending on the level of the obstruction, one or both ureters may
also be dilated.

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TUMORS
Pg 539 542
Renal Cell Carcinoma
These arise from renal tubular epithelium and account for ~80% of kidney tumors. It
affects men > women in the 6-7th decade: increased risk with smoking, cadmium
exposure, and chronic dialysis. Characteristic triad of clinical symptoms: painless
hematuria (always present microscopically but intermittently macroscopic), long-standing
fever, and dull flank pain. Causes Polycythemia if cancer cells express EPO. The three
most common forms are:
(A) Clear Cell Carcinomas (70-80%)
These tumor cells have a clear or granular cytoplasm.
There are falmilial and sporadic forms of this cancer.
Regardless of the form, the underlying common genetic
defect is in the VHL gene: this is a tumor suppressor gene,
and if you lose both of your copies, you develop clear cell
carcinoma.
(B) Papillary Renal Cell Carcinomas (10-15%)
These tumors take on a papillary growth pattern and affect
the proximal tubule. There are familial and sporadic forms
with the underlying genetic defect being in the MET protooncogene (a tyrosine kinase receptor for hepatocyte growth
factor) which is on chromosome 7. If you have too much
MET, you have too much receptor, and your cells growtoo
much. Familial forms frequently exhibit trisomy of
chromosome 7.
(C) Chromophobe Renal Carcinomas (~5%)
These tumors affect the cortical collecting ducts. They stain
more darkly (than clear cells) and are characterized by loss
of an entire chromosome. They have a good prognosis.von

Hippel-Lindau disease (VHL)

VHL is an autosomal dominant disease characterized by predisposition to a variety of
neoplasms, but particularly to hemangioblastomas of the cerebellum and retina. The
understanding of clear cell carcinoma came from studying this disease.
Wilms tumor
This is the most common tumor in children (peak incidence between 2-4 years old). It
usually presents with a palpable flank mass that originates from primitive metanephric
tissue. It is composed of a variety of cells. Genetics: is often associated with deletions of
the short arm of chromosome 11 (WT-1 & 2 cancer suppressor genes are located here).

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Papilloma
Tumors arising in the urinary bladder range from small benign papillomas to large
invasive cancers. The very rare benign papillomas are 0.2-1.0-cm, frond-like structures
having a delicate fibrovascular core covered by multilayered, well-differentiated
transitional epithelium.
Urothelial (transitional) cell carcinoma
Tumors of the lower urinary tract are about
twice as common as renal cell carcinomas.
Painless hematuria is the dominant clinical
presentation. It affects men > women between
their 50-70s. Bladder tumors are more common
in people with industrial exposure to betanaphthylamine. Cigarette smoking, some
drugs, and schistosomiasis also increase the
risk. Tumors affecting the renal pelvis also
present with pain in the costovertebral angle as
hydronephrosis develops.

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CHAPTER 18
MALE GU
THE PENIS
Pg 657 659
MALFORMATIONS
Hypospadias
The more common of the malformations, designates an abnormal opening of the urethra
anywhere along the ventral aspect of the penis. The urethra is often constricted causing
urinary obstruction.
Epispadias
The other malformation involving the urethra, this indicates the presence of the urethral
orifice on the dorsal aspect of the penis. This too may cause urinary obstruction due to a
constricted urethra, or incontinence.
INFLAMMATORY LESIONS (lesson to be learned: keep it clean)
Balanitis/Balanoposthitis
Both terms refer to local inflammation of the glans penis or the glans and overlying
prepuce. It is usually secondary to poor hygiene in uncircumcised males. The distal
penis is usually red, swollen, and tender (a purulent discharge may be present).
Smegma: the irritant in balanitis is an accumulation of desquamated epithelial
cells, sweat, and debristermed smegma.
Phimosis: a condition where the prepuce is not easily retracted over the glans
penis. It can be congenital but is usually a result of balanoposthitis.
Paraphimosis: when the prepuce is forcibly retracted over the glans, the
circulation is interrupted with resultant congestion, swelling, and pain of the distal
penis. This could lead to urinary retention.
Genital candidiasis
Candida growth is favored in warm, moist areas with poor hygiene. Erosive, painful,
intensely pruritic lesions involving the glans penis and scrotum. Scraping show the
characteristic budding yeast and pseudohyphae.
NEOPLASMS
Human papillomavirus
Cancers of the penis are usually squamous cell and are rare (0.25% of all male cancers).
They are usually associated with uncircumcised males, over 40 with poor hygiene
(smegma) and HPV infection, particularly types 16 and 18.

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Carcinoma in situ
Like other squamous cell carcinomas, carcinomas of the penis are usually preceded by
the appearance of malignant cells confined to the epidermis, termed carcinoma in situ.
There are three forms of carcinoma in situ (all associated with HPV):
(1) Bowen disease: appears grossly as a solitary, plaquelike lesion on the shaft
of the penis. Histologically, there are malignant cells within the epidermis with
no invasion of the underlying stroma. 10% of cases progress to invasive SCC and
has been associated with visceral malignancy.
(2) Erythroplasia of Queyrat: appears grossly as an erythematous patch on the
glans penis.
(3) Bowenoid papulosis: a venerally transmitted viral lesion involving the penile
shaft.
Squamous cell carcinoma
Grossly, this appears as a gray, crusted, papular lesion, most commonly on the glans
penis or prepuce. It often infiltrates the underlying tissue to form an ulcerated lesion with
irregular margins. Inguinal lymph nodes present in 25%, distant metastases are rare, and
5 year survival is 70%.
Verrucous carcinoma
The tumor may grow in a predominantly papillary pattern. These are characterized by
less striking cytologic atypia and bulbous, rounded, deep margins.
SCROTUM, TESTIS, & EPIDIDYMIS
Pg 659 664
Hydrocele
This is the most common cause of scrotal enlargement and is an accumulation of serous
fluid within the tunica vaginalis. Other causes of scrotal enlargement include hematocele
(blood within the tunica vaginalis) and chylocele (lymphatic fluid within the tunica
vaginalis).

Elephantiasis
In extreme cases of lymphatic obstruction
(filariasis), the scrotum and lower
extremities may become unbelievably
enlarged, a condition termed elephantiasis.

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Cryptorchidism
This is failure of one or both testicles to descend from the coelomic cavity into the pelvis
and then the scrotum during development. This can be caused by many factors including
hormonal abnormalities and mechanical problems. Complications include sterility and
the a four-fold increase for the risk of testicular cancer in either testis.
Orchiopexy: surgical placement of the undescended testis into the scrotum. If
done before puberty, this may decrease the likelihood of atrophy, but does not
guarantee fertility. Affect on cancer development is unclear.
Epididymitis
Inflammation of the epididymis producing tenderness, pain in the groin area, fever, and
chills. It can be associated with UTI with secondary ascending infection of the testis
through the vas deferens or lymphatics of the spermatic cord. Tuberculosis can also
affect the epididymis causing a granulomatous reaction.
Orchitis
Inflammation of one or both testes characterized by pain and swelling. It can occur with
mumps and syphilis. It can also be associated with UTI with secondary ascending
infection of the testis through the vas deferens or lymphatics of the spermatic cord.
Testicular Neoplasms
This is the most important cause of firm, painless enlargement of the testis. Virtually
all arise from the germ cells and are malignant. Neoplasms arising from the sertoli or
leydig cells are rare, but may come to attention because they can secrete steroid
hormones causing endocrine abnormalities.

Sertoli cell
The Sertoli cells produce androgen binding proteins
(ABP), in response to FSH. ABP helps maintain an
androgen rich microenvironment in the seminiferous
tubules.
Leydig cell (Interstitial Cells)
The Leydig cells produce androgens in response to LH.
High levels of androgens in the seminiferous tubules are
essential for spermatogenesis.
Schematic: seminferous tubule cross-section

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Testicular dysgenesis
Syndromes characterized by testicular dysgenesis (abnormal development of the testis),
including testicular feminization and Klinefelter syndrome, are associated with an
increased risk of testicular cancer.
Klinefelter syndrome: In Klinefelter syndrome, a male is XXY. The condition is
common and affects 1 in 500 men. The infant appears normal at birth, but the
defect usually becomes apparent in puberty when secondary sexual characteristics
fail to develop (or develop late). At this time, testicular changes occur that
eventually result in infertility.
Intratubular germ cell neoplasia
Most testicular tumors arise from in situ lesions characterized as intratubular germ cell
neoplasms. This lesion is present in conditions associated with a high risk of developing
germ-cell tumors. Foci of such in situ lesions are seen in testicular tissue adjacent to a
testicular tumor 90% of the time.
Seminoma (50%)
They are large, soft, well-demarcated, usually
homogeneous gray-white tumors that bulge from the
cut surface of the affected testis. They are confined
beneath an intact tunica albuginea. Microscopic
examination reveals large cells with distinct cell
borders, pale nuclei, prominent nucleoli, and a sparse
lymphocytic infiltrate. Is associated with an increase in
hCG and metastases are common.
Spermatocytic seminoma: a less common form of seminoma characterized by a
mixture of medium-sized cells, large uninucleate or multinucleate cells, and small
cells with round nuclei. (usually occurs in older patients)
Embryonal carcinoma (2-3%)
These are ill-defined invasive masses containing foci of
hemorrhage and necrosis. Metastases are common.
Histologically, the cells are large and primitive looking,
with basophilic cytoplasm, indistinct cell borders, and
large nuclei with prominent nucleoli. The cells may be
arranged undifferentiated, solid sheets or glandular
structures.

Left, Embryonal is a bulky, hemorrhagic mass versus seminoma

(right) which appears as a fairly well circumscribed, pale, fleshy,
homogenous mass.

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Yolk sac tumor (endodermal sinus tumor)

Grossly, these tumors are typically large and may be well demarcated. Microscopically,
they appear as low cuboidal to columnar epithelial cells forming sheets, glands, papillae,
and microcysts, often associated with hyaline globules. This is the most common
primary testicular neoplasm in children younger than 3 years old. Alpha-feto-protein
(AFP) can be demonstrated within the cytoplasm of these neoplastic cells.
Schiller-Duvall body: structures resembling primitive glomeruli, a distinctive
feature of yolk sac tumors.
Choriocarcinoma
These tumors represent differentiation of pluripotent neoplastic germ cells along
trophoblastic lines. Grossly, the primary tumors are often small, nonpalpable lesions.
Microscopically, choriocarcinomas are composed of sheets of small cuboidal cells
irregularly intermingled with or capped by large, eosinophilic syncytial cells containing
multiple dark, pleomorphic nuclei; these represent cytotrophoblastic and
syncytiotrophoblastic differentiation, respectively. hCG is elevated.

Choriocarcinoma shows clear cytotrophoblastic cells

with central nuclei and syncytiotrophoblastic cells with
multiple dark nuclei embedded in eosinophilic
cytoplasm. Hemorrhage and necrosis are prominent.

Teratoma
These represent differentiation of neoplastic germ cells along somatic cell lines.
Teratomas are firm masses that on cut surface often contain cysts and recognizable areas
of cartilage. Histologically, there are three major variants:
Mature: contain fully differentiated tissues from one or more germ-cell layers
(neural tissue, cartilage, adipose, bone, epithelium)in a haphazard array.
Immature: contain immature somatic elements reminiscent of those in developing
fetal tissue.
With malignant transformation: characterized by the development of frank
malignancy in preexisting teratomatous elements, usually in the form of a
squamous cell or adeno-carcinoma. Usually occurs in adults.

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Figure 18-9. Teratoma. Testicular

teratomas conatin mature cells from
endodermal, mesodermal, and
ectodermal lines. Pictured here are
four different fields from the same
tumor containing neural (A),
glandular (endodermal (B),
cartilaginous (mesodermal (C), and
squamous epilthelial (D) elements.

Mixed germ-cell tumor (60%; Robbins math doesnt add up)

Combinations of any of the described patterns may occur in mixed tumors, the most
common of which is a combination of teratoma, embyronal carcinoma, and yolk sac
tumors. hCG and AFP are elevated.
hCG/AFP
These are both tumor markers and are important in the clinical evaluation of germ-cell
neoplasms. They can also be useful for monitoring patients for persistent or recurrent
tumors after therapy. AFP, however, can also be elevated in liver cancer.

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PROSTATE
Pg 664 669
Protatitis
Clinically apparent, acute or chronic, inflammation of the prostate. The classification of
prostatitis is based on clinical, microscopic, and often urine characteristics. It can be
caused by the same organisms that cause UTI. Manifestations of protstatitis include:
dysuria, urinary frequency, lower back pain, and poorly localized pelvic pain.
Acute: characterized by the presence of an acute, neutrophilic inflammatory
infiltrate, congestion, and stromal edema. As the infection progresses,
microabscesses may form. The prostate is often enlarged and accompanied by
leukocytosis and fever.
Chronic: evidence of tissue destruction and fibroblastic proliferation, along with
the presence of other inflammatory cells, such as neutrophils, is required for a
histologic diagnosis of chronic prostatitis. Can be a cause of recurrent UTI, if
bacteria take up residence in the prostate.
Granulomatous: a morphologic variant of chronic prostatitis. It usually occurs in
the setting of systemic diseases that cause granuloma formation (TB, sarcoidosis,
etc). Morphologically, there are multinucleate giant cells and variable numbers of
foamy histiocytes, sometimes accompanied by eosinophils.
Nodular hyperplasia of the prostate
An extremely common abnormality of the prostate. It is characterized by proliferation of
both epithelial and stromal elements, with resultant enlargement of the gland and, in
some cases, urinary obstruction (the most common clinical manifestation). There can
be hesitancy, interruption of the urinary stream while voiding, painful distention of the
bladder, and sometimes, hydronephrosis.

Figure 21-30 Adult prostate. The normal prostate contains

several distinct regions, including a central zone (CZ), a
peripheral zone (PZ), a transitional zone (TZ), and a
periurethral zone. Most carcinomas arise from the
peripheral glands of the organ and may be palpable during
digital examination of the rectum. Nodular hyperplasia, in
contrast, arises from more centrally situated glands and is
more likely to produce urinary obstruction early on than is
carcinoma.

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Dihydrotestosterone (DHT)/5-reductase
DHT is an androgen derived from testosterone through the action of 5-reductase, and its
metabolite, 3-androstanediol, appear to be the major hormonal stimuli for glandular and
stromal proliferation in patients with nodular hyperplasia.
Corpora amylacea
The glanular lumina of the hyperplastic glands in nodular hyperplasia often contain
inspissated, proteinaceous secretory material termed corpora amylacea.
Adenocarcinoma of the prostate
Most prostatic carcinomas are adenocarcinomas composed of small glands that infiltrate
the adjacent stroma in an irregular, haphazard fashion. The glands often lie back-toback and appear to dissect sharply though the native stroma. The glands are lined by a
single layer of cuboidal cells with conspicuous nucleoli.
A, a small focus of adenocarcinoma
of the prostate demonstrating small
glands crowded in between larger
benign glands. B, shows several
small malignant glands with
enlarged nuclei, prominent
nucleoli, and dark cytoplasm,
compared to the larger benign
gland (top).

Prostatic intraepithelial neoplasia (PIN): Glands adjacent to areas of invasive

carcinoma of the prostate often contain foci of epithelial atypia, and may be a
precursor to adenocarcinoma.
Osteoblastic metastasis: Bone metastases are common and can be either osteolytic
or osteoblastic in nature. The presence of osteoblastic metastases is strongly
suggestive of advanced prostatic carcinoma.
Prostate-specific antigen (PSA)
This enzyme is produced by normal and neoplastic prostatic epithelium. The serum PSA
level can be elevated in hyperplasia and carcinoma. A normal value is less than 4 ng/L.
PSA is of limited use as a screening test, but is more useful when used with other tests
(digital rectal exam). Several refinements in the interpretation of PSA are being tested to
enhance diagnostic value. These include: the rate of change of PSA values over time
(PSA velocity), and determination of the ratio between serum PSA value and volume of
the prostate gland (PSA density). PSA is useful to monitor progression or recurrence of
disease.
Gleason grade
A histologic grading scale for prostatic carcinoma based on degree of glandular
differentiation, architecture of the neoplastic glands, nuclear anaplasia, and mitotic
activity.
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SEXUALLY TRANSMITTED DISEASES

Pg 669 677
Syphilis
Syphilis is a sexually transmitted disease caused by T. pallidum. Syphilis progresses
through a series of stages, primary (2-6 weeks post-infection), secondary (4-6 weeks after
primary resolves), latent, and tertiary (after latent period of 5 years or more):
Primary syphilis: is characterized by the presence of a hard chancre at the site of
inoculation. The chancre begins as a small, firm papule, which gradually enlarges
to produce a painless ulcer with well-defined margins and a clean, moist base.
Serologic tests for syphilis are often negative during this period, so one must
either look for spirochetes in the ulcer using darkfield microscopy or direct
fluorescent antibody testing.
Secondary syphilis: is typically characterized by generalized lymph node
enlargement and a variety of mucocutaneous lesions. There is often a rash that
involves the palms of the hands and soles of the feet. Moist skin areas develop
broad-based, elevated lesions termed condyloma lata. This usually clears up over
several weeks and the patient then enters the early latent phase during which time
any symptoms of secondary syphilils may recur.
Proliferative endarteritis
Treponemes cause endothelial hypertrophy and proliferation, followed by
intimal fibrosis and narrowing of the vessel lumen. This leads to local
ischemia and accounts for some of the cell death and fibrosis in syphilis.
This becomes histologically evident during secondary syphilis.
Tertiary syphilis: this phase is divided into three major categories: cardiovascular,
neuro-, and benign tertiary syphilis.
Syphilitic aortitis: this is the cardiovascular portion of tertiary syphilis and
involves the endarteritis of the vasa vasorum of the proximal aorta leading
to dilationof the aortic root and arch, with resultant aortic insufficiency
and aneurysms of the proximal aorta.
Neurosyphilis: is manifested by Tabes dorsalis (muscle weakness and
sensory deficit due to damage to the spinal cord) and/or general paresis.
Gumma: this is the benign tertiary syphilis component. Large areas of
parenchymal damage result in the formation of a gumma, an irregular,
firm mass of necrotic tissue surrounded by resilient connective tissue.
These most often occur in bone, skin, upper airway, and mouth and are
believed to be the development of delayed type hypersensitivity.

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Congenital syphilis
T. pallidum can be transmitted across the placenta. Manifestations of congenital syphilis
include stillbirth (hepatomegaly, bone abnormalities, pancreatic fibrosis, and
pneumonitis), infantile syphilis (congenitally acquired that presents during infancy as the
snuffles and a rash similar to secondary syphilis), and late congenital syphilis, which
presents with the Hutchinson triad.
Hutchinson triad: notched central incisors, interstitial keratitis with blindness, and
deafness from eighth cranial nerve injury.
Nontreponemal antibody test (Screening test; 15% are false-positives)
Measures antibody to cardiolipin, an antigen that is present in both host tissues and the
treponemal cell wall. These antigens are detected by the rapid plasma reagin (RPR) and
Venereal Disease Research Laboratory (VDRL) tests. Tests become positive 1-2 post
infection maintain elevated for 4-6 weeks and titers fall after treatment.
Treponemal antibody test
Treponemal tests include the fluorescent treponemal antibody absorption test (FTA-Abs)
and the microhemagglutination assay for T. pallidum antibodies (MHATP). They
become positive within 4-6 weeks and remain positive indefinitely (even after
treatment)!
Gonorrhea (Gram negative diplococci)
This is a sexually transmitted disease of the lower genitor-urinary tract that is caused by
Neisseria gonorrhoeae. The bacteria initially attaches to the mucosal epithelium by pili
and then pentrate into deeper tissues. Ascending infection can cause acute prostatitis,
epididymitis, and/or orchitis.
Purulent urethral discharge: N. gonorrhoeae provokes an intense, suppurative
inflammatory reaction, that in males, manifests most often as a purulent urethral
discharge associated with an edematous, congested urethral meatus.
Ophthalmia neonatorum: gonococcal infection can be transmitted to infants
during passage through the birth canal. The affected neonate may develop
purulent infection of the eyes, an important cause of blindness.
Non-gonoccal urethritis
This is the most common form of STD today and most cases are caused primarily by
Chlamydia trachomatis (gram negative, intracellularexists as elementary body or
reticulate body) and sometimes U. urealyticum. It manifests and creates disease similar
to gonococcal urethritis (painful urination and mucopurulent discharge).
Reiter syndrome: uveitis, arthritis, and painful urination. It can be associated with
Non-gonococcal urethritis.

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Lymphogranuloma venereum (LGV)

This is also caused by certain serotypes of C. trachomatis. It may present with
nonspecific urethritis, papular or ulcerative lesions involving lower genitalia, regional
adenopathy, or an anorectal syndrome. The regional lymphadenopathy is characterized
by a granulomatous inflammatory reaction associated with irregularly shaped foci of
necrosis and neutrophilic infiltration.
Chancroid (soft chancre)
This is an acute, ulcerative infection caused by Haemophilus ducreyi (gram-negative
coccobacillus). Four-seven days post inoculation, the patient develops a tender,
erythematous papule involving the external genitalia. The primary lesion erodes to
produce an irregular ulcer, which is painful. The ulcer is not indurated, and multiple
lesions may be present. The base of the ulcer is covered by a shaggy, yellow-gray
exudate.
Granuloma inguinale
A chronic inflammatory disease caused by Calymmatobacterium donovani (encapsulated
coccobacillus). This begins as a raised, papular lesion on the genitalia and progresses to
ulceration with the formation of granulation tissue (grossly looks like a soft, painless
mass). Regional lymph nodes are usually spared.
Pseudoepitheliomatous hyperplasia: examination of active lesions reveals marked
epithelial hyperplasia at the borders or the ulcer, sometimes mimicking
carcinoma.
Trichomaniasis
Trichomonas vaginalis is a sexually transmitted protozoan. The trophozoite form
adheres to the mucosa and causes lesions. In females, it causes itching and a profuse,
frothy, yellow vaginal discharge. In males it is usually asymptomatic, but can present as
a non-gonococcal urethritis.
Genital herpes
Genital herpes, spread by sexual contact, is usually caused by HSV-2, but can also be
caused by HSV-1. The primary lesion appears as painful, erythematous vesicles on the
mucosa or skin of the lower genitalia and adjacent extra-genital sites.
Cowdry type A inclusion: viral inclusions that appear as a light purple,
homogeneous intra-nuclear structure surrounded by a clear halo.
Neonatal herpes infection: the viral infection is acquired during passage through
the birth canal. The manifestations typically develop during the second week of
life, and include rash, encephalitis, pneumonitis, and hepatic necrosis.

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Human papillomavirus (HPV)

HPV is the cause of a number of squamous proliferations in the genital tract, including
condylomata accuminata, some precancerous lesions, and some carcinomas.
Condylomata accuminata: also known as genital warts, are caused by HPV types
6 & 11. They occur on the penis and female genitalia as small sessile lesions to
large papillary proliferations. The more superficial epithelial cells of the lesions
contain irregular, hyperchromatic nuclei surrounded by a characteristic clear
perinuclear halo, a change referred to as koilocytosis.

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CHAPTER 20
ENDOCRINE
THE ENDOCRINE SYSTEM
Feedback inhibition
The goal of the endocrine system is to maintain a state of metabolic equilibrium. It
accomplishes this through the secretion of hormones. Typically, increased activity of the
target tissue down-regulates the activity of the gland secreting the hormone (feedback
inhibition).
PITUITARY
Pg 721 726
Pituitary gland
The pituitary gland is a small, bean shaped structure that lies at the base of the brain
within the confines of the bony sella turcica. It is connected to the hypothalamus through
the pituitary stalk. Functionally, along with the hypothalamus, the pituitary gland
controls most of the other endocrine glands. The gland is divided into the:
Adenophysis: or anterior pituitary. It is
composed of eosinophilic, basophilic, and
chromophobic cells. These staining
characteristics correspond to the type of hormone
secreted. The release of these hormones is
governed by the hypothalamus.
Neurohypophsis: composed of modified glial
cells and axonal processes extending from nerve
cell bodies in the supraoptic and paraventricular
nuclei of the hypothalamus. Neurons produce
ADH and oxytocin.

