Lung Pathology: Need to Know

American Society of Clinical Pathology

Resident Review Course

Henry D. Tazelaar, M.D.

Professor of Pathology
Mayo Clinic College of Medicine
Mayo Clinic Arizona
13400 E. Shea Blvd.
Scottsdale, Arizona 85259
Phone: 480-301-5530
tazelaar.henry@mayo.edu

Obstructive Pulmonary Disease

Emphysema

Definition: “a condition of the lung characterized by abnormal, permanent enlargement of

airspaces distal to the terminal bronchiole, accompanied by destruction of their walls, and
without obvious fibrosis.” [1]

Four major types found in four different clinical settings [2]:

Centriacinar:
- most common form of emphysema
- most common correlate of severe airflow obstruction in smokers
[3]
- also seen in coal workers i.e. simple coal worker’s
pneumonconiosis
-upper lobes most affected
- destruction of alveoli affects the alveoli immediately adjacent to
second and third order respiratory bronchioles. Lung at the
periphery of the lobule appears normal.
- in severe cases, there is overlap with panacinar
Panacinar:
- alpha-1-protease inhibitor deficiency (ZZ), intravenous drug
abuse, Ritalin, Swyer James syndrome, aging lung,
- involves destruction of entire acinus
- lower lobes most affected initially
 Distal acinar:
- least common form
- not usually associated with airflow obstruction
- acini adjacent to pleura and interlobular septae most destroyed
- upper lobes most often involved
- may contribute to spontaneous pneumothoraces and bullae
formation in tall, asthenic male adolescents
Paracatricial airspace enlargement (so-called irregular or “scar”
emphysema):
- airspace enlargement next to foci of fibrosis
- may not have clinical correlate depending on underlying
disease e.g. Langerhans’ cell histiocytosis

Blebs and Bullae [4]

Bleb- air within the visceral pleural layers, so a form of interstitial “emphysema” (the
term emphysema really being a misnomer here by the definition above)

Bullae- emphysematous space more than 1 cm in diameter in the distended state

Chronic Bronchitis

Definition:

Clinical- productive cough of unknown cause occurring on most days for 3 or

more months for at least 2 successive years.

Pathologic- usually refers to a non-specific combination of

goblet cell metaplasia of bronchial luminal lining cells
thickened basement membrane
submucosal gland hyperplasia
smooth muscle hypertrophy
chronic inflammation

Obviously, pathology is not the way to make the diagnosis!

Reid index: thickness of mucous gland layer/thickness of bronchial wall (normal

< 0.4)

Submucosal gland hyperplasia appears to contribute the most to mucus

hypersecretion, but goblet cell metaplasia likely also contributes.

The pathogenesis of chronic bronchitis appears related to inflammatory

mechanisms in which neutrophils appear to play a key role. [5]
Significance of Small Airways in Obstructive Lung Disease

Small airways “disease”- probably a term that should be abandoned, as it

has meant many different things since it was first introduced. Does not
refer to a specific disease. [4]

Thickness of small airways in patients who smoke (due to fibrosis,

inflammation and mucus), however, does appear to correlate with
emphysema. [6]

Asthma [4]

As with chronic bronchitis, pathology is not diagnostic in patients with asthma!

However, there are characteristic findings.

Macroscopic-
in patients dying in status asthmaticus
mucous plugging of airways
air trapping
late:
saccular bronchiectasis, especially in upper lobe

Microscopic

thickened basement membranes;

intraluminal mucous plugs with
Charcot-Leyden crystals
Curschmann spirals- coiled mucus plugs
Creola bodies-small groups of shed epithelial cells

goblet cell metaplasia

submucosal gland hyperplasia
inflammation, including eosinophils, mast cells, mononuclear
smooth muscle hypertrophy

Miscellaneous Diseases affecting Large and Small Airways

Allergic Bronchopulmonary Fungal Disease

Definition: syndrome affecting asthmatics and patients with cystic fibrosis resulting from
an allergic reaction to fungi. While aspergillus sp are the most notorious fungi to cause
this allergic phenomenon (allergic bronchopulmonary aspergillosis), multiple other fungi
can cause the disease.
 Diagnostic criteria: the presence of 6, including the first 5 of the following [7, 8]

• History of asthma or cystic fibrosis (10-15% of cases)

• Immediate skin reactivity to fungal (usually Aspergillus) extract
• Precipitating antibodies to fungi (usually Aspergillus)
• Elevated total serum IgE (> 1000ng/mL)
• Elevated IgE &/or IgG to fungi, usually Aspergillus fumigatus antigens
• Central bronchiectasis
• Recurrent pulmonary infiltrates
• Peripheral eosinophilia (> 500/mm3)

Pathology: includes a complex constellation of findings in various combinations

- bronchiectasis
- mucoid impaction of bronchi (MIB)
- bronchocentric granulomatosis (BCG)
- eosinophilic bronchiolitis
- chronic eosinophilic pneumonia

Bronchiectasis and Mucoid Impaction of Bronchi [4, 9]

Macroscopic

- dilated large airways filled with tenacious mucous plugs and casts of
variable color from green-grey, to yellow to white

Microscopic

- lamellated mucus as seen in other allergic syndromes such as allergic

fungal sinusitis rich in eosinophils in various stages of degeneration and
Charcot Leyden crystals

- rare degenerating fungal hyphae (not as many as one would see in an

infection

Bronchocentric Granulomatosis

-extremely rare (most cases of possible BCG are not BCG, but true infection)
- bronchioles appear replaced by necrotizing granulomas centrally located within
the airway

-fungal hyphae may be identified in the necrotizing granuloma, but they should be
rare, and non-invasive

- airways adjacent to those with BCG may contain an exudate not unlike that
described above in the context of mucoid impaction of bronchi
Acute Bronchiolitis [9]

- many causes, most significantly infection, aspiration (may be associated with

foreign material e.g. food

- pathology
ulceration of mucosa
inflammation, usually including neutrophils
intraluminal exudate

Chronic Bronchiolitis [10]

Non-specific pathologic term used to describe

Presence of chronic inflammation around and in wall of bronchiole
Presence of fibrosis around and in wall of bronchiole
Presences of peribronchiolar metaplasia

