Lung tumors
Last revised 9 August 2008
Last major update November 2003
Copyright (c) 2003-2007, PathologyOutlines.com, Inc.
See also Lung-nontumor, Mediastinum, Pleura, Trachea
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Benign tumors: adenoma, benign metastasizing leiomyoma, clear cell (sugar) tumor, diffuse pulmonary lymphangiomatosis, granular cell tumor, hamartoma, hemangioma, hemangiomatosis, inflammatory pseudotumor, Langerhans cell histiocytosis, leiomyoma, lipoma, lymphangiomyomatosis, micronodular pneumocyte hyperplasia, paraganglioma, sclerosing hemangioma, solitary fibrous tumor, squamous papilloma
Dysplasia/CIS: general, bronchioalveolar atypical adenomatous hyperplasia
Carcinoma: general, acinic cell, adenocarcinoma, adenocarcinoma-fetal lung type, adenocarcinoma-well differentiated fetal, adenocarcinoma vs mesothelioma, adenoid cystic, adenosquamous, bronchioloalveolar, epithelial-myoepithelial, giant cell, large cell, large cell neuroendocrine, lymphoepithelioma-like, metastatic, metastatic endometrial stromal sarcoma, micropapillary, mucoepidermoid, papillary, pleomorphic, pleuropulmonary blastoma, pulmonary blastoma, sebaceous, small cell, spindle cell, squamous cell
Carcinoid and related tumors: carcinoid, atypical carcinoid, tumorlet
Hematologic: BALT lymphoma, Burkitt’s lymphoma, diffuse large B cell lymphoma, follicular bronchitis, Hodgkin’s lymphoma, lymphomatoid granulomatosis, MALT lymphoma, Nasal type NK/T cell lymphoma, plasmacytoma, SLL/CLL, Waldenström macroglobulinemia
Other malignancies: angiosarcoma, desmoplastic small round cell tumor, epithelioid hemangioendothelioma, histiocytic-dendritic, HIV lymphoproliferative, Kaposi’s sarcoma, leiomyosarcoma, melanoma, rhabdomyosarcoma, synovial sarcoma
Other: staging, features to report, cytology, grossing, frozen section
Go to Lung: non-tumors
Benign tumors
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Pleomorphic adenoma
Very rare (< 20 cases reported), ages 35-74 years
Usually in trachea and major bronchi, rarely in distal bronchi
Case report in 56 year old woman with incidental lesion, Archives 2003;127:621
Treatment: surgical excision, but may recur many years later
Gross: well circumscribed, no capsule, 2-16 cm, gray-white cut surface, may have tumor tongues outside their fibrous capsules
Micro: nests and trabeculae of epithelial cells in chondromyxoid stroma; lumina may contain PAS+ eosinophilic secretions; mixture of epithelial cells with small branching ductules, myoepithelial cells and fibromyxoid stroma with focal hyalinization; mild nuclear atypia, occasional multinucleated giant cells, no/rare mitosis
Gross/micro images: image1
Positive stains: epithelium - CK7, CAM5.2, AE1/AE3, alpha-1-antitrypsin, lysozyme; myoepithelial cells - S100, vimentin
DD: primary salivary gland tumors (have ducts with single layer of cells, lack PAS+ material in lumens, lack S100+ / vimentin+ myoepithelial layer)
Alveolar adenoma: usually in peripheral lung, consists of small cystic spaces lined by type II pneumocytes and containing fluid
Bronchial gland adenomas: include oncocytoma and mucus gland adenoma
Papillary adenomas: arise in peripheral lung, composed of type II pneumocytes or Clara cells
Benign metastasizing leiomyoma
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Rare, <60 cases reported through April 2003
Usually women ages 36-64 years, mean 44 years, often with prior history of uterine leiomyomas; regress during pregnancy or after oophorectomy
May represent a well differentiated leiomyosarcoma of low malignant potential, metastatic to lung
Usually no symptoms or mild cough and shortness of breath; nodule(s) on chest Xray
Good prognosis
Case report in 76 year old woman, Archives 2003;127:501
