Sandbox lung cancer differential

• Differentiation of primary and secondary lun tumors is difficult due to overlapping histologic features.
• Topography, size and form of pulmonary growth pattern are important aspects for the differential diagnosis.
• Primary lung tumors are mainly localized in upper lobes as singular nodules, metastases in lower lobes as multiple lesions.
• On the contarary, endobronchial primary or secondary squamous cell carcinomas findings of severe dysplasia and CIS of the bronchial epithelium are important.
• Stroma and vascularisation pattern of primary and secondary lung tumors differ in distribution, arrangement and extracellular matrix components.
• Pulmonary vascular changes in primary tumors are characterized by vascular infiltration, destruction and occlusion whereas in secondary tumors intravascular embolisation and extravasation predominate.

Malignant lung carcnimoma
			Risk Factors/Epidemiology	Pleuripotent cell	Topography	Histology	Gross	Immunohistochemistry	Imaging	Mets	Other differentiating features
Squamous cell carcinoma	Papillary		Cigarette smokers Arsenic		Centrally in the mainstem	Exophytic Intra-epithelial Without invasion	White or grey and, depending on the severity of fibrosis Firm with focal carbon pigment deposits in the centre and star-like retractions on the periphery. Cavitations. Intraluminal polypoid masses and / or infiltrate through the bronchial wall into the surrounding tissues	High molecular weight keratin (34ßE12 Cytokeratins (5/6) Carcinoembryonic antigen (CEA) Low molecular weight keratin (35ßH11) Thyroid transcription factor-1 (TTF-1) Cytokeratin 7 (CK7)	lobar or entire lung collapse In central SCC, Shift of the mediastinum to the ipsilateral side. Extension into regional lymph nodes Hilar, perihilar or mediastinal masses Peripheral tumours Presents as solitary pulmonary nodules (< 3 cm) or masses (> 3 cm). Cavitations Hilar opacities, atelectasis or peripheral masses Mediastinal enlargement Hemidiaphragmatic elevation
	Clear cell					Cells with clear cytoplasm
	Small cell					Poorly differentiated cells Focal squamous No characteristic nuclear features of SCC. Intercellular bridges or keratinization.
	Basaloid					Peripheral palisading of nuclei. Poor differentiation
Small cell carcinoma	Combined small cell carcinoma		Smoking Active Passive Radon exposure	Bronchial precursor cell		Sheet-like growth Nesting, Trabeculae Peripheral palisading Rosette formation Tumor cells are usually less than the size of lymphocytes. Nuclear chromatin is finely granular Nucleoli are absent or inconspicuous. Cell borders are rarely seen and nuclear moulding is common. High mitotic rate	White-tan, soft, friable perihilar masses. Extensive necrosis. 5% peripheral coin lesions	CD56 Chromogranin Synaptophysin TTF-1	Hilar or perihilar masses Mediastinal lymphadenopathy Lobar collapse	Bone marrow Liver metastases
Adeno carcinoma	Adenocarcinoma, mixed sub type		Smokers		Peripheral		Single or multiple lesions Different in size Peripheral distribution. Gray-white central fibrosis Pleural puckering Anthracotic pigmentation. Necrosis, Cavitation Hemorrhage. Lobulated or ill defined edges.	Epithelial markers (AE1/AE3, CAM 5.2) Carcinoembryonic antigen CK7 TTF-1	Peripheral nodules under 4.0 cm in size Central location as a hilar or perihilar mass Rarely show cavitations. Hilar adenopathy Adenocarcinomas account for the majority of small peripheral cancers identified radiologically.	Brain Bone Adrenal glands Liver
	Acinar adenocarcinoma
	Papillary adenocarcinoma					Characterized by Papillae (secondary and tertiary papillary structures) Necrosis Surrounding invasion Cuboidal to columnar epithemlial linning Mucinous or non-mucinous
	Bronchio-alveolar carcinoma	Non-mucinous				Consists of Clara cells Columnar cells with cytoplasmic snouts and pale eosinophilic cytoplasm. Nuclei may be apical in location. Type II cells Cuboidal or dome-shaped cells Fine cytoplasmic vacuoles or clear to foamy cytoplasm. Intranuclear eosinophilic inclusions
		Mucinous				Low grade differentiation Composed of Tall columnar cells Basal nuclei Pale cytoplasm resembling goblet cells Varying amounts of cytoplasmic mucin Cytologic atypia Aerogenous spread is characteristic Extensive consolidation
		Mixed non-mucinous and mucinous or indeterminate
	Solid adenocarcinoma with mucin production	Fetal adenocarcinoma				Consists glandular elements Tubules of glycogen-rich Non-ciliated cells Subnuclear and supranuclear glycogen vacuoles Rounded morules of polygonal cells with abundant eosinophilic and finely granular cytoplasm.