Usually part of the spectrum of pathology seen in a variety of primary airway

diseases and as a component of many classically “interstitial” diseases e.g.
extrinsic allergic alveolitis

Respiratory (Smokers’) Bronchiolitis

- defined as the presence of pigmented macrophages within respiratory

bronchioles and surrounding alveoli (mild chronic inflammation and fibrosis of
bronchiole may be seen)

- incidental findings in smokers [11]

- may be responsible for asymptomatic small nodules on imaging in smokers

- Histology the same in respiratory bronchiolitis-interstitial lung disease

Follicular Bronchiolitis

- form of lymphoid hyperplasia associated with connective tissues diseases (esp

Sjögren syndrome and rheumatoid arthritis) and immunodeficiencies

- chronic inflammation with germinal centers around bronchioles

Constrictive (Obliterative) Bronchiolitis

Multiple clinical settings

lung transplantation (chronic rejection)

bone marrow transplantation (graft vs. host disease
drug toxicity
connective tissue disease
idiopathic disease
exposures
di-acetyl - popcorn workers
sulfur mustard gas
infection e.g. post adenoviral

Pathology:

- bronchiolar and peribronchiolar fibrosis with narrowing and eventual

obliteration of the lumen
- may be preceded by acute and chronic bronchiolitis

- histology is similar regardless of etiology

Diffuse Lung Disease

Diffuse Alveolar Damage (DAD)/Acute Interstitial Pneumonia (AIP)

Clinical: Most common pathologic correlate of acute respiratory distress syndrome [12]
- Causes include pulmonary edema, septic shock, oxygen toxicity, drugs, radiation,
infection (influenza, PCP), trauma
- Associated with connective tissue disease e.g. “acute lupus pneumonitis”
- Idiopathic variant is represents acute interstitial pneumonia (AIP)—Hamman-Rich
syndrome [2, 13]
Microscopic pathology
- Temporally uniform (homogenous) injury so lungs look the same from field to field
- Two phases: acute and organizing (often overlapping due to attempted repair at the
same time there is ongoing injury)
Acute (exudative): interstitial edema, Type I pneumocyte sloughing and hyaline
membrane formation
Organizing: proliferating/reactive Type II pneumocytes and interstitial fibroblasts
with focal airspace organization (these areas may look like typical organizing
pneumonia:
 Acute and organizing thrombi within vessels are common
Metaplastic bronchiolar epithelium may be very atypical and mimic carcinoma
Differential Diagnosis
Cryptogenic organizing pneumonia:
More subacute course
Process is patchy around bronchioles
Hyaline membranes are not seen
Organization is only intraalveolar and intraluminal, not interstitial

“Idiopathic” Interstitial Pneumonias (IIP) [13]

A heterogeneous group of pneumonias with acute e.g. AIP, and more chronic
presentations

Although causes for other interstitial pneumonias are not always known e.g.
sarcoidosis, the IIP’s are characterized histologically by varying combinations of
interstitial fibrosis, organization, and chronic inflammation in both, or either the
interstitium and alveolar spaces without the presence of granulomas or specific
cell types e.g. Langerhans’ cells

Usual Interstitial Pneumonia (UIP) [4]

Clinical: Idiopathic disease = clinical diagnosis of idiopathic pulmonary fibrosis (IPF)

- Common in connective tissue disease, as a manifestation of drug reaction
and rarely as manifestation of chronic hypersensitivity pneumonitis
Gross
- Lower lobe and peripheral predominant fibrosis and honeycomb change
Microscopic

- Geographic heterogeneity: looks different from field to field e.g.

variegated

fibrosis worse in subpleural and paraseptal regions

areas of normal lung in between areas of fibrosis (usually

centrilobular)

- Temporal heterogeneity: refers to type of “fibrosis”

dense collagen

fibromyxoid fibroblastic foci (look similar to small flat areas of

organizing pneumonia)
 - Inflammatory infiltrate usually consists of chronic inflammatory cells

Germinal centers and dense lymphoid infiltrates associated with

UIP in connective tissue diseases e.g. rheumatoid arthritis

70% of patients are smokers so pigmented alveolar macrophages

as seen in RB and Desquamative Interstitial Pneumonia (DIP) are
common

- Honeycomb changes are most advanced at bases and periphery

Work by some investigators [14, 15] have shown a correlation between survival
and the number of “fibroblast foci,” a finding that suggests the critical pathway to
end-stage fibrosis is not “alveolitis” (as has been supposed for many years) but
ongoing epithelial damage and repair

Differential Diagnosis

Desquamative interstitial pneumonia (DIP)

- Macrophage accumulation is diffuse

- Temporally uniform

Cryptogenic organizing pneumonia (COP)

- Injury is temporally uniform

- Areas of recent organization are more pronounced and intraalveolar
- Areas of dense collagen deposition absent

Nonspecific interstitial pneumonia (NSIP)

- Fibrosis is geographically and is temporally more uniform

Accelerated(acute exacerbation of) Idiopathic Pulmonary Fibrosis [16-18]

Underlying UIP can be recognized clinically (previous history of slowly

progressive interstitial fibrosis with characteristic features of IPF),
radiographically, and/or on the basis of findings at the time of surgical lung
biopsy

Wedge lung biopsy show underlying UIP with DAD or, likely due to sampling,
either just DAD or just UIP. In some cases, only OP is seen on top of UIP.
Non-specific Interstitial Pneumonia/Fibrosis [19, 20]

A pattern of interstitial pneumonia. Can be idiopathic (most), a manifestation of

connective tissue disease, drug reaction, or organic antigen exposure.