Treatment: hysterectomy, bilateral salpino-oophorectomy, long term hormonal therapy
Micro: well circumscribed, single or multiple nodules of smooth muscle, composed of elongated cells with abundant eosinophilic cytoplasm, oval nuclei, inconspicuous nucleoli; large, irregularly shaped thick walled vessels; no atypia, no vascular invasion, no mitotic figures; may contain cysts
Micro images: image1
DD: hamartoma, low grade leiomyosarcoma
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Usually adults, may occur in children
Derived from perivascular epithelioid cells (also angiomyolipomas, lymphangioleiomyomas)
Treatment: simple excision
Gross: small, sharply outlined, red-tan mass, usually in peripheral lung
Micro: sheets of large cells with clear to eosinophilic granular cytoplasm and numerous PAS+ glycogen granules; small uniform nuclei, prominent vasculature, may have extracellular amorphous eosinophilic material with variable calcification, minimal stroma; no fat, no mitotic figures
Positive stains: HMB45, S100 (focal)
EM: membrane bound glycogen in lysosome-like organelles, intracytoplasmic filaments
DD: carcinoma with clear cell pattern, metastatic renal cell carcinoma
Diffuse pulmonary lymphangiomatosis
Men, women or children with wheezing and shortness of breath
No cysts, no pneumothorax
May be progressive and fatal
Micro: prominent lymphatics in pleura and alveolar septa, variable smooth muscle proliferation that may appear kaposiform
Negative stains: HMB45
Polypoid intrabronchial mass that may cause obstruction
May be multicentric
Also called pulmonary chondroma
Benign, occurs in adults
Usually solitary, subpleural
Common, presents as incidental coin lesion (rounded abnormality) with popcorn pattern of calcification on chest Xray
May present as intrabronchial polypoid mass causing obstruction
Xray images: contributed by Dr. Hanni Gulwani, New Delhi (India) - Chest Xray #1; #2; CT scan
Treatment: excision
Nonfamilial syndrome: pulmonary chondroma, gastric epithelioid leiomyosarcoma, functional extra-adrenal paraganglioma
Gross: 4 cm or less, sharply delineated and lobulated, glistening cut surface (cartilage) with ill defined clefts
contributed by Dr. Hanni Gulwani, New Delhi (India) - lobulated tumor
Micro: principally composed of islands of mature hyaline cartilage, fat, smooth muscle and clefts lined by respiratory epithelium (ciliated or not); cartilage may be calcified or ossified; periphery of cartilage may contain immature myxomatous tissue; resembles breast fibroadenoma if no cartilage present
15% have papillary projections resembling immature placental villi (placental transmogrification), with stromal macrophages and lymphocytes and abundant mast cells
Gross/micro images: hamartoma, placental transmogrification
micro images contributed by Dr. Hanni Gulwani, New Delhi (India) - image #1; #2; #3
Virtual slides: hamartoma
References: Archives 2002;126:562
Multiple pulmonary leiomyomatous hamartomas
Very rare, almost always in asymptomatic middle-aged women
Case report in 46 year old man associated with bronchogenic cyst, Archives 2003;127:e194
Micro: excessive smooth muscle, not associated with tumor nodules
Micro images: smooth muscle proliferations
Negative stains: HMB45
DD: reactive smooth muscle proliferation in chronic interstitial pneumonitis, benign metastasizing leiomyoma, leiomyosarcomas, lymphangioleiomyomatosis, native pulmonary muscle proliferation
Hemangioma
Usually children
Endobronchial or parenchyma
May present with symptoms of pulmonary hypertension or interstitial lung disease
Poor prognosis; may be a variant of veno-occlusive disease
Micro: proliferation of benign-appearing capillaries in alveolar septa that appear to compress pulmonary veins; also hemorrhage, hemosiderosis
DD: veno-occlusive disease
