• Usual interstitial pneumonia (UIP)

• Nonspecific interstitial pneumonia.

• Cryptogenic organizing pneumonia.
• Pulmonary involvement in autoimmune disease.
 Rheumatoid arthritis .
 Systemic sclerosis
 Lupus erythromatous.
Normal lung
Usual interstitial pneumonia (UIP)
• Patchy interstitial fibrosis with alternating areas of normal
lung.
Usual interstitial pneumonia (UIP)
Fibrosis in subpleuarl region

dense fibrosis with smooth muscle hyperplasia.

Usual interstitial pneumonia (UIP)

Fibroblastic foci
Usual interstitial pneumonia (UIP)
• Disease of old individual.
• One of the most common and most lethal lung
diseases.
• Gross: the pleural surface are cobblestone.
• Miro: honeycomb fibrosis.
• Lung transplantation is the only definite therapy.
• Risk factor: cigarette smokers, viral infection, gastric
reflux, etc…
 Gross photographs of usual interstitial pneumonia-associated lung.
Honeycomb changes are seen along the periphery and lung bases (A).
There is a prominent cobblestone appearance of the pleural surface (B).
Usual interstitial pneumonia (UIP)
Summary:
1.area of dense fibrosis
2.Normal lung
3. Fibroblastic foci.
Nonspecific interstitial pneumonia
• Lung biopsy lack the diagnostic features of any of the
other well characterized interstitial disease.
• Nonsmoker female.
• Better prognosis the UIP.

• Fibroblastic foci, honeycombing , hyaline membrane

and granulomas are absent.

• Key feature on CT: bilateral, symmetric, predominantly lower

lobe reticular opacities.
Nonspecific interstitial pneumonia

bilateral, symmetric, predominantly lower lobe reticular opacities

 Cryptogenic organizing pnemonia
• characterized by the formation of organized buds of
granulation tissue obstructing the alveolar lumen and
bronchioles resulting in respiratory failur.

• characterized by polypoid fibroblastic aggregations

which plug alveolar sacs, ducts and bronchioles.

( alveolar space filled with balls of fibroblasts (Masson

bodies) while alveolar wall are relatively normal)

Note: Bronchiolitis obliterans is a feature of cryptogenic organizing pneumonia, an

uncommon, nonspecific reaction to a lung injury, such as an infection or toxic exposure.
 Cryptogenic organizing pnemonia
• No interstitial fibrosis
• No honeycomb lung.
• Lung architecture is normal
• TX: oral steroid for 6 months.
Cryptogenic organizing pnemonia
Masson
body

Hematoxylin & eosin stain demonstrating the hallmark intra-alveolar buds of

granulation tissue that are characteristic of organizing pneumonia.
Cryptogenic organizing pnemonia
Cryptogenic organizing pnemonia

(a): HRCT; subpleural consolidation in the right lower lobe

 Question??
Which of the following two findings are against
the histological diagnosis of organizing
pneumonia?

1. Dense interstitial fibrosis

2. Fibrin deposition
3. Fibroblastic focus
4. Foamy macrophage accumulation
5. Masson body
Pulmonary involvement in autoimmune disease

 Rheumatoid arthritis .
 Systemic sclerosis
 Lupus erythromatous.
Pulmonary involvement in autoimmune disease
Rheumatoid arthritis.

1-Chronic pleuritis with/without

pleural effusion.

2-Diffuse inerstitial pneumonia

3-Pulmonary hypertension.

4-Intrapulmonary rheumatoid
nodules.

5- Follicular bronchiolitis
Pulmonary involvement in autoimmune disease
Rheumatoid arthritis.

4.Intrapulmonary rheumatoid
nodules.
 Pulmonary involvement in autoimmune disease
Rheumatoid arthritis.
5. Follicular bronchiolitis: prominent bronchial associated lymphoid tissue with or
without germinal center formation.