Geographic hemogeneity: looks same from field to field e.g. fibrosis and
interstitial thickening with inflammation is NOT variegated

- Some cases lack fibrosis altogether

- Fibrosis when present is not worse in subpleural and paraseptal regions,
but uniform

- Honeycomb change absent with rare exception

Temporal homogeneity: refers to type of “fibrosis”

- dense collagen may be present, but when present is the only type
of fibrosis present

- fibromyxoid fibroblastic foci absent, with rare exception

Desquamative Interstitial Pneumonia (DIP) [21, 22]

Clinical- Closely related to respiratory bronchiolitis-interstitial lung disease (RB- ILD),

see below

- ~90% of patients are cigarette smokers

Microscopic
-much more uniform at low magnification and lacks the variegated
appearance of UIP

-alveolar septa are thickened by an inflammatory infiltrate that often

includes mononuclear cells and occasional germinal centers

- most striking (and definitional) feature is the presence of numerous

lightly pigmented macrophages within most of the distal air spaces

- collagen fibrosis occurs and may be associated with honeycomb change

Respiratory Bronchiolitis Interstitial Lung Disease (RB-ILD) [11, 23-25]

Clinical- A diagnosis of exclusion, as the histology of RB may be seen in any active or

past smoker

Microscopic
 - Respiratory bronchiolitis (pigmented alveolar macrophages in and
around respiratory bronchioles)

- Lacks significant fibrosis, interstitial inflammation or germinal centers

Differential Diagnosis

- RB-ILD and DIP represent points along a spectrum and some cases fall
somewhere in between and their separation may not always be possible.
Such cases may be diagnosed as “smoking-related interstitial lung
disease”.

Organizing Pneumonia (OP) a.k.a. bronchiolitis obliterans organizing pneumonia

BOOP) [12, 26]

Definition: myxoid appearing intraluminal (alveolar, alveolar duct and terminal and
respiratory bronchioles) fibroblastic proliferation (“fibrosis”) associated with mild
chronic interstitial inflammation

OP now preferred over BOOP as the bronchiolitis obliterans component (which could be
called proliferative obliterative bronchiolitis) is often difficult to appreciate
pathologically 47 and it is rare for patients to present as having “bronchiolitis.”

Clinical settings or as a histologic component of the following:

Idiopathic (cryptogenic organizing pneumonia)
Connective Tissue Disease
Drug Reaction e.g. bleomycin, Amiodarone
Resolving bacterial and viral infection
Extrinsic allergic alveolitis
Non-specific interstitial pneumonia (may be seen focally in 50% of cases)
Radiation
Reaction to tumor, infarct
Wegener granulomatosis
Chronic eosinophilic pneumonia

Pathology:

The same regardless of clinical category

Polypoid plugs of proliferating fibroblasts in alveoli and alveolar ducts (strictly

speaking this would have constituted the OP of BOOP), and terminal respiratory
bronchioles (the BO of BOOP)

Mild interstitial pneumonia confined to areas of organization

 Intra-alveolar foamy macrophages (from a failure to clear secretions due
to small airway obstruction)

No collagen (dense) fibrosis

Relationship Between Proliferative Obliterative Bronchiolitis in OP and Constrictive

Obliterative Bronchiolitis

The exact relationship between the two is uncertain

In most cases, they appear to be separate and distinct entities with different
clinical, radiographic, and morphologic features

In certain circumstances, such as lung transplant recipients, silo filler’s disease,

and, occasionally rheumatoid arthritis, there is evidence to suggest that intraluminal
organization localized to membranous and respiratory bronchioles can cause obstructive
airways disease and can “progress” to a lesion that is indistinguishable from the late stage
of constrictive bronchiolitis

Lymphoid Interstitial Pneumonia (LIP) [27-29]

Clinical -A distinct clinicopathologic syndrome that can occur in a variety of

settings including connective tissue disease and immunodeficiency states

Microscopic

- Exquisitely interstitial and bronchovascular infiltrate of small

lymphocytes and plasma cells

- Immunophenotypic studies have demonstrated that T-cells predominate

in the alveolar septal infiltrates, while B-lymphocytes predominate in the
peribronchiolar zones with polycloncal plasma cells

-Poorly formed nonnecrotizing granulomas with multinucleated giant cells

are present in a minority of cases,. There is polyclonal light-chain expression in
the plasma cell component in HIV and non-HIV–associated cases.

Pulmonary Langerhans Cell Histiocytosis (PLCH) [2, 4, 12]

Microscopic

- Bronchiolocentric nodular to stellate lesions

- Variable fibrosis
 - Diagnostic cell: Langerhans’ cell with convoluted nuclei (kidney-bean
shaped, grooved, resemble “buttocks”)

Usually admixed with some eosinophils and smoker’s

macrophages

Immunohistochemistry

S100 protein +, CDla +, Langerin +, HLR-DR +

Electron Microscopy

Birbeck granule (pentilaminar structure with “tennis

racket” morphology)

“Cystic” change seen radiographically

Results from dilated bronchioles, paracicatricial airspace

enlargement (so called “scar emphysema”), necrosis in
center of lesions

As lesions age they become less cellular and more fibrotic and may
be confused with the chronic interstitial pneumonias

Appears to start as a polyclonal process, but clonality may develop

[30]

Hypersensitivity Pneumonitis/Extrinsic Allergic Alveolitis [2, 4, 12]

Microscopic

- Classic triad (seen in ~80% of patients who undergo biopsy with a

clinical diagnosis)

1. cellular interstitial pneumonia composed mainly of

lymphocytes, plasma cells, and macrophages occasionally admixed
with eosinophils (only 10% of cases) and neutrophils

2. chronic bronchiolitis with organizing pneumonia

3. vague poorly formed nonnecrotizing granulomas or giant cells

-Fibrosis may develop and be indistinguishable from UIP [31]

 - Well proven cases clinically have been reported to resemble NSIP, COP,
UIP [32]

Hot Tub Lung [33-35]

Clinical-May represent an infection or a hypersensitivity reaction to

Mycobacterium avium-intracellulare organisms

Microscopic

- nonnecrotizing granulomatous inflammation but granulomas are often

larger and more exuberant than seen in classic hypersensitivity
pneumonitis

-patchy, chronic interstitial pneumonia that resembles that seen in

hypersensitivity pneumonitis

Sarcoidosis [2, 4, 12]

Diagnosis

- Usually requires pathologic demonstration of granulomatous

inflammation

- Transbronchial biopsy has become the method of choice and can be

expected to yield a diagnosis in nearly 80% of patients, including 70%
with stage 1 disease

- Likelihood of obtaining a diagnostic biopsy is related to the number of

specimens obtained, and the best results require a minimum of 4
specimens in patients with stage 2 or 3 disease and as many as 10 in
patients with stage 1 disease

Microscopic (berylliosis looks identical)