Also called inflammatory myofibroblastic tumor, plasma cell granuloma
Often children and adults age 30 or less; most common lung tumor in children age 16 and younger
Treatment: excision; rarely causes death due to local extension
Poor prognostic factors: metastases, necrosis >15% of surface area examined, local recurrence, bizarre giant cells, > 3 mitotic figures/50 HPF, advanced stage, high cellularity, poor circumscription
Gross: well circumscribed, non-encapsulated, usually solitary, white, firm, parenchymal nodule; 3% bilateral; may have hemorrhage, necrosis or calcification
Micro: plasma cells, lymphocytes, histiocytes and myofibroblasts; may have vascular proliferation, collagenous or hyalinized stroma, myxoid change, xanthoma cells, hemosiderin; may resemble nodular fasciitis, fibrous histiocytoma or fibromatosis
Gross/micro images: spindle cells in collagenous stroma
Positive stains: spindle cells - vimentin, smooth muscle actin
EM: elongated cytoplasmic processes with pinocytotic vesicles, subplasmalemmal plaques, thin filaments, abundant endoplasmic reticulum
DD: hemangiopericytoma, carcinoid tumor, plasmacytoma, amyloid tumor, metastatic carcinoma, TB in immunosuppressed patients, organizing pneumonia, lipid pneumonia, benign and malignant fibrous histiocytoma, other spindle cell tumors, mycobacterial pseudotumor
Childhood inflammatory pseudotumor
Most common isolated lung lesion in children, usually asymptomatic
Benign, although rare cases of malignant behavior have been reported
Treatment: excision or radiation therapy
Gross: solitary, small peripheral nodules, yellow, firm, covered by intact pleura or polypoid bronchial mass
Micro: see above; often rich in plasma cells
Also called eosinophilic granuloma, Langerhans cell granulomatosis, histiocytosis X (“H-X”), Hand-Schuller-Christian disease, Letterer-Siwe disease
Usually ages 20-39 years; strongly associated with smokers
20% with multicentric disease (bone, skin, lymph nodes, spleen, pituitary) have lung involvement
50% of cases only involve lung
Often associated with pneumothorax, Pneumocystis carinii pneumonia
Usually lung disease resolves or stabilizes, but 10-20% may progress to respiratory failure
Case report of 40 year old woman with Stage IV diffuse large B cell lymphoma, Archives 2002;126:747
Gross: lesion of upper lobes, local or diffuse, with nodules and cavitary lesions and late honeycombing
Micro: interstitial scarring with nodular aggregates of Langerhans cells with a bronchiolocentric distribution; also prominent eosinophils and mesothelial cells; Langerhans cells have abundant eosinophilic cytoplasm and grooved nuclei with indented nuclear membranes; frequent hemosiderin, necrosis, alveolar lining cell hyperplasia, pigmented alveolar macrophages; variable vasculitis; older lesions have fewer eosinophils and more interstitial fibrosis; sarcomatous variant has significant atypia and mitotic figures
Micro images: fibrotic nodule with histiocyte-like cells, Langerhans cells, CD1a
Positive stains: CD1a, S100, HLA-DR
EM: Birbeck’s granules (pentilaminar intracytoplasmic structures, tennis racket shaped)
EM images: Birbeck’s granules
DD: eosinophilic pleuritis (no Langerhans cells although mesothelial cells may appear similar), reactive Langerhans cells in inflammatory conditions (no sheets or groups of Langerhans cells), desquamative interstitial pneumonitis
Rare, associated with HIV-infected children
See also benign metastasizing leiomyoma (above)
DD: spindle cell carcinoma
Usually endobronchial, usually men ages 50+
Micro images: mature adipose tissue with small blood vessels
Also called lymphangioleiomyomatosis
Rare, unknown etiology, may diffusely involve both lungs
Almost always in women, usually white and of reproductive age; rare cases in men or postmenopausal women on hormone replacement