Hyperpituitarism
A disorder that arises from excess secretion of trophic hormones and is most commonly
caused by a functional adenoma within the anterior lobe.
Sella turcica
Radiographic abnormalities of the sella turcica, including sellar expansion, bony erosion,
and disruption of the diaphragma sellae, are evidence of a mass lesion affecting the
pituitary gland.
Bitemporal hemianopsia
Due to the proximity of the pituitary gland to the optic chiasm, when a mass lesion
affects the pituitary it often impinges on the optic chiasm (this is where the temporal
visual field nerve endings cross) leading to lateral visual field deficit.
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Obstructive hydrocephalus
Any expanding mass lesion within the cranium; pituitary adenomas cause headache,
naseau, and vomiting. Adenomas that extend beyond the sella turcica into the base of the
brain produce seizures and obstructive hydrocephalus (the flow of CSF is compromised
and fluid builds up).
Pituitary apoplexy
Acute hemorrhage into an adenoma is associated with clinical evidence of rapid
enlargement of the lesion and depression of consciousness. Apoplexia = bleeding into an
organ.
Functional Adenoma
These are the most common cause of excess anterior pituitary hormone and are usually
composed of a single cell type, and thus produce a single hormone. Adenomas are
classified based on the type of hormone they secrete. Pituitary adenomas are termed
macroadenoma if they are over 1cm in diameter and microadenoma if under 1cm.
Prolactinoma
Most common type of hyperfunctioning pituitary adenoma. This tumor causes
hyperprolactinemia (excess prolactin production leading to amenorrhea), galactorrhea,
loss of libido, and infertility. Symptoms are more easily seen in premenopausal females.
Hyperprolactinemia can also be caused by pregnancy, estrogen therapy, renal failure,
hypothyroidism, hypothalamic lesions and dopamine inhibiting drugs.
Stalk effect: a mass in the suprasellar compartment may disturb the inhibitory
influence of hypothalamic dopamine on prolactin secretion leading to
hyperprolactinemia.
Bromocriptine: treatment for prolactinomas, bromocriptine is a dopamine
receptor agonist causing shrinkage of the neoplasm.
Growth hormone adenoma
The second most common type of functional pituitary adenoma. Musculoskeletal
abnormalities are usually accompanied by other disturbances such as abnormal glucose
tolerance and diabetes mellitus, generalized muscle weakness, hypertension, arthritis,
osteoporosis, and CGH. Subtypes of GH adenoma:
Gigantism: adenoma occurs before the epiphyses close (prepubertal children).
Characterized by generalized increase in body size, w/disproportionately long
arms and legs.
Acromegaly: elevated GH levels persist or present after closure of the epiphyses.
Growth is most conspicuous in soft tissues, skin, viscera, and in the bones of the
face hands, and feet. Enlargement of the jaw results in its protrusion
(prognathism), with broadening of the lower face and separation of the teeth.
Hands and feet are enlarged with broad, sausage like fingers. Usually, gigantism
is accompanied by acromegaly.

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Corticotroph cell adenoma

Most of these adenomas are microadenomas at time of diagnosis. May be clinically
silent or may cause hypercortisolism (Cushing Syndrome). There are many different
causes, but symptoms are: moon facies, obesity, easy bruising, slow wound healing, and
hypokalemia.
Cushing Disease: hypercortisolism caused by excessive production of ACTH by
the pituitary.
Nelson Syndrome: aggressive corticotroph adenomas may develop in patients
after surgical removal of the adrenal glands for treatment of Cushing syndrome.
Occurs because there was already an unknown corticotroph microadenoma, and
the adrenal glands are no longer present to inhibit it. There is no Cushings
symptoms because the adrenals are gone. ACTH is part of a larger molecule that
also produces MSH, as such, this may present with hyperpigmentation.
Null cell adenoma
Adenomas with no demonstrable hormonal product. Cytoplasm usually has numerous
mitochondria, but few granules. Symptoms are usually mass effect and hypopituitarism.
Gonadotroph adenoma
Usually seen in middle-aged men and women. They cause decreased libido in men but
no endocrine abnormalities.
Thyrotroph adenoma
1% of all pituitary adenomas and are a rare cause of hyperthyroidism.
Hypopituitarism
Can occur with loss or absence of 75% or more of the anterior pituitary parenchyma.
Can be congenital, or acquired. When it is accompanied by posterior pituitary
dysfunction (diabetes insipidus) it is almost always hypothalamic in origin.
Nonsecretory pituitary adenoma: may compress and compromise the anterior
pituitary resulting in hypopituitarism.
Sheehan syndrome: postpartum necrosis of the anterior pituitary. Most common
form of clinically significant ischemic necrosis of the anterior pituitary. During
pregnancy, the anterior pituitary enlarges, but it is not accompanied by an increase
in blood supply from the low-pressure portal venous system, making it especially
vulnerable to ischemic injury in patients who develop hemorrhage and
hypotension during the peripartum period.
Empty sella syndrome: an enlarged and empty sella turcica caused by chronic
herniation of the SAS into the sella turcica. A defect in the diaphragma sellae
allows arachnoid mater and cerebrospinal fluid to herniate into the sella causing
expansion of the sella and compression of the pituitary. Classically seen in obese

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women with a history of multiple pregnancies. Associated with the stalk effect,
but not hypopituitarism because functioning parenchyma is preserved.
Pituitary dwarfism: results from GH deficiency in children.
Antidiuretic hormone
A nonapeptide hormone synthesized predominantly in the supraoptic nucleus and stored
in the neurohypophysis. It acts on the collecting tubules of the kidney to promote the
resorption of free water.
Oxytocin
Oxytocin is not associated with any significant clinical abnormalities, but ADH is
associated with:
Diabetes insipidus
Caused by a deficiency in ADH, it is characterized by excessive urination (polyuria)
caused by an inability of the kidney to properly reabsorb water from the urine. Can result
from head trauma, neoplasms, and inflammatory disorders or surgery of the
hypothalamus or pituitary. When it occurs from ADH deficiency it is central. When it is
a result of renal tubular unresponsiveness to circulating ADH it is nephrogenic.
Clinically they appear the same.
Syndrome of inappropriate ADH secretion (SIADH)
Disorders resulting in excess ADH secretion causing re-absorption of excessive free
water leading to hyponatremia. Commonly caused by the secretion of ectopic ADH by
malignant neoplasms (small cell carcinoma in lungs), non-neoplastic diseases of the lung,
and local injury to the hypothalamus/neurohypophysis. Clinically manifested as
hyponatremia, cerebral edema, and resultant neurological dysfunction.

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THYROID
Pg 726 738
Thyroid gland
Bilobed gland located anterior to the larynx that develops from an evagination of the
pharyngeal epithelium and descends to its position in the neck. It is composed of
spherical follicles that are lined by follicular epithelial cells and filled with
thyroglobulin-rich colloid. There are also cells between the follicles termed, parafollicular cells (C cells).
TSH/thyroxine(T4)/triiodothyroxine (T3): the anterior pituitary secrets thyroid
stimulating hormone (TSH) which stimulates the follicular epithelial cells to
pinocytize colloid and convert the thryroglobulin to mostly thryoxine (T4) and
some triiodothryroxine (T3). T4 and T3 travel the circulation and interact with
intracellular receptors to up-regulate carbohydrate and lipid metabolism and
stimulate protein synthesis. The net effect is to increase basal metabolic rate.
Para-follicular cells/calcitonin: Para-follicular cells synthesize and secrete
calcitonin which is a hormone that promotes absorption of calcium by bones
and inhibits osteoclast activity.
Homeostasis in the hypothalamus-pituitary-thyroid axis
and mechanism of action of thyroid hormones. Secretion
of thyroid hormones (T3 and T4 ) is controlled by trophic
factors secreted by both the hypothalamus and the
anterior pituitary. Decreased levels of T3 and T4 stimulate
the release of thyrotropin-releasing hormone (TRH) from
the hypothalamus and thyroid-stimulating hormone (TSH)
from the anterior pituitary, causing T3 and T4 levels to
rise. Elevated T3 and T4 levels, in turn, suppress the
secretion of both TRH and TSH. This relationship is
termed a negative-feedback loop.

Hyperthyroidism: Disease condition associated with excessive release of thyroid

hormones.
Thyrotoxicosis: refers to a hypermetablic state caused by elevated levels of free
T3 and T4 either due to (1) thyroid hyperfunction (hyperthyroidism), (2)
excessive release of preformed hormones (thyroiditis), or (3) ectopic production.

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Hyperthyroidism (cont)
Hyperthyroidism is the most common thyrotoxicosis and the terms are used
interchangeably. The clinical manifestations of hyperthyroidism are caused by the
hypermetablic state and sympathetic overactivity: they include, heat intolerance,
weight loss with increased appetite, diarrhea, heart palpitations and tachycardia,
tremor, and lid lag.
Thyroid storm: the abrupt onset of severe hyperthyroidism resulting from an
acute elevation in catecholamine levels. It is a medical emergency: untreated
patients can die of cardiac arrhythmias.
Hypothyroidism
Disease condition associated with thyroid hormone deficiency. It is caused by anything
that interferes with the production of adequate levels of thyroid hormone. The clinical
manifestations of hypothyroidism include, cretinism and myxedema:
Cretinism: hypothyroidism developing in infancy or early childhood. It can be
caused due to iodine deficiency or rarely an inborn error of metabolism.
Manifests as mental retardation, short stature, and protruding tongue. If a mother
is iodine deficient (which means low T3 and T4 levels) during pregnancy, there
will be some level of mental retardation in the child.
Myxedema: hypothyroidism developing in older children and adults.
Manifests as: apathy, mental sluggishness, cold intolerance, and a
mucopolysaccharide-rich edema accumulating beneath the skin, tissue, and
several visceral sites.
Graves Disease
This is an autoimmune disease characterized by the presence of auto-antibodies against
the TSH receptor (several types of this antibody) usually seen in women between 20-40.
Labs show an increase in T3 and T4 levels, with a decrease in TSH levels. The most
common cause of endogenous hyperthyroidism, it is manifested by a triad of symptoms:
(1) Thyrotoxicosis all have hyperplasia of the thyroid gland
(2) Infiltrative ophthalmopathy orbital fibroblasts posses TSH receptors. The
anti-TSH antibodies stimulate them to differentiate into adipocytes and secrete
GAGs which contributes to the orbital protrusion. There is also
accompanying lid lag and lymphocytic infiltrate.
(3) Graves Dermopathy (Pretibial myxedema) pre-tibial fibroblasts also posses
TSH receptors that are triggered by anti-TSH antibodies to secrete GAGs.
The result is a lumpy, reddish thickening of the skin over the shin due to a
build-up of protein.

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Graves disease (cont)

Thyroid stimulating immunuglobulin (TSI): This is an antibody that binds the
TSH receptor to stimulate the adenylate cyclase/cyclic AMP pathway, with
resultant increased release of thyroid hormones.
Thyroid growth-stimulating immunoglobulin (TGI): implicated in the
proliferation of thyroid follicular epithelium.
TSH-binding inhibitor immunoglobulin (TBII): prevent TSH from binding
normally to its receptor on thyroid epithelial cells resulting in the stimulation of
thyroid epithelial activity or inhibiting thyroid cell function.
Goiter
This is simple enlargement of the thyroid gland and is the most common thyroid
disease. The presence of goiter reflects an impaired synthesis of thyroid hormone,
usually due to dietary deficiency of iodine. The low levels of T3 and T4 lead to an
increase in TSH which causes hypertrophy and hyperplasia of the thyroid gland.
Endemic: goiter in areas where the soil, water, and food supply contain low levels
of iodine. Endemic implies that more than 10% of the population has goiter.
Sporadic: may be caused by iodine deficiency, increased iodine demand due to
growth, or the ingestion of substances (cabbage and turnips) that decrease
production of thyroid hormones.
Diffuse nontoxic goiter: initially, increased TSH leads to diffuse, symmetric
enlargement of the thyroid gland. The follicles may become crowded with
columnar cells which pile up and form projections.
Colloid goiter: if dietary iodine increases or if demand decreases, the stimulated
follicular epithelium involutes to form an enlarged, colloid-rich gland. Grossly,
the gland is brown, glassy, and translucent. Microscopically, the epithelium
becomes flattened and cuboidal.
Multi-nodular goiter: if there are repeated episodes of stimulation followed by
involution, a more irregular, nodular enlargement of the thyroid appears. Grossly,
multi-nodular goiters are coarsely nodular and contain areas of fibrosis and cystic
change.

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Thyroiditis
Inflammation of the thyroid gland. There are three common types of thyroiditis:
(1) Lymphocytic (Hashimoto) thyroiditis
This is an autoimmune inflammatory condition of the thyroid and is the most common
cause of hypothyroidism in the US, usually occurring in females 45-65 years old. It is
caused primarily by a defect in T-cells which infiltrate the thyroid and cause
parenchymal destruction which leads to release of normally sequestered thyroid antigens
and an increase in auto-antibodies. B cells secrete inhibitory anti-TSH receptor
antibodies that block the action of TSH. There is painless enlargement of the thyroid
and lab results eventually show a decrease in T3 and T4 and a rise in TSH.

Pathogenesis of
Hashimoto thyroiditis.
Three proposed models
for mechanism of
thyrocyte destruction in
Hashimoto disease.
Sensitization of
autoreactive CD4+ T cells
to thyroid antigens
appears to be the initiating
event for all three
mechanisms of thyroid
cell death.

Hurthle (oxyphil) cell: Thyroid follicles are atrophic and lined in many areas by
epithelial cells distinguished by the presence of abundant eosinophilic, granular
cytoplasm, termed Hurthle (oxyphil) cells. This is a metaplastic response to
ongoing injury.
(2) Subacute granulomatous (de Quervain) thyroiditis
The cause of this type of thyroiditis is unknown though it is normally preceeded by an
upper respiratory tract infection (viral origin?) There is disruption of the thyroid gland
with an extravasation of colloid which provokes a granulomatous response with lots of
giant cells. Clinically, the patient presents with a pain in the neck!
(3) Subacute lymphocytic thyroiditis
This is a painless enlargement of the thyroid (like Hashimotos), however in this case,
the thyroiditis often follows pregnancy (at least in women) and there are no metaplastic
oxyphil cells.

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Riedel thyroiditis
This is a thyrioditis of unknown etiology though it may be autoimmune. It is
characterized by fibrosis of the thyroid and contiguous neck structures. There may be
associated with fibrosis of other parts of the body as well.
Palpation thyroiditis
This is caused by vigorous clinical palpation of the thyroid gland, resulting in multifocal
follicular disruption with chronic inflammatory cells and occasional giant cell formation.
There is no decrease in thyroid function.
NEOPLASMS OF THE THYROID
Carcinomas of the thyroid are uncommon, accounting for well under 1% of solitary
thyroid nodules. The risk of a nodule being neoplastic increases if it is a solitary or solid
nodule, and/or the nodule is in a young, male patient. There is an increased risk in
developing thyroid cancer if there is exposure to ionizing radiation during the first twodecades of life, as in radiation therapy or survivors of atomic bomb/nuclear plant
disasters (in the latter situation the prevalent cancer is papillary thyroid cancer with
RET gene rearrangements). There is also increased risk associated with long-standing
multi-nodular goiter.
Cold nodule/hot nodule
Nodules that do not take up radioactive iodine in imaging studies (cold nodules)
are more likely to be neoplastic. Nodules that do take up radioactive iodine (hot
nodules) are almost always benign.
Thyroid Adenoma
Benign, usually solitary neoplasms derived from follicular epithelium. Often spherical in
shape, with a well-formed capsule (critical in helping to distinguish adenomas from a
carcinomas), and compresses the surrounding non-neoplastic thyroid. It is composed of
well formed follicles that contain colloid. Presents as a painless, cold nodule.
Thyroid Carcinomas
There are four major subsets of carcinomas: papillary (75-85%), follicular (10-20%),
medullary, and anaplastic.
RET protooncogene: mutations in this gene have been seen in both familial and
sporadic medullary and papillary thyroid carcinomas. It is frequently activated in
papillary thyroid carcinomas by its juxtaposition to other constitutively active
genes.

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(1) Papillary carcinoma

These may occur at any age and account for the majority of carcinomas associated with
exposure to ionizing radiation. They are often nonfunctional tumors and present as
painless masses that can metastasize to the cervical lymph nodes. A papillary
architecture is usually present (with dense fibrovascular cores) though there is a
follicular variant. The diagnosis of papillary carcinoma is based on nuclear features.
Optically clear (ground-glass/Orphan Annie) nuclei: the nuclei of papillary
carcinoma cells contain very finely dispersed chromatin, which imparts a groundglass appearance.
Psammoma body: concentrically calcified structures often present within the
papillae.
Papillary carcinoma of the thyroid. A,
The macroscopic appearance of a
papillary carcinoma with grossly
discernible papillary structures. This
particular example contains well-formed
papillae (B), lined by cells with
characteristic empty-appearing nuclei,
sometimes termed "Orphan Annie eye"
nuclei (C). D, Cells obtained by fineneedle aspiration of a papillary carcinoma.
Characteristic intranuclear inclusions are
visible in some of the aspirated cells.

(2) Follicular carcinoma

Typically presents as solitary, cold nodules that metastasize through the blood to the
lungs, bone, and liver (nodal metastases are uncommon). The morphology ranges from
well circumscribed to highly infiltrative, penetrating into the soft tissues of the neck.
They are usually composed of uniform cells forming small follicles resembling the
normal thyroid gland. Vascular and Capsular invasion.
In adenomas (A), a
fibrous capsule
surrounds the
neoplastic follicles
and no capsular
invasion is seen
(arrowheads);
follicular
carcinomas
demonstrate
capsular invasion
(B, arrow-heads) with extension into local structures of the neck. The presence of vascular invasion is
another feature of follicular carcinomas.

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(3) Medullary carcinoma

Neuroendocrine neoplasms that arise from the parafollicular cells of the thyroid and
secrete calcitonin. There are both sporadic (80%) and familial forms (20%). Presents
as a neck mass, but it may also present with a hormone problem: these carcinomas
sometimes secrete VIP.
Multiple endocrine neoplasia 2A/2B: this carcinoma can be associated with MEN
types 2A (intermediate prognosis) and 2B (poor prognosis). It usually appears in
young adults, is multi-focal and bilateral, and C cell hyperplasia is almost always
present.
Amyloid deposits: derived from altered calcitonin molecules, are present in the
adjacent tissue. This is a distinctive feature.
C-cell hyperplasia: this is a feature of familial medullary carcinoma and is the
presence of multiple prominent clusters of C cells scattered throughout the
parenchyma. These may be the precursor lesions of medullary carcinoma.
(4) Anaplastic carcinoma
These are the most aggressive neoplasms in humans and usually affect the elderly in
areas of endemic goiter. Clinically, they present as rapidly growing, bulking neck
masses that quickly impinge on neck structures and cause death within one year. The
cells are usually of three types: giant cells, spindle cells, and/or squamoid cells.

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PARATHYROID GLANDS
Pg 738 743
Parathyroid gland
Small endocrine glands derived from the pharyngeal pouches that are located in posterior
connective tissue capsule of thyroid. They are composed of chief and oxyphilic cells, and
secrete parathyroid hormone (PTH). Tumors usually present because of excessive PTH
secretion.
Parathyroid Hormone (PTH): is released from the parathyroid glands when serum
calcium is low. They act to raise serum calcium levels by: activating osteoclasts
and increasing renal tubular reabsorption and phosphate excretion.
Primary hyperparathyroidism
This is an autonomous, spontaneous over-production of PTH that causes hypercalcemia
and is caused by an adenoma, primary hyperplasia, or carcinoma. Clinical symptoms
include those caused by an increase in PTH: painful bones, renal stones, abdominal
groans, and psychic moans.
Osteitis fibrosa cystica: the cortex of the bone is grossly thinned and the marrow
contains increased amounts of fibrous tissue accompanied by foci of hemorrhage
and cyst formation.
Brown tumors: aggregates of osteoclasts, reactive giant cells, and hemorrhagic
debris occasionally forms masses that may be mistaken for neoplasms.
Parathyroid adenoma
The most frequent cause of primary hyperparathyroidism. It is confined to a single
gland and is a small, well-circumscribed, soft, tan nodule with a delicate capsule. It is
made of oxyphil cells and lacks adipose tissue, which differentiates adenoma from
normal parathyroid tissue.
Parathyroid hyperplasia
Characteristically a multiglandular process with a pattern of chief cell hyperplasia.
Again, stromal fat is inconspicuous within foci of hyperplasia.
Parathyroid carcinoma
Firm or hard tumors, adhering to the surrounding tissue owing to fibrosis or infiltrative
growth. These are larger than adenomas. The only two valid criteria for malignancy:
invasion of surrounding tissue and metastatic dissemination.
PRAD1 gene
Parathyroid adenomatous gene 1 is a common genetic anomaly leading to adenomas.
Mutation causes overexpression of Cyclin D1 leading to dysregulation of the cell cycle
and adenoma formation.

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PTH-related protein (PTHrP)

Lung and kidney tumors can also produce hypercalcemia by secretion of PTHrP. To
differentiate these tumors from primary hyperparathyroidism, radioimmunoassays have
been developed.
Secondary hyperparathyroidism
This is compensatory parathyroid hyperplasia in response to any condition causing
chronic decreased serum calcium (most commonly chronic renal failure). This can lead
to bone abnormalities due to osteoclast activity like lytic lesions, fractures (renal
osteodystrophy), and ischemic damage to skin and organs caused by metastatic
calcification of vessels (calciphylaxis).
Hypoparathyroidism
This is uncommon, but may be caused by DiGeorge syndrome (congenital absence of
the parathyroid glands, thymic aplasia, and cardiac defects). It can also be caused by
surgical ablation (most common) or an autoimmune disorder. Clinically, this may cause
severe hypocalcemia due to lack of PTH which leads to increased neuromuscular
excitability (tetany, cardiac arrhythmia, tingling, spasms, grimacing).

ADRENAL CORTEX
Pg 743 751
Hypercortisolism (Cushing syndrome)
This is caused by any condition that produces an elevation in glucocorticoid levels. Most
cases are caused by administration of exogenous glucocorticoid medication. Endogenous
causes include: primary hypothalamic-pituitary diseases associated with hypersecretion
of ACTH (Cushings Disease), adrenocortical hyperplasia/neoplasia, or secretion of
ectopic ACTH. Early symptoms include: hypertension and weight gain, and later central
obesity, moon facies, and buffalo hump (fat in the back).
Cushings Disease: usually occurs in middle aged women and accounts for half of
hypercortisolism. There is usually an ACTH producing adenoma present that are
less sensitive to negative feedback from cortisol, but often there is simply
corticotroph-cell hyperplasia.
Primary Adrenocortical Neoplasms/Hyperplasia: sometimes called adrenal
Cushings Syndrome, is caused by a unilateral neoplasm or bilateral nodular
hyperplasia (the nodules are often pigmented).
Ectopic ACTH: this is usually a small cell carcinoma of the lung although other
tumors exist that secrete ACTH. Some tumors secrete CRH which leads to more
ACTH being produced.

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Zona fasciculata & Zona reticularis

If the cause of hypercortisolism is due to exogenous glucocorticoids, suppression of
endogenous ACTH results in bilateral atrophy of the adrenal cortices owing to a lack of
stimulation of the zona fasciculata and zona reticularis. If endogenous
hypercortisolism is present, the adrenals are hyperplastic due to an increase in size of the
zona fasciculata and zona reticularis.
Nodular adrenal hyperplasia
Some degree of nodularity is common and may be pronounced with endogenous
hypercortisolism. Primary micronodular hyperplasia is associated with brown-black
pigment in the adrenal cortices, owing to prominent lipofuscin and neuromelanin in the
zona fasciculata.
Primary Adrenocortical Neoplasms
Adrenocortical adenomas are encapsulated, expansile, yellow tumors composed of lipidrich cells similar to those of the zona fasciculate. The adjacent cortex is atrophied.
Carcinomas tend to be larger and their morphology is identical to that of nonfunctional
adrenocortical carcinomas.
Crooke hyaline change
This is a change in the pituitary gland due to endogenous or exogenous excess of
glucocorticoids. The normal granular basophilic cytoplasm of the ACTH producing cells
in the anterior pituitary is replaced by homogenous, lightly basophilic material due to the
accumulation of intermediate cytokeratin filaments.
Diagnosing Cushing Syndrome
This is based on the 24 urinary free cortisol level, which is always increased and loss of
the diurnal corticosteroid secretion. Localization of the cause of Cushing syndrome
depends on the level of serum ACTH and the measurement of urinary steroid secretion
after administration of Dexamethasone (a synthetic glucocorticoid).
Pituitary Cushing: ACTH cannot be suppressed by low dose dexamethasone so
there is no reduction in urinary excretion of 17-hydroxycorticosteroids. They do
respond to high doses.
Ectopic ACTH: this is completely insensitive to low or high doses of
dexamethasone.
Adrenal Tumor: ACTH is very low because of feedback inhibition of the
pituitary. This is insensitive to dexamethasone.

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A schematic representation of the

various forms of Cushing syndrome,
illustrating the three endogenous
forms as well as the more common
exogenous (iatrogenic) form. ACTH,
adrenocorticotropic hormone.

Hyperaldosteronism
Excessive levels of aldosterone cause sodium retention and potassium excretion, with
resultant hypertension and hypokalemia. It may be primary (adrenal cause) or
secondary (extra-adrenal):
Primary hyperaldosteronism: adrenal overproduction of aldosterone with
suppression of the RAAS and decreased levels of renin. It is caused by an
adenoma (80%) or hyperplasia.
Secondary hyperaldosteronism: aldosterone is increased due to activation of the
RAAS and is associated with increased levels of renin. It is seen in conditions
that involve decreased renal perfusion, arterial hypovolemia and edema, and
pregnancy.
Conn syndrome
This is an aldosterone-secreting adenoma in a single adrenal gland. The adenoma is
usually single and encapsulated. It does not suppress ACTH production so the adjacent
cortex is not atrophied. It usually occurs in females during midlife.
Primary Adrenocortical Hyperplasia
In 15% of cases, this causes primary hyperaldosteronism. There is proliferation of the
cells of the zona glomerulosa. This occurs more often in children and young adults and
surgical intervention is usually not helpful.