- granulomatous inflammation without bronchiolitis or cellular interstitial

pneumonia

- granulomas
compact, well-circumscribed collections of plump epithelioid
histiocytes and multinucleated giant cells surrounded by a
rim of lymphocytes and collagen fibrosis
central necrosis (~20%)
distributed along lymphatic routes (bronchovascular bundles,
interlobular septa, and visceral pleura)
 - multinucleated giant cells may contain a variety of cytoplasmic
inclusions which should not be confused with foreign material (these are
not specific for sarcoid, however)

Schaumann (conchoidal) bodies: blue, calcified

asteroid bodies: star shaped protein
sheet-like and needle-shaped birefringent crystalline
inclusions (often endogenous calcium oxalate)

- granulomatous vasculitis ~ 70%

- nodular sarcoidosis: coalescence of the granulomas combined with dense

collagen fibrosis

- necrotizing sarcoidosis- sarcoid background of lymphangitic non-

necrotizing granulomatous inflammation associated with broad foci of
parenchymal necrosis and vasculitis

Pulmonary Alveolar Proteinosis [2, 4, 12, 36, 37]

Three forms
Congenital- surfactant deficiency
Secondary -silica, titanium
Acquired- defect in alveolar macrophage function due to anti-GM-CSF antibodies

Microscopic
- Accumulation of granular eosinophilic material in alveoli (positive with
stains for Periodic Acid Schiff, PAS)
- Minimal if any interstitial pneumonia
- Fibrosis late

-Electron Microscopy

-Lamellar bodies of surfactant

Lymphangioleiomyomatosis (LAM) [2, 4, 12]

Gross

- Randomly distributed cystic airspaces with thin walls involving upper

and lower lobes

Microscopic
 -Main pathology

Disorderly proliferation of smooth-muscle cells

Cystic “emphysematous” spaces are common and usually contains
smooth-muscle bundles within at least a portion of their
walls

Hemosiderin laden macrophages may be present within air spaces

due to pulmonary hemorrhage

Immunohistochemistry of smooth muscle cells

Positive for
HMB45
Actin, desmin
Melan A
Estrogen and progesterone receptor protein
Beta-catenin

Other pathology

- Micronodular pneumocyte hyperplasia: circumscribed proliferations of

cytologically bland type 2 pneumocytes in a pattern resembling
bronchioloalveolar adenocarcinoma [38]

Evidence suggests that LAM cells may either metastasize or develop from
progenitor cells capable of migrating to the lung[39]

Eosinophilic Pneumonia (EP) [2, 4, 12]

Chronic EP

- Histologic features are constant regardless of clinical context (Table 6)

major abnormality is filling of distal air spaces by a cellular exudate of
eosinophils and histiocytes including multinucleated giant cells

- Relative proportions of the two cell types are variable

- Alveolar septa are thickened and contain a similar inflammatory infiltrate

- OP is a frequent associated finding

Acute EP

- Diffuse alveolar damage with prominent tissue eosinophilia

Wegener Granulomatosis [2, 4, 12]

Classic pathology

- Necrotizing granulomatous inflammation with geographic borders

(appears more like parenchymal necrosis than a true granuloma since the
foci usually lack significant numbers of epithelioid histiocytes)

- Centrally in foci of necrosis there is amorphous eosinophilic to

basophilic debris with remnants of necrotic neutrophils and other
inflammatory cells (so-called “dirty” necrosis)
- early lesions described as “palisading granulomas” and microabscesses

- Palisading granulomas are tiny granulomas composed of a single layer of

palisading epithelioid histiocytes that either radiate around a central point
or surround a central eosinophilic structure resembling a collagen bundle.
As the palisaded granulomas enlarge, they become more microabscess-
like.

- Necrotizing segmental (involving portion of the wall) vasculitis of

arteries and veins

- Randomly dispersed, darkly staining multinucleated giant cells common

Variants

Gross/Clinical

- Solitary pulmonary nodule

- Limited (lung only)

Microscopic

- Hemorrhage with or without capillaritis (vasculitis involving

capillaries recognized by presence of neutrophils in alveolar walls
- Bronchocentric
- Organizing Pneumonia-like
- Eosinophilic Pneumonia-like

c-ANCA titers positive in approximately 90% of patients with active generalized

disease, 60 to 85% of patients with active limited disease, and 30 to 35% of
patients with quiescent disease
 Positive p-ANCA titers generally representing autoantibodies directed against
myeloperoxidase are less specific but have been reported positive in some patients
with WG

Pneumoconioses [4, 40]

Asbestos-Related Reactions

Asbestosis
Macroscopic

Firm, fibrotic lungs with areas of honeycomb change

Microscopic

Marked interstitial fibrosis with minimal inflammatory

infiltrate; UIP-like reactions

The presence of asbestos bodies, fibrosis, and exposure

history are needed for definitive diagnosis

Asbestos bodies

- Iron-encrusted fibers (one type of ferruginous body, which is a more

generic term)

- typically beaded and dumbbell shaped with a thin translucent core

- no generally accepted criteria defining how many asbestos bodies must

be identified in any given case for a diagnosis of “asbestosis), but the
presence of even a single asbestos body in a routine tissue section usually
signifies “above background” asbestos exposure.

Silicosis

Gross

- Firm, discrete, rounded lesions with variable amounts of black pigment

- Nodules in lymphatic distribution: around broncho-vascular bundles, in

subpleural and interseptal areas
 Microscopic

- Discrete foci of concentric layers of hyalinized collagen

- Dust-filled histiocytes are abundant

- Birefringent particles usually present (often a mix of silica and silicates)

- When necrosis is present, consider complication by tuberculosis

- Nodules may expand and eventually coalesce to form larger masses;

when these masses measure >¦1 cm in diameter, they are referred to as
conglomerate nodules (complicated silicosis)

Pathology of Lung Transplantation [41, 42]

Acute Rejection

The grading scheme is strictly pathologic and does not rely on clinical parameters
(eg, for the diagnosis of obliterative bronchiolitis syndrome)

Grade 0 Negative for rejection: normal pulmonary parenchyma without evidence

of mononuclear infiltration or alveolar hemorrhage

Grade 1 Minimal acute rejection: infrequent perivascular mononuclear infiltrates

venules are usually involved before arterioles.
mononuclear cell cuff is usually more than two to three cells thick and is
composed of small round, plasmacytoid, and transformed lymphocytes

Grade 2 Mild acute rejection: frequent perivascular inflammatory cell infiltrates

surrounding venules and arterioles

- Infiltrates readily recognizable and are usually five to six cells in

thickness in the vascular adventitia

-No obvious infiltration by inflammatory cells into the adjacent alveolar

septae or airspaces.