Associated with tuberous sclerosis, renal angiomyolipomas
May involve mediastinal or periaortic lymph nodes
Derived from perivascular epithelioid cells (also angiomyolipomas, clear cell [sugar] tumor of lung)
Symptoms: dyspnea with pneumothorax or emphysema, without a smoking history
Have severe impairment of diffusion with air trapping and expanding lung volumes
Disease is progressive, prognosis poor, death due to respiratory failure or cor pulmonale
Disease worsened by pregnancy or menstruation, improved post-menopause
Complications: respiratory insufficiency and death, spontaneous pneumothorax, chylous pleural effusion; may be due to metastases or migration of progenitor cells
Treatment: oophorectomy, hormone manipulation (progesterone or antiestrogens), lung transplantation (but may recur in lung allografts, Hum Path 2003;34:95)
Gross: emphysematous-like changes to widespread cystic spaces separated by thick, gray-white septa
Micro: cystic air spaces and patchy disordered nodular proliferation of bland smooth muscle around airways, lymphatics, blood vessels; proliferating smooth muscle cells expand lung parenchyma; resembles renal angiomyolipoma in that smooth muscle appears to spin off muscle coats of these structures, extending towards adjacent alveoli; muscle cells have optically clear cytoplasm, intracytoplasmic glycogen; hemosiderin pigment is common
Micro images: figure 4 is HMB45
Positive stains: HMB45, ER, PR
DD: metastatic endometrial sarcoma, benign metastasizing leiomyoma, idiopathic pulmonary hemosiderosis (all HMB45 negative), micronodular pneumocyte hyperplasia
Micronodular pneumocyte hyperplasia
Associated with tubular sclerosis; may coexist with lymphangioleiomyomatosis
Usually women with shortness of breath
Considered a hamartoma
Not progressive
Micro: bland multifocal proliferation of alveolar type II pneumocytes
Negative stains: HMB45, ER, PR
DD: lymphangioleiomyomatosis
Rare in lung
Usually benign; rarely malignant
May be hyperplastic, not neoplastic
Gross: solitary or multiple, usually peripheral mass, often microscopic
Micro: zellballen pattern (islands of cells) with sustentacular cells at periphery of nests
Positive stains: neuroendocrine markers; S100 (sustentacular cells)
Negative stains: keratin, mucin, CEA
EM: resembles meningeal arachnoid granulations
DD: carcinoid tumor (ribbons, festoons, rosettes)
Also called sclerosing pneumocytoma
Usually adult women, ages 30-50 years, with incidental solitary nodule on chest Xray
Apparently derived from type II pneumocytes or with differentiation towards these cells
Almost always benign, 2-4% have nodal metastases that don’t appear to affect prognosis (Archives 2003;127:321)
Sclerosis and hemorrhage are probably secondary changes
Gross: well circumscribed, non-encapsulated, easily shelled out, tan-yellow, may be hemorrhagic, usually peripheral lung
Gross images: tan-yellow tumor
Micro: papillary pattern or islands filled with bland polygonal cells with abundant eosinophilic cytoplasm and indistinct cell borders; may have sclerotic stroma, may be continuous with bronchial epithelium; frequent hemorrhage, aggregates of histiocytes; no/rare granulomatous reaction, no/rare mitotic figures; no angiolymphatic invasion, no necrosis
Gross/micro images: sclerotic areas #1, #2, papillary tumor #1, #2, solid area, hemangioma-like, foam cells, hemosiderin, tumors with nodal metastases #1, #2
Contributed images: by anonymous - young Asian woman with lung tumor: image#1; #2; #3; #4; #5
Positive stains: EMA, keratin (focal), LeuM1, TTF1, PR, ER (weak), surfactant proteins
Negative stains: CEA, S100, smooth muscle actin, chromogranin, CD34