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Adrenogenital syndrome (adrenal virilism)

Adrenal androgen production is governed by ACTH, thus excess secretion can occur
either as a pure syndrome or as a component of Cushing syndrome.
Congenital adrenal hyperplasia
Represent a group of autosomal recessive disorders, each characterized by a
hereditary defect in an enzyme involved in cortisol biosynthesis which leads to
an increase in ACTH production. This increase in ACTH production leads to
hyperplasia of the adrenal and subsequent increase in androgens and cortisol
precursors. Most commonly the enzyme affected is, 21-hydroxylase due to a
mutation in chromosome 6.
21-hydroxylase deficiency: excess androgen activity causes masculinization in
females ranging from clitoral hypertrophy to oligomenorrhea and acne problems.
In males, it is associated with enlargement of the genitalia and precocious
puberty.
Chronic adrenocortical insufficiency (Addison disease)
This is characterized by progressive destruction of the adrenal cortex. Clinical symptoms
usually do not present until at least 90% of the gland is destroyed. It can be caused by
many different entities, but usually autoimmune adrenalitis. It can also be caused by
TB, Histoplasma, Coccidioides, and metastatic neoplasms from the breast and lung.
Symptoms include: progressive weakness, easy fatigue, and GI symptoms. Primary
adrenal disease can be associated with skin hyperpigmentation, hyperkalemia,
hyponatremia, and hypotension (due to decreased mineralocorticoids).
Acute adrenocortical insufficiency
This can occur alone or as the end state of Addison disease when something taxes the
system.
Waterhouse-Friedrichsen suffering from overwhelming sepsis usually
associated with N. gonorrhea, and is due to endotoxin induced vascular injury
with associated DIC.
Adrenocortical Carcinomas
Rare neoplasms that can occur at any age. Li-Fraumeni syndrome and BeckwithWiedemann syndrome are inherited causes. These are usually large, invasive lesions that
efface the native adrenal gland. On cut surface, they are typically variegated, poorly
demarcated and contain necrosis and cystic change. The readily metastasize and median
survival is two years. They may be functional or non-functional.

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ADRENAL MEDULLA
Pg 751 752
Pheochromocytoma
These are neoplasms composed of chromaffin cells which synthesize and release
catecholamines. The major clinical manifestation is hypertension. There is usually an
abrupt increase in pressure with accompanying tachycardia and palpitations. This can
occur chronically or as paroxysmal episodes of hypertension.
There is a risk of
catecholamine induced myocardial irritability and ventricular arrythmias.
They usually subscribe to a convenient Rule of 10s:
10% arise in association with familial syndromes (incl. MEN IIA & B)
10% are extra-adrenal (paraganglioma - from extra-adrenal chromaffin cells)
10% are bilateral
10% are malignant
Zellballen: they are composed of polygonal to spindle-shaped chromaffin cells
and their supporting cells, compartmentalized by a rich vascular network into
small nests, or Zellaben.
Vanillylmandelic acid (VMA) and Metanephrine: increased urinary excretion of
metabolites of free catecholamines (epinephrine & nor-epinephrine) present in
urine support the diagnosis of pheochromocytoma.
Neuroblastoma
This is the most common extracranial solid tumor of childhood (during the first five
years). They are most common in the abdomen, with most cases arising in the adrenal
medulla or retroperitoneal sympathetic ganglion.
They are highly malignant,
catecholamine-producing tumor that cause hypertension. Urinary catecholamines and
metabolites (VMA, metanephrine) are present.

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MULTIPLE ENDOCRINE NEOPLASIA SYNDROMES

Pg 752 753
Multiple Endocrine Neoplasia (MEN)
MEN syndromes are a group of inherited diseases resulting in proliferative lesions of
multiple endocrine organs. The tumors arising in this type of syndrome differ from
tumors that arise sporadically in that they: affect young people, multiple organ systems
with multifocal lesions within each organ, and are typically more aggressive recurring
lesions. There are three types of MEN.
MEN1: inherited in an autosomal dominant pattern. The MEN1 gene, a tumor
suppressor gene, is lost leading to cell proliferation. The organs most often
affected are the three Ps: Parathyroid, Pancreas (may cause Zollinger-Ellison
syndrome), and Pituitary (most often a prolactin-secreting tumor).
MEN2: There are two subsets of MEN2, both of which are characterized by an
autosomal dominant pattern of inheritance and an activating mutation in the RET
protooncogene.
MEN2A: usually affects the thyroid, adrenal medulla (usually adrenal
pheochromocytomas), and parathyroid (hyperparathyroidism).
MEN2B: like MEN2A the thyroid and adrenal medulla are affected, however
MEN2B is different in that there is no hyperparathyroidism, and there is
development of extra-endocrine manifestations (gangalionueromas and
marfanoid habitus).

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CHAPTER 19
GYN AND BREAST
VULVA
Pg 680 683
Vulva
The mons pubis, the labia majora and minora, the clitoris, the vestibule of the vagina, the
bulb of the vestibule, and the greater vestibular glands are collectively referred to as the
vulva.
Vulvitis
There are many nonspecific microbe-induced inflammations and dermatologic disorders
that cause inflammation of the vulva. Some specific infections: HPV, HSV-2, N.
gonorrhea, and Syphilis.
Non-neoplastic epithelial disorder
The epithelium of the vulvar mucosa may undergo atrophic thinning or hyperplastic
thickening. Either may appear as leukoplakia (white, pigmented lesions)There are two
forms, both of which may coexist in different areas in the same patient.
(1) Lichen sclerosus
Thinning of the epidermis and disappearance of the rete pegs, accompanied by
superficial hyperkeratosis and dermal fibrosis. The lesions appear as smooth,
white plaques or papules that can grow and coalesce. Most common in postmenopausal women, and 1-4% develop cancer.
(2) Lichen simplex chronicus (squamous hyperplasia)
Thickening of the epidermis with significant hyperkeratosis. Presents as
leukoplakia that is suspiciously found at the margins of established vulvar cancer
though no link has yet been found.
Condyloma acuminate
These are ano-genital warts (usually large and multifocal) that may be papillary and
distinctively elevated or somewhat flat and rugose. Characteristically, cells have
perinuclear cytoplasmic vacuolization with nuclear angular pleomorphism (koilocytosis),
hallmarks of HPV infection. They can be sexually transmitted.
Low-risk HPV (types 6 and 11): There is a strong relationship between
condyloma acuminate (anogenital warts) and HPV subtypes 6 and 11. These are
not considered pre-cancerous but may coexist with foci of vulvar intraepithelial
neoplasia (cancerous changes confined to the epithelium). There are three
grades: low-risk is VIN I, while VIN II and III (carinoma in situ) are associated
with cancer.

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Vulvar Cancer
Carcinoma of the vulva represents ~3% or all genital tract cancers in women, most of
which are squamous cell carcinomas. In women under 40, cancer is usually associated
with HPV 16, while in older women it is usually preceded by non-neoplastic epithelial
changes. It initially appears as leukoplakia and sometimes melanin pigemented, then
transform into exophytic or endophytic lesions.
Extramammary Paget disease
Intraepithelial carcinoma with distinctive scattered
single cells and small clusters of recognizable
carcinomatous cells. These cells are set off from
surrounding cells by cleared halos of
mucopolysaccharide secreted by cancer cells.
Clinically, the lesions appear as red-crusted
inflammatory looking areas.
Melanoma
Highly aggressive neoplasms that are usually fatal. Microscopically, they look like Paget
disease except the cells are not surrounded by a clear halo of mucopolysaccharide.

VAGINA
Pg 683 684
Vaginitis
Inflammation of the vagina that produces a discharge (leukorrhea). The causative
organisms often represent normal flora that become pathogenic in predisposed
individuals. Frequent causes are Candida albicans, which produces a curdy, white
discharge, and Trichomonas vaginalis that produces a watery, copious, gray-green
discharge in which the parasite is often found.
Vaginal intraepithelial neoplasia (VAIN)
Extremely uncommon lesions that usually present in women over 60 and is usually
caused by a viral agent (HPV?).
Clear cell adenocarcinoma of the vagina
Appears in girls in their late teens whose mothers took diethylstilbestrol (an estrogen
once believed to prevent miscarriage) during pregnancy. In 1/3 of the at risk population,
small glandular or microcystic inclusions appear in the vaginal mucosa (vaginal
adenosis).
Sarcoma botryoides
A rare form of primary vaginal cancer encountered in children under 5 that produces soft
polypoid masses.

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CERVIX
Pg 684 689
Cervix
During development, the columnar mucus secreting epithelium
of the endocervix meets the squamous epithelial covering of the
external os. In time, there is down growth of the columnar
epithelium below the exocervical os ectropion. Thus, the
sqaumocolumnar junction comes to lie below the exocervix.
Transformation zone: the area where remodeling of the
cells continuously occurs with regeneration of both
squamous and columnar epithelium.
Nabothian cyst: overgrowth of the regenerating
squamousepithelium can block endocervical glands in the
transformational zone to produce these small cysts lined
by columnar mucus-secreting epithelium.
Cervicitis
Inflammation of the cervix, often caused by fungal or bacterial infection, characterized by
redness, vaginal discharge, itching, and burning. The microorganisms that cause
inflammation can be infectious or non-infectious (normal flora). The most important
cause of cervicitis is sexually transmitted infections by: Chlamydia trachomatis (40%),
Ureaplasma urealyticum, Neisseria gonorrhoeae, and herpes simplex.
Cervical intraepithelial neoplasia (CIN)
Most invasive cervical cancers arise from CIN, but not all CIN progresses to invasive
cervical cancer. Papanicolaou screening (Pap smear) is a screening tests that looks for
signs of CIN. Since the introduction of PAP smear, the incidence of cervical cancer has
declined dramatically, and the incidence of CIN has increased. Risk factors for
development of CIN include: early age at first intercourse, multiple partners, high-risk
HPV infection.
Squamous intraepithelial lesion (SIL)/low-grade/high-grade
SIL seems to be synonymous with CIN. CIN is divided into three grades with the higher
the grade, the greater the likelihood of progression to cancer:
CIN I: Mild dysplasia (low grade) = flat condylomas (HPV 6 and 11)
CIN II: Moderate dysplasia (high grade)
CIN III: Severe dysplasia and carcinoma-in-situ (high grade)
High-risk HPV (types 16, 18, 31, 33): these infections can be detected in 85-90%
of precancerous lesions and invasive neoplasms. HPV 16 and 18 integrate into
the hosts DNA and inactivate TP53 and RB1, allowing cell proliferation.

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Flat condyloma
This lesion is characterized by koilocytotic (nuclear angulation surrounded by
perinuclear vacuolization produced by HPV CPE) changes mostly in the superficial
layers of the epithelium.
Cone biopsy
This is a surgical procedure, performed in the hospital under either intravenous sedation
or general anesthesia, to diagnose and treat a precancerous change in the cervix.
Endocervical polyp
These polyps may be a few centimeters in diameter, are soft and yielding to palpation,
and are covered by a smooth, glistening surface with underlying cystically dilated spaces
filled with mucinous secretion. Superimposed infection may cause bleeding, but there is
no malignant potential.
A, Pathogenesis of cervical
neoplasia. Conditions influencing
progression are listed at the lower
center of the diagram. B, Risks of
acquiring HPV infection (left) and
dying of cervical cancer (right).
The intermediate steps include risks
of infection with high-risk HPV,
development of advanced (CIN),
and progression to invasive
carcinoma.

BODY OF UTERUS
Pg 689 694
Endometritis
The uterus is lined by endometrium and is relatively resistant to infection. Infection may
occur acutely following parturition or miscarriage and is related to retained products of
conception. Chronic endometritis can occur in association with chronic gonorrheal pelvic
disease, miliary tuberculosis, IUDs, or spontaneously. Histologically, there is irregular
proliferation of the glands with chronic inflammatory cells present.

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Adenomyosis
Growth of the basal layer of the endometrium down into the myometrium. The uterine
wall becomes thickened due to reactive hypertrophy of the myometrium. Marked
involvement may produce menorrhagia, dysmenorrheal, and pelvic pain prior to
menstruation, but is unusual since the proliferating stratum basalis is nonfunctional.

This slide shows endometrium (left) and a

portion of the underlying myometrium
(right). The tubular glands of the
endometrium are straight throughout most of
their length. This is characteristic of uterine
glands during the proliferative phase of the
uterine cycle. During this phase, the
endometrial cells are proliferating in response
to estrogen from the ovaries.

Endometriosis
This condition is marked by the appearance of foci of recognizable endometrial tissue in
the pelvis (ovaries, pouch of Douglas), sometimes in the peritoneal cavity, and rarely in
the nodes, bone, and lungs. Clinical manifestations depends on lesion distribution, but
can include dyspareunia (painful intercourse), and almost always dysmenorrhea
(painful menstruation) with pelvic pain. Theories to explain how the endometrial tissue
got somewhere it shouldnt:
Regurgitation theory: menstrual backflow through the fallopian tubes with
subsequent implantation.
Metaplastic theory: endometrial differentiation of coelomic epithelium, which is
the origin of the endometrium.
Vascular or lymphatic dissemination theory: this has been proposed to account for
how endometrial tissue gets into the vascular and lymphatic vessels, since the
other theories do not.
Chocolate cyst: endometriosis nearly always contains functional endometrium
which causes cyclic bleeding. When the endometrial tissue invades the ovaries,
the lesions may form large, blood filled cysts that are called chocolate cysts as
the blood ages. The histological diagnosis of endometriosis, at all sites, needs two
of three: endometrial glands, stroma, or hemosiderin pigment.
Metrorrhagia
The most common reason women seek medical attention is disturbance in menstrual
function: menorrhagia (heavy or prolonged menstrual periods), metorrhagia (irregular
bleeding between periods), or ovulatory bleeding (intermenstrual bleeding). Many of the
common causes are listed below:

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Dysfunctional uterine bleeding

Abnormal bleeding in the absence of a well-defined organic lesion in the uterus is called
dysfunctional uterine bleeding. The probable cause depends on the patients age:
Anovulatory cycle: failure of ovulation, commonly occurring at each end of
reproductive life. An excess in estrogen relative to progesterone causes the
endometrium to enter the proliferative phase without a subsequent secretory
phase. The large, unsupported endometrium collapses with rupture of the spiral
arteries (causing bleeding).
Inadequate luteal phase: corpus luteum fails to mature normally or may regress
prematurely, leading to a relative lack of progesterone.
Endometrial hyperplasia
An excess of estrogen relative to progestin (as in failure of ovulation and excess
estrogenic steroids without balancing progestin) can induce endometrial hyperplasia
ranging from simple to complex. Areas of hyperplasia can progress to carcinoma
depending on the severity of the hyperplastic changes and any cellular atypia. This
can also cause irregular uterine bleeding.
Endometrial polyp
These are sessile, hemispherical lesions 0.5-3cm in diameter that may progress to
carcinoma. The polyps are covered by columnar cells and often contain cystically dilated
glands. The stromal cells are the monoclonal, neoplastic cells. The first clinical
symptom is abnormal bleeding.
Leiomyoma (fibroid)
Leiomyomas (often referred to as fibroids) are the most common benign tumors and arise
from the smooth muscle cells in the myometrium. Estrogens may stimulate growth.
Grossly, they are sharply circumscribed, firm gray-white masses with a characteristic
whorled cut surface. The most common clinical manifestation is menorrhagia.
Intramural: tumors embedded within the myometrium
Submucosal: tumors directly beneath the endometrium.
Subserosal: tumors directly beneath the serosa.
Leiomyosarcoma
Arise from the mesenchymal cells of the myometrium, not from preexisting
leiomyomas. They can look like leiomyomas but diagnostic features include relatively
frequent mitoses, with or without cellular atypia, or less numerous mitoses with cellular
atypia. There is a 40% 5 year survival rate (the more anaplastic, the worse the prognosis.

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Endometrial carcinoma
This is the most frequent cancer of the female genital tract, with peak incidence between
55-65 years old. Risk factors include: obesity, diabetes, hypertension, and infertility.
Overall, too much estrogen is bad. The first clinical manifestations are leucorrhea and
irregular bleeding (a red flag in post-menopausal women).
Endometrioid: carcinomas frequently arise on a backdrop of endometrial
hyperplasia. These tumors are termed endometrioid because they appear similar
to normal endometrial glands. They originate in the mucosa and may infiltrate the
myometrium and enter the vascular spaces, with metastases to regional lymph
nodes. Grading and staging parallel outcome.
Papillary serous and Clear cell: these are poorly differentiated cancers that do not
arise from endometrial hyperplasia and are much more aggressive tumors.
FALLOPIAN TUBES
Pg 694 695
Pelvic inflammatory disease
This is a general term for infection of the uterus, fallopian tubes, or the ovaries. It is the
most common affliction of the tubes. Inflammation is almost always bacterial
(Chlamydia, mycoplasma hominis, tuberculosis) with non-gonococcal infections being
more invasive and more likely to cause blood borne infections.
Salpingitis
Fancy talk for inflammation or infection of the fallopian tubes. It is usually accompanied
by fever, lower abdominal discomfort (pelvic pain), and pelvic masses when the tubes
become filled with exudates. The most serious complication is obstruction of the tube
leading to increased risk for ectopic pregnancy, and/or sterility.
OVARIES
Pg 695 701
Salpingo-oophoritis
Primary inflammations of the ovaries are rarities, but salpingitis of the tubes frequently
causes a pre-ovarian reaction called salpingo-oophoritis.
Follicle cyst and Luteal cyst
These are common lesions that orginate in unruptured follicles or folliciles that rupture
and quickly seal. The cysts are usually multiple, small, and are filled with serous fluid.
They are lined by lined by granulose or luteal cells. Sometimes cysts grow large and
rupture, producing intraperitoneal bleeding and abdominal pain.
Section of the ovary. 1. Outer covering. 1. Attached border. 2. Central
stroma. 3. Peripheral stroma. 4. Bloodvessels. 5. Vesicular follicles in their
earliest stage. 6, 7, 8. More advanced follicles. 9. An almost mature follicle.
9. Follicle from which the ovum has escaped. 10. Corpus luteum.

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Polycystic ovary/Stein-Leventhal syndrome

Oligomenorrhea (light or infrequent menstruation), hirsutism (excessive hairiness),
infertility, and sometimes obesity may appear in girls after menarche, secondary to
excessive production of androgens (sometimes estrogens) by multiple cystic follicles in
the ovaries. The ovaries are twice normal size and studded with cortical cysts. There is
cortical stromal fibrosis beneath which are innumerable cysts.
Luteinizing hormone (LH): high levels are present in polycystic ovary patients.
Follicle-stimulating hormone (FSH): low levels are present in polycystic ovary
patients.
Derivation of various ovarian neoplasms
and some data on their frequency and age
distribution.
Molecular Ovarian Tumor Markers
A majority of hereditary ovarian cancers
appear to caused by mutations in the
BRCA genes (BRCA1 and BRCA2).
ERBB2 is over expressed in 35% of
ovarian cancers and is associated with a
poor prognosis. K-RAS is over expressed
in 30% of tumors, mostly mucinous
cystadenocarcinomas. TP53 is mutated
about 50% of the time.

Surface epithelial-stromal tumor

Neoplasms derived from coelomic epithelium that can be strictly epithelial (serous or
mucinous), or have a stromal component (cystadenoma, Brenner). These tumors have a
designation for tumors between benign and malignant:
Low malignant potential (LMP): low-grade cancers with limited invasive
potential.
Serous tumor
Serous tumors are usually large (>30-40cm), spherical or ovoid in shape, and cystic
(called cystadenomas or cystadenocarcinomas). Jutting into the cystic cavities are
polypoid or papillary projections. Benign tumors are often bilateral and have a smooth
serosal covering. When frank carcinoma develops, the cells lining the cysts (tall
columnar cells) become anaplastic, and the tumor invades the stroma (nodular serosal
covering). Even tumors with low malignant potential can seed the peritoneal cavity.
Psammoma body: concentrically laminated concretions frequently found on the
tips of papillae.

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Mucinous tumor
The epithelium of these tumors consists of mucin-secreting cells. They are normally
unilateral, multilocular lesions. Papillary formations are less common than serous
tumors, and psammoma bodies are absent. Most of these tumors are benign, with only
10% being malignant cystadenocarcinomas. Low malignant potential (LMP) and
malignant tumors are frequently composed of intestinal-type epithelium.
Pseudomyxoma peritonei: mucinous deposits in the peritoneum. This can be
caused by rupture of a mucinous tumor, or more commonly, a GI tumor that
metastasized to the ovary ruptures.
Endometrioid tumor
These are malignant tumors that are distinguished by the formation of tubular glands,
similar to those of the endometrium, within the linings of the cystic spaces. They are
bilateral (30%), and frequently coexist with endometrial carcinoma (15-30%).
Cystadenofibroma
This is a benign version of the serous cystadenoma, except there is prominent
proliferation of the fibrous stroma underneath the columnar epithelium.
Brenner tumor
An uncommon tumor, usually solid and unilateral, consisting of abundant stroma
containing nests of transitional-like epithelium resembling that of the urinary tract. They
are smoothly encapsulated and gray-white in appearance. Malignancy is rare.
Benign (mature) cystic teratoma
These neoplasms are marked by ectodermal differentiation
usually forming cysts lined by epidermis, hence the term
dermoid cyst. They are usually found in young women and
frequently contain a mix of all tissue types: hair, teeth, bone,
etc. Rarely do they exceed 10-cm. They can cause infertility
and torsion. Image: opened mature cystic teratoma (dermoid
cyst) of the ovary. Hair (bottom) and a mixture of tissues are
evident.
Immature malignant teratoma
Average age of patient is 18, these tumors are bulky, mostly solid masses with areas of
necrosis. Microscopically, the distinguishing feature is a variety of barely recognizable
areas of differentiation toward cartilage, bone, muscle, and nerve (bad sign).
Struma ovarii/Strumal carcinoid
Struma ovarii is an ovarian tumor composed of mature thyroid tissue that may
hyperfunction and produce hyperthyroidism. Strumal carcinoid may produce carcinoid
syndrome.

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CA 125
Elevated levels have been reported in 75-90% of women with epithelial ovarian cancer.
It is most valuable as a screening test in asymptomatic post-menopausal women, and as a
monitoring response to therapy.
DISEASES OF PREGNANCY
Pg 701 705
Placenta
The organ of metabolic interchange between the mother and the fetus.

Diagram of placental anatomy. Within the

outer boundary of myometrium is a layer of
decidua, from which the maternal vessels
originate and deliver blood to and from the
intervillous spaces. Umbilical vessels branch
and terminate in placental villi, where nutrient
exchange takes place.

Ascending infection
Ascending infection is infection that reaches the placenta through the birth canal.
Usually bacterial (mycoplasmas, Candida, and normal flora), it is associated with
premature birth and premature rupture of the membranes.
Chorioamnionitis: Chorioamnion shows leukocytic PMN infiltration associated
with edema and congestion of the vessels.
Villitis
Uncommonly, the placental infections may arise by the hematogenous spread of bacteria
and other organisms. Histologically, the villi are most often affected (villitis).
TORCH complex: all of the torch organisms can cause villitis.
To=toxoplasmosis, R=rubella, C=cytomegalovirus, H= HIV, Herpes.
Ectopic pregnancy
Ectopic pregnancy is implantation of the fertilized ovum in any site other than the normal
uterine location. Most commonly (90%), implantation is in the oviducts (tubal
pregnancy). Until rupture occurs, it is indistinguishable from normal pregnancy.
Clinically, there is intense abdominal pain followed by shock. This is a surgical
emergency.

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Intratubal hematoma (hematosalpinx)

With tubal pregnancy, the invading placenta eventually burrows through the wall of the
oviduct, causing intratubal hematoma (hematosalpinx), intraperitoneal hemorrhage, or
both.
Gestational trophoblastic disease
Tumors affecting the trophoblast are divided into three overlapping morphologic
categories: (1) hyaditiform mole (least aggressive), (2) invasive mole, and (3)
choriocarcinoma (most aggressive). All elaborate human chorionic gonadotropin (hCG)
at levels considerably higher than normal pregnancy. hCG titers aid diagnosis and helps
monitor the effectiveness of treatment.
(1) Hydatidiform mole
A voluminous mass of swollen, sometimes cystically dilated, chorionic villi, appearing
grossly as grape-like structures. There are two subtypes are recognized based on
abnormal fertilization.
Complete hydatidiform moles: do not
permit embryogenesis and therefore never
contains fetal parts (all villi are abnormal
and chorionic epithelial cells are diploid).
There is hydropic swelling of the villi
(hydropic villi) and absence of
vascularization.
Partial hydatidiform moles: are
compatible with early embryo formation
and contain fetal parts, have some normal
villi, and are almost always triploid.
(2) Invasive mole
These are complete moles that are locally invasive but do not have the aggressive
metastatic potential of a choriocarcinoma. They retain hydropic villi which can
penetrate the uterine wall and cause severe hemorrhage. Metastases do not occur,
however surgical removal is difficult due to local invasionchemotherapy is usually
curative.
(3) Choriocarcinoma
Aggressive, malignant tumors arising mostly from gestational chorionic epithelium, or
rarely totipotential cells within the gonads. The tumors are very hemorrhagic, necrotic
masses within the uterus. Chorionic villi are not present: the tumor is purely epithelial,
composed of anaplastic cuboidal cytotrophoblast and syncytiotrophoblast. Clinically, it
presents with bloody, brownish discharge and rising hCG titer. Metastases travel through
the blood and seed the lung (50%) and vagina (35%). Chemotherapy is curative.