(a) of the chest in patient 2 at 11 months of age demonstrates tiny nodules at the left
lung base as well as area of focal opacity within the right middle lobe and lingula

hematoxylin and eosin stain of left lower lobe biopsy (b) demonstrates nodular
lymphoid hyperplasia (black arrows) associated with the airways (white arrows)
Pulmonary involvement in autoimmune disease
 Granulomatous disease
• Sarcoidosis
• Mycobacteria and fungal infection.
• Berylliosis
• Hypersensitivity pneumonitis.
Non caseating granuloma
 Sarcoidosis
• Sarcoidosis is a systemic granulomatous disease of unknown cause that may
involve many different tissues and organs.
• Sarcoidosis presents in many clinical patterns, but bilateral bilateral hilar
lymphadenopathy or lung involvement is most common, occuring 90% of
cases.
• ■ Sarcoidosis is a multisystem disease of unknown etiology; the diagnostic
histopathologic feature is the presence of noncaseating granulomas in various
tissues.
• ■ Immunologic abnormalities include high levels of CD4+ T cells in the lung that
secrete TH1-dependent cytokines such as IFN-γ and IL-2 locally.
• ■ Clinical manifestations include lymph node enlargement, eye involvement
(sicca syndrome [dry eyes], iritis, or iridocyclitis), skin lesions (erythema
nodosum, painless subcutaneous nodules), and visceral (liver, skin, marrow)
involvement.
• Lung involvement occurs in 90% of cases, with formation of granulomas and
interstitial fibrosis.
 Hamazaki-Wesenberg bodies LN

Hamazaki-Wesenberg bodies are a benign lymph node finding associated with sinus
histiocytosis
They are also known as yellow bodies, yellow‐brown bodies and Hamazaki corpuscles.
hypersensitivity pneumonitis
 hypersensitivity pneumonitis
• Hypersensitivity pneumonitis is a type III (and type IV) hypersensitivity
response to an inhaled allergen.

• Secondary eosinophilia can occur.

 hypersensitivity pneumonitis
• Hypersensitivity pneumonitis has acute symptoms that occur soon after
exposure to an antigen, often actinomycetes or fungi (molds) growing in
contaminated HVAC systems (air conditioner or ventilation ducts).

• The symptoms improve when the patient leaves the environment where the
antigen is located.

• The pulmonary pathologic changes are usually minimal, with interstitial

mononuclear infiltrates.

• It is mainly a type III hypersensitivity reaction, but with more chronic

exposure to the antigen, there may be a component of type IV
hypersensitivity with granulomatous inflammation and fibrosis .
• Farmer’s lung is a form of hypersensitivity pneumonitis caused by
inhalation of actinomycete spores in moldy hay.

• These spores contain the antigen that incites the hypersensitivity reaction.
Because type III (early) and type IV immune hypersensitivity
reactions are involved, granuloma formation can occur.

• The disease abates when the patient is no longer exposed to the antigen.

• Chronic exposure can lead to more extensive interstitial lung disease.

• Pulmonary tuberculosis can produce granulomas, but the pattern would

be miliary, and it is unlikely that it would continue for 15 years.
interstitial infiltrates of lymphocytes and plasma cells, minimal interstitial
fibrosis, and small granulomas
 hypersensitivity pneumonitis
Triad:
-non caseating granuloma.
-interstitial pneumonia
-Interstitial fibrosis+ obliterative bronchiolitis.

Note:
Bronchiolitis obliterans is a feature of cryptogenic organizing pneumonia,
an uncommon, nonspecific reaction to a lung injury, such as an infection or
toxic exposure.
Q: A 64-year-old alfalfa farmer has a 15-year history of increasing dyspnea. On
physical examination, his temperature is 37.6° C. A chest radiograph shows
a bilateral increase in linear markings. Pulmonary function tests show
reduced FVC with a normal FEV1. A transbronchial lung biopsy specimen
shows interstitial infiltrates of lymphocytes and plasma cells, minimal
interstitial fibrosis, and small granulomas.
What is the most likely cause of this clinical and pathologic picture?

A. Autoantibodies against alveolar basement membranes

B. Chronic inhalation of silica particles
C. Hypersensitivity to spores of actinomycetes
D. Infection with Mycobacterium tuberculosis
E. Prolonged exposure to inorganic dusts
 Pulmonary eosinophilia
Divided into:

• Acute eosinophilic pneumonia + respiratory failure.

• chronic eosinophilic pneumonia (idiopathic).
• Secondary eosinophilia.