DD: primary and metastatic carcinoma, clear cell (“sugar”) tumor, carcinoid tumor, papillary adenoma, alveolar adenoma, epithelioid hemangioendothelioma, Langerhans cell histiocytosis, meningiomas, meningothelial-like nodules
References: Archives 2003;127:377
May be intrapulmonary and not pleural
Peaks at ages 50-69 years
Larger tumors associated with hypoglycemia, pleural effusion, pulmonary osteoarthropathy (particularly if tumors 7cm+)
Gross: firm, rounded, lobulated; variable cysts, hemorrhage, necrosis
Micro: highly variable cellularity, markedly collagenous stroma with irregularly distributed thick walled vessels; may have myxoid stroma; often has malignant features (pleomorphism, tumor giant cells, mitotic figures); may have MFH, hemangiopericytoma, fibrosarcoma or neural patterns
Positive stains: CD34, vimentin; variable smooth muscle actin
Occur in large bronchi, often with associated tracheal or laryngeal lesions
Due to HPV
Often associated with dysplasia, carcinoma in situ or invasive squamous cell carcinoma
May contain mucus cells
Micro: papillary lesion covered by squamous epithelium
DD: mucoepidermoid carcinoma (for papillomas with mucus cells)
Dysplasia/carcinoma in situ
Usually associated with bronchial lesions; often present in uninvolved bronchus near carcinoma
No distinct criteria for dysplasia versus carcinoma in situ
Expert confirmation recommended before signing out case as carcinoma in situ
Gross: either unremarkable or papillary, granular with loss of folds
Micro: focal to full thickness replacement of epithelium by squamous cells with increased nuclear to cytoplasmic ratio, nuclear pleomorphism, mitotic activity but intact basement membrane; no invasive growth although may extend into ducts of submucosal glands
Virtual slides: bronchial squamous cell carcinoma in situ
Bronchioalveolar atypical adenomatous hyperplasia
Diagnostic variability exists - also called adenoma, well differentiated bronchioalveolar carcinoma of Clara cell or type II pneumocyte type
Associated with coexisting bronchioloalveolar carcinoma and papillary adenocarcinoma
If malignant appearing but noninvasive, recommended to call bronchioloalveolar carcinoma of nonmucinous type
Gross: focal
Micro: alveolar lining cells replaced by cuboidal cells with uniform, mildly to highly atypical nuclei, scanty cytoplasm, minimal mitotic figures
References: Hum Path 2002;33:697 (telomerase expression).
Carcinoma
95% of lung tumors are bronchogenic carcinoma; also bronchial carcinoids, mesenchymal, miscellaneous neoplasms
In US, lung cancer is #1 cause of cancer death in men and women; causes 30% of cancer deaths in men
In 2002, 164,000 new cases in US; incidence in men is 74 per 100,000 vs. 31 per 100,000 for women
Peaks at ages 50-69 years; 2% occur before age 40
Young patients (age 40 or less) have higher incidence of 20q gains/amplifications compared to older patients (56% vs. 8%), Mod Path 2002;15:372
Cigarette smoking: causes most cases of lung cancer; relative risk of smokers vs. nonsmokers is 10:1; increases to 20:1 for >40 cigarettes/day; risk is strongly related to number of cigarettes smoked, described in pack years (number of packs per day x number of years smoking)
Also associated with carcinomas of lip, tongue, pharynx, larynx, esophagus, bladder, pancreas, kidney, floor of mouth
10% of smokers have atypia or hyperplasia of bronchial epithelium
Carcinogens in tobacco smoke are benzo [a] pyrene (an initiator) and phenol derivatives (promoters)
Usually associated with squamous cell and small cell carcinoma, less likely with adenocarcinoma
Other causes: radiation exposure, uranium (RR with uranium exposure is 4:1 for nonsmokers, 10:1 for smokers vs. general population); asbestos (RR with asbestos exposure is 5:1 for nonsmokers, 50-90:1 for smokers vs. general population), exposure to nickel, chromate, coal, mustard gas, arsenic, beryllium, iron, vinyl chloride, radon radiation, gold miners