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Placental site trophoblastic tumor

Uncommon tumors that are diploid, often XX in karyotype, and are derived from the
placental site or intermediate trophoblast. hCG levels are only slightly elevated and the
prognosis is poor if the tumor has spread (not as sensitive to chemotherapy).
Preeclampsia/eclampsia
Preeclampsia is defined as the development of hypertension, accompanied by
proteinuria and edema in the third trimester of pregnancy. Eclampsia is a more severe
form that is accompanied by convulsive seizures. Historically, these two situations have
been referred to by the misnomer, toxemia of pregnancy. Severe eclampsia may lead to
DIC. The cause is believed to be related to inadequate maternal blood flow to the
placenta secondary to inadequate development of the spiral arteries.
BREAST
Pg 705 716
Supernumerary nipple
This is the presence of additional nipples.
Galactocele
A cystic dilation of an obstructed duct that arises during lactation.
Fibrocystic change
Fibrocystic changes are common, benign changes involving the tissues of the breast that
causes a lump. This range of changes is the consequence of an exaggeration and
distortion of the cyclic breast changes that occur normally in the menstruel cycle. It is
divded into (1) nonproliferative and (2) proliferative changes.
(1) Non-proliferative (cysts and fibrosis)
The most common type, it is characterized by an increase in fibrous stroma associated
with dilation of ducts and formation of cysts of various size without epithelial cell
hyperplasia. The secretions within the cysts can calcify and appear on mammograms.
Blue dome cyst: the cysts vary in diameter, and unopened, they appear as brown
to blue (blue dome cysts) and are filled with serous, turbid fluid.
Apocrine metaplasia: frequently, cysts are lined by large, polygonal cells that
have an abundant granular, eosinophilic cytoplasm, with small, round deeply
chromatic nuclei, so called apocrine metaplasia.
(2) Proliferative (hyperplasia and sclerosing adenosis)
The terms epithelial hyperplasia and proliferative fibrocystic change encompass a range
of lesions within the ductules, terminal ducts, and sometimes lobules of the ducts.
Atypical hyperplasia is associated with the development of carcinoma.

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(2) Proliferative (cont)

Fenestration: the ducts, ductules, or lobules may be filled with orderly cuboidal
cells, within which small gland patterns with irregular lumina at the periphery can
be discerned fenestrations
Ductal papillomatosis: sometimes the proliferating epithelium projects in multiple
small papillary excrescences into the ductal lumen. Florid papillomatosis can be
associated with a serous nipple discharge.
Atypical lobular hyperplasia: describes hyperplasias that cytologically resemble
lobular carcinoma in situ, but the cells do not fill or distend more than 50% of
the terminal duct units. It is associated with increased risk for invasive
carcinoma.
Sclerosing adenosis
This is deceptively similar to carcinoma, and is characterized by proliferation of lining
epithelial cells and myoepithelial cells in small ducts and ductules, yielding masses of
small gland patterns within a fibrous stroma. The presence of double layers of
epithelium and the identification of myoepithelial elements are helpful in suggesting a
benign diagnosis. There is minimal risk of carcinoma.

An attempt to depict by the thickness of

the arrow the risk of malignant
transformation of the various patterns of
fibrocystic change.

Acute mastitis
Inflammation of the breast develops when bacteria gain access to the breast tissue
through ducts, inspissation of secretions, fissures, or dermatitis involving the nipple.
Staphylococcal infections can abscess formation with or without scarring.
Mammary duct ectasia
This is a non-bacterial inflammation of the breast associated with inspissation of breast
secretions in the main excretory ducts causing a prominent lymphocytic and plasma cell
infiltration and occassionally granulomas to form in the periductal stroma. It leads to
retraction of the nipple, mimicking breast cancer.

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Traumatic fat necrosis

An uncommon and innocuous lesion that is significant only because it produces a mass.
It may follow some antecedent trauma to the breast. The lesion consists of a central
focus of necrotic fat cells surrounded by PMNs, which later is enclosed by fibrous tissue,
and then scars.
Fibroadenoma
The most common benign tumor of the female breast, and is thought to be caused by an
increase in estrogen activity. Grossly, they are firm with a uniform tan-white color on cut
section, punctuated by softer yellow-pink specs. Clinically, they present as solitary,
discrete, movable masses and rarely become malignant.
Phyllodes tumor
Arises from the intralobular stroma and rarely from pre-existing fibroadenoma. Most
grow to a massive size, distending the breast. On gross section, they exhibit leaf-like
clefts and slits (phyllodes is Greek for leaf). Only about 15% are malignant lesions.
Intraductal papilloma
This is a neoplastic papillary growth (double layered epithelial cells overlying a
myoepithelial layer) within a duct, most often within the principal lactiferous ducts or
sinuses. They can cause serous or bloody nipple discharge, subareolar tumors, or, rarely,
nipple retraction. There may be a single papillary growth or multiple (more likely to be
malignant).
Li-Fraumeni syndrome/Cowden disease
Less common familial, genetic diseases associated with breast cancer are Li-Fraumeni
syndrome caused by a germ-line mutation in TP53, Cowden disease caused by germline mutations in PTEN, and carriers of the ataxia-telangectasia gene.
HER2/NEU protooncogene
Overexpression of the ERBB2 (HER2/NEU) protooncogene has been found to be
amplified in up to 30% of sporadic breast cancers, is a member of the epidermal growth
factor receptor family, and is associated with a poor prognosis.
Estrogen and progesterone receptors
It is believed that estrogen and progesterone receptors normally present in breast
epithelium, and often present in breast cancer cells, may interact with various growth
promoters to create an autocrine mechanism of tumor development.
NON-INVASIVE CARCINOMA
(1) Ductal carcinoma in situ (DCIS)
This is a non-invasive (not penetrated the limiting basement membrane) breast carcinoma
that usually arises from the terminal duct lobular unit, and tends to fill, distort, and unfold
involved lobules and, thus, appears to involve duct-like spaces.

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Comedo: a subtype of DCIS that is characterized by cells with high-grade nuclei

distending spaces with extensive central necrosis.
(2) Paget disease of the nipple
This is caused by the extension of DCIS up to the lactiferous ducts and into the
contiguous skin of the nipple. Clinically, there is a unilateral crusting exudate over the
nipple and areolar skin. Paget cells have an abundant clear cytoplasmsee the
previous picture with Extramammary Paget disease.
(3) Lobular carcinoma in situ (LCIS)
LCIS also involves the terminal duct lobular unit, is confined by a basement membrane,
and usually expands but does not alter the underlying lobular architecture. It has a
uniform appearance of monomorphic cells with bland, round nuclei and occurs in
discohesive clusters in ducts and lobules. Signet ring cells are common. LCIS is both a
marker of increased risk of developing breast cancer in either breast, and a direct
precursor of some cancers.
INVASIVE CARCINOMA
(1) Invasive (infiltrating) ductal carcinoma
This is a term used for all carcinomas that cannot be sub-classified into one of the
specialized types listed below and accounts for most cancers (70-80%). It is usually
associated with DCIS. Invasion of lymphovascular spaces or along nerves may be seen.
About 2/3 express estrogen-progestagen receptors and about 1/3 overexpress ERBB2.
(2) Inflammatory carcinoma
Defined as the clinical presentation of an enlarged, swollen, erythematous breast, usually
without a palpable mass. The blockage of numerous dermal lymphatic spaces by
carcinoma results in the clinical appearance. Most of these have distant metastases and
an extremely poor prognosis.
(3) Invasive lobular carcinoma
The cells are morphologically the same as LCIS. The cells invade individually into
stroma and are often aligned in strands or chains. Lobular carcinomas more often than
ductal carcinomas metastasize to CSF and elsewhere. Nearly all of these tumors
express hormone receptors.
(4) Medullary carcinoma
This cancer consists of sheets of large anaplastic cells with pushing, well-circumscribed
borders. Clinically, they can be mistaken for fibroadenomas. They contain a pronounced
lymphoplasmacytic infiltrate, occur with increased frequency in women carrying the
BRCA1 mutation, and uniformly lack hormone receptors.
(5) Colloid (mucinous) carcinoma
These tumors produce abundant quantities of extracellular mucin that dissects into the
surrounding stroma. Most express hormone-receptors.
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(6) Tubular carcinoma

They usually present as irregular mammographic densities. The carcinoma consists of
well-formed tubules with low-grade nuclei. Metastases are rare, prognosis is good, and
hormone-receptors are normally expressed.
Fixation/retraction (dimpling)/lymphedema/peau dorange
These are all common presentations of invasive cancers. Invasive carcinomas
have a tendency to adhere to the chest wall, with subsequent fixation of the
lesion, as well as adherence to the overlying skin, with retraction and dimpling
of the skin or nipple. Involvement of the lymphatics may cause lymphedema
causing the skin to become thickened around hair follicles, a change known as
peau dorange (orange peel skin).
Sentinel node biopsy
This has been introduced as an alternative, less morbid procedure to replace a full axillary
dissection. The first 1-2 draining nodes are identified with a dye or radiolabel. A
negative sentinel node is highly predictive of no metastatic cancer in the remaining
nodes. However, the significance of finding micrometastases is unknown.
Lymphovascular invasion
The presence of tumor within vascular spaces around the primary tumor is a poor
prognostic indicator.
Aneuploidy
Carcinomas with an abnormal DNA content (aneuploidy) have a slightly worse prognosis
compared with carcinomas having normal DNA content.
Herceptin
The importance of evaluating ERBB2 is to predict responsiveness to a monoclonal
antibody to the gene called Herceptin. It is one of the first antitumor antibody therapies
based on specific genetic abnormalities.
Gynecomastia
Once again, we are asked to know the medical fancy-pants talk for MAN BOOBS! There
is a different spin this time. Yes, it is still enlargement of the male breast, and it may
occur in response to absolute or relative estrogen excesses and is the male analogue of
fibrocystic change in the female.

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CHAPTER 22
THE SKIN
TERMINOLOGY
Pg 789 791
Langerhans cell
These are bone-marrow derived, carried to the skin by the blood, and capable of binding,
processing, and presenting antigens to T-lymphocytes, thus participating in the
stimulation of these cells. Consequently, they have a significant role in immunologic
skin reactions.
Keratinocyte
Keratinized squamous cells that participate in maintaining homeostasis through the
secretion of various cytokines which regulated the epidermal cells and influence the
dermal microenvironment.

The skin is composed of an epidermal layer (e) from which specialized adnexa (hair follicles, h; sweat
glands, g; and sebaceous glands, s) descend into the underlying dermis (d). B, This projection of the
epidermal layer (e) and underlying superficial dermis demonstrates the progressive upward maturation of
basal cells (b) into cornified squamous epithelial cells of the stratum corneum (sc). Melanin-containing
dendritic melanocytes (m) (and rare Merkel cells containing neurosecretory granules) and midepidermal
dendritic Langerhans cells (lc) are also present. The underlying dermis contains small vessels (v),
fibroblasts (f), perivascular mast cells (mc), and dendrocytes (dc), potentially important in dermal
immunity and repair.

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DEFINITIONS OF MACROSCOPIC TERMS

Macule: Circumscribed lesion of up to 5 mm in diameter characterized by flatness and usually
distinguished from surrounding skin by its coloration.
Papule: Elevated dome-shaped or flat-topped lesion 5 mm or less across.
Nodule: Elevated lesion with spherical contour greater than 5 mm across.
Plaque: Elevated flat-topped lesion, usually greater than 5 mm across (may be caused by
coalescent papules).
Vesicle: Fluid-filled raised lesion 5 mm or less across.
Bulla: Fluid-filled raised lesion greater than 5 mm across.
Blister: Common term used for vesicle or bulla.
Pustule: Discrete, pus-filled, raised lesion.
Scale: Dry, horny, platelike excrescence; usually the result of imperfect cornification.
Lichenification: Thickened and rough skin characterized by prominent skin markings; usually the
result of repeated rubbing in susceptible persons.
Excoriation: Traumatic lesion characterized by breakage of the epidermis, causing a raw linear
area (i.e., a deep scratch); often self-induced.
DEFINITIONS OF MICROSCOPIC TERMS
Hyperkeratosis: Thickening of the stratum corneum, often associated with a qualitative
abnormality of the keratin.
Parakeratosis: Modes of keratinization characterized by the retention of the nuclei in the stratum
corneum. On mucous membranes, parakeratosis is normal.
Acanthosis: Diffuse epidermal hyperplasia.
Papillomatosis: Surface elevation caused by hyperplasia and enlargement of contiguous dermal
papillae.
Dyskeratosis: Abnormal keratinization occurring prematurely within individual cells or groups of
cells below the stratum granulosum.
Acantholysis: Loss of intercellular connections resulting in loss of cohesion between
keratinocytes.
Spongiosis: Intercellular edema of the epidermis.

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ACUTE INFLAMMATORY DERMATOSES

Pg (791 793)
Uritcaria (hives)
This is a common disorder characterized by localized mast cell degranulation and
resultant dermal microvascular hyperpermeability, culminating in pruritic, edematous
plaques called wheals. Edema is limited to the perivascular spaces of the superficial
dermis. Uticaria usually results from antigen-induced (pollens, foods, etc) release of
vasoactive mediators from mast cell granules via sensitization with specific IgE
antibodies (Type I hypersensitivity).
Hereditary angioneurotic edema: is the result of an inherited deficiency of C1
esterase inhibitor that results in uncontrolled activation of the early components of
the complement cascarde.
Eczema (5 categories)
Eczema is a clinical term for a number of pathogenically related conditions that are
characterized by red, papulovesicular, oozing, and crusted lesions at an early stage, which
develop into raised, scaling plaques.
Spongiotic dermatitis: spongiosis, the accumulation of edema fluid within the
epidermis, characterizes acute eczematous dermatitis, hence the synonym
spongiotic dermatitis. Edema seeps into the intercellular spaces of the
epidermis, splaying apart keratinocytes.

Type

Cause or Pathogenesis

Histology

Clinical Features

(1) Contact
dermatitis

Topically applied antigens Spongiotic dermatitis

(poison ivy); DTH
Reaction

Marked itching, burning, or both;

requires antecedent exposure

(2) Atopic dermatitis

Unknown; may be
heritable

Erythematous plaques in flexural

areas; family history of eczema, hay
fever, or asthma

(3) Drug-related
eczematous
dermatitis

Systemically administered Spongiotic dermatitis;

antigens or haptens (e.g.
infiltrate often deeper with
penicillin)
abundant eosinophils

Temporal relationship to drug

administration; remits with
cessation of drug

(4) Photoeczematous
eruption

Ultraviolet light

Spongiotic dermatitis;
infiltrate that diminishes
gradually with depth

Occurs at sites of sun exposure;

may require associated exposure to
systemic or topical antigen;
photopatch testing may help in
diagnosis

(5) Primary irritant

dermatitis

Repeated trauma or
chemical irritants (as in
detergent)

Spongiotic dermatitis in
Localized mechanical or chemical
early stages; acanthosis
irritants (nonimmunologic)
predominates in later stages

Spongiotic dermatitis

*All types, with time, may develop chronic changes, with prominent acanthosis of the epidermal layer.

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Erythema multiforme
This is an uncommon, self-limited disorder that appears to be a hypersensitivity response
to certain infections and drugs. This is probably caused by cytotoxic T cells targeting
cross-reactive antigens in or near the basal cell layer of the skin and mucosae.
Stevens-Johnson syndrome: a symptomatic, febrile version that is marked by
erosions and crusting of the mucosal surfaces of the lips, conjunctiva, oral cavity,
urethra, and anogenital region.
Toxic epidermal necrolysis: yet another version. This one results in diffuse
necrosis and sloughing of cutaneous and mucosal epithelial surfaces, producing a
clinical situation analogous to an extensive burn.
CHRONIC INFLAMMATORY DERMATOSES
Pg (793 795)
Desquamation
The skin surface in some chronic inflammatory dermatoses is roughened as a result of
excessive or abnormal scale formation and shedding (desquamation).
Psoriasis
Psoriasis is common and frequently affects the skin of the elbows, knees, scalp,
lumbosacral areas, and even the glans penis. The most typical lesion is a welldemarcated, pink to salmon-colored plaque covered by loosely adherent scales that are
characteristically silver-white. The pathogenesis is unclear, though it seems to be
multifactoral (genetic and environment). The disease results from sensitized T cells
entering the skin which create an abnormal microenvironment via cytokines.
Onycholysis: nail changes occur in 30% of patients, to include separation of the
nail plate from the underlying bed (onycholysis).
Pustular psoriasis: This is a rare variant of Psoriasis characterized by multiple
small pustule formation on erythematous plaques.
Stratum granulosum: morphologically, the stratum granulosum is thinned or
absent, and extensive overlying parakeratotic scale is seen.
Dermal papilla: typical of psoriatic plaques is thinning of the epidermal layer that
overlies the tips of dermal papillae (suprapapillary plates) and dilated, tortuous
blood vessels within these papillae.
Auspitz sign: the above mentioned blood vessels readily bleed when the scale is
peeled back and the surpapapillary plates are unroofed, giving rise to multiple
minute bleeding points. This is Auspitz sign.
Spongiform pustule: neutrophils form small aggregates within slightly spongiotic
foci of the epidermis (spongiform pustules) and within the parakeratotic stratum
corneum (Munro microabscess).
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Lichen planus
Pruritic, purple, polygonal papules are the presenting signs of this disorder of skin and
mucous membranes. It is usually resolves spontaneously in 1-2 years, often leaving
zones of post-inflammatory hyperpigmentation. Typically, there are multiple lesions
on the extremities, wrists, elbows, or even the glans penis. In 70% of cases, oral lesions
are present.
Wickham striae: Cutaneous lesions of lichen planus consist of itchy, violaceous,
flat-topped papules, which may coalesce to form plaques. These papules are often
highlighted by white dots or lines, called Wickham striae.
Stratum spinosum: histologically, lymphocytes infiltrate along the dermoepidermal junction and are closely associated with basal keratinocytes, which
show degeneration, necrosis, and a resemblance in size and contour to more
mature cells of the stratum spinosum (squamatization).
Dermoepidermal interface: the inflammation causes this interface to assume an
angulated, zigzag contour (sawtoothing).
Civatte body: anucleate, necrotic basal cells may become incorporated into the
inflamed papillary dermis, where they are referred to as colloid, or Civatte
odies.
Hypergranulosis: this disease is differentiated from erythema multiforme because
ichen planus exhibits epidermal hyperplasia and thickening of the granular cell
layer (hypergranulosis).
BLISTERING (BULLOUS) DISEASES
Pg (795 798)
Schematic representation of sites of blister
formation. A, In a subcorneal blister, the
stratum corneum forms the roof of the bulla
(as in impetigo or pemphigus foliaceus). B,
In a suprabasal blister, a portion of the
epidermis including the stratum corneum
forms the roof (as in pemphigus vulgaris).
C, In a subepidermal blister, the entire
epidermis separates from the dermis (as in
bullous pemphigoid and dermatitis
herpetiformis).

Pemphigus (4 variants)
This is a rare autoimmune blistering disorder resulting from loss of the integrity of
normal intercellular attachments within the epidermis and mucosal epithelium. It is
caused a type II hypersensitivity reaction. Sera from patients contain pathogenic IgG
antibodies to the intercellular cement substance (desmogleins) of skin and mucous
membranes (anti-desmogleins (IgG)).
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Acantholysis: this is the term for dissolution, or lysis, of the intercellular adhesion
sites within a squamous epithelial surface. This is common to all forms of
pemphigus.
Suprabasal acantholytic blister: in pemphigus vulgaris and vegetans, acantholysis
selectively involves the layer of cells immediately above the basal layer, giving
rise to suprabasal acantholytic blister characteristic of pemphigus vulgaris.
(1) Pemphigus vulgaris (80%)
This involves the mucosa and skin, especially the scalp, face, axilla, groin, trunk, and
points of pressure. The primary lesions are very superficial vesicles and bullae that
rupture easily leaving shallow erosions covered with dried serum and crust.
(2) Pemphigus vegetans
Rare form that usually presents not with blesters but with large, moist, wart-like,
vegetating plaques studded with pustules on the groin, axilla, and flexural surfaces.
(3) Pemphigus foliaceus
A more benign form of pemphigus, occurs in epidemic form in South America. Bullae
are confined to skin, with only rare involvement of mucous membranes.
(4) Pemphigus erythematosus
Localized, less severe form of pemphigus foliaceus that may selectively involve the
malar are of the face in a lupus erythematosus-like fashion.
Bullous pemphigoid
Lesions are tense bullae, filled with clear fluid, on normal or erythematous skin. The
bullae do not rupture as easily as the blisters seen in pemphigus and they usually heal
without scarring. It is characterized by a subepidermal, nonacantholytic blister. This
is also caused by a type II hypersensitivity reaction but the autoantibodies are targeting
hemidesmosomes.
Direct immunofluorescence
Fish-net: In pemphigus vulgaris, there is deposition of immunoglobulin
along the plasma membranes of epidermal keratinocytes in a fishnet-like
pattern

Linear: Linear deposition of complement along the dermoepidermal

junction in bullous pemphigoid; the pattern has been likened to ribbon
candy.

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Dermatitis herpetiformis
Rare disorder characterized by extremely pruritic urticaria and group vesicles mainly
along the extensor surfaces. This disease is associated with celiac disease and responds
to a gluten free diet. Why? The IgA antibodies developed against gluten cross-react
with reticulin (a component of the anchoring fibrils that tether the epidermal basement
membrane to the superficial dermis).
Microabscess: fibrin and neutrophils accumulate at the tips of dermal papillae,
forming microbascesses. Overlying basal cells show vacuolization and minute
zones of dermoepidermal separation (microscopic blisters). These zones
coalesce to form a true subepidermal blister.
TUMORS
Pg (798 804)
Seborrheic keratosis
Seborrheic keratosis is a common epidermal tumor that arises spontaneously (mainly on
the trunk) and is clinically described as round, flat, coin-like plaques that vary in
diameter. The lesions are tan to dark brown (due to melanin pigment of basaloid cells)
and show a velvety to granular surface. It is benign and easily treated by excision.
Horn cyst: the presence of small keratin-filled cysts (horn cysts) and
downgrowths of keratin into the main tumor mass (pseudo-horn cysts) are
characteristic features.
Keratoacanthoma
Rapidly developing neoplasm that mimics squamous cell carcinoma, affects mostly white
males over 50, and appears as flesh-colored, dome-shaped nodules with a central, keratinfilled plug, imparting a crater-like topography. They tend to occur on the face and backs
of the hands.
Verrucae (Warts)
Common warts caused by human papillomaviruses (HPV) that are usually self-limited.
Features of all warts include epidermal hyperplasia that is undulant in character, and
cytoplasmic vacuolization (koilocytosis) that preferentially involves the more superficial
epidermal layers producing halos of pallor around infected nuclei. There are several types
of warts, each one being caused by a different HPV:
Verruca vulgaris: the most common type of wart occurring mainly on the hands
where they appear as gray-white to tan, flat to convex papules with a rough,
pebble-like surface.
Verruca plana (flat wart): these are common the face or dorsum of the hands, are
flat, smooth, tan papules generally smaller than those of verruca vulgaris.
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Verruca plantaris/palmaris: occur on the soles and palms, respectively, are rough,
scaly lesions up to 2-cm in diameter, and may coalesce, and be confused for
calluses.
Condyloma acuminatum: venereal warts that appear as soft, tan, cauliflower-like
masses that sometimes reach many centimeters in diameter.
Actinic keratosis
These are pre-malignant (dysplastic) lesions that result from chronic sun exposure, and
are associated with a build-up of excess keratin. Lesions are <1-cm and skin colored with
a sandpaper consistency.
Cutaneous horn: lesions may produce so much keratin that a cutaneous horn
develops. Imagine a horn made of keratin protruding from areas frequently
exposed to sun.
Solar elastosis: the dermis contains thickened, blue-gray elastic fibers (elastosis),
a probable result of abnormal dermal elastic fiber synthesis by sun-damaged
fibroblasts.
Squamous cell carcinoma
The most important tumor arising on sun-exposed sites in older people. Exposure to UV
light with un-repaired DNA damage is the most frequent cause though others exist. Prior
to breaking through the basement membrane, SCC appears as a sharply defined, red,
scaling plaque. It can become invasive, nodular, develop hyperkeratosis, and may
ulcerate. Histologically, atypia is present at all layers of the epidermis. Only 5%
metastasize.
Dyskeratosis: premature keratinization in individual epithelial cells that have not
reached the keratinizing surface layer.
Xeroderma pigmentosum: these people cannot repair damaged DNA and
rapidly develop skin atrophy (thinning), splotchy pigmentation, telangiectasia,
and skin cancers.
Basal cell carcinoma
These common, slow growing tumors also arise from chronic sun exposure. Clinically,
these tumors present as pearly papules, often containing prominent, dilated subepidermal
blood vessels (telangectasia).
Rodent ulcer: advanced lesions that ulcerate with extensive invasion of bone and
facial sinuses that occur after many years of neglect.
Palisading: the cells forming the periphery of the tumor cell islands tend to be
arranged radially with their long axes in approximately parallel alignment.
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Separation artifact: the stroma shrinks away from the epithelial tumor nests,
creating clefts or separation artifacts, which assist in differentiating basal cell
carcinomas from certain appendage tumors.
Nevocellular nevus
Nevus denotes any congenital lesion of the skin. Nevocellular nevus, refers to any
congenital or acquired neoplasm of melanocytes. Clinically, these are tan to brown
uniformly pigmented papules with well defined, rounded borders. Histologically, the
basal cells grow in nests along the dermo-epidermal junction.
Junctional nevus: this is an early developmental stage of nevocellular nevi where
nuclei of nevus cells are uniform and show little or no mitotic activity.
Compound nevus: arises from junctional nevi that grow into the underlying
dermis as nests of cords of cells.
Dermal nevi: in older lesions the epidermal nests may be lost entirely to leave
pure dermal nevi.
Maturation: the growth of nevus cells from the dermo-epidermal junction down
into the dermis is accompanied with cellular maturation. Cells start as large nest
of melanin producing cells and end up in the dermis as small, non-pigmented, and
growing in cords.
Nevus Variant

Diagnostic Architectural
Features

Diagnostic Cytologic
Features

Clinical Significance

Congenital nevus

Deep dermal and sometimes

subcutaneous growth around
adnexa, neurovascular bundles,
and blood vessel walls

Identical to ordinary
acquired nevi

Present at birth; large variants

have increased melanoma risk

Blue nevus

Non-nested dermal infiltration,

often with associated fibrosis

Highly dendritic,
heavily pigmented
nevus cells

Black-blue nodule; often

confused with melanoma
clinically

Spindle and epithelioid Fascicular growth

cell nevus (Spitz nevus)

Large, plump cells with Common in children; red-pink

pink-blue cytoplasm;
nodule; often confused with hem
fusiform cells
clinically

Halo nevus

Lymphocytic infiltration
surrounding nevus cells

Identical to ordinary
acquired nevi

Dysplastic nevus

Large, coalescent intraepidermal Cytologic atypia

nests

Host immune response against

nevus cells and surrounding
normal melanocytes
Potential precursor of malignant
melanoma

Dysplastic nevi
These are larger (>5-mm), flat macules with a pebbly surface that may occur as hundreds
of lesions on the body surface and appear in sun and non-sun exposed areas of the body.
Nevus cells nests within the epidermis may be enlarged and exhibit abnormal fusion with
adjacent nests, which begin to replace the normal basal layer along the dermo-epidermal
junction, producing so-called lentiginous hyperplasia.
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MALIGNANT MELANOMA
Pg (805 807)
Malignant melanoma (sunlight is bad)
In contrast to nevi, melanomas exhibit striking variations in pigmentation, appearing in
shades of black, brown, red, dark blue, and gray. The borders of melanomas are irregular
and notched. Clinical warning signs include; a mole that has enlarged, begins itching, or
becomes painful, development of newly pigmented lesions in adults, irregular borders,
and variegation of color within a pigmented lesion. The most important clinical sign is
a change in color or size of a pigmented lesion.
Radial growth: this indicates the initial tendency of a melanoma to grow
horizontally within the epidermal and superficial dermal layers. During this
time, melanoma cells do not have the ability to metastasize.
Vertical growth: the melanoma now begins to grow downward into the deeper
dermal layers as an expansile mass lacking cellular maturation, without any
tendency for the cells to become smaller as they descend into the reticular dermis.
These cells now have metastatic potential and angiogenesis is stimulated.
Ocular melanoma
These arise from the uvea (iris, ciliary body, and choroids) but they can originate in the
pigmented epithelium of the retina. Unlike cutaneous types, ocular melanomas consist of
two populations of cells: spindle and epithelioid. Predominance of spindle cells means
a less aggressive melanoma compared with an epithelioid melanoma which is highly
aggressive and lethal.
Enucleation: surgical removal of a whole tumor or whole organ (like the eye in
this case).