NOTE: Acute eosinophilic pneumonia: onset in 1 - 4 days, accompanied by fever,

cough, dyspnea and chest pain; unknown cause, prominent eosinophils in
bronchoalveolar lavage fluid
 Idiopathic eosinophilic pneumonia
Definition / general
• Diagnosis of exclusion

• Lung disease associated with eosinophils in alveolar and interstitial spaces, usually with
peripheral eosinophilia, but excluding Langerhans cell histiocytosis

• Must exclude:
– drug reactions (antibiotics, cytotoxic or anti-inflammatory drugs).
– immune disorders (Churg-Strauss syndrome, collagen vascular disease, asthma, hypereosinophilic
syndrome, chronic eosinophilic leukemia NOS, myeloid and lymphoid neoplasms with eosinophilia and
rheumatoid arthritis).
– infections (bacteria, Aspergillus, HIV, parasites, Dirofiliaria and filarial)
– tobacco (new onset smoker)
 Secondary eosinophilia
which occurs in a
– parasitic, fungal, and bacterial infections.
– hypersensitivity pneumonitis.
– drug allergies;
– in association with asthma, allergic bronchopulmonary
aspergillosis.
– vasculitis (Churg-Strauss syndrome)
 Simple eosinophilic pneumonia:
Loeffler syndrome:
• Acute eosinophilic pneumonia with transient diffuse pulmonary infiltrates
composed primarily of eosinophils and serum eosinophilia
• Characteristic imaging findings, so biopsy is rarely performed
• Eosinophils may be present in sputum
• Often associated with ascaris infection
• Self limited - lasts only up to 1 month
 Smoker related interstitial diseases
• Desquamative interstitial pneumonia.
– (DIP) is an uncommon interstitial disease in which monocytes gather
to form intra-alveolar macrophages; DIP is not related to idiopathic
pulmonary fibrosis
• Respiratory bronchiolitis associated interstitial lung
disease.

• Note:
Pulmonary Langerhans Cell Histiocytosis , 95% of affected patients are relatively young
adult smokers who get better after smoking cessation, suggesting that in some cases the
lesions are a reactive inflammatory process .
 Pulmonary Langerhans Cell Histiocytosis
• Langerhans cells are immature dendritic
cells with grooved, indented nuclei and
abundant cytoplasm.

• They are positive for S100, CD1a, and

CD207 (langerin) .
• negative for CD68.

• BRAF mutation.

• Often accompanied by eosinophils.

Pulmonary Alveolar Proteinosis
 Pulmonary Alveolar Proteinosis
• Pulmonary alveolar proteinosis is a rare idiopathic condition in which there are
gelatinous alveolar proteinaceous exudates.

• PAP have impaired surfactant clearance by alveolar macrophages, leading to

accumulation of gelatinous alveolar exudate.

• caused by defects related to granulocyte-macrophage colony-stimulating

factor (GM-CSF)

• pulmonary macrophage dysfunction that results in the accumulation of

surfactant in the intra-alveolar and bronchiolar spaces.

• PAP is characterized radiologically by bilateral patchy asymmetric

pulmonary opacifications.
 Pulmonary Alveolar Proteinosis
• The disease is characterized by a peculiar homogeneous, granular
precipitate containing surfactant proteins within the alveoli, causing
focal-to-confluent consolidation of large areas of the lungs with minimal
inflammatory reaction.
• a marked increase in the size and weight of the lung.

• The alveolar precipitate is periodic acid-Schiff positive, and contains

cholesterol clefts and surfactant proteins (which can be demonstrated by
immunohistochemical stains).

• Ultrastructurally, the surfactant lamellae in type II pneumocytes are

normal.
Q: A 33-year-old woman has had increasing dyspnea with cough for the past
10 days. Over the past 2 days, her cough has become productive of chunks
of gelatinous sputum. On physical examination, she is afebrile. There is
extensive dullness to percussion over all lung fields. A chest radiograph
shows diffuse opacification bilaterally. A transbronchial biopsy is
performed and the microscopic appearance with H&E staining is shown in
the figure. On electron microscopy, there are many lamellar bodies.
Antibody directed against which of the following substances is most likely
to cause her illness?

A. α1-Antitrypsin
B. Chloride channel protein
C. DNA topoisomerase I
D. Glomerular basement membrane
E. GM-CSF
F. Neutrophilic myeloperoxidase
• The acquired form of pulmonary alveolar proteinosis (PAP) is an uncommon condition of
unknown etiology characterized by autoantibodies against granulocyte-macrophage
colony-stimulating factor (GM-CSF).
• 10% of PAP cases are congenital secondary to mutations in the GM-CSF gene.
• Both forms of PAP have impaired surfactant clearance by alveolar macrophages, leading
to accumulation of gelatinous alveolar exudate.

