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GENERAL PATHOLOGY

MANUAL

NEOPLASIA I-II

PATHOLOGY 201-2
MEDICAL STUDENTS - SECOND YEAR
20101-11

The George Washington University


Medical Center

Prepared by:
Department of Pathology
TABLE OF CONTENTS

Topic: Introduction to Neoplasia I and II Page

Lecture objectives 2

Lecture handout 4

Laboratory : Neoplasia I & II Virtual Slides 10

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Pathology #201-2
NEOPLASIA
Course Objectives (as of 2009-10)
(adapted from Group for Research in Pathology Education)

1. Define, explain and give an example of:adenoma


anaplasia grade pleomorphism
angiogenesis hamartoma polyp
benign hyperplasia prevalence
cachexia hypertrophy prognosis
cancer incidence promotion
carcinogen initiation invasion sarcoma
carcinogenesis malignant stage
carcinoma in situ metaplasia tumor
differentiation metastasis tumor antigens
desmoplasia neoplasia tumor marker
dysplasia papilloma oncogene
epidermoid paraneoplastic syndrome tumor suppressor gene
exophytic parenchyma

2. Discuss, explain, and identify the pathologic findings,


etiology, pathogenesis, differential characteristics, clinical
presentation and outcome of:

Hyperplasia, metaplasia, dysplasia, neoplasia, anaplasia, benign


tumors, malignant tumors

3. Define, explain and list examples of:

The classification scheme of tumor, tumor nomenclature, tumor


grading, tumor staging, tumor growth kinetics, tumor initiation and
promotion, extension and spread of malignant tumors

4. Define, explain and give an example of:

Tumor surveillance, tumor immunology, immune cells of host defense,


tumor infiltrating lymphocytes, techniques in diagnosis and
prognosis, tumor markers

5. List, define, explain and give an example of:

Physical, chemical, and biologic agents and their associated


tumors, mechanisms and characteristics of initiation and promotion,
and their link to oncogenes and tumor suppressor genes, sequential
pattern of carcinogenesis

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6. Define, explain and give an example of:

The role of the pathologist in the determination of tumor


screening, diagnosis, prognosis, tumor grading and staging, and
utilization of special techniques and studies

7. Define, explain and give an example of (as discussed in lecture


and in the manual):

Tumor incidence, prevalence, mortality, factors influencing


incidence and mortality, major tumors of adults and children in
terms of incidence and mortality, familial tumors,
environmental/occupational associated tumors, predisposing factors,
preneoplastic conditions

Readings

Cotran, Kumar, Robbins. Robbins Pathologic Basis of Disease, 8th


Edition, 2009, Chapter 7 – with emphasis on the information covered
in the lecture and labs

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Pathology #201-2

INTRODUCTION TO NEOPLASIA - I AND II


Samantha Easley, MD

Epidemiology

A. Cancer incidence: Over 1 million new diagnoses per year.


Approximately 20-25% of all deaths per year in USA are
due to cancer; cancer deaths are second in incidence
following cardiovascular disease and stroke.

B. Major causes of cancer deaths in men: lung, prostate,


colo-rectal, hematopoietic (leukemia, lymphoma), urinary
tract, and pancreas.

C. Major causes of cancer deaths in women: lung, breast,


colo-rectal, hematopoietic, ovary, and pancreas.

D. Major causes of cancer deaths in children: Leukemia,


lymphoma, brain, colo-rectal, bone and soft tissue,
endocrine.

E. Major changes in cancer deaths over last 50 years: lung,


stomach, uterus, pancreas; many of the changes due to
environmental, occupational, and social influences.

F. Major factors for cancer incidence: hereditary (familial


predisposition), age, social habits (smoking, alcohol),
environment/occupation, pre-existing disease states
(cirrhosis, chronic ulcerative colitis), chemo-radiation
therapy.