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PATHOLOGY PAO 2101

BLOCK IV

Uniformed Services University

School of Medicine

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CHAPTER 21
MUSCULOSKELETAL
DISEASES OF BONE
Pg 756 771
Hematopoietic
The skeletal bones house the bodys blood-forming (hematopoietic) elements.

Development and growth of a long bone. A. Formation

of primary and secondary ossification centers. B. Growth
in length occurs on both sides of the cartilaginous
epiphyseal plates (arrows). For growth to continue, the
bone formed from the primary center in the diaphysis
does not fuse with that formed from the secondary centers
in the epiphyses until the bone reaches its adult size

Vasculature and innervation of a long bone. The

epiphysis is supplied with blood by the epiphyseal artery.
The diaphysis, metaphyses, and bone marrow of a long
bone are supplied mainly by the large nutrient artery (or
arteries). Metaphyseal and epiphyseal arteries pierce the
compact bone and supply the spongy bone and marrow of
the ends of the bone. Branches of the periosteal arteries
supply the periosteum. The periosteum is rich in sensory
nerves-the periosteal nerves. The bulk of compact bone is
composed of haversian canal systems (osteons). The
haversian canal in the system houses one or two small
blood vessels for nourishing the osteocytes (bone cells).

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CONGENITAL DISEASES
Aplasia
Congenital absence of a bone (digit or rib).
Supernumerary digit (or ribs)
The formation of extra bones.
Achondroplasia
An inherited disorder characterized by impaired maturation of cartilage in the developing
growth plate. There is a mutation in FGFR3 causing the gene to be permanently
activated, which inhibits cartilage growth. It is the major cause of dwarfism (abnormally
short stature with underdeveloped limbs). Common presentation of heterozygotes:
shortening of extremities, bowing of legs, and lordotic posture (an excessive inward
curvature of the spine).
Osteogenesis imperfecta (OI)
A spectrum of disorders with varying severity united by a common feature of abnormal
collagen (type I) synthesis and resultant bone fragility (brittle bone disease). It is
characterized by multiple bone fractures, but can also affect teeth, hearing, and eyes (blue
sclera).
Osteopetrosis (marble bone disease)
A group of uncommon hereditary disorders caused by deficient osteoclastic activity.
There is abnormal thickening of the bones which fracture easily, causes a shrunken
medullary cavity (anemia and increased susceptibility to infections), and cranial nerve
palsies (if the bone compresses nerves).
OSTEOPOROSIS AND ACQUIRED METABOLIC DISEASES
Scurvy
Vitamin C deficiency leading to bone disease in growing children and to hemorrhages
and healing defects in both children and adults.
Rickets (children)/ Osteomalacia (adults)
Vitamin D deficiency leading to hypocalcemia and activation of PTH. This causes loss
of bone mass in adults (osteopenia) and bowing of the legs in children.
Osteoporosis
A group of skeletal disorders characterized by a low bone mass/density, and microarchitectural deterioration with a subsequent increase in bone fragility and fracture. It is
caused by an imbalance between bone formation and resorption with osteoclasts winning
out. The most common forms are post-menopausal (estrogen deficiency) and senile
osteoporosis. It appears that it is caused by dysregulation of the RANK-RANK ligandOPG pathway described below:
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RANK
The differentiation of macrophages into osteoclasts requires that
RANK ligand (found on the surface of stromal cells or
osteoblasts) binds to the RANK receptor on macrophages.
Activation of this receptor is a major stimulus in bone resorption.
RANK sensitivity is blunted by estrogens.
Osteoprotegerin (OPG):
Is a decoy receptor produced by stomal cells and osteoblasts
that binds RANK-ligand without stimulating the formation of
osteoclasts. In this way, it regulates the pathway. Production of
OPG is stimulated by estrogens.

Trabecular bone: The hallmark of osteoporosis is loss of bone which is most

obvious in parts of the skeleton containing abundant trabecular bone (vertebrae,
femoral heads). The bony trabeculae are thinner and more widely separated
which causes increased fragility. The Haversian canals are also found to be
widened.
DEXA: Reliable, early diagnosis of osteoporosis requires radiographic
measurements of bone density by techniques such as dual-energy x-ray
absorptiometry (DEXA).
Biphosphonate / SERM: New therapeutic treatment of osteoporosis includes
biphosphates (selectively decrease osteoclast-mediated bone resorption) and
selective estrogen receptor modulators (SERMs) which have effects similar to
estrogen without the negative side effects.
Parathyroid hormone (PTH)
PTH has the net effect to increase serum calcium which then causes the parathyroid to
turn-off PTH secretion. This can become pathologic if there is too much PTH.
Hyperparathyroidism: an increase in PTH caused by a primary (as in autonomous
secretion) or secondary (renal disease) mechanism leading to abnormal osteoclast
activity.
Hyperphosphatemia: suppresses the activity of 1-hydroxylase, further impairing
the synthesis of active vitamin D. Low vitamin D causes a decrease in calcium
absorption.
Cortical bone: cortical and trabecular bone are lost and replaced by loose
connective tissue when PTH is increased.

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Brown tumor of hyperparathyroidism: an accumulation of osteoclasts, giant cells,

and hemorrhagic debris in the marrow space which forms a distinct mass. Cystic
change is common in these lesions, hence the name osteitis fibrosa cystica.
Osteomyelitis
Denotes inflammation of the bone and marrow cavity by an infectious agent (usually
pyogenic bacteria and M. tuberculosis).
Pyogenic osteomyelitis
This can be caused by bacterial hematogenous dissemination to bone, direct extension
from a focus of acute infection, or traumatic injury/surgery. Staphylococcus aureus is
the most common cause of infection. Escherichia coli and group B strep are important
causes of acute osteomyelitis in neonates, and Salmonella osteomyelitis is frequent in
patients with sickle cell disease.
Acute osteomyelitis
This is characterized by an intense, neutrophilic inflammatory infiltrate at the site of
bacterial invasion. The vascular channels are compressed and the bone becomes necrotic
within days. In children, the mateaphysis of long bones are typically involved (due to
sluggish blood flow).
Periosteum: in long bones, infection can spread through the cortical bone and
penetrate the periosteum. Subperiosteal abscesses may form (particularly
common in children).
Epiphysis: in infants, loosely attached periosteum and anastomses between
metaphyseal and epiphyseal vessels allows infection to spread to the epiphyses,
then joint capsule.
Chronic osteomyelitis
A sequela of acute infection characterized by osteoclasts activation, fibroblastic
proliferation, and new bone formation. Residual necrotic bone (sequestrum) may be
resorbed by osteoclasts. Large sequestra are surrounded by a rim of reactive bone
(involucrum). When a well-defined rim of sclerotic bone surrounds a residual abscess, it
is called a Brodie abscess.
Tuberculous osteomyelitis
Mycobacterium can spread to and infect bone (usually the long bones and vertebrae) via
the bloodstream. The tubercle bacillus requires high O2 pressures to live, a criterion that
is met by the synovium. The infection then spreads to the epiphysis and causes a
caseating granuloma with bone destruction.
Pott disease: when the infection spreads to the vertebrae, it is called Pott disease.
Infection at this site causes vertebral deformity and collapse with secondary
neurologic deficits.

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Paget disease (osteitis deformans)

An episodic disease that results in skeletal deformity caused by an accumulation of
excessive amounts of abnormal and unstable bone. The causative agent may be a slow
Paramyxovirus infection which increases expression of the RANK receptor. It affects
males more than females, rarely presents before 40, affects spine, skull, and vertebrae
most often, and can lead to osteogenic sarcoma. Paget disease may present as a solitary
lesion (monostotic) or may be multifocal (polystotic). There are three morphologic
phases in Paget disease:

(1) Primary osteolytic phase: there is focal replacement of the

marrow by loose, highly vascular connective tissue. Large
osteoclasts line the bony trabeculae destroy bone.
(2) Mixed phase: osteoblastic proliferation is superimposed on
osteoclastic activity leading to simultaneous bone destruction and
formation.
(3) Osteosclerotic phase: osteoblastic activity ceases but
abnormal osteoblastic activity continues. The new bone lacks the
lamellar architecture or normal bone and is referred to as woven
bone.
Mosaic pattern: new bone formation occurs in an erratic pattern,
with areas of new bone juxtaposed in a random mosaic pattern, a
virtually pathognomonic finding of Paget disease.

Alkaline phosphatase
AP is elevated in patients with this disease, reflecting an increase in osteoblastic activity.
Chalkstick fracture
Transverse fractures of the brittle, weight bearing long bones have been likened to
breakage of chalk, hence the term chalkstick fracture.

BONE TUMORS
Osteolytic/osteoblastic
Primary bone tumors are much less common than metastatic bone tumors. Metastatic
bone tumors can be either destructive (osteolytic) as in breast metastases, or associated
with new bone formation (osteoblastic), as in prostatic metastases.

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Osteoid
Neoplasms that are characterized by bone-formation secrete osteiod (newly formed
organic matrix prior to calcification). The osteoid is made by neoplastic cells, not
osteoblasts as in metastatic bone cancer.
Osteoma
These are benign, solitary, hard, exophitic growths attached to the surface of bone. They
usually affect the head (paranasal sinuses) and neck, and are actually developmental
aberrations or reactive growths.
Osteoid osteoma
Benign lesions most often arising in the proximal
femur and tibia of males (more than females) during
the 2nd-3rd decades of life. They are less than 2-cm in
size and cause pain that can be relieved by aspirin. It is
composed of haphazardly interconnecting trabeculae of
woven bone that are rimmed by prominent osteoblasts.
The intertrabecular spaces are filled by vascular loose
connective tissue.

Osteoblastoma
Benign lesions most often arising in the vertebral column of males (more than females)
during the 2nd-3rd decades of life. They are greater than 2-cm in size and cause pain that
is unrelieved by aspirin. They may recur following excision.
Nidus: both osteoblastoma and osteoid osteoma are well-circumscribed lesions
with a central area (the nidus) that is characteristically radiolucent but may
become mineralized and sclerotic.
Osteosarcoma (Osteogenic Sarcoma)
Malignant mesenchymal neoplasms in which the neoplastic cells produce osteoid. They
typically present as progressively enlarging, painful masses that come to attention
because of fracture of the involved bone. Histologic diagnosis is required in all cases.
There are several different forms:
Primary vs. secondary: primary forms arise de novo, while secondary forms arise
as a complication of a known underlying process (Paget disease). Primary
osteosarcoma is divided into conventional and variant forms.
Conventional vs. variant: the conventional form accounts for of cases, most
often arise around the knee in the 2nd decade of life, and mostly in males.
Codman triangle: this tumor causes an elevation of the periosteum on radiographs
forming the Codman triangle.

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Osteochondroma
Benign proliferations of mature bone with a cartilaginous cap. These represent
malformations rather than true neoplasm. Most often, they are solitary lesions arising
from the metaphysis (near the growth plate) of long bones and may cause cosmetic
deformities.
Chondroma (Endochondroma)
Benign lesions arising from the medullary cavity, composed of mature hyaline cartilage.
They occur most often in the small bones of the hands and feet in the 3rd-5th decade of
life.
Ollier disease: characterized by multiple chondromas involving one side of the
body.
Maffuci syndrome: multiple chondromas associated with benign vascular tumors
(angiomas) of the soft tissue.
Chondrosarcoma
Malignant neoplasms that arise from the medullary cavity, populated by mesenchymal
cells that produce a cartilaginous matrix. They occur more often in males during the 6th
decade of life in the shoulder, pelvis, proximal femur, or ribs. Enlarging, painful
masses that may metastasize via the blood (to the lung), is the usual presentation. They
do not produce osteoid!
Giant cell tumor of bone
Neoplasms that consist of two cell types: multinucleated giant cells resembling
osteoclasts, and neoplastic, proliferating mononuclear cells. They cause local pain near
joints (mimicking arthritis) in the epiphyses of long bones. There is a slight female
predominance with peak age between 20-40. The lesions are solitary, radiolucent, and
appear dark-brown due to abundant vascularity.
Ewing sarcoma & Primitive neuroectodermal tumor (PNET)
These bone tumors are part of the same tumor family characterized by the presence of
one of two translocations: t(11;22) or t(21;22). The translocations cause dysregulation of
cell proliferation and differentiation. These are highly aggressive neoplasms of neural
origin (small blue cells histologically), are most common in children, and arise from the
medullary cavity in the diaphysis. They present with fever, pain, and local inflammation.
MIC2 (CD99) antigen: Ewing sarcoma cells express this surface antigen which
can be identified with monoclonal antibody. It is important to distinguish this
small blue cell tumor from others (neuroblastoma) because the treatment is
different.

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Fibrous dysplasia
Benign, tumor-like lesions that appear to be a developmental defect in bone formation in
which the normal trabecular bone is replaced by proliferating fibrous tissue and
disorderly islands of malformed bone. There are three forms:
Monostotic fibrous dysplasia (70%): involves a single bone, appears during
adolescence and becomes quiescent after bone growth is complete. It is usually
asymptomatic .
Polystotic fibrous dysplasia (35%): involves multiple bones, presents at an earlier
age, frequently has craniofacial involvement, and is more likely to have fractures
and bone deformity that monostotic.
McCune-Albright syndrome (3%): this is polystotic fibrous dysplasia with
endocrine abnormalities characterized by unilateral bone lesions, caf-au-lait
spots, and precocious puberty. It more often affects females.
DISEASES OF THE JOINTS
Pg 771 778
Osteoarthritis (DJD)
Also termed degenerative joint disorder, this is the most common disorders of the joint
and is characterized by degeneration of the articular cartilage. Articular cartilage
functions to reduce friction at the joints and evenly distribute weight across the joint
surface in weight bearing bones. It is composed of type II collagen and proteoglycans
(decreased in DJD) and is maintained by chondrocytes (decreased in DJD). It usually
has a slow onset, presents after 50, affects the weight bearing joints and hands, and has
the common complaints of joint stiffness, swelling, and pain.
Fibrillation: early changes in DJD include enlargement and disorganization of
chondrocytes at the surface of the articular cartilage accompanied by matrix
changes resulting in fibrillation (splitting).
Eburnation: the fissures begin to extend through the full thickness of cartilage, the
cartilage becomes completely eroded and the underlying bone becomes thickened
and polished to an ivory-like consistency (eburnation).
Joint mice: dislodged bone and cartilage fragments floating in the joint cavity.
Subchondral cyst: synovial fluid leaks through residual cartilage and underlying
bone to form cysts within the bone.
Osteophyte: bone proliferation at the margins of the joints produces bony
excrescences (osteophytes).

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Heberden node: small osteophytes on the DIP joints are most often encountered in
women with primary osteoarthritis.
Rheumatoid arthiritis: in the differential with DJD, but RA is immunologically
mediated (rheumatoid factor) and presents as symmetric arthritis affecting the
small joints that may eventually lead to fusion of the joints (ankylosis).

Comparison of the
morphologic features of
rheumatoid arthritis and
osteoarthritis.

Gout
Recurrent episodes of acute arthritis caused by the tissue accumulation of excessive
amounts of uric acid (an end product purine metabolism) due to overproduction or
under-excretion. The increased level of uric acid is termed hyperuricemia. The arthritis
may be accompanied by crystalline aggregates (tophi) which result from precipitation of
monosodium urate crystals from supersaturated body fluids (synovial fluid). These
crystals activate compliment and recruit neutrophils leading to joint destruction. Gout
typically affects men over 30 most often (90%) in the great toe.
Primary Gout (90%): is gout in which the basic cause is unknown or when the
cause is an inborn metabolic abnormality.
Secondary Gout (10%): the cause of hyperuricemia is known but gout is not the
main or dominant clinical disorder (lymphoma, leukemia, chronic renal failure).

The pathogenesis of gout is

related to the overproduction
of uric acid resulting from
some abnormality in the
metabolism of purines (the
horrible schematic to the
left).

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HGPRT: the conversion of PRPP to purine nucleotides is catalyzed by amido PRT

in the de novo pathway and by APRT and HGPRT (hypoxanthine-guanine
phosphoribosyltransferase) in the salvage pathway.
Lesch-Nyhan syndrome: this is an X-linked condition with complete lack of
HGPRT leading to excessive amounts of uric acid, mental retardation, and selfmutilation.
Chronic tophaceous arthritis: recurrent episodes of urate deposition leads to large
amounts of chalky white sodium urate (tophi) deposition on articular cartilage
triggering a chronic granulomatous reaction which can lead to ankylosis.
Gouty nephropathy: uric acid crystals can precipitate within and obstruct renal
tubules. Patients undergoing chemotherapy have a rapid cell turnover rate leading
to hyperuricemia (Tumor lysis syndrome) causing gouty nephropathy.
Acute suppurative arthritis
Infection of the joints may occur during episodes of bacteremia, through traumatic
implantation, or from direct spread of an infection from the adjacent bone or soft tissues.
It is manifest as local pain, fever, and a neutrophilic joint infiltrate (pus). The
immunocompromised, IV drug users, and compliment deficient are at increased risk.
Common pathogens gonococci and Salmonella.

Lyme disease
Lyme disease is caused by the spicrochete
Borrelia burgdorferi and is transmitted to
humans by the deer tick, Ixodes dammini.
Similar to other spirochete infections, it
involves three stages. The initial stage of
Lyme disease is characterized by a
progressively enlarging, bulls-eye rash
termed erythema chronicum migrans. If
untreated, a destructive arthritis may
develop mainly affecting the large joints.
Clinical stages of Lyme disease.

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DISEASES OF SKELETAL MUSCLE

Pg 778 782
Motor unit
A motor unit is composed of a motor neuron in the brain stem or spinal cord, the
peripheral axon emanating from the motor neuron, and the neuromuscular junction
between the axon and the skeletal muscle fiber (two types): type I (slow-twitch) fiber
and type II (fast-twitch) fiber.
Neurogenic atrophy
If deprived of their normal innervation (as in diseases affecting the spinal motor neurons
or axons), skeletal muscle fibers undergo progressive atrophy. Muscle fibers appear
angular and atrophic. This will present as muscle weakness.
Small group atrophy: often the atrophic fibers lie in small clusters.
Fiber type grouping: a regenerating axons sprouts tend to inervate contiguous
fibers, resulting in back-to-back aggregation of muscle fibers of the ssame
histochemical type leading to a loss of randomness.
Infantile spinal muscular atrophy type I (Werdnig-Hoffman disease): is a severe
autosomal recessive disorder characterized by loss of spinal motor neurons. It can
lead to generalized hypotonia in the neonate (floppy infant syndrome). The
atrophic muscle fibers are round and in large groups with scattered hypertrophic
fibers.
Type II myofiber atrophy
Type II atrophy occurs in patients who develop disuse atrophy when bedridden, or in
patients with hypercortisolism (for any reason). This can be distinguished from
neurogenic atrophy based on histochemical staining (will show only Type II fiber
atrophy).
Myasthenia gravis (MG)
An acquired autoimmune disorder of neuromuscular transmission. Antibodies to the
acetylcholine receptor (AchR) on skeletal muscle fibers, present in 90% of patients,
inhibit signal transmission leading to weakness. Thymic abnormalities (thymic
hyperplasia and thymoma) frequently accompany MG, as are other autoimmune
disorders. The most common site of initial involvement are the muscles of the eyelids
and muscles controlling eye movement leading to drooping of the eyelids (ptosis) and
double vision.
Lambert-Eaton myasthenic syndrome
This syndrome is frequently associated with neoplasms (small cell carcinoma of the
lung) and is the result of antibodies directed against the presynaptic side of the
neuromuscular junction. Electrophysiologic tests differentiate this from MG.

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Trichinosis
Ingestion of inadequately cooked meat infected with Trichinella spiralis cysts can cause
Trichinosis. The Trichinella larvae mature in the small intestine, migrate through the
bloodstream, and enter skeletal muscle (form cysts). Once here, the larvae enlarge,
encapsulate, and provoke an immune response. Muscle pain and weakness, as well as
facial edema, are common presentations.
Duchenne muscular dystrophy (DMD)
DMD is an X-linked disorder caused by the absence of the structural protein dystrophin.
Dystrophin is found in all types of muscle and acts to attach the sarcomere to the cell
membrane. Its absence results in contractile dysfunction of both skeletal and cardiac
muscle. In muscular dystrophy, the muscle fibers vary considerably in size, shape, and
there is an increase in interstitial connective tissue.
Becker muscular dystrophy: another X-linked disorder related to a mutation in the
dystrophin gene. Here, dystrophin is present, but in an abnormal form causing a
less severe disease.
SOFT TISSUE TUMORS
Pg 782 787
Lipoma (most common soft tissue tumor)
Lipomas appear as solitary, soft, yellow masses composed of mature adipose tissue in the
subcutaneous tissues of adults. Most are slowly enlarging masses that rarely cause
complication and can be cured by excision.
Angiomyolipoma: are variants of lipomas that contain a mix of fat, smooth
muscle, and blood vessels. They occur in the kidney of patients with tuberous
sclerosis and may undergo spontaneous hemorrhage.
Liposarcoma
Malignant neoplasms of adipocytes commonly affecting the soft tissue of adults in their
5th-6th decades of life. The normally appear in the deep soft tissues or visceral sites of the
lower extremities and abdomen. There are several morphologic variants.
Nodular fasciitis
A self-limited, reactive fibroblastic proliferation presenting in young adults as a rapidly
enlarging (maybe painful) growth. It usually affects the upper extremities and trunk, and
may be associated with an area of previous trauma. The lesion is less than 3-cm in
diameter and is composed of plump, immature-appearing fibroblastic cells arranged in a
myxoid matrix.