Grade 3 Moderate acute rejection: all of the histologic features of mild acute
rejection

- inflammatory cell infiltrate extends into perivascular and peribronchiolar

alveolar septae and airspaces

Grade 4 Severe acute rejection

 - Diffuse perivascular, interstitial, and airspace infiltrates of inflammatory
cells including neutrophils

-Alveolar pneumocyte damage usually associated with necrosis, airspace

hemorrhage, and sometimes a necrotizing vasculitis.

Antibody mediated rejection

Pulmonary hemorrhage, capillaritis and complement deposition

Neoplasia [4, 43]

Squamous Cell Carcinoma

Gross
- Vary from small to large, obstructive lesions; commonly cavitate

Microscopic

- Keratinization and intercellular bridges

- Variants include papillary, clear cell, small cell, and basaloid

Immunohistochemistry

- Usually TTF 1 –

- Cytokeratin 5/6 and p63 +

Adenocarcinoma

Since the 2004 WHO Classification of Lung Carcinoma has been published there

have been significant advances in our understanding of all types of lung cancer, but

particularly adenocarcinoma, now the most common histologic subtype in most countries

of the world, including the United States and Canada. Because of this the American

Thoracic Society (ATS), European Respiratory Society (ERS) and the International
Association for the Study of Lung Cancer (IASLC) have published a “multidisciplinary”

classification of lung adenocarcinoma.[44]

The IASLC/ATS/ERS classification scheme has separate terminology for

resection specimens (Table 1) and small biopsies/cytologic specimens (see Table 2).

For diagnosis on small biopsies the predominant morphologic pattern should be

described, e.g. acinar, lepidic, colloid. If the tumor is purely lepidic (formerly

bronchioloalveolar pattern) it is suggested that one state that invasion cannot be excluded.

If morphologic adenocarcinoma patterns are not present then this should be supported by

negative special stains (histochemical and immunohistochemical).

Atypical adenomatous hyperplasia (AAH)

- defined as a small (usually <0.5 cm) proliferation of mild to

moderately atypical type II or Clara cells lining alveolar walls

and respiratory bronchioles. Double nuclei are common in this

setting.

- alveolar walls may be thickened and pseudo-papillary tufts

may be present.

Adenocarcinoma –in-situ (AIS)

-replaces the term bronchioloalveolar carcinoma (no invasion or

necrosis may be present)

- tumors are <3 cm, solitary adenocarcinomas with a pure lepidic

growth (growth along intact alveolar septae)

- Tumors classified as AIS that measure ≤3 cm have 100% disease

free survival
 -Minimally invasive adenocarcinoma

-small (≤3 cm) solitary adenocarcinomas with predominant

lepidic growth and invasion ≤5 mm

- this diagnosis should only be used in the presence of a

solitary nodule

- If multiple areas of microinvasion are present, the largest

area should be ≤5 mm (this means that separate foci of

microinvasion should not be added together).

- Defining invasion can be a challenge. It does not equate with alveolar

collapse, septal widening or sclerosis. Features which favor the presence

of invasion include

- Angulated glands or single cells infiltrating a desmoplastic

stroma

- Cribriform growth

- Destruction of the elastic framework of the lung (which can be

demonstrated by either elastic tissue stains or basement

membrane stains, such as laminin)

- The presence of a histologic type other than a lepidic pattern

(acinar, micropapillary, etc)

Invasive adenocarcinoma

- The main subtypes of adenocarcinoma are lepidic, acinar, papillary,

micropapillary and solid.

- lepidic pattern consists of a proliferation of type II pneumocytes and Clara cells

along surface alveolar walls

- acinar pattern consists of round oval shaped malignant glands invading a fibrous

stroma

- papillary adenocarcinoma consists of malignant cuboidal to columnar tumor

cells growing on the surface of fibrovascular cores

- micropapillary adenocarcinoma consists of small papillary clusters of glandular

cells growing within air spaces most of which do not show fibrovascular cores

- solid adenocarcinoma with mucin production consists of sheets of tumor cells

with abundant cytoplasm mostly vesicular nuclei and several conspicuous

nucleoli. No acinar, papillary or lepidic patterns are seen but multiple cells have

intracytoplasmic globules which can be identified by the presence of periodic acid

Schiff or mucin stains.