I. Definitions and Nomenclature

A. Neoplasia is “new growth”. Tumors are abnormal growths:


proliferative (mitotically active), un-coordinated,
autonomous, genetically unstable. Tumors are composed of
(1) a proliferating neoplastic parenchyma, and (2) a
fibro-vascular supporting stroma.

B. Benign tumors tend to be slow growing (low mitotic


activity), well-differentiated, and localized (pushing or
encapsulated margins). Benign tumors usually follow a
benign clinical course, and may be treated with surgical
excision. Some benign tumor may have lethal
complications: meningioma (hydrocephalus), gastric

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leiomyoma (hemorrhage), insulinoma (hypoglycemia), atrial
myxoma (cardiac obstruction).

C. Malignant tumors are capable of invasion and metastases


and tend to be rapid growing (higher mitotic activity),
moderate or poorly differentiated, and infiltrative.

Microscopic characteristics of malignant tumors are


cellular and architectural pleomorphism, mitotic and
apoptotic activity with tumor necrosis, stromal and
lympho-vascular invasion, and distant metastases.

D. Hamartoma is a benign aberrant differentiation composed


of mature disorganized tissue, particular to its site of
origin. Adenoma is a benign epithelial tumor with gland-
like differentiation. Carcinoma is a malignant
epithelial tumor.An adenocarcinoma is an epithelial
cancer which forms glands. Squamous cell (or epidermoid
since it resembles squames in the epidermis of the skin)
carcinoma resembles squamous epithelium, and can have
variable degrees of differentiation. Sarcoma is a
malignant mesenchymal tumor. Lymphoma and leukemia are
malignant hematopoietic tumors

II. Pathobiology of Neoplasia.

A. Differentiation is an indicator of the morphologic and


physiologic characteristics of the tumor in relation to
the comparable normal tissue. In general structure and
function are concordant. Benign tumors tend to be well
differentiated with tumor cells resembling but possessing
a growth advantage over normal cells. Malignant tumors
tend to show a range of differentiation with increased
proliferative activity and variable loss of functional
properties.

B. Dysplasia is an abnormal or disordered growth due to


genetic changes that occurs in the epithelium or mucosa
of tissues and result in a loss of maturation, polarity,
and architectural orientation of epithelial cells.
Dysplastic cells show abnormalities in size and shape
(pleomorphism) and increased mitotic activity. Full
epithelial thickness of dysplasia, without invasion of
the basement membrane, is referred to as carcinoma-in-
situ and is a premalignant (non-invasive) state.

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C. Tumor Grade refers to the level of morphologic
differentiation. Tumor cells are evaluated according to
their size and shape, nuclear:cytoplasmic ratio, nuclear
and nucleolar characteristics, cytoplasmic differentiation,
mitotic activity, and tissue organization.

D. Tumor Stage refers to the distribution and extent of


cancer at the time of diagnosis. The components of stage
are (T) tumor characteristics, such as tumor size,
location, depth and extent of local invasion, (N) nodal
involvement, and (M) metastatic spread.

E. Carcinogenesis is a multistep process of genetic changes


and aberrations. Classical concepts included initiation
(cellular mutation), promotion (clonal expansion of the
initiated cell with proliferation secondary to continued
promoter stimulation), progression (autonomous growth,
genomic instability, and tumor heterogeneity), and cancer
(invasion and metastasis).

IV. Chemical and Physical Carcinogenic Agents

A. Carcinogenesis resulting from chemical or radiation exposure


was initially proposed based on epidemiologic data from
occupational, social, or environmental settings. Certain
work environments, social behavior, and environmental
exposures predispose to specific cancers.

B. Carcinogenesis is a multistep process that was


experimentally divided into two steps: initiation and
promotion. Initiation occurs as a result of an irreversible
toxic injury to DNA that can undergo replication and appear
in daughter cells following mitosis. Promotion is a
reversible, non-tumorigenic proliferative process that
induces tumor formation following initiation. Initiators
may act directly on DNA to cause damage (carcinogens) or
indirectly, following metabolic activation (procarcinogens).
Most carcinogens in vivo are mutagens in vitro.