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Fibromatoses
A group of fibroblastic proliferations distinguished by their tendency to grow in a locally
infiltrative fashion (but rarely metastasize). They are composed of plump fibroblasts that
have a uniform appearance. There are two major groups:
(1) Superficial Fibromatoses: arise in the superficial fascia. Examples include
Dupuytren contracture (palmar fibromatosis) and Peyronie disease (penile
fibromatosis). They usually present when they cause deformity.
(2) Deep Fibromatoses: include the Desmoid tumors which occur in the muscles
of the extremities and in the abdomen. They can also occur as a part of Gardner
syndrome (adenomatous colon polyps, osteomas, and fibromatoses).
Fibrosarcoma
Malignant neoplasms of fibroblasts that occur in the thigh, knees, and retroperitoneal
area of adults. They grow slowly, recur following excision, and can metastasize via the
blood (most often to the lung). Histologically, they are composed of interlacing fascicles
of fibroblasts (herringbone pattern).
Fibrous histiocytoma
Benign lesions that present as mobile nodules in the dermis of subcutaneous tissue of
adults. They have a unique genetic abnormality with PDGF- and COL1A1.
Dermatofibromasarcoma protuberans (DFSP)
This is an intermediate tumor between benign and malignant fibrous histiocytomas. They
are slow growing nodules in the dermis and subcutaneous tissues of adults. Metastases
rarely develop, though they are locally infiltrative. Microscopically, they appear as
plump, fibroblastic cells arrayed in a storiform pattern.
Malignant fibrous histiocytoma
A group of clinically aggressive soft tissue sarcomas that occur in people between 50 and
70. They arise in deep muscular tissues of the extremities and retroperitoneal area. Half
of patients will have metastases. Microscopically, atypical spindle cells are arranged
in whorls, sometimes admixed with bizarre, histiocyte-like cells.
Rhabdomyosarcoma
These are malignant mesenchymal neoplasms that exhibit skeletal muscle
differentiation and are usually pediatric tumors occurring in the first decade of life.
The most common variants are embryonal (arises in the head, neck, GU tract, or
retroperitoneum), and alveolar (arises in the extremities and sinonasal tract).
t(2;13): is a common translocation found in alveolar rhabdomyosarcoma. This
translocation causes dysregulation of the muscle differentiation via the newly
formed protein PAX3-FKHR.

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Sarcoma botryoides: tumors arising near mucosal surfaces of the lower GU or

head and neck (embryonal variant), may present as soft, gelatinous, grape-like
masses. The malignant cells tend to cluster immediately beneath mucosal
surfaces, forming the so called cambium layer.
Leiomyoma
Benign, smooth muscle cell tumors arising most frequently in the uterus.
Leiomyosarcoma
Arise de novo (not from leiomyomas) in the uterus or GI tract and have an infiltrative
growth pattern and greater mitotic activity.

Synovial sarcoma
A common tumor derived from the mesenchymal
cells around joint cavities and sometimes arise in
sites outside of joints. The t(X;18) translocation is
a unique genetic abnormality to synovial
sarcomas. Synovial sarcoma has a classic biphasic
spindle cell and glandular-like histologic
appearance.

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CHAPTER 23
THE NERVOUS SYSTEM
Brain Parenchyma
The brain parenchyma is composed of glial cells (astrocytes, oligodendrocytes, and
ependymal cells), blood vessels, and microglia. The processes of these cells combine to
form a delicate fibrillar background termed neuropil.
Neuron Injury
Injury to neurons can cause:
Coagulation Necrosis: is characterized by a loss of cytoplasmic
ribonucleoproteins and denaturation of the cytoskeleton resulting in cytoplasm
eosinophilia (red neurons), pyknosis and karyolysis (loss of the nucleus).
Chromatolysis: is a reaction to axonal injury characterized by dispersion of the
Nissel substance and swelling of the neuronal body.
Apoptosis: also occurs in the CNS as a result of normal development and
pathologic conditions.
Astrocytes
Astrocytes provide structural support to nervous tissue, help maintain the intercellular
environment and repair damaged tissue.
Glial fibrillary acidic protein (GFAP): in response to injury, astrocyte cytoplasm
swells in association with increased synthesis of GFAP, the astrocytes major
cytoskeletal protein.
Corpora amylacea: are glycoprotein-rich materials that accumulate in astrocytic
processes with age.
Oligodendrocytes
These cells are found in the white matter and form myelin in the CNS. A single cell may
wrap myelin sheaths around many axons. These cells are injured in multiple sclerosis.
Ependymal Cells
These cells line the cerebral ventricles and are closely related to the cuboidal cells of the
choroids plexus. They can become infected with CMV, and their disruption forms small
irregularities (ependymal granulations) on the ventricular surfaces.
Microglia
Microglia are rod shaped cells, derived from monocytes that act as the macrophages of
the CNS. Their numbers increase during CNS damage and function to remove cellular
debris (when they accumulate lots of lipid, they are called gitter cells).

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EDEMA, HERNIATION, AND HYDROCEPHALUS

Pg 811 813
Cerebral Edema
Indicates the presence of increased water content within the brain parenchyma. Grossly,
the gyri become flattened, the sulci narrowed, and the ventricles compressed. It can be
classified as vasogenic or cytotoxic edema:
Vasogenic Edema: results from disruption of the blood-brain barrier, which
allows fluid to escape. There are no lymphatics in the brain, so this fluid
accumulates (interstitial edema).
Cytotoxic Edema: implies an increased intracellular fluid (intracellular edema)
secondary to cellular injury as in ischemia.
Herniation
Cerebral edema can lead to herniation. The expanding brain and increased intracranial
pressure within the rigid skull displaces brain tissue. There are three common patterns:
Transtentorial: the medial aspect of the temporal lobe is compressed
against the free margin of the tentorium cerebelli impinging on CN III
(pupillary dilation and impaired ocular movements).
Subfalcine: unilateral or asymmetric expansion of the cerebral
hemisphere displaces the cingulate gyrus under the falx cerebri
(compression of anertior cerebral artery with ischemic injury to primary
sensory and/or motor cortex).
Tonsillar: life-threatening displacement of the cerebral tonsils through
the foramen magnum (damages respiratory centers of medulla
oblongata). It is accompanied by hemorrhagic lesions in the midbrain
and pons (Duret hemorrhages).

Hydrocephalus
Is the accumulation of CSF within the ventricular system of the brain due to decreased
absorption or increased production. This causes increased intracranial pressure.
Obstruction within the ventricles to CSF flow (tumor) is termed non-communicating
hydrocephalus, while an obstruction outside the ventricular system allowing CSF to
continue flowing is termed communicating hydrocephalus.
Hydrpcephalus ex vacuo: is dilation of the ventricular system with compensatory
increase in CSF production (associated with parenchymal atrophy)

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VASCULAR DISEASES
Pg 813 818
Global Hypoxic-Ischemic Encephalophathy
Global refers to the entire brain, hypoxia is decreased tissue oxygenation, and ischemia is
decreased tissue perfusion. The causes include cardiac dysrhythmia, shock, increased
intra-cranial pressure.
Symptoms range from transient deficit to brain death.
Morphologically, signs of necrosis are present (no inflammatory reaction).
Arterial Border Zones: are areas of the brain located at the junctions of arterial
territories and are susceptible to ischemic injury (first areas to lose blood flow
during hypotension).
Laminar Cortical Necrosis: is an irregular, linear zone of softening and
discoloration in the cortical mantle reflecting the vulnerability of specific layers
of neurons to ischemic injury.
Infarcts
Infarcts are caused by local interruption of blood flow (due to atherosclerosis or
emoboli), are more common in men than women, and usually present in the 7th decade.
Those caused by atherosclerosis (thrombosis) usually affect the internal carotid arteries,
while emboli typically affect the middle cerebral artery.
Middle Cerebral Artery: infarcts cause contra-lateral hemi-paresis and spasticity,
loss of sensation, visual field abnormalities, and speech abnormalities (aphasia).
Transient Ischemic Attacks (TIA): are episodes (minutes-24 hours) of neurologic
dysfunction and represent self-limited vascular obstruction. They predict
subsequent infarct.
Primary Brain Parenchymal Hemorrhage
Bleeding into the brain is associated with chronic hypertension, coagulation disorders,
vasculitis, and aneurysms. The peak incidence of 60, and typically affects the basal
ganglia. Grossly, a well-circumscribed hematoma is formed that can dissect through the
brain parenchyma and cause mass affects responsible for the presenting symptoms of
severe headache, vomiting, and loss of consciousness.
Charcot-Bouchard microaneurysms: are minute arterial aneurysms occurring in
vessels less than 300-m in diameter, most commonly in the basal ganglia.

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Subarachnoid Hemorrhage
The most common cause of spontaneous
subarachnoid hemorrhage is rupture of a saccular
(berry) aneurysm. Common presenting complaints,
involve acute onset of headache, nausea, and
vomiting. Neck rigidity and grossly bloody CSF are
also present.
Saccular (berry) aneurysms
Usually less than 3-mm in diameter (giant aneurysm
if greater than 25-mm), and appear as rounded bulges
off the arterial wall. The aneurysms wall is
composed of intima and adventitia (no media).
Common sites of saccular (berry)
aneurysms in the circle of Willis.

Vascular Malformations
There are four major types of vascular malformation, all of which can cause intracranial
hemorrhage: arteriovenous (the most common), capillary telangiectases (punctate
lesions of the pons and white matter), venous angiomas (thin, dilated veins in the spinal
cord and meninges), and cavernous angiomas (thick walled venous channels with dense
fibrous stroma).
Arteriovenous: malformations are conglomerates of haphazardly arranged vessels
of varying sizes, usually in the cerebral hemisphere, and are supplied by the
middle cerebral artery. The most common clinical manifestation is hemorrhage
after the first decade of life.
CENTRAL NERVOUS SYSTEM TRAUMA
Pg 818 821
Epidural Hematoma
Most frequently caused by middle meningeal artery rupture secondary to skull fracture.
These hematomas rapidly expand and increase intra-cranial pressure leading to flattening
of the gyral crests, herniation, brain stem compression, and death. Surgical intervention
is needed immediately.
Subdural Hematoma
Collection of blood between the dura and arachnoid mater most often caused by rupture
of bridging veins in association with rapid changes in head velocity (shaking, whiplash).
They can be divided into acute and chronic:
Acute: are associated with clear history of trauma, preserved gyral contours, and
contain clotted blood. The onset of symptoms is slower than that of epidural
hematoma. With time, it progresses to the chronic form.
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Chronic: are composed of liquefied blood separated from the inner surface of the
dura and underlying brain by neomembranes composed of granulation tissue and
collagen. Clinical symptoms show slowly deteriorating mental status.

Epidural hematoma (left) in which rupture of a

meningeal artery, usually associated with a skull
fracture, leads to accumulation of arterial blood
between the dura and the skull. In a subdural hematoma
(right), damage to bridging veins between the brain and
the superior sagittal sinus leads to the accumulation of
blood between the dura and the arachnoid.

Concussion
Refers to a transient loss of consciousness and widespread paralysis (sometimes seizures)
followed by recovery over a period of hours to days (usually with some memory loss
surrounding the injury).
Diffuse Axonal Injury
These lesions result from sudden deceleration/acceleration forces that stretch or tear
nerve cell processes in cerebral white matter resulting in axonal swelling and formation
of axonal spheroids (sites where axons were damaged). Causes post-traumatic dementia.
Contusions
Hemorrhages in the superficial brain parenchyma occurring in areas where the brain
comes in contact with the skull. When contusions are most pronounced in the area of
brain immediately under the point of impact (a hammer falls on your head), they are
called coup contusions. When contusions occur at the areas opposite the point of injury
(during falls), they are called coutercoup contusions.
Traumatic intracerebral hemorrhage
Usually multiple frontal or temporal lobe, or deep gray matter hemorrhages in association
with trauma. Brain swelling may occur due to cerebral congestion and true edema.

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CONGENITAL MALFORMATIONS AND PERINATAL BRAIN INJURY

Pg 821 824
Neural Tube Defects
The neural tube usually closes by the 28th day of gestation. Defects associated with
abnormal closure are referred to as neural tube defects, and include the following:
Anencephaly: is the most severe neural tube defect with occurrence of 1/500
births. Folate deficiency and increased age of the mother are risk factors.
Encephaloceles: protrusion of a variable amount of meninges and brain
parenchyma through a defect in the cranial bones (usually occipital).
Cranial Meningoceles: distinguished from encephloceles by the presence of only
meninges and CSF in the herniated tissue.
Spina bifida
Is the absence or hypoplasia of one or more vertebral arches (usually lumbosacral), with
variable abnormality in the meninges and spinal cord. There are two variants:
(1) Meningomyeloceles: is herniation of spinal meninges and cord through a
posterior vertebral defect to form a cyst-like out-pouching (spina bifida cystica).
If only the meninges herniate through the defect, it is termed meningocele.
(2) Spina bifida occulta: is a defect in posterior vertebral arch closure with
intact meninges and spinal cord. The overlying skin may be dimpled.
Arnold-Chiari Malformation
This malformation is characterized by an abnormally shallow posterior cranial fossa with
caudal extension of the medulla oblongata and portions of the cerebellar vermis through
the foramen magnum.
It is usually associated with meningomyelocele and
hydrocephalus.
Dandy-Walker Malformation
Is characterized by aplasia/hypoplasia of the cerebellar vermis, dilation of the fourth
ventricle, and enlarged posterior fossa, and is usually associated with hydrocephalus.
Holoprosencephaly
A group of malformations associated with abnormal division of the cerebral hemispheres
(sometimes associated with trisomy 13 and 15). These forebrain abnormalities are
accompanied by facial deformities ranging from cyclopia to mild facial defects.
Cerebral cortical malformations
This is a range of malformations that can include the formation of multiple, small
abnormally complex gyri (polymicrogyria) to a complete absence of gyri (lissencephaly).

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Neurocutaneous syndrome (phakomatosis)

A group of disorders characterized by malformations and a variety of non-neoplastic and
neoplastic proliferations involving the nervous system, skin, eyes, and other organ
systems. Included in this group are Sturge-Weber syndrome, neurofibromatosis type 1,
and von Hippel-Lindau disease.
Perinatal Injury
Perinatal injury referes to exogenous insults that may harm development; in this case,
development of the brain.
Germinal Matrix Hemorrhage: the germinal matrix of the developing brain is
composed of primitive cells fed by thin-walled vessels. Insult (hypoxia,
hypercarbia, acidosis) can injury these delicate vessels causing hemorrhage into
the matrix. Many infants die, but those who survive have scarring and obstructive
hydrocephalus.
White Matter Necrosis (periventricular leukomalacia): is caused by local hypoxicischemic injury and appears as chalky discolorations frequently adjacent to lateral
cerebral ventricles. It occurs in term and premature infants, and can be fatal or
case delayed development with quadriplegia.
Gray Matter Injury: can result from hypoxic-ischemic injury or infection. It can
give rise to long-term neurologic damage in the form of cerebral palsy or
multicystic encephalopathy (extensive parenchymal defects accompanied by
widespread gliosis).
INFECTIONS OF THE NERVOUS SYSTEM
Pg 824 832
Epidural abscess and Subdural empyema
Rare but lethal infections usually associated with staphylococci and streptococci. They
occur as complications of para-nasal or mastoid sinus infection, or from trauma.
Leptomeningitis (meningitis)
Refers to inflammation of the leptomeninges and subarachnoid space. It can be divided
into acute (bacterial), lymphocytic (viral), or chronic meningitis.

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Acute (Purulent) Leptomeningitis

Nearly all cases are caused by bacteria which
reach the CSF via the blood after colonizing the
nasopharynx. The meninges become congested
and contain creamy exudates in the subarachnoid
space.
Clinical presentation includes fever,
headache, stiff neck, altered mental status, and
turbid CSF with an increase in neutrophils and
decrease in glucose.
Different bacteria affect different age groups.

Age
Neonatal
Children > 6
months of age
Older Children,
Adolescence, and
young adult
Elderly and
immunocompromised
Brain Surgery
Patients

Bacteria
group B strep
E. coli
L.monocytogenes
S. pneumoniae
H. influenzae
N. meningitides
S. pneumoniae
L.monocytogenes
S. aureus

Acute Lymphocytic (Viral) Meningitis

This is typically a self-limited meningitis with a better prognosis than bacterial
meningitis, though the clinical presentation is similar. The difference is in the CSF:
lymphocytes are present and the glucose level is normal.
Chronic Meningitis
Is most often caused by bacteria or fungi, to include M. tuberculosis, C. neoformans, and
T. palladium. Clinically, the classic meningeal signs may not be present. The CSF is
characterized by significantly elevated protein, a mononuclear infiltrate, and a decreased
glucose concentration.
Meningeal syphilis
Meningeal syphilis can be a component of secondary or tertiary, congenital or acquired
syphilis. Morphologically, a plasma cell infiltrate suggests syphilis. Meningo-vascular
lesions involving the subarachnoid portions of the dorsal nerve roots may cause
degeneration of ascending sensory fibers in the posterior columns of the spinal cord, with
resultant sensory and gait abnormalities; a condition known as tabes dorsalis.
General paresis: is also associated with Treponemal infection of the brain
parenchyma and is characterized by cortical atrophy, neuronal loss, and
proliferation of elongated microglial cells (rod cells).
Brain abscess
Staphylococci and streptococci can cause brain abscess, which usually occur in the
cerebral hemispheres and begin as areas of softening (cerebritis) that gradually liquefy.
The lesions become delimited from the rest of the brain and contain green-yellow pus.
Clinically, they present with fever, neurologic deficit, and increased cranial pressure.
CNS tuberculosis
CNS infection with TB is usually a result of hematogenous spread from the lung to the
brain causing focal lesions known as tuberculomas (small nodules of caseous necrosis).
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CNS toxoplasmosis
Toxoplasmosis causes areas of necrosis and a mononuclear infiltrate with T. gondii in the
form of pseudocysts found at the margins of the necrotic areas. It is frequently associated
with AIDS patients.
Viral encephalitis
Generalized infection of the brain parenchyma associated with viral infections (which can
cause inclusion bodies). If the viral encephalitis is associated with leptomeningitis, it is
designated as meningoencephalitis. Perivascular inflammatory infiltrates are
characteristic of most types of viral encephalitis. Localized aggregates of microglial cells
(microglial nodules) are present and associated with phagocytosis of neurons
(neuronophagia). A number of viruses can cause encephalitis:
Arbovirus encephalitis: arthropod-borne viruses (EEE, WEE) most common in
late summer. Prognosis is worse if occurring at the extremes of age.
Herpes simplex encephalitis (HSV I): is the most common cause of sporadic viral
encephalitis affecting the temporal lobes and orbital frontal area causing
hemorrhagic, necrotizing encephalitis. Treat with anti-virals.
CMV encephalitis: is associated with AIDS patients and commonly affects the
ependymal cells.
HIV encephalitis: can present shortly after seroconversion and is indistinguishable
from other forms of self-limited viral meningitis clinically.
Progressive multifocal leukoencephalopathy (PML)
A slowly evolving encepahlopathy caused by the Papovirus, JC, and affects the
immunocompromised (AIDS). The virus infects oligodendrocytes resulting in areas of
demyelination.
Spongiform encephalopathy
A group of uncommon, transmissible disorders that include Ceutzfeldt-Jakob disease
(CJD) and Kuru. They are caused by infectious proteins called prions which are
modified forms of normal structural proteins. Clinically, they present as rapidly
progressive dementia accompanied by gait abnormalities and startle myoclonus.
PrP gene: hereditary cases are characterized by a mutant PrP gene
which encodes a form of PrP that spontaneously changes to the
structurally abnormal disease causing protein at high rates.
Spongiform change: is the presence of vacuoles within the
neuropil and cell bodies in gray matter and is the hallmark of CJD.
Spongiform change in the cerebral cortex (left) and Kuru plaques
(right).

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Kuru plaques: are amyloid-rich deposits that may be encountered in some forms
of spongiform encephalopathy.
New-variant CJD: is a newly recognized form associated with eating the tissues of
cattle with infected with bovine spongiform encephalopathy. These are
dominated early in their course by behavioral and psychiatric problems.
NEOPLASMS OF THE CNS
Pg 832 837
Astrocytoma
The most common group of primary CNS tumors. They are sub-classified into groups,
the most common being fibrillary astrocytic neoplasms and pilocytic astrocytomas.
Fibrillary Astrocytic Neoplasms
This group usually affects adults, is commonly found in the cerebral hemispheres, and is
characterized by an infiltrative growth pattern. Treatment involves surgery and
radiation/chemotherapy. They are subdivided based on degree of differentiation:
Anaplastic astrocytomas: appear very similar to well-differentiated astrocytomas,
but contain permeable vessels that are easily identified using radiographic studies
with contrast medium enhancement (the contrast leaks out).
Gliobastoma multiforme: are irregular, hemorrhagic tumors distinguished from
anaplastic astrocytomas by areas of microvascular proliferation and palisading
necrosis (areas of necrosis surrounded by neoplastic nuclei).
Pilocytic astrocytoma
Children are more often affected with common tumor sites including the cerebellum,
third ventricle, and optic nerves. They are less infiltrative than fibrillary astrocytomas.
Cystic areas, brightly eosinophilic Rosenthal fiber, and esopinophilic, protein-rich
droplets (hyaline granular body) are often present. Treatment is surgical.
Oligodendroglioma
These present in adults as tumors in the cerebral hemispheres. Tumors are usually soft,
well-circumscribed, and calcification is common. Classically, the neoplastic cells tend to
cluster around native neurons, a phenomenon referred to as satellitosis.
Ependymoma
Ependymomas occur at any age and arise within the ventricular cavities leading to
hydrocephalus (usually the patient is under 20), or in the central canal of the spinal cord
(adults). Microscopically, there are elongated cells with processes radiating around blood
vessels (perivascular pseudorosette) or lumina (ependymal rossete). Myxopapillary
ependymoma is another variant encountered in the filum terminale.

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Primitive neuroepithelial neoplasm (PNET)

A group of tumors (including Ewing sarcoma and Neuroblastoma) composed of
embryonal small blue cells that occur predominantly in children. The member of this
group affecting the CNS is medulloblastoma.
Medulloblastoma: lesions of the cerebellum (causing gait abnormalities)
occurring during the first two decades of life. They are composed of small blue
cells which sometimes form small rosettes (Homer Wright rosette) around a
fibrillar core.
Ganglion cell tumor
Tumors arising in the temporal lobes of children and young adults causing seizures.
They are composed of mature, dysplastic ganglion cells mixed with glial cells. If the
tumor is composed of a mixture of neurons and glial cells, they are called ganglioglioma.
Dysembryoplastic neuroepithelial tumor (DNT)
DNTs again affect young people, are associated with a long history of seizures, and are
composed of a mix of neurons, oliogodendroglioma-like areas, and astrocytes.
Central neurocytoma
Presents as a well-circumscribed, calcified intra-cranial mass in the lateral ventricle,
corpus callosum, or septum pellucidum of young adults.
Primary CNS lymphoma (usually B-cell type)
This is increasing in frequency due to AIDS and is an AIDS defining condition. A
characteristic feature of these tumors is their tendency to grow around and within the
walls of blood vessels (angiocentric growth).
Germ-cell Neoplasms
Occur in young people, usually in the pineal and suprasellar areas. The most common
types are intracranial germinomas (morphologically identical to testicular seminomas)
and teratomas.
Hemangioblastoma
Well-circumscribed, cystic lesions composed of delicate vascular channels and
intervening lipid-laden, foamy stromal cells which occur in the cerebellum and meninges.
Meningioma
Meningiomas are tumors derived from the meningothelial cells that invest the arachnoid
mater and affect women more than men. These tumors are firm, lobulated lesions
attached to the dura mater. Calification may be present and takes the form of psammoma
bodies.

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Leptomeningeal carcinomatosis
Metastatic lesions to the brain parenchyma are usually from the breast, lung, or malignant
melanomas. Less commonly, they metastasize to the meninges (leptomeningeal
cacinomatosis) which causes a vague opacification of the meninges with malignant cells
present in the CSF.
PRIMARY DISEASES OF MYELIN
Pg 837 839
Multiple sclerosis (MS)
MS is a demyelinating disease of the CNS, typically presenting in young adults (18-40)
as visual disturbances, paresthesias, spasticity, speech disturbances, or gait abnormalities.
These neurologic deficits wax and wane, and involve different areas of the CNS.
Evidence suggests an autoimmune disease involving T-cell and antibody-mediated injury
to myelin sheaths and/or oligodendroglial cells.
Plaque: on cut surface, MS is characterized by the presence of multiple areas of
demyelination, termed plaques. Common sites include periventricular white
matter, optic nerves, and spinal cord white matter.
Shadow plaques: contain axons invested by abnormally thin, faintly staining
myelin sheaths and are believed to represent areas of remyelination.
Oligoclonal band: gamma globulin is increased, and CSF electrophoresis reveals
discrete bands of immunoglobulins known as oligoclonal bands.
Myelin basic protein: is the suggested target of autoantibodies and T-cell activity,
and is often present in the CSF during periods of active demyelination.
Acute disseminated encephalomyelitis
This is a monophasic, immune-mediated demyelinating disease of abrupt onset that may
follow certain infections (measles, chicken pox, and rubella) and vaccinations.
Central pontine myelinolysis
Condition characterized by demyelination within the basis pontis. It has been associated
with alcoholism and patients who had hyponatremia corrected too rapidly.