• α1-Antitrypsin deficiency leads to panlobular emphysema with hyperlucent lungs on

radiographs.

• CFTR gene mutations lead to cystic fibrosis and widespread bronchiectasis.

• Anti–DNA topoisomerase I antibodies are seen in diffuse scleroderma, which

produces pulmonary interstitial fibrosis.

• Anti–glomerular basement membrane antibody is present in Goodpasture syndrome

with extensive alveolar hemorrhage.

• Neutrophilic myeloperoxidase is a form of anti– neutrophil cytoplasmic autoantibody

seen in ANCA-associated vasculitis.
Pulmonary Embolism
■ Almost all large pulmonary artery thrombi are embolic in origin, usually arising
from the deep veins of the lower leg.

■ Risk factors include:

1. prolonged bed rest
2. leg surgery
3. severe trauma
4. CHF
5. use of oral contraceptives (especially those with high estrogen content),
6. disseminated cancer
7. genetic diseases of hypercoagulability.

■ The vast majority (60% to 80%) of emboli are clinically silent,

a minority (5%) cause acute cor pulmonale, shock, or death (typically from
large “saddle emboli”),
and the remaining cause pulmonary infarction.

■ Risk of recurrence is high.

 Pulmonary Embolism and Infarction
• Pulmonary embolism usually occurs in patients with a predisposing condition that produces an
increased tendency to clot (thrombophilia).
Rarely pulmonary embolism may consist of fat, air, or tumor.

• Small bone marrow emboli are often seen in patients who die after chest compressions performed
during resuscitative efforts. (Q)

• Patients often have cardiac disease or cancer, or have been immobilized for several days or weeks
prior to the appearance of asymptomatic embolism.

• Those with hip fractures are at particularly high risk.

• Hypercoagulable states, are important risk factors

primary ( factor V Leiden, prothrombin mutations, and antiphospholipid syndrome)
secondary (obesity, recent surgery, cancer, oral contraceptive use, pregnancy)

• Indwelling central venous lines can be a nidus for formation of right atrial thrombi, which can
embolize to the lungs.
 Pulmonary Embolism and Infarction
• The pathophysiologic response and clinical significance of pulmonary
embolism depend on:
1. the extent to which pulmonary artery blood flow is obstructed,
2. the size of the occluded vessels.
3. the number of emboli.
4. cardiovascular health of the patient.

• Emboli have two deleterious pathophysiologic consequences:

– respiratory compromise due to the nonperfused, although ventilated, segment;
– hemodynamic compromise due to increased resistance to pulmonary blood flow caused by the embolic
obstruction.

• Sudden death often result of the blockage of blood flow through the lungs.

• Death may also be caused by acute right-sided heart failure (acute cor
pulmonale).
• Findings on chest radiograph are variable and can be normal or disclose a pulmonary infarct,
usually 12 to 36 hours after it has occurred, as a wedge-shaped infiltrate.

• Large emboli lodge in the main pulmonary artery or its major branches or at the bifurcation as a
saddle embolus.

• Smaller emboli travel out into the more peripheral vessels, where they may cause hemorrhage or
infarction. (Small emboli are silent or induce only transient chest pain and cough)

• Pulmonary embolus can be distinguished from a postmortem clot by the presence of the lines
of Zahn in the thrombus

• In patients with adequate cardiovascular function, the bronchial arterial supply sustains the
lung parenchyma; in this instance, hemorrhage may occur, but there is no infarction.

• In those in whom the cardiovascular function is already compromised, such as patients with
heart or lung disease, infarction may occur. Overall, about 10% of emboli cause infarction.

• About three fourths of infarcts affect the lower lobes, and in more than half,multiple lesions
occur.

• In many cases, an occluded vessel is identified near the apex of the infarct
•The pulmonary infarct is classically hemorrhagic and
appears as a raised, red-blue area in the early stages .

•Often, the apposed pleural surface is covered by a

fibrinous exudate.

•The red cells begin to lyse within 48 hours, and the

infarct becomes paler and eventually red-brown as
hemosiderin is produced

• With the passage of time, fibrous replacement begins at the margins as a gray-
white peripheral zone and eventually converts the infarct into a contracted
scar.

• Histologically, the hemorrhagic area shows ischemic necrosis of the alveolar walls,
bronchioles, and vessels.