		Mucinous (“colloid”) carcinoma				Dissecting pools of mucin containing neoplastic cells.
		Mucinous cystadenocarcinoma				Circumscribed tumor with Partial fibrous tissue capsule. Central cystic change with mucin pooling Neoplastic mucinous epithelium grows along alveolar walls.
		Signet ring adenocarcinoma
		Clear cell adenocarcinoma
Large cell carcinoma	Giant-cell carcinoma of the lung
	Basaloid large cell carcinoma of the lung
	Clear cell carcinoma of the lung
	Lymphoepithelioma-like carcinoma of the lung
	Large-cell lung carcinoma with rhabdoid phenotype
	Large cell neuroendocrine carcinoma of the lung
Sarcomatoid carcinoma	Pleomorphic carcinoma
	Carcinosarcoma
	Spindle cell carcinoma
	Giant cell carcinoma
	Pulmonary blastoma
Carcinoid tumour	Typical carcinoid
	Atypical carcinoid
Salivary gland tumours	Mucoepidermoid carcinoma
	Adenoid cystic carcinoma
	Epithelial-myoepithelial carcinoma
Preinvasive lesions	Squamous carcinoma in situ
	Atypical adenomatous hyperplasia
	Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia
Mesenchymal tumors	Epithelioid haemangioendothelioma / Angiosarcoma		Caucasian 80% are women.	Endothelial cells	Intravascular	Round to oval-shaped nodules Central sclerosis Hypocellular zone Peripheral cellular zone Calcifications Intranuclear cytoplasmic inclusions	0.3-2.0 cm circumscribed mass Gray-white or gray-tan firm tissue Yellow flecks Central calcifications Cut surface has a cartilaginous consistency.	CD31 CD34 factor VIII (von Willebrand factor) Fli1 FKBP12 Cytokeratin	Multiple Bilateral Small nodules 1-2 cm in size. Can mimic pulmonary Langerhans’ cell histiocytosis. Calcifications	Liver Bone Soft tissue
	Pleuropulmonary blastoma		Most common in children Median age of diagnosis is 2 years.	Thoracic splanchnopleural mesenchyme.	Pleura Lung	Type I Purely cystic Lined by respiratory type epithelium Underneath malignant cells Type II Partial or complete overgrowth of the septal stroma Type III Mixed cells	Purely cystic Thin-walled Rarely solid Firm to gelatinous Upto 15 cm	Vimentin S-100 protein	Unilateral Localized airfilled cysts Septal thickening or an intracystic mass	Brain Spinal cord Skeletal system Eyes Pancreas
	Chondroma		Young women	Chondrocytes, Cartilaginous cells	Peripheral lesions in lung 1o seen in Stomach Bone Paraganglia	Capsulated lobules Hypocellular Features of malignancy are absent	Peripheral Solid lesions Calcified	N/A	Multiple Well circumscribed lesions “Pop-corn” calcifications	Benign tumor
	Congenital peribronchial myofibroblastic tumor		Rare Sporadic Complicated by Polydramnios Non-immune hydrops fetalis	Spindle cells		Fascicles of spindle cells. Bronchial invasion Peribronchial distribution Cystic foci of haemorrhage	5-10 cm Well-circumscribed Non-encapsulated Smooth or multinodular surface The cut surface has a tann-grey to yellow-tan fleshy appearance. Haemorrhage Necrosis	Vimentin	Well circumscribed Opacifying the hemithorax Heterogeneous mass