C. Carcinogens often act through those genes whose expression


governs cellular function and activity such as cell cycle
activity, signal transduction, DNA repair mechanisms, and
apoptosis.

III. Pathology of Tumor Growth

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A. Tumors begin as monoclonal proliferations, yet acquire
heterogeneity as a result of growth and genetic instability.
Tumor progression occurs with the appearance of
subpopulations having phenotypic features of increased rate
of growth, invasiveness, metastatic potential, hormone or
growth factor responsiveness, and chemotherapeutic
resistance.

B. Rate of tumor growth usually correlates with the morphologic


grade and mitotic activity. Malignant tumors tend to grow
more rapidly than their benign counterparts. Tumor growth
rate is dependent on the nature of the neoplasm, supportive
stroma and neovascularization, hormone and growth factor
dependence, and interventional treatments. Tumors grow as a
result of increased cellular proliferation relative to cell
loss and growth of supporting stroma.

C. Tumors grow in phases: clonal transformation and malignant


change, local growth and angiogenesis, regional invasion,
metastatic spread. Tumors of 1 cm3 approximately weigh 1
gram and have 109 cells. About 10 more doubling times would
cause the tumor to weigh 1 kg. and contain 1012 cells.
Growth fraction (proliferating component) of tumors
represents a minority of the tumor cells and are most
susceptible to cell-cycle based chemotherapy.

D. Benign tumors tend to have a pushing or encapsulated margin.


Malignant tumors tend to have an infiltrative growth margin
and spread by (1) local invasion into adjacent tissues, (2)
direct seeding of body cavities (pleura, peritoneum,
subarachnoid or ventricles), (3) lymphatic spread, and (4)
hematogenous spread. The clinical presentation of most
tumors is in their site of origin; approximately 20% of
cancers present as a metastasis.

E. Tumors develop a supportive stroma and neovascularization


(angiogenesis) in order to growth and spread. Growth
factors produced by the tumor (VEGF, bFGF, PDGF, TGFbeta)
and host factors induce angiogenesis. Tumor and host cells
produce proteinases that digest basement membrane and
stromal matrix and enable tumor cell infiltration.
Angiogenesis and matrix digestion are balanced by anti-
angiogenic and anti-proteinase factors.

F. Tumor invasion occurs by a complex process of detachment of


tumor cells from a solid mass due to down-regulation of
cohesion proteins (cadherins), attachment of tumor cells to

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matrix by induction of surface matrix receptors (integrins),
degradation of extracellular matrix by proteinases, and
migration of tumor cells by motility and attractive factors.

G. The predilection for metastatic sites is governed by a


variety of factors: anatomic, vascular, and host-tumor
paracrine effects. Metastases to brain tend to arise from
lung, breast, kidney, GI, and melanoma. Metastases to liver
tend to arise from GI, pancreato-biliary, breast, and lung.
Metastases to bone tend to arise from prostate, breast,
lung, kidney, thyroid, and testes.

V. Host-Tumor Interactions

A. Tumors produce a series of factors (Tumor Antigens) that may


act as antigens and stimulate host immune response. Tumor
immunity may be induced by CD4 T-helper cells and by CD8 T-
cytotoxic cells. Tumor antigens may be specific to the
tumor, arise from mutations or overexpressions of surface
factors, represent inappropriate expression of oncofetal
antigens, or be shared with normal host cells.

B. Cell mediated and humoral immunity have anti-tumor effects.


Cell mediated activity occurs through sensitized cytotoxic T
cells, activated NK cells and macrophages. Tumors develop
mechanisms to evade normal host immunity by reduction of HLA
antigens, reduction of immuno-regulatory processes, or
immune suppression. Immuno-deficiency diseases are prone to
an increase in the development of malignancies, especially
lymphomas, and a decreased ability to prevent tumor growth
and spread.