• If the infarct is caused by an infected embolus, the neutrophilic inflammatory

reaction can be intense. Such lesions are referred to as septic infarcts, some which
turn into abscesses.
45-year-old man has had progressive dyspnea on exertion with fatigue for the
past 2 years. On auscultation of his chest he has a prominent pulmonary
component of S2, a systolic murmur of tricuspid insufficiency, and bruits over
peripheral lung fields. Jugular venous distension is present to the angle of his
jaw when sitting. Laboratory studies show antiphospholipid antibodies. CT
angiography shows eccentric occlusions with pulmonary arteries and
mosaic attenuation of pulmonary parenchyma. Which of the following is the
most likely disease process causing his pulmonary disease?

A. Atherosclerosis
B. Pneumonitis
C. Sarcoidosis
D. Thromboembolism
E. Vasculitis
• Over half of persons with chronic pulmonary thromboembolism with
pulmonary hypertension do not have a history of recurrent pulmonary
embolism.
• Rather than one large life-threatening embolus, chronic thromboembolism
occurs from multiple smaller emboli that reduce the pulmonary vascular
bed and increase pulmonary pressures, leading to cor pulmonale.

• Recanalization of thrombi leads to narrow channels causing the bruits.

• Antiphospholipid antibodies pose a risk for thrombosis.

Q: A 68-year-old woman had a cerebral infarction and was hospitalized for 3
weeks. Her condition improved, and she was able to get up and move
about with assistance. A few minutes after walking to the bathroom, she
experienced sudden onset of severe dyspnea with chest pain and
diaphoresis. Despite resuscitative measures, she died 30 minutes later. The
major autopsy finding is shown in the figure. Which of the following is the
most likely mechanism for sudden death in this patient?

A. Bronchoconstriction
B. Compression atelectasis
C. Hemorrhagic infarction
D. Interstitial edema
E. Acute cor pulmonale
• The figure shows a saddle pulmonary thromboembolus in the opened
main pulmonary arteries.

• Sudden death occurs from hypoxemia or from acute cor pulmonale with
right-sided heart failure.

• Because the airways are not obstructed, the lungs do not collapse, and
there is no mass effect upon lung parenchyma.

• There is no bronchoconstriction.

• With such an acute course, there is not enough time for a hemorrhagic
pulmonary infarction to occur.

• Edema is not a feature of thromboembolism.

 Pulmonary Hypertension
• Pulmonary hypertension is defined as a mean pulmonary artery pressure
greater than or equal to 25 mm Hg at rest.

• The World Health Organization has classified pulmonary hypertension into five
groups:
 (1) pulmonary arterial hypertension, a diverse collection of disorders that all primarily
impact small pulmonary muscular arteries
 (2) pulmonary hypertension secondary to left-heart failure;
 (3) pulmonary hypertension stemming from lung parenchymal disease or hypoxemia;
 (4) chronic thromboembolic pulmonary hypertension
 (5) pulmonary hypertensionof multifactorial basis.
 Lung
Neuroendocrine tumors

Typical carcinoid / Neuroendocrine tumor, grade 1

Atypical carcinoid / Neuroendocrine tumor, grade 2
CAP NOTE:
Neuroendocrine tumors continue to be classified based on their diagnostic
criteria as :

• low-grade (typical carcinoid/neuroendocrine tumor, grade 1),

• intermediate-grade (atypical carcinoid/neuroendocrine tumor, grade 2)
and
• neuroendocrine carcinoma (large cell carcinoma and small cell
carcinoma).
• Pulmonary carcinoids are well differentiated neoplasms with
neuroendocrine differentiation further divided into typical
and atypical carcinoids.

• Classification is based on
mitotic count per 2 mm2 and presence / absence of necrosis
(Ki67 proliferative index is currently not recommended to
distinguish between typical and atypical carcinoids)

Typical carcinoids have a mitotic rate of 2 mitoses/2 mm2 and no necrosis,

while atypical carcinoids have a mitotic rate 2 - 10 mitoses/2 mm2 or a
presence of necrosis
 Typical carcinoid
Essential features
• Pulmonary carcinoids are classified according to
mitotic count per 2 mm2 and the presence of necrosis