Causes of death for asbestos workers are: 20% lung cancer, 10% mesothelioma, 10% GI carcinomas
Symptoms: cough, weight loss, chest pain, shortness of breath, increased sputum production
Systemic symptoms: Lambert-Eaton myasthenic syndrome (muscle weakness due to antibodies to neuronal calcium channel), sensory peripheral neuropathy, acanthosis nigricans, leukemoid reaction, hypertrophic pulmonary osteoarthropathy (clubbing), superior vena cava syndrome (compression/invasion of SVC causes venous congestion, circulatory compromise, dusky head, arm edema), pain in distribution of ulnar nerve and Horner’s syndrome (enophthalmos, ptosis, miosis, anhidrosis) due to apical lung tumors called Pancoast tumors
Classification: broad classification is non-small cell carcinoma (80%) versus small cell carcinoma (20%)
50% of non-small cell carcinomas are metastatic at diagnosis vs. 80% of small cell carcinomas
Many have mixed histologic subtypes
Scar cancers: scar is desmoplastic response to tumor
Spread: along bronchus distally and proximally, into lung parenchyma to mediastinum or pleura, causing pleural seeding, pleural effusion, involvement of diaphragm and chest wall
Metastases: 50% have nodal involvement at resection (usually hilar, mediastinal and supraclavicular); also metastases to adrenals (50%), liver (30%), brain, bone; also opposite lung, pericardium, kidneys
Treatment: complete excision for non-small cell lung carcinoma; radiation therapy (usually non-curative), chemotherapy (rarely curative, even for small cell carcinoma)
Survival: overall 5 year survival is 10-15%; only 30% have limited disease at diagnosis making resection for cure an option
For stage I non-small cell carcinoma, 5 year survival is 60%, poor prognostic factors are p53+, HER2+, angiolymphatic invasion or tumor size > 3 cm, Hum Path 2002;33:105
Poor prognostic factors (clinical): high TNM stage, weight loss >10% of body weight, age < 40 years or women (usually are high stage), small cell or giant cell subtypes, angiolymphatic invasion, pleural effusion, lack of lymphoplasmacytic reaction
Favorable subtypes: non-mucinous bronchioloalveolar, well differentiated squamous cell
Gross: arise near hilus; hemorrhage, necrosis, cavities are common; 2-5% are multiple; peripheral tumors are usually adenocarcinomas
Micro (see also specific subtypes): begins with atypia, then warty excrescence, then fungates into lumen, penetrates wall of bronchus growing along broad front to produce a cauliflower like intraparenchymal mass; 80% have vascular invasion
Virtual slides: tumor emboli
Positive stains (see also specific subtypes): may be positive for neuroendocrine markers but with no neuroendocrine morphology - recommended to either ignore neuroendocrine stain results or to diagnose as tumor with neuroendocrine features
Negative stains: CDX2 (marker of intestinal origin, AJSP 2003;27:141), Hep Par1 (hepatocyte marker, Mod Path 2003;16:137)
Molecular: dominant oncogenes are K-ras (adenocarcinomas), c-myc (small cell carcinomas), p53, Rb, 3p suppressor gene; non-small cell carcinogenesis may be related to loss of Cables protein expression at 18q11-12, Hum Path 2003;34:143
Bronchial gland tumor with low grade malignancy
Very rare at this site, usually in parotid gland, less commonly in submandibular and sublingual glands
Case report in 30 year old woman, Archives 2003;127:e216
May arise from pluripotent cells of tracheobronchial submucosal serous and mucus glands
Treatment: surgical excision
Micro: predominantly acinar cells, also ductal cells, myoepithelial cells, reserve/stem cells; solid areas recapitulate salivary gland acinar differentiation with large polyhedral cells containing round, bland nuclei and abundant granular cytoplasm; microcystic areas recapitulate terminal duct-acinar unit; no/rare perineural invasion (unlike salivary gland tumor)