VI. Clinical Features of Tumors

A. Cancers may clinically present with an asymptomatic mass,


pain or tenderness, non-healing lesion, persistent cough,
abnormal bleeding, perforation or obstruction, or non-
specific weakness and fatigue. Tumors may produce signs and
symptoms by mass effects of compression or obstruction,
secretory or physiologic effects, bleeding due to ulceration
or vascular injury, secondary infection, or generalized
cachexia (weakness, anorexia, weight loss, and anemia).

B. Tumors of endocrine or neuro-endocrine cells may present


with absence of function or overproduction of hormone,
causing symptoms by the suppression or overstimulation of
hormonal activity.

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C. Tumor markers are cellular and/or secretory products of the
neoplasm that may be detected in the tumor cells, serum, or
body fluids (effusions). Tumor markers are indicators of a
specific cancer or family of cancers and may be utilized to
confirm diagnosis, assess tumor staging, monitor for
response to therapy, or identify recurrent disease. These
markers include PSA (prostatic cancer), !-hCG (gestational
trophoblastic disease, choriocarcinoma, certain gonadal
cancers), "-fetoprotein (certain testicular cancers,
hepatocellular cancer), CEA (GI and pancreato-biliary
cancers), and CA-125 (ovarian cancers).

D. Paraneoplastic syndromes arise from the elaboration of


hormones or factors secondary to tumor progression. These
syndromes may appear as endocrinopathies, neuro-muscular
deficiencies, dermatologic conditions, bone changes, or
hematologic abnormalities. Treatment of the underlying
primary malignancy often corrects the paraneoplastic
condition.

VII. Pathologic Diagnosis of Tumors

A. Tumors may be identified by history, physical exam,


radiologic observations, or lab tests, but a precise
diagnosis is made by pathologic exam of tumor cells and/or
tissue. Tumors are recognized as abnormal cellular
proliferations that replace normal tissue. Malignant tumors
are recognized by their ability to invade and metastasize.
Cytologically, tumors are diagnosed by their abnormal
nuclear and cytoplasmic features.

B. The pathologic techniques to diagnose tumors include


cytologic methods (PAP smears, and fine needle aspirations),
surgical methods (biopsy, excisions, resections),
ultrastructural methods (electron microscopy), or molecular
methods (flow cytometry, immunohistochemistry, molecular
biology).

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Pathology #201-2
Lab Exercise
Neoplasia I

Folder: All slides are in Folder Neoplasia

Microslides Virtual Slide

CASE 1: Fibroadenoma Neoplasia 1


CASE 2A: Chondroid hamartoma of lung Neoplasia 2A
CASE 2B: Invasive squamous cell carcinoma Neoplasia 2B
CASE 3: Invasive breast adenocarcinoma Neoplasia 3

CASE 1: FIBROADENOMA
FIBROADENOMA
At low power, this tumor demonstrates many features of benignancy.
The mass is well-circumscribed and demarcated from the surrounding
breast tissue. A partial capsule can also be seen. This tumor is
biphasic, consisting of a glandular and stromal component. The
stroma is collagenous and eosinophilic in some areas and shows
bluish, myxoid change in others. At high power, the epithelium
lining the ducts is bland. The overall cellularity of the stroma
is low with no evidence of mitotic activity, necrosis or
pleomorphism.

CASE 2A: Chondroid hamartoma of lung


CHONDROID HAMARTOMA OF LUNG
Notice the well-circumscribed appearance of this benign hamartoma
at low power. The surrounding lung tissue shows normal alveolar
spaces. At high power, the hamartoma is composed of grayish-blue
cartilaginous (or chondroid) stroma and chondrocyes characterized
by small, dark nuclei sitting in open lacunar spaces. The hamartoma
resembles mature appearing cartilage. Within the neoplasm are
epithelial clefts which are lined by columnar epithelium and likely
represent entrapped respiratory epithelium.