• Histologic features include neuroendocrine growth pattern and

monotonous tumor cells with salt and pepper chromatin and
inconspicuous nucleoli, along with moderate to abundant eosinophilic
cytoplasm
• Treatment is based on surgical resection.
• prognosis is excellent for typical carcinoid.
 Typical carcinoid
• Not recommended: well differentiated lung neuroendocrine carcinoma
• G1 - G3 neuroendocrine neoplasm classification is not currently applied in
pulmonary carcinoids
• Diagnosis of carcinoid can be made on biopsy or cytology specimen but
the distinction between typical and atypical carcinoid usually requires a
surgical specimen, unless necrosis or mitoses are seen

• Sample pathology report

Right lung, superior lobe, transbronchial biopsy:
– Carcinoid tumor, not further classified (see comment)
Comment: In the absence of necrosis or increased mitoses on the biopsy,
a definitive diagnosis of typical versus atypical carcinoid will be made
on the resection specimen.
 Typical carcinoid
• < 1% of all lung cancers and 2% of resected lung tumors

• More frequent:
– Patients aged < 60 years
– Female
– Caucasian

• Risk factors:
– Family history
– Mutation in MEN1 gene
– Unrelated to smoking
• Clinical features mostly due to tumor location :
– Peripheral carcinoids are commonly asymptomatic
– Centrally located carcinoids may present with dyspnea, cough,
wheezing, hemoptysis, recurrent infection and pneumonia due to
airway obstruction
• Paraneoplastic syndromes are uncommon and usually present
in the setting of liver metastases:
– Carcinoid syndrome (< 2%): flushing, diarrhea, valvular disease
– Cushing syndrome (4%)
– Other rare endocrine syndromes

• Bronchoscopy shows polypoid endobronchial lesion in central

airway
 Typical carcinoid
Gross description
• Well circumscribed, round to oval tan colored tumors
• Localization:
– Frequently in bronchial lumen, sessile or pedunculated with partial
or complete obstruction of the lumen.
– Peripheral tumors may not be evidently located in airways
• Size range: 0.5 - 9.5 cm
Typical carcinoid
 Atypical carcinoid:
Well differentiated
neuroendocrine tumor with
• Diagnostic criteria of typical carcinoid: > 2 mitoses/2mm2 or
– Neuroendocrine tumor with presence of necrosis

size > 5 mm with

< 2 mitoses/2 mm2 and
absence of necrosis

• Neuroendocrine growth pattern (organoid, trabecular, rosette

formation, nested) or pseudoglandular, follicular and papillary growth
• Tumor cells are uniform with a polygonal shape, round to oval nuclei
with salt and pepper chromatin and inconspicuous nucleoli, along
with moderate to abundant eosinophilic cytoplasm
– Spindle cells and clear cell features can be seen Carcinoid tumorlet:
Well differentiated
neuroendocrine
• Stroma is fine and highly vascularized. tumor with
size < 5mm and with
• hyalinization, cartilage or bone formation are possible. < 2 mitoses/2 mm2
and
absence of necrosis
Positive stains
• Chromogranin, synaptophysin, CD56: diffusely and strongly positive.

• Pancytokeratins: positive, useful to distinguish from paraganglioma

(keratin-, TTF1-)

• Ki67: typical and atypical carcinoid < 20%,

useful to discriminate between high grade neuroendocrine tumors (small cell
carcinoma and large cell neuroendocrine carcinoma), in particular on
small or crushed biopsies
– Utility not proven to differentiate between typical and atypical
carcinoid
• TTF1: useful marker of pulmonary lineage in typical and atypical carcinoids
but only positive in < 50% of cases
– TTF1+ carcinoids are more commonly seen in peripheral lesions and
staining is commonly focal and weak.
 Differential diagnosis
• Atypical carcinoid:
• Carcinoid tumorlet:
• Small cell carcinoma:
– Scant cytoplasm, elevated nuclear to cytoplasmic ratio, nuclear molding, absence of nucleoli
– Ki67 proliferative index > 50%
• Large cell neuroendocrine carcinoma:
– Large cells, high grade nuclei
– High mitotic index, Ki67 proliferative index > 50%
• Paraganglioma:
– Cytokeratins are negative
– Also can have S100+ sustentacular cells
• Thyroid medullary carcinoma
– Calcitonin+, CEA+

• Well differentiated neuroendocrine tumor of the gastrointestinal tract:

– CDX2+ (clinical correlation required if TTF1 and CDX2 are both negative)

• Type A thymoma:
– p40+
– Neuroendocrine markers (chromogranin, synaptophysin) are negative
Frozen section description
• Homogenous population of cells with mild atypia
• Organoid pattern helps to distinguish from inflammatory cells
• Fine chromatin
• Mitoses are rarely seen on frozen section
• Hyalinization of the stroma and the presence of blood vessels may help to distinguish
from carcinoma
 Question??
A 55 year old woman had a lower left lobectomy showing a well circumscribed
flesh colored tumor. Histologic details are shown in the image below.
Regarding this entity, which of the following statements is true?