Micro images: acinic cell carcinoma
Positive stains: cytokeratin, EMA
Negative stains: amylase
EM: no melanosomes, no abundant cytoplasmic glycogen, no neurosecretory granules, no abundant mitochondria or fat globules
DD: metastastic salivary gland tumor, primary lung adenocarcinoma, clear cell (sugar) tumor of lung, oncocytic carcinoma, bronchial oncocytoma, bronchial granular cell tumor, metastatic renal cell carcinoma
Arises from terminal bronchioles
In US, 50% of lung carcinomas in women are adenocarcinoma; is the most common subtype in nonsmokers
80% contain mucin
Grow slower than squamous cell; may be associated with scarring
5 year survival: stage I - 69%, II - 40%, IIIA - 17%, IIIB - 5%, IV - 8%
Peripheral tumors with bronchioloalveolar and invasive areas < 5 mm had low rates of vascular and pleural invasion and no nodal involvement, AJSP 2003;27:937
More likely TTF1 negative in males or smokers
Gross: 77% involve visceral pleura producing puckering/pleural retraction, 65% are peripheral; poorly circumscribed gray-yellow lesions, single or multiple, may be mucoid; usually not cavitary; often is associated with a peripheral scar or honeycombing (scar appears to be response to tumor); rarely spreads into pleural space to coat visceral and parietal pleura and resemble diffuse mesothelioma
Gross images: peripheral tumor #1, #2
Micro: glandular differentiation with tubules or papillae and mucin secretion; bronchioloalveolar (BAC), colloid, hepatoid, signet ring and undifferentiated subtypes; tumors 1.5 cm or less are usually one cell type, larger tumors are often mixed; vascular invasion common; rarely choriocarcinoma foci, pagetoid spread along bronchial mucosa, eosinophilic intracytoplasmic globules, clear cell change (glycogen)
Periphery of tumor often has minimal atypia, with marked atypia centrally
Micro images: cytology
Virtual slides: moderately differentiated adenocarcinoma
Positive stains: mucin, low molecular weight keratin (CK7), EMA, CEA, TTF1 (72%), surfactant apoprotein (50%), mesothelin (50%), vimentin (9%), S100 (Langerhans cells), p53, CD57/Leu7 (50% of well/moderately differentiated tumors), calretinin (11%)
Negative stains: CK20, vimentin (usually), keratin 5 (usually), P504S
EM: goblet cells, mucus cells, nonciliated bronchiolar cells, Clara cells
DD: melanoma (may be mucin positive)
References: AJSP 2003;27:150, AJSP 2002;26:767 (TTF1)
Subtypes:
Bronchial surface cell type with little/no mucin
8% of adenocarcinoma cases
Gross: cartilage bearing bronchus with polypoid growth or in distal airways
Micro: papillary or tubular groups of tall columnar cells resembling ciliated columnar cells, but without cilia
EM: numerous mitochondria and smooth surfaced vesicles, basal bodies but usually no cilia, no secretory granules
Goblet cell type
Gross: lobar pneumonia-like or nodular
Micro: tumor cells resemble goblet cells, with cytoplasmic mucin displacing the nuclei to basal portion; usually in bronchioloalveolar pattern, rarely in papillary pattern
Positive stains: lysozyme
Bronchial gland cell type
5% of adenocarcinoma cases
Gross: cartilage bearing bronchus with polypoid growth or in distal airways as nodular tumor
Micro: acini, tubules, ducts, cribriform patterns or solid nests of cuboidal or polygonal cells, often with mucin; may have signet ring cells; resemble bronchial glands; nests surrounded by myoepithelial type cells
Clara cell type
50% of adenocarcinoma cases
Gross: pleura indented toward area of central fibrosis