CASE 2B: Lung cancer, squamous cell carcinoma


SQUAMOUS CELL CARCINOMA OF LUNG
The normal lung tissue in this section is entirely replaced by
squamous cell carcinoma. These large epithelial cells appear in
sheets with an intermittent swirling pattern. The cells have open-
appearing nuclei and a high nuclear:cytoplasmic ratio. The tumor is

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moderately to poorly differentiated meaning that there is
occasional keratin formation and moderate pleomorphism.
Intercellular bridges are more difficult to see in this image but
is also a finding characteristic of squamous cell carcinoma.

CASE 3: Invasive breast adenocarcinoma


INVASIVE BREAST ADENOCARCINOMA

This digitized image shows invasive ductal carcinoma. Notice the


disorganized appearance and desmoplastic stromal reaction at low
power. There is no evidence of normal terminal duct lobular units
within the tumor. At high power, the malignant cells infiltrate the
stroma in cords and tubules. The cells have an increased
nuclear:cytoplasmic ratio with some prominent nucleoli and nuclear
hyperchromasia. At its periphery, the malignant cells infiltrate the
breast parenchyma and fat.

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Pathology #201-2
Lab Exercise
Neoplasia II

Folder: All slides are in Folder Neoplasia

Microslides Virtual Slides

CASE 4: Angiosarcoma, breast Neoplasia 4


CASE 5: Poorly differentiated breast carcinoma Neoplasia 5
CASE 6A: Carcinoid tumor, small bowel Neoplasia 6A
CASE 6B: Metastatic neuroendocrine tumor carcinoid) Neoplasia 6B
to liver

CASE 4: Angiosarcoma, Breast


ANGIOSARCOMA OF BREAST
This image of an angiosarcoma of the breast exhibits extensive
necrosis which has a bluish-purple appearance on low power. Notice
that a portion of the slide contains normal appearing breast tissue
with well defined terminal ducts and acini. The remainder of the
breast is involved by a vascular tumor composed of
interanastomosing channels lined by cytologically atypical,
hyperchromatic, ovoid cells. At high power, mitotic figures can be
identified.

CASE 5: Poorly differentiated breast carcinoma


POORLY DIFFERENTIATED BREAST CARCINOMA
This slide contains an infiltrating tumor composed of sheets and
nests of neoplastic cells. The tumor cells lack tubule formation
and have a prominent associated lymphocytic infiltrate. At high
power, the cells are moderately pleomorphic with an increased
nuclear to cytoplasmic ratio, coarse chromatin and prominent
nucleoli. An in situ component is not identified.

CASE 6A: Carcinoid tumor, small bowel


CARCINOID TUMOR OF SMALL BOWEL
At low power, three hyperchromatic tumor nodules can be
appreciated. The nodules are submucosal with only focal surface
involvement. The overlying and adjacent small intestinal
epithelium is mostly unremarkable with normal appearing, tall
villi. At intermediate power, the tumor appears to proliferate in
well defined nests. Occasional rosette formation can also be seen.
At high power, the tumor cells are monotonous with a stippled “salt
and pepper” chromatin pattern and scant cytoplasm. In some areas,

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intracytoplasmic granules are identified. These findings are
characteristic of a neuroendocrine (carcinoid) tumor.

CASE 6B: Metastatic neuroendocrine tumor (carcinoid) to liver


METASTATIC NEUROENDOCRINE TUMOR (CARCINOID) TO LIVER
This is a core needle biopsy of a liver lesion. Notice at low
power that the tumor cells are arranged in well defined nests that
appear hyperchromatic. At high power, the nests are made up of
round, uniform tumor cells with round nuclei and a scant amount of
cytoplasm. Eosinophilic granules characteristic of neuroendocrine
tumors can be faintly seen.

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