Table 1. IASLC/ATS/ERS Classification of Lung Adenocarcinoma in Resection
Specimens
Preinvasive lesions
Atypical adenomatous hyperplasia
Adenocarcinoma in situ (≤3 cm formerly BAC)
Nonmucinous
Mucinous
Mixed mucinous/nonmucinous
Minimally invasive adenocarcinoma (≤3 cm lepidic predominant tumor with ≤5 mm
invasion
Nonmucinous
Mucinous
Mixed mucinous/nonmucinous
Invasive adenocarcinoma
Lepidic predominant (formerly nonmucinous BAC pattern, with >5 mm invasion)
Acinar predominant
Papillary predominant
Micropapillary predominant
Solid predominant with mucin production
Variants of invasive adenocarcinoma
Invasive mucinous adenocarcinoma (formerly mucinous BAC)
Colloid
Fetal (low and high grade)
Enteric
BAC, bronchioloalveolar carcinoma; IASLC, International Association for the Study of
Lung Cancer; ATS, American Thoracic Society; ERS, European Respiratory Society.
Table 2. Proposed IASLC/ATS/ERS Classification for Small Biopsies/Cytology
2004 WHO Classification Small Biopsy/Cytology: IASLC/ATS/ERS
ADENOCRCINOMA Morphologic adenocarcinoma patters clearly
Mixed subtype present:
Acinar Adenocarcinoma, describe identifiable patterns
Papillary present (including micropapillary pattern not
Solid included in 2004 WHO classification)
Comment: If pure lepidic growth – mention an
invasive component cannot be excluded in this
small specimen
Bronchioloalveolar carcinoma Adenocarcinoma with lepidic pattern (if pure,
(nonmucinous) add note: an invasive component cannot be
excluded)
Bronchioloalveolar carcinoma Mucinous adenocarcinoma (describe pattern
(mucinous) present)
Fetal Adenocarcinoma with fetal pattern
Mucinous (colloid) Adenocarcinoma with colloid pattern
Signet ring Adenocarcinoma with (describe patterns
present) and signet ring features
Clear cell Adenocarcinoma with (describe patterns
present) and clear cell features
No 2004 WHO counterpart – most will Morphologic adenocarcinoma patterns not
be solid adenocarcinomas present (supported by special stains):
Non-small cell carcinoma, favor
adenocarcinomas
SQUAMOUS CELL CARCINOMA Morphologic squamous cell patterns clearly
Papillary present:
Clear cell Squamous cell carcinoma
Small cell
Basaloid
No 2004 WHO counterpart Morphologic squamous cell patterns not
present (supported by stains):
Non-small cell carcinoma, favor squamous cell
carcinoma
SMALL CELL CARCINOMA Small cell carcinoma
LARGE CELL CARCINOMA Non-small cell carcinoma, not otherwise
specified (NOS)
Large cell neuroendocrine carcinoma Non-small cell carcinoma with neuroendocrine
(LCNEC) (NE) morphology (positive NE markers),
possible LCNEC
Large cell carcinoma with NE Non-small cell carcinoma with NE morphology
morphology (LCNEM) (negative NE markers) – see comment
 Comment: This is a non-small cell carcinoma
where LCNEC is suspected, but stains failed to
demonstrate NE differentiation
ADENOSQUAMOUS CARCINOMA Morphologic squamous cell and
adenocarcinoma patterns present:
Non-small cell carcinoma, with squamous cell
and adenocarcinoma patterns
Comment: this could represent adenosquamous
carcinoma
No counterpart in 2004 WHO Morphologic squamous cell or adenocarcinoma
classification patterns not present but immunostains favor
separate glandular and adenocarcinoma
components
Non-small cell carcinoma, NOS, (specify the
results of the immunohistochemical stains and
the interpretation)
Comment: this could represent adenosquamous
carcinoma
Sarcomatoid carcinoma Poorly differentiated NSCLC with spindle
and/or giant cell carcinoma (mention if
adenocarcinoma or squamous carcinoma are
present)
IASLC, International Association for the Study of Lung Cancer; ATS, American
Thoracic Society; ERS, European Respiratory Society; WHO, World Health
Organization; NSCLC, non-small cell lung cancer; IHC, immunohistochemistry; TTF,
thyroid transcription factor
Small Cell Carcinoma

Gross

- 70% of cases present as perihilar mass

- Extensive lymph node metastases are common

- Typically peribronchial; endobronchial lesions are uncommon

Microscopic

- Round to fusiform nuclei; nuclear molding; faint or absent nucleoli;

scant cytoplasm

- Extensive necrosis

- 5% may be combined with a non small cell component

Immunohistochemistry

- 0% of cases may be negative classic for neuroendocrine markers

Large Cell Carcinoma

Gross

-Central or peripheral; typically large

Microscopic

- Sheets and nests growth pattern with extensive necrosis

- Large nuclei with prominent nucleoli

- No evidence of squamous or glandular differentiation by light

microscope

- Variants include large cell neuroendocrine carcinoma, basaloid,

lymphoepithelioma-like, and clear cell
Electron Microscopy

- 80% show glandular differentiation; 10% show squamous

differentiation
Carcinoid Tumorlet

Clinical - Incidental microscopic findings

- Multiple tumorlets may mimic metastatic tumor e.g. breast cancer [45,
46]

- Rarely associated with syndrome of airflow obstruction [45]

Microscopic
- Nests of neuroendocrine cells embedded in fibrotic stroma
< 0.5 cm

- Usually adjacent to bronchiole

Diffuse Pulmonary Neuroendocrine Cell Hyperplasia [47] (DIPNCH)

Increased neuroendocrine cells within bronchiolar epithelium

Typical and Atypical Carcinoid

Microscopic

- Neuroendocrine cells with organoid, trabecular, insular, palisading

ribbon, rosette-like architecture

- Round to oval nuclei with finely granular chromatin and inconspicuous

nucleoli

- Stromal changes include bone, cartilage, dense fibrosis, and amyloid

- Atypical carcinoids have 2–10 mitoses/10 high powered fields and/or

focal necrosis

Large Cell Neuroendocrine Carcinoma

Microscopic

-Organoid, palisading, trabecular patterns

-Large, polygonal nuclei and low nuclear/cytoplasmic ratio; frequent

nucleoli

-High mitotic rate (>10 mitoses/10 high powered fields)

necrosis can be prominent
 Immunohistochemistry

- Chromogranin: 80% +; Synaptophysin: 40% +; Bombesin: 40% +

- By definition, one of the above neuroendocrine markers must be positive

Lymphomatoid Granulomatosis-Lymphoma

Described at a time when the existence of extranodal lymphomas was not

accepted, but this disease IS a malignant lymphoma[48, 49]

Gross

-Nodular consolidation; nodules may have central necrosis

Microscopic

- Nodules or diffuse infiltrates of lymphoid cells

- Central necrosis and cavitation can be seen in larger nodules; prominent

vascular invasion

-Cell population heterogeneous, but large ayptical cells are malignant

Immunohistochemistry

-Most cells are positive for T-cell markers (CD4,CD8), but the majority of
the malignant cells are B-cells

Molecular Studies

- Either immunoglobulin rearrangements (B-cell) or T-cell receptor

rearrangements (in the few that represent T cell lymphomas) EBV DNA
often detected by polymerase chain reaction

Sarcomatoid Carcinoma

Definition: group of poorly differentiated non-small cell lung carcinomas that contain
either sarcoma-like (spindle cell and/or giant cell) or frank sarcomatous differentiation.

- five major types

- in general they are very aggressive tumors, having a worse prognosis than most
other non-small cell lung carcinomas.
 Pleomorphic carcinoma: poorly differentiated non-small cell carcinoma
(squamous, adeno or large cell) associated with either spindle cells and/or giant cells, or a
carcinoma consisting only of spindle cells or giant cells. Spindle or giant cells should
comprise at least 10% of the tumor.

Spindle cell carcinoma: non-small cell carcinoma consisting only of spindle cells
identical to the spindle cell component of pleomorphic carcinoma. The spindle cells
generally are reactive with antibodies to keratin.