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Leukodystrophy
A group of disorders usually seen in infancy and childhood in which an intrinsic defect
interferes with the generation and/or maintenance of myelin.
Disorder
Metachromatic
leukodystrophy

Inheritance

Metabolic Abnormality

Autosomal recessive

Arylsulfatase A deficiency

Krabbe disease

Autosomal recessive

Adernoleukodystrophy

X-linked and
autosomal recessive

Galactocerebroside B-galactoside
deficiency
Peroxisomal defect; elevated
levels of very-long-chain fatty
acids

ACQUIRED METABOLIC AND TOXIC DISTURBANCES

Pg 839 841
Wernicke-Korsakoff syndrome
Thiamine deficiency causes this syndrome and is most commonly associated with chronic
alcoholics.
Wernicke encephalopathy: is characterized by fairly rapid onset of confusion,
paralysis of extraocular muscles, and ataxia. If untreated, Korsakoff psychosis
may result.
Korsakoff psychosis: is characterized by an inability to either form new memories
or retrieve oldones, often accompanied by confabulation.
Subacute combined degeneration of the spinal cord
Deficiency of B12 causes pernicious anemia and in the nervous system, is associated with
the development of this disorder, a condition characterized by myelin vacuolation in the
dorsal and lateral white matter columns of the spinal cord.
Megaloblastic madness: is a confusional state associated with B12 deficiency.
Hepatic encephalopathy
Patients with systemic derangement (like hepatic encephalopathy) also develop evidence
of CNS dysfunction. In the brain, there is an increase in astrocytes related to the
increase in ammonia levels due to poor liver function.
Asterixis: hepatic encephalopathy is characterized by altered levels of
consciousness and a characteristic flapping tremor termed asterixis.

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DEGENERATIVE DISEASES
Pg 841 846
Alzheimer disease (AD)
AD is the most common cause of dementia (memory impairment and other cognitive
deficits with preservation of a normal level of consciousness) in the elderly (most cases
occur over 50).
Amyloid precursor protein (APP): a genetic mutation on chromosome 21 causes
the production of APP. The breakdown of APP is the source of the -amyloid
deposits (which form the senile plaques) in the brains of patients with AD.
Tau protein: is an intracellular protein that is involved in the assembly of intraaxonal microtubules. Patients with AD have a hyper-phosphorylated Tau protein
which accumulates leading to cytoskeletal abnormalities (another feature of AD).
Apoprotein E: is expressed with increased frequency in patients with late-onset
AD. It may be involved with the transport and processing of APP.
Amyloid precursor protein (APP) is a
transmembrane protein, with potential
cleavage sites for three distinct enzymes (-,
- and -secretases) as shown in A. The A
domain extends from the extracellular side of
the protein into the transmembrane domain.
When APP is cleaved by -secretase (B),
subsequent cleavage by -secretase does not
yield A. In contrast, cleavage by -secretase
followed by -secretase (C) results in
production of A, which can then aggregate
and form fibrils. In either pathway,
intramembranous cleavage by -secretase
follows cleavage at a site located closer to the
N-terminus of the protein.

Neurofibrillary tangle: are microscopic changes in the brain, which appear as

coarse, filamentous aggregates within the cytoplasm of neurons. They are
composed of protein-rich paired helical filaments (PHF), the main component of
which is hyper-phosphorylated Tau protein.
Senile plaque: appear as aggregates of course, tortuous neuritis in the neuropil of
the cerebral cortex with a central amyloid core.
Amyloid angiopathy: refers to the deposition of -amyloid in the meningeal and
parenchymal vessels, as well as senile plaques.

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Parkinsonism
Usually presenting after the 6th decade, this is a progressive disturbance in motor function
with insidious onset characterized by rigidity, expressionless facies, stooped posture, gait
disturbances, slowing of voluntary movements, and a characteristic pill-rolling tremor. It
is a degenerative disorder involving the dopamine-secreting neurons of the substantia
nigra, as well as the locus ceruleus.
Substantia nigra and Locus ceruleus: are two areas that become depigmented as a
result of loss of melanin-containing neurons. The neuropil is gliotic and some of
the remaining neurons in these areas contain concentrically laminated
esoinophilic, intracytoplasmic inclusions known as Lewy bodies (made of synuclein).
Huntington disease (HD)
HD is a hereditary (autosomal dominant), progressive (15-20 years), fatal disorder
involving the extrapyramidal motor system characterized by involuntary, writhing
movements (chorea) and dementia. It usually presents between the 4th and 5th decade.
Trinucleotide repeat mutation: (CAG repeats) affecting the huntingtin gene on
chromosome 4 has been identified as the cause of HD. The result of this mutation
is some manner of impairment of the normal protein produced by the huntingtin
gene (gain of function mutation).
Amyotrophic lateral sclerosis (ALS)
ALS is a fatal degenerative disorder involving the upper and lower motor neurons of the
pyramidal system, with resultant progressive muscle weakness, atrophy, and spasticity.
As such, it presents with the slow onset of weakness progressing to atrophy and small
involuntary muscle contractions (fasciculations). It exists in hereditary and sporadic
forms, but the cause is unknown. Some suggest an SOD mutation.
Precentral gyrus: is the location of the primary motor cortex in the brain and is the
location of upper motor neuron atrophy in patients with severe ALS.
Babinski reflex: is a sign of upper motor neuron damage and is seen as the
upgoing toes in response to a painful stimulus applied to the sole of the foot.
Werdnig-Hoffmann disease (infantile spinal muscular atrophy type 1)
An autosomal recessive disorder manifested by congenital hypotonia (floppy infant
syndrome). It is characterized by a progressive loss of motor neurons in the anterior
horns of the spinal cord, resulting in atrophy of anterior spinal roots and peripheral motor
nerves and denervation in multiple skeletal muscle groups. Death occurs before 1 year.

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DISEASES OF THE PNS

Pg 846 849
Axonal degeneration
Designates a pattern of nerve injury characterized by primary injury to the axon followed
by secondary disintegration of the myelin sheath.
Wallerian degeneration: if the proximal segment of an axon is injured, the axon
distal to the site of injury rapidly degenerates and ultimately disappears, a process
termed Wallerian degeneration. This can be caused by trauma, vasculitis, and
ischemic injury.
Distal degeneration: develops when axonal degeneration begins in the most distal
part of the axon and extends proximally in a progressive, continuous fashion.
This can be caused by nutritional neuropathies (thiamine deficient) and toxic
injury.
Segmental demyelinaiton
Is characterized by primary injury to the myelin sheath, with relative preservation of
axons leading to poor impulse conduction. There is re-myelination and with repeated
injury causes a histologic pattern termed onion bulb formation. Clinical presentation
depends on the type of nerves affected: slowly evolving seonsory loss in a glove and
stocking pattern, muscle weakness, and diminished deep tendon reflexes.
Guillain-Barre syndrome
This syndrome can follow a viral or mycoplasma infection, allergic reaction, or surgical
procedure. It is characterized by rapidly progressive, ascending motor weakness that
may lead to death from respiratory failure. Sensory deficit is less pronounced.
Schwannoma
These present as masses (made of Schwann cells) attached to peripheral nerves, cranial
nerves, or spinal nerve roots. CN VIII (vestibulo-cochlear nerve) is commoly affected
and is termed an acoustic neuroma. Schwannomas typically contain areas of densey
packed spindle cells (Antoni A tissue) and looser, myxoid regions (Antoni B tissue). In
denser areas, cell nuclei may form orderly palisades (Verocay body).
Neurofibroma
Peripheral nerve sheath tumors that may present as diffusely infiltrative nodular lesions
involving the skin (cutaneous neurofibromas) and subcutaneous tissues (subcutaneous
neurofibromas), or as an expansile intraneural lesion involving the larger nerve trunks
(plexiform neurofibromas). They are a mix of Schwann cells and fibroblasts.
Malignant peripheral nerve sheath tumor (MPNST)
Sarcomas that arise from the peripheral nerve sheath that can arise from plexiform
neurofibromas. They are firm lesions of fibroblast-like cells with foci of necrosis and
hemorrhage.
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CHAPTER 7
GENETIC DISEASES
Hereditary Disorders
Disorders derived from ones parents, are transmitted in the gametes through the
generations, and therefore are familial.
Congenital Disease
Something that is congenital is present at birth and is not always genetic (syphilis).
MUTATIONS
Pg 213 214
Mutation
Refers to permanent changes in the DNA. Germ line mutations are past along to
offspring, and somatic mutations, though not transmissible, can cause cancers and
congenital malformations.
Point Mutations: result from the substitution of a single nucleotide base by a
different base. If this substitution results in the replacement of one amino acid for
another, it is called a missense mutation. If the substitution results in a stop codon
being formed, it is termed a nonsense mutation.
Frameshift Mutations: occur when one or two (not a multiple of three) amino
acids is either inserted or deleted from a reading frame of the DNA strand.
Trinucleotide Repeat Mutations: are a category of mutations characterized by the
amplification of a sequence of three nucleotides. Each disorder has a unique
repeat, but all share the nucleotides G and C and all disorders are amplified during
gametogenesis.
Codominance
Occurs when both alleles of a gene pair may be fully expressed in the heterozygote (like
the AB blood group).
Polymorphism
The presence of multiple allelic forms of a single gene.
Pleiotropy
A single-gene mutation that may lead to many phenotypic effects (Marfan Syndrome).
Genetic Heterogeneity
Mutations at several different loci may produce the same trait (Retinitis Pigmentosa).

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MENDELIAN DISORDERS:
DISORDERS CAUSED BY SINGLE GENE DEFECTS
Pg 214 217
Autosomal Dominant
These disorders are manifested in the heterozygous state, so at least one parent of an
index case is usually affected, both males and females are affected, and both can transmit
the condition. These mutations usually affect structural (non-enzyme) proteins and
appear later in life.
Reduced penetrance: is the term applied when an individual inherits an autosomal
dominant disorder, but are phenotypically normal.
Variable expressivity: is when a trait is seen in all individuals carring the mutant
gene but is expressed differently among indivudals.
Dominant negative: refers to a mutant allele that impairs the function of a normal
allele.
Autosomal Recessive
These disorders occur when both of the alleles at a given gene locus are mutants, and are
characterized by the following: (1) the trait does not usually affect the parents, but
siblings may show the disease, (2) siblings have once chance in four of being affected,
and (3) enzyme mutations are common, and they frequently present early in life.
Lysosomal storage diseases: are a group of disorders caused by excessive
accumulation of complex substrates within the lysosomes occurring as a result of
a deficiency of degradative enzymes.
Albinism: is caused by a lack of tyrosinase, which is necessary for the
biosynthesis of melanin from its precursor, tyrosine.
X-linked
Most disorders are recessive in nature and are characterized by the following: (1) they are
transmitted by heterozygous females, (2) the female carrier usually does not express the
full phenotypic change, and (3) an affected male does not transmit the disorder to his
sons, but all daughters are affected.
DISORDERS CAUSED BY MUTATIONS IN STRUCTURAL PROTEINS
Pg 217 218
Marfan Syndrome
Is an autosomal dominant disorder of connective tissue with an abnormality in fibrillin 1
(a component of extracellular microfibrils that is needed in the formation of elastin).
Clinical presentation is variable because there are over a hundred different gene
mutations causing this disease; however, the following systems are affected most often:
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Skeletal abnormalities: patients have a slender, elongated habitus with abnormally

long legs, arms, and fingers (arachnodactyly), and hyper-extensible joints.
Ocular change: occurs in the form of bilateral dislocation, or subluxation, of the
lens owing to weakness of its suspensory ligaments.
Cardiovascular system: fragmentation of the elastic fibers in the tunica media of
the aorta predisposes to aneurismal dilation and aortic dissection. The cardiac
(mitral) valves are also affected, leading to floppy valve syndrome.
Lungs: spontaneous pneumothorax may occur due to damaged tissue in the lungs.

Ehlers-Danlos Syndromes
(EDS: over 10 variants)
Are all characterized by defects
in collagen synthesis or
structure.
They all have
similar clinical presentation,
affecting the skin, ligaments,
and joints.
The skin is
hyperextensible,
stretchable,
and vulnerable to trauma. The
joints are hypermobile.

DISORDERS CAUSED BY MUTATIONS IN RECEPTOR PROTEINS

Pg 218 220
Familial Hypercholesterolemia
Is caused by mutations in the LDL receptor gene that
impair the intracellular transport and catabolism of LDL,
resulting in accumulation of LDL cholesterol in the
plasma. The increased plasma cholesterol causes a
marked increase of cholesterol traffic into the monocyte
macrophages and vascular walls via the scavenger
receptor. This accounts for the appearance of skin
xanthomas (cholesterol deposits) and premature
atherosclerosis.
Schematic illustration of low-density lipoprotein (LDL) metabolism
and the role of the liver in its synthesis and clearance.

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DISORDERS CAUSED BY MUTATIONS IN ENZYME PROTEINS

Pg 220 225
Phenylketonuria (PKU)
An autosomal recessive disorder caused by a lack of phenylalanine hydroxylase leading
to hyperphenylalaninemia and PKU (musty or mousy odor to urine). Affected infants
are normal at birth but within weeks develop seizures, decreased skin/hair pigmentation,
and eczema in addition to mental retardation. The Guthrie test screens for PKU in
infants and treatment involves restricting phenylalanine intake early in life.
Maternal PKU: affects children born to mothers with PKU due to the teratogenic
effects of phenylalanine crossing the placenta.
Benign hyperphenylalaninemia:
occurs with a partial lack of
phenylalanine hydroxylase and
results in a slight increase in
blood phenylalanine but no other
defects.

Galactosemia
An autosomal recessive disorder of galactose metabolism due to a lack of galactose-1phosphate uridyltransferase (helps convert galactose to glucose) resulting in
accumulation of galactitol, mainly in the eye, kidney, and cerebral cortex. Infants fail to
thrive. Vomiting and diarrhea follows milk ingestion. Jaundice and hepatomegaly
present, followed by cataracts, and finally mental retardation. Treatment involves
removing galactose from the diet.
Lysosomal Storage Diseases
A group of autosomal recessive disorders characterized by an inherited lack of a
lysosomal enzyme leading to accumulation of partially degraded insoluble metabolites
within lysosomes (mostly affecting the phagocyte system).
The disorders are
differentiated based on the type of metabolite accumulating.

Schematic diagram illustrating the pathogenesis

of lysosomal storage diseases. In the example
shown, a complex substrate is normally degraded
by a series of lysosomal enzymes (A, B, and C)
into soluble end products. If there is a deficiency
or malfunction of one of the enzymes (e.g., B),
catabolism is incomplete and insoluble
intermediates accumulate in the lysosomes.

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Lysosomal Storage Diseases (Cont)

Tay-Sachs Disease (Gangliosidosis): is characterized by an accumulation of
gangliosides, principally in the brain, as a result of a deficiency in the enzyme
hexosaminidase A, which is necessary for the degradation of GM2. Affected
cells have a whorled appearance on EM. Prevalent among Ashkenazi Jews,
infants born with this disease suffer from mental retardation, blindness, and
neurologic dysfunction that leads to death within 3 years.
Neimann-Pick Disease (Type A): is one of three disorders in this group of
diseases. There is a lack of sphinomyelinase leading to excess sphingomeylin
accumulation in all phagocytic cells and neurons, principally affecting the spleen,
liver, bone marrow, lymph nodes, and lungs. It presents in infancy with
massive visceromegaly and severe neurologic detorioration.
Gaucher Disease: results from a mutation in glucocerebrosidase, which normally
cleaves the glucose residue from ceramide, leading to an accumulation of
glucocerebrosides in phagocytic cells forming Gaucher cells (cytoplasmic
appearance of wrinkled tissue paper). There are three types: Type I
(hepatosplenomegaly with no brain problems), Type II (hepatosplenomegaly with
brain involvement), and Type III (jeuvenille; severity between I and II).
Mucopolysaccharidoses (MPS): is a group of seven disorders characterized by a
loss of an enzyme responsible for the degradation of mucopolysaccharide. All
share the clinical features of coarse facial features, clouding of the cornea, joint
stiffness, and mental retardation.
Hurler Syndrome (MPS I): results from a deficiency of L-iduronidase with
an accumulation of dematan and heparan sulfate. Those affected have an
appearance called gargoylism, and usually die from cardiac problems
before the age of 10.
Hunter Syndrome: is an X-linked variant that results from a deficiency of
L-iduronate sulfatase with accumulation of dematan and heparan sulfate.
There is an absence of corneal clouding.
Glycogen Storage Diseases
A deficiency of any one of the enzymes involved in glycogen synthesis or degradation
leading to accumulation of glycogen most often within the cytoplasm. There are three
pathophysiological forms: hepatic (deficiency of liver enzymes causing hepatomegaly
and failure of glucose production), myopathic (absence of muscle enzymes that
breakdown glycogen causing muscle weakness, cramps after exercise, and failure of
exercise to induce increased blood lacate levels), and other.

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Von Gierke disease: prototype of hepatic glycogen

storage diseases and is caused by a lack of glucose-6phosphatase.
McArdle disease: prototype of the myopathic glycogen
storage disease and is caused by a deficiency of muscle
phophorylase.
Pompe disease: is in the other group, is caused by a
deficiency of lysosomal acid maltase, and is associated
with prominent cardiomegaly.

MUTATIONS IN PROTEINS REGULATING CELL GROWTH

Pg 225 227
Neurofibromatosis (Type I: 90% of cases)
An autosomal dominant disorder of hereditary tumors with three major features: (1)
multiple neurofibromas (pedunculated nodules protruding from the skin), (2) pigemented
skin lesions known as caf-au-lait spots, and (3) pigmented iris harmatomas called Lisch
nodules. It is caused by a mutation in the NF1 gene, which produces neurofibromin (a
down regulator of the RAS oncoprotein).
Neurofibromatosis (Type II)
Is a more rare form characterized by caf-au-lait spots, bilateral acoustic schwannomas,
and multiple meningiomas. The mutant gene for this type is found on 22q12, which
encodes merlin (a tumor suppressor gene).

DISORDERS WITH MULTIFACTORAL INHERITANCE

Pg 227
Multifactoral inheritance
A multi-factoral trait is governed by the additive effect of two or more genes of small
effect but conditioned by environmental, non-genetic influences. Presumably, there is
some threshold effect, so that a disorder becomes manifest only when a certain number of
genes, as well as conditioning environmental influences, are involved. Examples include:
hypertension, diabetes mellitus, gout, and bipolar disorder.

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CYTOGENETIC DISORDERS
Pg 227 234
Karyotype
A photographic representation of a stained metaphase spread in which the chromosomes
are arranged in order of decreasing length and stained (usually Giemsa) which allows
visualization of each chromosomes unique banding pattern.
Euploid
The normal human cell contains 46 chromosomes (2n = 46). Any exact multiple of n is
called euploid. Chromosome numbers such as 3n and 4n are termed polyploidy, while
any number that is not an exact multiple of n is called aneuploid.
Trisomy: referes to the presence of an extra chromosome, while monosomy refers
to the absence of a chromosome.
Mosaicism: is a term used to describe the presence of two or more populations of
cells in the same individual.
Translocation: Implies transfer of a part of one chromosome to another chromosome and
is usually a reciprocal process. Balanced translocations involve the entire broken
fragments being exchanged without loss of genetic material; however, Robertsonian
translocation involves the loss of genetic material.
Isochromosomes: result when the
centromere divides horizontally rather
than vertically.
Deletion: involves loss of a portion of a
chromosome.
Inversion: occurs when there are two
interstitial breaks in a chromosome, and
the segment reunites after a complete
turnaround.
Ring chromosome: occurs when, after
loss of segments from each end of the
chromosome, the arms unite to form a
ring.

Chromosome 22q11 Deletion Syndrome

This syndrome encompasses a range of disorders including DiGeorge syndrome and
velocardiofacial syndrome. When T-cell immunodeficiency and hypocalcemia are the
dominant features, the patient is said to have DiGeorge, whereas patients with
velocardiofacial syndrome have mild immunodeficiency with pronounced
dysmorphology and cardiac defects.
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Trisomy 21 (Down Syndrome)

Increased maternal age has been correlated
with an increased incidence of Down
syndrome. The degree of mental retardation
seen with trisomy 21 is severe with IQs
ranging from 25-50. Approximately 40% of
patients have cardiac malformation which
account for most of the deaths in early
childhood. There is also an increased risk for
developing acute leukemia (megakaryocytic
leukemia mostly). In those without cardiac
defects, 80% will live to age 30, though most
will develop changes consistent with
Alzheimer disease.

Patau Syndrome (Trisomy 13)

Edwards Syndrome (Trisomy 18)

Lyonization
The phenomenon that wherever there are two or more haploid sets of X-linked genes in
each cell, all but one of the genes are inactivated at random and have no phenotypic
expression. The inactived X-chromosome (Barr body) appears as a prominent clump of
chromatin attached to the nuclear membrane in the interphase nuclei.
Klinefelter Syndrome
A syndrome of male hypogonadism that develops when there are at least two X
chromosomes and one or more Y chromosomes with most patients being 47, XXY. The
classic presentation includes: appearance of an elongated body, reduced body hair, and
gynecomastia. Due to testicular atrophy, there are low levels of testosterone and sterility
is a frequent complication due to impaired spermatogenesis. Histologically, there is
hyalinization of the spermatic tubules, which appear as ghostlike structures and
prominent Leydig cells.

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Turner Syndrome
Is characterized by primary hypogonadism in
phenotypic females resulting from partial or
complete monosomy of the short arm of the X
chromosome with most patients being 45, X.
Affected girls fail to develop secondary sex
characteristics, the genitalia remains infantile,
and little pubic hair appears. In adult patients, a
combination of short stature and primary
amenorrhea should prompt strong suspicion of
Turner Syndrome.

SINGLE GENE DISORDERS WITH ATYPLICAL INHERITANCE

Pg 234 238
Fragile X Syndrome
This mutation is characterized by a long repeated sequence of three nucleotides (CGG) in
the FMR1 gene. Normally, there are 29 repeats, but those with this syndrome have 2304000. Those with 52-230 repeats have permutations. This trinucleotide amplification
disrupts normal gene function. The syndrome manifests as mental retardation, a long
face with large mandible, large everted ears, large testicles (macro-orchidism), and a
visible abnormality in the X chromosome on karyotyping.
Mitochondrial Mutations
Mutations in mitochondrial DNA are unique in that they follow maternal inheritance.
Mothers transmit mitochondrial genes to all of their offspring, both male and female;
however, daughters but not sons transmit the DNA further to their progeny. The
prototype of this group is Leber hereditary optic neuropathy which manifests as
progressive bilateral loss of central vision leading to blindness.
Genomic Imprinting
In some genes, functional differences exist between paternal and maternal genes. These
differences arise from genomic imprinting, whereby certain genes are inactivated during
paternal and maternal gametogenesis. Transcriptional silencing of the maternal allele is
maternal imprinting, while silencing of the paternal allele is paternal imprinting.

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Prader-Willi Syndrome: is a syndrome characterized by mental retardation, short

stature, hypotonia, obesity, small hands and feet, and hypogonadism. In all cases
there is a deletion affecting the paternally derived chromosome 15.
Angelman Syndrome: is caused by a deletion that affects the maternally derived
chromosome 15. This syndrome presents with ataxic gait and inappropriate
laughter (happy puppet syndrome). Seizures are also present.

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CHAPTER 7
PEDIATRIC DISEASES
Congenital Anomalies
Structural defects present at birth, although some may not present until later in life.
Malformations: are primary errors in morphogenesis, indicating an intrinsically
abnormal developmental process.
Disruptions: result from secondary destruction of an organ or body region that
was previously normal in development due to an extrinsic disturbance in
morphogenesis. Amniotic bands, denoting rupture of amnion with resultant
formation of bands that encircle parts of the developing fetus, are the classic
example of a disruption.
Deformations: are caused by extrinsic disturbances causing a localized or
generalized compression of the growing fetus by abnormal biochemical forces,
leading to a variety of structural abnormalities.
Sequence: refers to multiple congenital anomalies that result from secondary
effects of a single localized aberration in organogenesis. Potter sequence is
caused by the decreased amount of amniotic fluid leading to compression of the
fetus. It can cause flattened facies, hand and foot abnormalities, and the lungs
may be poorly developed.
Malformation syndrome: refers to the presence of several defects that cannot be
explained on the basis of a single localizing initiating error in morphogenesis.
Organ specific malformation
Agenesis refers to the complete absence of an organ, whereas aplasia and hypoplasia are
used to indicate incomplete development or underdevelopment. Atresia describes the
absence of an opening.
CAUSES OF CONGENITAL MALFORMATIONS
Pg 240 242
Rubella embryopathy
Environmental influences, such as viral infections, can cause malformations. The tetrad
of congenital heart defects, cataracts, deafness, and mental retardation due to maternal
infection with rubella (usually during the first 12 weeks of gestation), is termed rubella
embryopathy.
Teratogenic
Substances or agents that can interfere with normal embryonic development.

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Fetal Alcohol Syndrome

Consuming alcohol during pregnancy can cause fetal alcohol syndrome. Affected infants
show prenatal and postnatal growth retardation, facial anomalies (microcephaly, short
palpebral fissures, maxillary hypoplasia), and psychomotor disturbances.
Diabetic Embryopathy
The incidence of major malformations in infants of diabetic mothers is between 6-8%.
Maternal hyperglycemia induces fetal hyperinsulinemia resulting in fetal macrosomia
(organomegaly and increased body fat/muscle mass), cardiac anomalies, neural tube
defects, and CNS anomalies.

Critical periods during development.