Micro: papillary, tubular or bronchioloalveolar patterns of peg-shaped cells or low columnar cells with tongue-shaped projections; fibrotic focus representing collapsed alveoli may be present; variable nuclear atypia and mitotic activity; frequent intranuclear eosinophilic inclusion bodies
EM: microvilli on free cell surface of peg cells, scattered rough endoplasmic reticulum, 200-900 nm round, dense, neurosecretory granules
DD: type II alveolar epithelial cell type
Type II alveolar epithelial cell type
Gross: solitary nodular of rarely diffusely distributed tumor
Micro: papillary or bronchioloalveolar patterns of cuboidal to low columnar cells with dome-shaped free cell border; finely vacuolated cytoplasm
EM: cytoplasmic lamellar inclusion bodies
Hepatoid
Resembles hepatocellular carcinoma (HCC); more common in gastric adenocarcinomas
Old age, high serum AFP, aggressive behavior, often with liver metastases
Micro: tubular and papillary adenocarcinoma with hepatic morphology; liver metastases are difficult to distinguish from HCC
Positive stains: same as HCC - AFP, CK8, CK18, canalicular staining with polyclonal CEA
Positive stains: different from HCC - CK19, CK20, negative for HepPar1, negative for CK7
Molecular: 4q-, 8p-, Xq+ (seen in hepatocellular carcinoma and hepatoblastoma)
References: AJSP 2003;27:1302
Adenocarcinoma of fetal lung type
Rare, high grade variant is very aggressive
May be a variant of pulmonary blastoma without malignant mesenchymal components
Associated with upregulation of Wnt signaling pathway, Mod Path 2002;15:617
Micro: irregular tubular structures of columnar epithelial cells with clear cytoplasm and oval nuclei, optically clear nuclei rich in biotin; resembles fetal lung in pseudoglandular stage; fibrous stroma without atypia; no morules
Micro images: high grade
DD: well-differentiated fetal adenocarcinoma (has morules)
Adenocarcinoma - well differentiated fetal type
Mean ~40 years
Better prognosis than pulmonary blastoma
Variant of bronchioloalveolar carcinoma
Associated with upregulation of Wnt signaling pathway, Mod Path 2002;15:617
Gross: well-defined, non-encapsulated, not related to visible bronchi
Micro: irregular tubular structures of columnar epithelial cells with clear cytoplasm and oval nuclei, continuous with morular structures; nuclei in morules are optically clear and rich in biotin; fibrous stroma without atypia
Micro images: image1
Positive stains: chromogranin A, synaptophysin, N-CAM
Negative stains: p53
DD: adenocarcinoma of fetal type (no morules)
Adenocarcinoma vs. mesothelioma
Difficult to differentiate histologically if adenocarcinoma does not produce mucin
Stains recommended to differentiate these 2 tumors: calretinin, cytokeratin 5/6 or WT1 and CEA, MOC31 (or B72.3, Ber-EP4 or BG8), AJSP 2003;27:1031
Stains that are specific for adenocarcinoma vs. mesothelioma: MOC31 (100% vs. 8%), Ber-EP4 (100% vs. 18%), BG8 (96% vs. 7%), CEA (88% vs. 0%), B72.3 (84% vs. 0%), TTF1 (74% vs. 0%), CD15/LeuM1 (72% vs. 0%)
Stains that are specific for mesothelioma vs. adenocarcinoma: calretinin (100% vs. 8%), cytokeratin 5/6 (100% vs. 2%), WT1 (93% vs. 0%), thrombomodulin (77% vs. 14%), N-cadherin (73% vs. ?)
Stains frequently positive in both tumors: EMA, E-cadherin, HBME, CD44S, mesothelin, vimentin
EM: long, slender microvilli in mesothelioma
May arise from submucus bronchial glands
Usually in large bronchi, may involve the trachea
Frequent metastases to regional lymph nodes and lung parenchyma
Prolonged course, but overall prognosis is poor
Treatment: radiation therapy (palliative)
Gross: large, polypoid, intrabronchial mass or may grow subepithelially along the bronchi causing thickened bronchial wall
DD: basaloid carcinoma with adenoid cystic carcinoma-like pattern (microcystic spaces containing mucin, surrounded by small tumor cells)
Substantial amounts of squamous and glandular differentiation