Giant cell carcinoma: non-small cell carcinoma comprised of highly pleomorphic

multi- and/or mono-nucleated tumor giant cells. They are often associated with a lot of
inflammatory cells including neutrophils.

Carcinosarcoma: a malignant spindle cell tumor with a mixture of carcinoma and

differentiated sarcoma such as malignant cartilage, bone or skeletal muscle. Squamous
carcinoma is the most commonly associated type of differentiated carcinoma in this
setting.

Pulmonary blastoma: biphasic tumor consisting of adenocarcinoma resembling fetal

adenocarcinoma and a primitive mesenchymal stroma resembling Wilms tumor.
- can occasionally have foci of osteosarcoma, chondrosarcoma or
rhabdomyosarcoma.
- different from pleuropulmonary blastoma which is a pediatric lung, pleura and
chest wall tumor with a cystic component lined by rhabdomyoblasts.

Molecular Genetics of Lung Cancer

In almost half the cases of lung carcinoma a specific genetic mutation is not identifiable.
The single most common mutation is K-ras. The highest frequency of KRAS mutations
occurs in non-Asians (20%-30%), older men with a smoking history. The mutation is
associated with poor survival and is mutually exclusive to mutations in BRAF and HER-
2. The mutation is usually associated with mucinous tumors.

EGFR mutations tend to occur in those tumors which are better differentiated non-
mucinous and TTF-1 positive. Many of them have a prominent lepidic growth pattern.

Other mutations are less common but include mutations in EML4-ALK, BRAF, PIK3CA
and HER-2.

Mesothelioma

Known causes of malignant mesothelioma include asbestos exposure (particularly

exposure to amosite or crocidolite and occasionally tremolite). Chrysotile asbestos is a
very weak carcinogen in humans.
Erionite (a natural occurring fibrous material associated with volcanic ash) and
therapeutic radiation. It’s possible that pleural scarring may be associated with the
development of malignant mesothelioma but the evidence is less strong than that for
those factors previously mentioned. There has been a long debate about the association
of the virus SV40 (simiam virus 40), but most of the evidence would suggest that SV40 is
not associated with the development of mesothelioma. Many cases remain idiopathic.

Pleural mesotheliomas are seen in older patients, generally over the age of 60, due to the
extremely long latent period associated with those associated with asbestos.

- epithelial malignant mesothelioma: most common form and associated with a

slightly better prognosis than those with a sarcomatous component.

-sarcomatoid mesothelioma: those comprised predominantly of spindle cells often

resembles fibrous sarcoma.
- desmoplastic mesothelioma represents a specific type with
deceptively bland histologic appearance and abundant fibrous
tissue

-biphasic mesothelioma: tumors comprised of at least 10% sarcomatous and

epithelial foci

-Well-differentiated papillary mesothelioma: a distinct tumor more common in

the peritoneum in women
- comprised of broad papillary fronds with more stroma than surface
epithelium
- unlike standard malignant mesotheliomas patients with this tumor often
have an indolent course with prolonged survival
 References

Note to participants: There are some primary sources quoted, but the textbooks
have additional photos worth studying.