A. CDX2 is usually negative in the lung and is useful to differentiate from a

metastasis of an intestinal origin
B. Ki67 proliferative index is essential to grade this tumor
C. Rb expression is typically lost in this tumor
D. TTF1 is always positive
 Question??
Regarding typical carcinoid tumors of the lung, which of the following
statements is true?

A. Diagnostic criteria are based on mitotic rate and Ki67 proliferation

index
B. Most patients are smokers
C. They are mostly found in peripheral airways
D. They may arise in the context of diffuse idiopathic pulmonary
neuroendocrine cell hyperplasia and tumorlets
 Lung
Neuroendocrine tumors
Small cell carcinoma
 Small cell carcinoma
• Neuroendocrine tumor that arises in the hilum of smokers with a poor prognosis and no
current targeted therapy.
• High grade, usually advanced at diagnosis
• Almost exclusively associated with smoking / tobacco exposure

• Positive for at least one neuroendocrine marker.

• Clinical feature:
– Paraneoplastic syndromes
• Adrenocorticotropic hormone (ACTH) production → Cushing syndrome
– Superior vena cava syndrome

• Diagnosis: Biopsy: based on H&E morphology

• Sample pathology report
Lung, left upper lobe, endobronchial biopsy:
– Malignant tumor present, consistent with small cell carcinoma (see comment)
– Comment: positive immunoreactivity for keratin, CD56 and TTF1 with negative staining
for CD45 supports the diagnosis of small cell carcinoma
• Round / oval blue cells with minimal cytoplasm; usually small to medium
sized
• Nuclear features: finely dispersed chromatin, no distinct nucleoli, molding,
smudging, high mitotic rate
• Stroma: thin, delicate, scant, fibrovascular
• Necrosis and apoptosis of individual cells common
• Synaptophysin, chromogranin A, INSM1 (90 - 100%, low sensitivity but
highly specific), CD56, TTF1 (negative in 15 - 20%), napsin (perinuclear
dot-like stain) - in some reported studies however napsin has been
reported to be negative (Br J Cancer 2003;88:1229)
Crushed blue cells
 Lung
Neuroendocrine tumors
Large cell neuroendocrine carcinoma
Microscopic (histologic) description
• Neuroendocrine architecture may include organoid, nesting, palisading,
trabecular, solid patterns and rosette-like structures.

• >10 mitoses / 2 mm2, extensive / geographic necrosis

• Large cells (~3x size of small cell carcinoma) with abundant cytoplasm, variably
coarse chromatin, nuclear pleomorphism, prominent nucleoli

• Larger tumor cells than atypical carcinoid, high nuclear grade, increased
mitotic activity and necrosis.

• Positive stains:
– Neuroendocrine markers, focal to diffuse (chromogranin, synaptophysin, CD56), CD117
(60%), TTF1 (50%)
– Cytokeratins AE1 / AE3, Cam5.2 variable CK7
– High Ki67 (40 - 80%) helpful to differentiate from carcinoid tumors, especially in small
biopsies.
c-KIT expression in large-cell neuroendocrine carcinoma. Large-cell neuroendocrine
carcinoma displays positive expression of c-KIT by immunohistochemical staining
 HER2 expression in large-cell neuroendocrine carcinoma.
Large-cell neuroendocrine carcinoma displays overexpression (3+) of HER2
by immunohistochemical staining
EGFR
 Question??
Pulmonary large cell neuroendocrine carcinoma, in contrast with small
cell carcinoma, is associated with:

A. > 10 mitoses / 2 mm2

B. Extensive necrosis
C. Nonsmokers
D. Paraneoplastic syndrome
E. Prominent nucleoli
Gross diagnosis?
Lymphangioleiomyomatosis
centrilobular emphysema
• DLBL
Inflammatory fibroplastic
tumor
• Pulmonary
alveolar
micolithiasis
• emphysema
Fat embolism
• Miliary Tuberculosis