	Diffuse pulmonary lymphangiomatosis		Children Young adults of both sexes	Smooth muscles cells of lymphatic vessels.	Along the lymphatic distribution.	Anastomosing endothelial-lined cells along lymphatic routes. Spindle cells Intra alveolar siderophages	Prominence of the bronchovascular bundles along Pleura Interlobular pulmonary septa Mediastinum	FVIIIrAg Vimentin UEA	Increased interstitial markings Thickening of the Interlobular septa Fissures Central airways Pleura
	Inflammatory myofibroblastic tumor		Previous viral infections HHV8 Children	Myofibroblastic cells	Localized to bronchia	Mixture of spindle cells Fibroblastic Myofibroblastic Arranged in fascicles Cytologic atypia Touton type giant cells. Plasma cells Lymphoid follicles	Solitary Round rubbery masses Yellowish-gray discoloration Average size of 3.0 cm Non encapculated Calcifications No local invasion	Vimentin Actin ALK1 p80	Solitary mass Regular borders Spiculated appearance Accompanied by Post-obstructive pneumonia Atelectasis	Rare
	Synovial sarcoma Monophasic Biphasic							Epithelial membrane antigen Cytokeratin CD99
	Pulmonary artery sarcoma
	Pulmonary vein sarcoma

Benign lung tumor
			Risk factors	Gross pathology	Histopathology	Immunohistochemistry	Topography	Prognosis
Papilloma	Squamous cell papilloma	Exophytic and Inverted	HPV 6 and 11	Cauliflower-like tan-white soft to semifirm excrescences protruding into bronchial lumens	Loose fibrovascular core Stratified squamous epithelium Acanthosis Wrinkled nuclei Binucleate forms and perinuclear halos Koilocytosis Dyskeratotic cells Large atypical cells Occasional mitotic figures	N/A	Endobronchial	Condylomatous papillomas have malignant potential Papillomatosis may be lethal due to obstructive complications
	Glandular papilloma		Not specific	White to tan endobronchial polyps that measure from 0.7-1.5 cm	Central lesions: Noninflamed thick arborizing stromal stalks Thin-walled blood vessels Necrosis is absent Epithelium may be nonciliated or ciliated, cuboidal or columnar or a mixture Clear cytoplasm Nuclei lack atypia and mitoses	N/A	Endobronchial	Benign tumours that may recur following incomplete resection No malignant transformation
	Mixed squamous cell and glandular papilloma		Smoking	Tan to red, polypoid and measure from 0.2-2.5 cm	Fibrovascular cores Scattered lymphoplasmacytic infiltrates Pseudostratified ciliated and nonciliated cuboidal to columnar cells Squamous atypia ranging from mild to severe dysplasia	N/A	Endobronchial	Complete resection appears to be curative
Adenomas	Alveolar adenoma
	Papillary adenoma
	Adenomas of the salivary gland type	Mucous gland adenoma
		Pleomorphic adenoma
	Mucinous cystadenoma
	Lymphoproliferative tumors	Marginal zone B-cell lymphoma of the MALT type
		Diffuse large B-cell lymphoma
		Lymphomatoid granulomatosis
		Langerhans cell histiocytosis
Miscellaneous tumors	Harmatoma
	Sclerosing hemangioma
	Clear cell tumor
	Germ cell tumors	Mature tratoma
		Immature teratoma
		Other germ cell tumours
	Intrapulmonary thymoma
	Melanoma
Metastatic tumors