PERINATAL INFECTIONS
Pg 242
Transcervical (Ascending) Infections
Involve the spread of infection (usually bacterial) from the cervicovaginal canal and may
be acquired by inhaling infected amniotic fluid into the lungs or by passing through the
birth canal. Chorioamnionitis is inflammation of the placental membranes and funisitis
is inflammation of the umbilical cord. -hemolytic strep/herpes simplex
Transplacental (hematologic) Infections
The infecting microbes (usually viral or parasitic) gain access to the fetal bloodstream
through chorionic villi. The most important of these infections can be remembered as the
TORCH complex:
TORCH Complex: is a mnemonic to assist in remembering the most important
transplacental infections and stands for: Toxoplasma, Rubella, Cytomegalovirus,
Herpes/HIV. Some people change the mnemonic to TORCHES adding
Enteroviruses and Syphilis to the list.

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PREMATURITY AND
INTRAUTERINE GROWTH RETARDATION
Pg 242 251
Prematurity
Is the most common cause of neonatal mortality and morbidity and is defined by a
gestational age less than 37 weeks. These infants weigh less than the normal 2500 g.
Preterm infants are vulnerable to several complications: respiratory distress syndrome,
necrotizing colitis, and intraventricular and germinal matrix hemorrhage.
Intrauterine growth retardation (IUGR)
Infants that are born at term and weigh less than 2500-g are said to be small for
gestational age (SGA) and suffer from intrauterine growth retardation (IUGR).
Respiratory Distress Syndrome (Hyaline membrane disease)
Is caused by the inability of the infant to produce surfactant leading to alveolar collapse
(atelectasis), and ultimately, epithelial-endothelial damage and the formation of hyaline
membranes. It is usually a disease of premature infants, although maternal diabetes
and twins is also a risk. Infants initially look fine, but within minutes-hours develop
labored breathing. Treatment involves ventilation and administration of surfactant, while
prevention involves administration of corticosteroid (stimulates surfactant production) to
the mother.

Bronchopulmonary dysplasia: is part of the long-term sequelae

that results in those who survive RDS and is seen as hyperplasia
and squamous metaplasia of bronchial epithelium, peribronchial
firbosis, fibrotic obliteration of bronchioles, and overdistended
alveoli.
Surfactant: is produced by type II pneumocytes, is made of
dipalmitoylphosphatidylcholine (lecithin), and acts to reduce
surface tension and decrease the pressure required to keep alveoli
open.

Necrotizing Entercolitis (NEC)

If a premature infant has the onset of bloody stools, abdominal distention, and the
development of circulatory collapse, think NEC. The cause is unknown but intestinal
ischemia is always seen, which can lead to intestinal perforation and peritonitis.
Pneumatosis intestinalis: gas within the intestinal wall (seen on radiograph).

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Sudden Infant Death Syndrome (SIDS)

The sudden and unexpected death (usually during sleep and without struggle) of an infant
less than 1 year of age whose death remains unexplained after the performance of a
complete autopsy (look for child abuse and congenital defects), examination of the scene
of death, and review of the case history. It is recommended that infants be placed in the
supine position to sleep, as there is increased risk for SIDS in infants who sleep in the
prone position.
Hydrops Fetalis (HF)
Is the term used for generalized edema of the feuts, a severe manifestation of progressive
fluid accumulation during intrauterine growth that is frequently lethal. HF represents the
most severe, generalized manifestation and lesser degrees of edema such as isolated
pleural, peritoneal, or postnuchal fluid collections can occur.
(1) Immune Hydrops (IH)
Results from an antibody-induced hemolytic disease in the
newborn that is caused by blood group incompatibility
between mother and fetus. This occurs when the fetus
inherits red cell antigenic determinants from the father that
are foreign to the mother. Currently, Rh-negative mothers
are administered anti-D globulin (RhIg) soon after the
delivery of an Rh-positive baby, thus preventing longlasting sensitization to Rh antigen. IH can be anticipated
by Coombs testing the fetal cord blood or looking for
increased levels of bilirubin on amniocentesis.
Fetomaternal bleed: fetal red cells may reach the maternal
circulation during the last trimester of pregnancy, when the
cytotrophoblast is no longer present as a barrier, or during
childbirth itself.

(2) Nonimmune Hydrops

Major causes include cardiovascular defects, chromosomal abnormalities (Turners and
trisomies 18 and 21 which cause cardiac anomalies), and fetal anemia (in those
homozygous for -thalassemia or infected with Parvovirus B19).
Cystic hygromas: can be seen in Turner syndrome and is post-nuchal fluid
accumulation due to an abnormality of lymphatic drainage from the neck.
Erythroblastosis Fetalis: refers to the presence of large numbers of immature red
cells in the peripheral circulation of the fetus with HF associated with fetal
anemia.
Kernicterus: severe hyperbilirubinemia in the neonatal period (secondary to
immune hydrolysis) results in deposition of bilirubin pigment in the brain
parenchyma (which turns a characteristic yellow) leading to long-term neurologic
sequelae.
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Cystic Fibrosis
Is the most common autosomal recessive disorder
affecting whites with the primary defect being a
mutation (there are many) in the cAMPdependent chloride channels, also called the
cystic fibrosis transmembrane conductance
regulators (CFTRs), rendering the epithelial
membranes relatively impermeable to Cl- ions.
This impermeability is responsible for the
increased NaCl in the sweat, as well as the viscid
secretions in the respiratory tract and pancreas.
Treatment is symptomatic, but gene therapy is
being investigated. The average life span of a CF
patient is 30 years.
Pulmonary lesions: are characterized by dilated bronchioles and bronchi due to
viscid secretions, with secondary infection (P. aeruginosa and S.aureus) leading
to severe chronic bronchitis, bronchiectasis, and lung abscesses. Persistent
infections are responsible for death in 80-90% of patients.
Pancreatic abnormalities: characterized by secretions that block the ducts and
cause atrophy of the exocrine glands resulting in malabsoprtion of fats. The
ducts may become cysts separated only by the Islets and an abundant fibrous
stroma (fibrocystic disease of the pancreas).
Meconium ileus: is obstruction of the small bowel secondary to impacted viscid
mucin, and may present in newborns soon after birth. If the obstruction
ruptures, it can cause meconium peritonitis.
Biliary cirrhosis: can occur due to mucus build-up within the bile ducts.
Azoospermia: can occur due to obstruction of the vas deferens, epididymis, and
seminal vesicles resulting in infertility.
Sweat Chloride Test: along with clinical presentation, is crucial to the diagnosis
of CF, and measures the increased level of NaCl in the patients sweat.

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BENIGN TUMORS AND TUMOR-LIKE LESIONS

Pg 251 252
Heterotopia (choristoma)
Refers to microscopically normal cells or tissues that are present in abnormal locations.
They are of little significance, except that they can be confused with neoplasms.
Harmatoma
Refers to an excessive but focal overgrowth of cells and tissues native to the organ in
which it occurs. The cellular elements are mature but the architecture is abnormal.
Hemangiomas
These are flat to elevated, irregular, red-blue masses composed of capillaries in the skin,
particularly the face and scalp. The flat, larger lesions are termed Port wine stains. They
are the most common tumors of infancy, and usually, spontaneously regress.
Lymphangiomas
Cystic and cavernous spaces lined by endothelial cells and surrounded by lymphoid
aggregates; the spaces contain pale fluid. They occur in the skin, but also deeper tissues.
They can increase in size after birth and encroach on mediastinal structures or nerve
trunks in the axilla.
Sacrococcygeal teratomas
The most common germ cell tumor of childhood, they most frequently occur in infants
younger than 4 months, and 75% of these are benign. They grow in the sacrococcygeal
area, protruding away from the body, and can be quite large compared to the size of the
infant.

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MALIGNANT TUMORS AND TUMOR-LIKE LESIONS

Pg 252 257
Neuroblastoma
Are tumors composed of solid sheets of small, round,
blue cells affecting children (usually younger than 5).
75% of the time they arise within the abdomen
(favorite sites being the adrenal, retroperitoneum, and
mediastinum) leading to the most common
manifestation of protuberant abdomen with
accompanying fever and weight loss. Grossly, the
tumors are gray-white masses with cysts,
hemorrhage, and often calcifications. They may
spontaneously regress or mature. Presence of the
MYCN (formerly known as N-myc) oncogene is a
harbinger of a poor prognosis.
Catecholamine-containing granuoles: are present in the cells of most
neuroblastomas. Vanillylmandelic acid (VMA) and homovanillic acid (HVA)
are secreted and can often be detected in the blood and urine.
Homer-Wright pseudorosettes: describe tumor cells that are arranged about the
periphery of a central space filled with fibrillar extensions of the cells. No lumen.
Ganglioneuroblastomas: are composed of larger cells having more abundant
cytoplasm with large vesicular nuclei and a prominent nucleolus, representing
ganglion cells admixed with primitive neuroblasts.
Ganglioneuromas: are composed of mature ganglion cells in the absence of
residual neuroblasts.
Retinoblastoma
Another one of the small, round, blue cell tumors. These are the most common malignant
eye tumors of childhood, usually presenting before the age of 4. The presentation
involves poor vision, strabismus, whitish hue to the pupil (cats eye reflex), and pain and
tenderness in the eye. Treatment with enucleation, chemotherapy, and radiation has
excellent survival. Grossly, they appear as nodular masses (often with satellite seedings),
in one or both eyes. Genetically are associated with RB1 gene mutation.
Flexner-Wintersteiner rosettes: consist of clusters of cuboidal or short columnar
cells arranged around a central lumen.
Osteosarcoma: patients with familial retinoblastoma are at increased risk for
osteosarcoma and other soft tissue tumors.

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Wilms Tumor
Also called nephroblastoma, Wilms tumor is the most common primary tumor of the
kidney affecting children between the ages of 2 and 5. A few syndromes are associated
with increased risk of Wilms tumor and are accompanied by congenital malformations.
Grossly, these tumors are tan-gray with areas of hemorrhage and necrosis. They can
become large enough to palpate an abdominal mass that extends beyond the midline and
into the pelvis. Tumors this size can cause intestinal obstruction. Histologically, there is
a variable mix of blastemal, stromal, and epithelial cell types.
Anaplasia: may be present and is associated with unresponsiveness to therapy.
Nephrogenic rest: is renal tissue lagging in maturation found in 30-40% of
Wilms tumor. They are associated with bilateral Wilms tumors.
WAGR syndrome: gigantism, macroglossia, hemihypertrophy, visceromegaly,
omphalocele-umbilical hernia.
Denys-Drash syndrome: Wilms, aniridia, genital anomaly, retardation.
Beckwith-Wiedemann syndrome: male pseudohermaphroditism, Wilms tumor,
chronic renal failure.
DIAGNOSIS OF GENETIC DISEASE
Pg 257 262
Fluorescence in Situ Hybridization (FISH)
DNA probes labeled with fluorescent dyes that recognize chromosome-specific
sequences are applied to metaphase spreads or interphase nuclei. Then, the probe binds
to its complimentary sequence and thus labels the specific chromosomal region that can
be visualized under a fluorescent microscope. FISH can be used to look for gene
amplifications, like HER2/NEU in breast cancer and MYCN amplification in
neuroblastomas.
Polymerase chain reaction (PCR)
PCR makes a huge number of copies of a gene from a very small number to allow further
genetic analysis. PCR does this in three steps. Step 1: the double stranded DNA is
melted to single stranded DNA (at ~94C), Step 2: the primers bind to the single strands
(about ~54C), and Step 3: the PCR polymerase adds dNTP's from the 5' to 3', reading the
template from 3' to 5' side, to make two double stranded molecules (at about 72C). These
PCR steps are repeated for ~30 or 40 cycles on an automated PCR thermal cycler that
rapidly heats and cools the PCR reaction mixture.

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MULTISYSTEM
REVIEW
AMYLOIDOSIS
Amyloidosis
This is a group of diseases that share in common the deposition of similar appearing
proteins. Amyloidosis affects many organs causing a wide-range of symptoms: renal
disease leading to nephrotic snydrome, hepatosplenomegaly may be a presenting clinical
finding though is often asymptomatic, or cardiac abnormalities which may present as
conduction abnormalities and arrhythmias. Cardiac and renal involvement are important
causes of death in amyloidosis.
Amyloid
Amyloid is the generic term for a variety of proteinaceous materials that are abnormally
deposited in tissue interstitium in a spectrum of clinical disorders. It appears as an
eosinophilic, extracellular substance that is constructed of non-branching fibrils arranged
in a -pleated sheet. It accumulates around and separates cells, and can cause pressure
atrophy. When stained with Congo red it displays apple-green birefringence, an
important diagnostic tool. There are three major forms of amyloid:
(1) AL (Amyloid light chain): is derived from plasma cells, contains
immunoglobulin light chains, and is associated with some form of monoclonal Bcell proliferation.
(2) AA (Amyloid-associated): is a unique non-immunoglobulin protein
synthesized by the liver and is typically deposited in the setting of chronic
inflammatory states.
(3) A amyloid: is found in the cerebral lesions of Alzeihmer disease, as well as
the blood vessels. The A is derived from the larger transmembrane glycoprotein,
called amyloid precursor protein (APP).
Transthyretin (TTR): is a normal serum protein that binds and transports
thyroxine and retinal. A mutant form of TTR is deposited in a group of genetic
disorders called familial amyloid polyneuropathies. Normal TTR is responsible
for senile amyloidosis affecting the heart.
2-microglobulin: is a normal serum protein and component of MHC I molecules
that is responsible for amyloidosis in patients on long-term hemodialysis (it
deposits in the synovium, joints, and tendon sheaths).

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Primary amyloidosis
This term is applied to amyloidosis when it is associated with some immunocyte
dyscaria. It is usually systemic in distribution and the amyloid is of the AL type.
Multiple myeloma: is a malignant neoplasm of B-cells that characteristically
synthesize abnormal amounts of a single specific immunoglobulin, producing an
M (myeloma) protein spike on serum electrophoresis.
Bence-Jones protein: are or light chains secreted by the malignant B-cells of
multiple myeloma. Nearly all patients with myeloma who develop amyloidosis
have these proteins in their blood and/or urine.
Secondary amyloidosis
This is the term applied to amyloidosis when it occurs as a complication of an underlying
chronic inflammatory or tissue destructive process. It is seen most often in the setting of
chronic inflammation caused by autoimmune states (rheumatoid arthritis, ankylosing
spondylitis, and inflammatory bowel disease). It may also occur with non-immunocytederived tumors, as in renal cell carcinoma and Hodgkin disease.
Familial Mediterranean Fever
Is an autosomal recessive condition characterized by attacks of fever accompanied by
inflammation of serosal surfaces, including peritoneum, pleura, and synovial membrane.
It is associated with systemic amyloidosis composed of AA proteins.

HEMOCHROMATOSIS
Hereditary Hemochromatosis
This is an autosomal recessive disease in which iron accumulates and is deposited in
parenchymal organs (liver, pancreas, and heart) over the lifetime of an individual due to
excessive intestinal absorption. Clinically, hemochromatosis affects males more than
females, rarely presenting before the age of 40. The classic triad of symptoms in fully
developed cases is: skin pigmentation, diabetes mellitus (from destruction of pancreatic
isles), and cardiac dysrythmia. Other major symptoms include liver cirrhosis and
atypical arthritis.
HFE gene: is the hemochromatosis gene and an intact HFE is necessary in the
regulation of iron uptake by the intestinal enterocyte.
In hereditary
hemochromatosis, there is a mutation (C282Y: a tyrosine substitution for cysteine
at amino acid 282) which disrupts a critical disulfide bond.
Body Iron Levels: are normally in the range of 2-6 grams; however, in a patient
with hemochromatosis, the body iron level may be in excess of 50 grams. Due to
screening and checking the body iron levels, hemochromatosis can be caught
before it manifests as the classic triad.
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Phlebotomy: or the removal of blood, along with iron chelating agents, is the
main treatment of hemochromatosis. If started early enough, treatment can
prevent further damage and allow cells not permanently damaged to recover.
Hepatocellular carcinoma: is a significant cause of death because treatment of
iron overload does not remove the risk for this aggressive neoplasm.
RHEUMATOID ARTHRITIS
Rheumatoid arthritis (RA)
RA is a systemic, chronic inflammatory disease affecting multiple tissues but principally
attacking the joints. The arthritis typically presents as a symmetric arthritis, mainly
affecting the small joints (excluding the DIP joints), may be accompanied by
constitutional symptoms, and causes joint pain and stiffness that is worse in the morning.
The joint inflammation is immunologically mediated; however, the initiating antigen is
not known.
Rheumatoid factor (RF): is circulating IgM autoantibodies
directed against the Fc portion of IgG and are present in 80% of
patients. RFs and IgG form immune complexes that fix
complement, attract neutrophils, and lead to tissue injury by a
type III hypersensitivity reaction.
Synovitis: in the affected joints is characterized by synovial cell
hyperplasia, perivascular infiltrates of CD4 T-cells, plasma cells,
and macrophages, angiogenesis, organizing fibrin on the
synovial surface in the joint space, and increased osteoclast
activity.

Pannus: is focal ulceration of the synovial membrane with proliferation of tissue

composed of synovial and inflammatory cells and granulation and fibrous
connective tissue that damages the underlying articular cartilage.
Rheumatoid subcutaneous nodule: are firm, nontender, masses up to 2-cm in
diameter that occur along the extensor surface of the forearm or other areas
subjected to pressure. They have a central focus of fibrinoid necrosis surrounded
by a palisade of macrophages, which is rimmed by granulation tissue.
Juvenile rheumatoid arthritis (JRA)
JRA refers to a group of disorders that cause chronic, idiopathic arthritis in children. RF
is usually absent, as are rheumatoid nodules. Some variants involve relatively few larger
joints such as knees, elbows, and ankles and are thus called pauciarticular.

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SYSTEMIC LUPUS ERYTHEMATOSUS

Systemic lupus erythematosus (SLE)
SLE is an autoimmune, multisystem disease that principally affects the skin, kidneys,
serosal membranes, joints, and heart. It is a disease of multifactoral origin, resulting in a
T-cell and B-cell activation that culminates in the production of several species of
autoantibodies. It affects women more than men and black women more than anyone
else.
Antinuclear antibodies (ANA): are directed against
several nuclear antigens and
can be grouped into
four categories, those against DNA, histones, nonhistone protein bound to RNA, and antibodies to
nucleolar antigens. They are present in nearly all
patients with SLE, but may be found in other immune
diseases.
Smith (Sm) antigen: the presence of antibodies to
double-stranded DNA, or to the so-called Smith (Sm)
antigen, is virtually diagnostic of SLE.
Lupus anticoagulant: phospholipids are required for
clotting and patients with anti-phospholipid antibodies
may display prolongation of in-vitro clotting tests, such
as the PT time; therefore, these antibodies are referred
to as lupus anticoagulants.

Antiphospholipid antibody syndrome: refers to the fact that SLE patients are
actually in a prothrombotic state despite the prolonged PT time. They tend to
have venous and areterial thromboses, thrombocytopenia, and recurrent
spontaneous miscarriages.
LE cell: a phagocytic cell that has engulfed the denatured nucleus of another
injured cell. When blood is withdrawn and agitated, a number of WBC are
damage to expose their nuclei to ANAs, with secondary compliment activation;
these nuclei are then phagocytized. This LE test is present in 70% of SLE
patients but is not used any longer.
Acute necrotizing vasculitis: is characterized by necrosis and by fibrinoid deposits
within vessel walls containing antibody, DNA, complement, and fibrinogen. In
chronic states, this can lead to thickening and luminal narrowing.
Photosensitivity: the skin is involved in the majority of patients and classically
manifests as a characteristic eryhtematous or maculopapular rash over the malar
eminences and bridge of the nose (butterfly pattern). Exposure to sunlight makes
the rash worse and the development of a new rash over other exposed areas.

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Libman-Sacks endocarditis: are valvular, non-bacterial lesions that take the form
of 1 to 3-mm warty deposits, distinctively on either surface of the leaflets and at
the margins.
Glomerulonephritis: involves deposition of DNA/anti-DNA complexes within the
glomeruli. These evoke an inflammatory response that may cause proliferation of
the endothelial, mesangial, and/or epithelial cells, and in severe cases, necrosis of
the glomeruli.

SARCOIDOSIS
Sarcoidosis
This is a multisystemic disease of unknown etiology characterized by noncaseating
granulomas in many tissues and organs. The primary manifestation is bilateral, hilar
adenopathy.
Schaumann body: These are found inside the granulomas that characterize
sarcoidosis. They are laminated concretions composed of calcium and proteins.
Asteroid body: These are found inside the granulomas that characterize
sarcoidosis. They are stellate inclusions enclosed within giant cells.
Lymphangitic distribution: The granulomas of sarcoidosis predominantly involve
the lung intersititium rather than air spaces, with some tendency to localize in the
connective tissue around bronchioles and pulmonary venules and in the pleura
(lympangitic distribution).
Erythema nodosum: This is the hallmark of sarcoidosis. It is characterized by
raised, red, tender nodules on the anterior aspects of the legs.

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Lupus pernio: is another characteristic skin lesion of sarcoidosis that consists

of indurated plaques associated with violaceous discoloration in the region of the
nose, cheeks, and lips.
Iritis: Inflammation of the Iris.
Sicca syndrome: occular lesions that affect the lacrimal glands, with suppression
of lacrimation, is called sicca syndrome.
Mikulicz syndrome: combined uveoparotid involvement is designated Mikulicz
syndrome.
GOUT & PSEUDOGOUT
Gout
Recurrent episodes of acute arthritis caused by the tissue accumulation of excessive
amounts of uric acid (an end product purine metabolism) due to overproduction or
under-excretion. The increased level of uric acid is termed hyperuricemia. Precipitation
of monosodium urate crystals from supersaturated synovial fluid activate compliment
and recruit neutrophils leading to joint destruction. Gout typically affects men over 30
and most often (90%) involves the great toe. The arthritis is usually asymmetric, affects
only a few joints, and may be accompanied by skin nodules called tophi.
Monosodium Urate crystals: can be identified by examining the synovial fluid.
These crystals appear yellow-white and are negatively birefringent.
Primary Gout (90%): is gout in which the basic cause is unknown or when the
cause is an inborn metabolic abnormality.
Secondary Gout (10%): the cause of hyperuricemia is known but gout is not the
main or dominant clinical disorder (lymphoma, leukemia, chronic renal failure).

The pathogenesis of gout is

related to the overproduction
of uric acid resulting from
some abnormality in the
metabolism of purines (the
horrible schematic to the
left).

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HGPRT: the conversion of PRPP to purine nucleotides is catalyzed by amido PRT

in the de novo pathway and by APRT and HGPRT (hypoxanthine-guanine
phosphoribosyltransferase) in the salvage pathway.
Lesch-Nyhan syndrome: this is an X-linked condition with complete lack of
HGPRT leading to excessive amounts of uric acid, mental retardation, and selfmutilation.
Chronic tophaceous arthritis: recurrent episodes of urate deposition leads to large
amounts of chalky white sodium urate (tophi) deposition on articular cartilage
triggering a chronic granulomatous reaction which can lead to ankylosis.
Gouty nephropathy: uric acid crystals can precipitate within and obstruct renal
tubules. Patients undergoing chemotherapy have a rapid cell turnover rate leading
to hyperuricemia (Tumor lysis syndrome) causing gouty nephropathy.
Pseudogout
Should be included in the differential of arthritis since it is often misdiagnosed as gout,
rheumatoid, or osteoarthritis. Pseudogout is the result of crystals precipitating out of the
synovial fluid.
In contrast to gout, these crystals are composed of calcium
pyrophosphate. Diagnosis is made by examining synovial fluid and visualization of
blue, positively birefringent crystals. The calcium may also be visualized on X-ray.
Acute suppurative arthritis
Infection of the joints may occur during episodes of bacteremia, through traumatic
implantation, or from direct spread of an infection from the adjacent bone or soft tissues.
It is manifest as local pain, fever, and a neutrophilic joint infiltrate (pus). The
immunocompromised, IV drug users, and compliment deficient are at increased risk.
Common pathogens gonococci and Salmonella.

PSORIASIS
Psoriasis
Psoriasis is common and frequently affects the skin of the elbows, knees, scalp,
lumbosacral areas, and even the glans penis. The most typical lesion is a welldemarcated, pink to salmon-colored plaque covered by loosely adherent scales that are
characteristically silver-white. The pathogenesis is unclear, though it seems to be
multifactoral (genetic and environment). The disease results from sensitized T cells
entering the skin which create an abnormal microenvironment via cytokines.
Onycholysis: nail changes occur in 30% of patients, to include separation of the
nail plate from the underlying bed (onycholysis).

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Pustular psoriasis: This is a rare variant of Psoriasis characterized by multiple

small pustule formation on erythematous plaques.
Stratum granulosum: morphologically, the stratum granulosum is thinned or
absent, and extensive overlying parakeratotic scale is seen.
Dermal papilla: typical of psoriatic plaques is thinning of the epidermal layer that
overlies the tips of dermal papillae (suprapapillary plates) and dilated, tortuous
blood vessels within these papillae.
Auspitz sign: the above mentioned blood vessels readily bleed when the scale is
peeled back and the surpapapillary plates are unroofed, giving rise to multiple
minute bleeding points. This is Auspitz sign.
Spongiform pustule: neutrophils form small aggregates within slightly spongiotic
foci of the epidermis (spongiform pustules) and within the parakeratotic stratum
corneum (Munro microabscess).

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