1. Snider, G., J. Keinerman, and W. Thurlbeck, The definition of emphysema.

Report of a National Heart, Lung, and Blood Institute, Division of Lung Diseases
workshop. Am Rev Respir Dis, 1985. 132(1): p. 182-5.
2. Travis, W., et al., Non-neoplastic disorders of the lower respiratory tract, in Atlas
of Nontumor Pathology2002, American Registry of Pathology and the Armed
Forces Institute of Pathology: Washington DC.
3. West, W., et al., The National Institutes of Health Intermittent Positive Pressure
Breathing trial--pathology studies. III. The diagnosis of emphysema. Am Rev
Respir Dis, 1987. 135(1): p. 123-9.
4. Churg, A., et al., Thurlbeck's pathology of the lung. Third ed2005, New York:
Thieme Medical Publishers, Inc.
5. Barnes, P., Chronic obstructive pulmonary disease. N Engl J Med, 2000. 343(4):
p. 269-80.
6. Hogg, J., et al., The nature of small-airway obstruction in chronic obstructive
pulmonary disease. N Engl J Med, 2004. 350(26): p. 2645-53.
7. Greenberger, P.A. and R. Patterson, Diagnosis and management of allergic
bronchopulmonary aspergillosis. Ann Allergy, 1986. 56(6): p. 444-8.
8. Cockrill, B.A. and C.A. Hales, Allergic bronchopulmonary aspergillosis. Annu
Rev Med, 1999. 50: p. 303-16.
9. Leslie, K.O. and M.R. Wick, Practical pulmonary pathology: a diagnostic
approach2005, Philadelphia: Churchill Livingstone. 813.
10. Visscher, D. and J. Myers, Bronchiolitis: the pathologist's perspective. Proc Am
Thorac Soc, 2006. 3: p. 41-47.
11. Fraig, M., et al., Respiratory bronchiolitis: a clinicopathologic study in current
smokers, ex-smokers, and never-smokers. Am J Surg Pathol, 2002. 26: p. 647-53.
12. Katzenstein, A. and F. Askin, Surgical Pathology of Non-neoplastic Lung
Disease. 4th ed2006, Philadelphia: W.B. Saunders. 503.
13. American Thoracic Society/European Respiratory Society International
Multidisciplinary Consensus Classification of the Idiopathic Interstitial
Pneumonias. This joint statement of the American Thoracic Society (ATS), and
the European Respiratory Society (ERS) was adopted by the ATS board of
directors, June 2001 and by the ERS Executive Committee, June 2001. Am J
Respir Crit Care Med, 2002. 165(2): p. 277-304.
14. King, T., Jr, et al., Idiopathic pulmonary fibrosis: relationship between
histopathologic features and mortality. Am J Respir Crit Care Med, 2001. 164(6):
p. 1025-32.
15. King, T., Jr, et al., Predicting survival in idiopathic pulmonary fibrosis: scoring
system and survival model. Am J Respir Crit Care Med, 2001. 164(7): p. 1171-81.
16. Churg, A., et al., Acute exacerbation (acute lung injury of unknown cause) in UIP
and other forms of fibrotic interstitial pneumonias. Am J Surg Pathol, 2007.
31(2): p. 277-284.
17. Parambil, J., J. Myers, and J. Ryu, Histopathologic features and outcome of
patients with acute exacerbation of idiopathic pulmonary fibrosis undergoing
surgical lung biopsy. Chest, 2005. 128(5): p. 3310-5.
18. Kim, D., et al., Acute exacerbation of idiopathic pulmonary fibrosis: frequency
and clinical features. Eur Respir J, 2006. 27(1): p. 143-50.
19. Katzenstein, A. and R. Fiorelli, Nonspecific interstitial pneumonia/fibrosis.
Histologic features and clinical significance. Am J Surg Pathol, 1994. 18(2): p.
136-47.
20. Travis, W.D., et al., Idiopathic nonspecific interstitial pneumonia: report of an
American Thoracic Society project. Am J Respir Crit Care Med, 2008. 177(12): p.
1338-47.
21. Aubry, M., J. Wright, and J. Myers, The pathology of smoking-related lung
diseases. Clin Chest Med, 2000. 21(1): p. 11-35, vii.
22. Ryu, J., et al., Smoking-related interstitial lung diseases: a concise review. Eur
Respir J, 2001. 17(1): p. 122-32.
23. Vassallo, R., et al., The overlap between respiratory bronchiolitis and
desquamative interstitial pneumonia in pulmonary Langerhans cell histiocytosis:
high-resolution CT, histologic, and functional correlations. Chest, 2003. 124(4):
p. 1199-205.
24. Myers, J., et al., Respiratory bronchiolitis causing interstitial lung disease. A
clinicopathologic study of six cases. Am Rev Respir Dis, 1987. 135(4): p. 880-4.
25. Yousem, S., T. Colby, and E. Gaensler, Respiratory bronchiolitis-associated
interstitial lung disease and its relationship to desquamative interstitial
pneumonia. Mayo Clin Proc, 1989. 64(11): p. 1373-80.
26. Elicker, B., et al., High-resolution computed tomography patterns of diffuse
interstitial lung disease with clinical and pathological correlation. J Bras
Pneumol, 2008. 34(9): p. 715-44.
27. Saldana, M. and J. Mones, Lymphoid interstitial pneumonia in HIV infected
individuals. Prog Surg Pathol, 1991. 12: p. 181-215.
28. Koss, M., et al., Lymphoid interstitial pneumonia: clinicopathological and
immunopathological findings in 18 cases. Pathology, 1987. 19(2): p. 178-85.
29. Cha, S., et al., Lymphoid interstitial pneumonia: clinical features, associations
and prognosis. Eur Respir J, 2006. 28: p. 364-9.
30. Yousem, S., et al., Pulmonary Langerhans' cell histiocytosis: molecular analysis
of clonality. Am J Surg Pathol, 2001. 25(5): p. 630-6.
31. Churg, A., et al., Chronic hypersensitivity pneumonitis. Am J Surg Pathol, 2006.
30(2): p. 201-8.
32. Ohtani, Y., et al., Chronic bird fancier's lung: histopathological and clinical
correlation. An application of the 2002 ATS/ERS consensus classification of the
idiopathic interstitial pneumonias. Thorax, 2005. 60(8): p. 665-71.
33. Khoor, A., et al., Diffuse pulmonary disease caused by nonturberculous
mycobacteria in immunocompetent people (hot tub lung). Am J Clin Pathol, 2001.
115(5): p. 755-62.
34. Hanak, V., et al., Hot tub lung: presenting features and clinical course of 21
patients. Respir Med, 2006. 100(4): p. 610-5.
35. Aksamit, T., Hot tub lung: infection, inflammation, or both? Semin Respir Infect,
2003. 18(1): p. 33-9.
36. Seymour, J. and J. Presneill, Pulmonary alveolar proteinosis: progress in the first
44 years. Am J Respir Crit Care Med, 2002. 166(2): p. 215-35.
37. Trapnell, B., J. Whitsett, and K. Nakata, Pulmonary alveolar proteinosis. N Engl
J Med, 2003. 349(26): p. 2527-39.
38. Muir, T., et al., Micronodular pneumocyte hyperplasia. Am J Surg Pathol, 1998.
22(4): p. 465-72.
39. Karbowniczek, M., et al., Recurrent lymphangiomyomatosis after transplantation:
genetic analyses reveal a metastatic mechanism. Am J Respir Crit Care Med,
2003. 167(7): p. 976-82.
40. Churg, A. and F.H.Y. Green, Pathology of Occupational Lung Disease. 2nd
ed1998, Baltimore: Williams & Wilkins.
41. Stewart, S., Pathology of lung transplantation. Semin Diagn Pathol, 1992. 9(3): p.
210-9.
42. Stewart, S., et al., Revision of the 1996 working formulation for the
standardization of nomenclature in the diagnosis of lung rejection. J Heart Lung
Transplant, 2007. 26(12): p. 1229-42.
43. World Health Organization classification of tumours, in Pathology and Genetics
of Tumours of the Lung, Pleura, Thymus and Heart, W.D. Travis, et al., Editors.
2004, IARC Press: Lyon.
44. Travis, W.D., et al., International association for the study of lung
cancer/american thoracic society/european respiratory society international
multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol, 2011.
6(2): p. 244-85.
45. Aubry, M.C., et al., Significance of multiple carcinoid tumors and tumorlets in
surgical lung specimens: analysis of 28 patients. Chest, 2007. 131(6): p. 1635-43.
46. Darvishian, F., et al., Carcinoid tumorlets simulate pulmonary metastases in
women with breast cancer. Hum Pathol, 2006. 37(7): p. 839-44.
47. Armas, O.A., et al., Diffuse idiopathic pulmonary neuroendocrine cell
proliferation presenting as interstitial lung disease. Am J Surg Pathol, 1995.
19(8): p. 963-70.
48. Liebow, A., C. Carrington, and P. Friedman, Lymphomatoid granulomatosis.
Hum Pathol, 1972. 3(4): p. 457-558.
49. Myers, J., et al., Lymphomatoid granulomatosis. Evidence of immunophenotypic
diversity and relationship to Epstein-Barr virus infection. Am J Surg Pathol,
1995. 19(11): p. 1300-12.