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
Squamous cell carcinoma	Papillary		Cigarette smokers Arsenic		Centrally in the mainstem	Exophytic Intra-epithelial Without invasion	White or grey lesions Focal carbon pigment deposits Cavitations. Intraluminal polypoid masses Infiltration	Keratin Cytokeratins CEA Thyroid transcription factor-1 (TTF-1)	Lobar or entire lung collapse Shift of the mediastinum to the ipsilateral side. Hilar, perihilar or mediastinal masses
	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			Smoking Radon exposure	Bronchial precursor cell		Sheet-like growth Nesting, Trabeculae Peripheral palisading Rosette formation 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.	Aerogenous spread is characteristic Brain Bone Adrenal glands Liver
	Acinar adenocarcinoma
	Papillary adenocarcinoma					Papillae Necrosis Surrounding invasion Cuboidal to columnar epithemlial linning Mucinous or non-mucinous
	Bronchio-alveolar carcinoma	Non-mucinous				Clara cells Type II cells
		Mucinous				Low grade differentiation Composed of Tall columnar cells Basal nuclei Pale cytoplasm resembling goblet cells Varying amounts of cytoplasmic mucin Cytologic atypia
		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				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			Neuro endocrine cells Suprabasal bronchial cells.			Soft, pink-tan tumor Necrosis and occasional hemorrhage Cavitations. Exophytic bronchial growth	Chromogranin Synaptophysin NCAM (CD56)   EBER-1 RNA + Cytokeratin	Large, peripheral masses	Pleura Liver Bone Brain Abdominal lymph nodes Pericardium
	Basaloid large cell carcinoma of the lung					Invasive growth pattern Peripheral palisading Small, monomorphic, cuboidal fusiform
	Clear cell carcinoma of the lung					Clear cells
	Lymphoepithelioma-like carcinoma of the lung					Syncytial growth pattern Eosinophilic nucleoli Lymphocytic infiltration Invasive amyloid deposition
	Large-cell lung carcinoma with rhabdoid phenotype					Eosinophilic cytoplasmic globules Small foci of adenocarcinoma Eosinophilic inclusions
	Mixed type					Mixture of Adenocarcinoma Squamous cell carcinoma Giant cell carcinoma Spindle cell carcinoma
Sarcomatoid carcinoma	Carcinosarcoma		Accounts for only 0.3-1.3% of all lung malignancies Mean age at diagnosis is 60 years Tobacco smoking Asbestos exposure	Undifferentiated epithelial cells	Central or peripheral Upper lobes	Biphasic Mixture of carcinomatous and sarcomatous cells	> 5 cm Well circumscribed Grey, yellow or tan creamy, gritty, Mucoid and/or hemorrhagic with significant necrosis. Sessile or pedunculated Infiltrative	Keratin S-100	No specific imaging features	Aggressive tumor Esophagus, jejunum, rectum Kidney
	Spindle cell carcinoma					Only spindle shaped tumor cells Lymphoplasmacytic infiltrates		Keratin EMA Cytokeratin Vimentin, CEA TTF-1
	Giant cell carcinoma					Multi- and/or mononucleated tumor giant cells
	Pleomorphic carcinoma					Poorly differentiated Mixture of spindle cells and/or giant cells Fibrous or myxoid stroma
	Pulmonary blastoma					Biphasic Mixture of epithelial and mesenchymal stroma		Keratin EMA CEA Chromogranin A
Carcinoid tumour	Typical carcinoid Atypical carcinoid			Neuroendocrine cells of lung	Typical carcinoids are throughout the lungs AC is more commonly peripheral	Uniform polygonal cells Nuclear atypia Pleomorphism The most common patterns are the organoid and trabecular Highly vascularized fibrovascular stroma Focal necrosis	Firm, well demarcated, tan to yellow tumors.	Cytokeratin Chromogranin Synaptophysin Leu-7 (CD57) N-CAM (CD56) S-100 protein	Well defined pulmonary nodules Calcifications is often seen. Intense contrast enhancement.	Liver Bone
Salivary gland tumours	Mucoepidermoid carcinoma		Most patients presents in the third and fourth decade Constitutes of less than 1% tumor No association with cigarette smoking or other risk factors.	Primitive cells of tracheobronchial origin	Bronchial glands	Exophytic endobronchial growth Surface epithelium lacking changes of insitu carcinoma Absence of individual cell keratinization Transitional areas to low grade mucoepidermoid carcinoma.	Ranging in size from 0.5-6 cm Soft, polypoid, and pink-tan in colour High-grade lesions are infiltrative		Well-circumscribed oval or lobulated mass Calcifications Post-obstructive pneumonic infiltrates	Rare Liver Bones Adrenal gland Brain
	Adenoid cystic carcinoma		Constitutes less than 1% of all lung tumors. Most commonly seen in fourth and fifth decades of life	Primitive cells of tracheobronchial origin	Trachea	Invades other cell layers. Heterogeneous cellularity Cribriform pattern Perineural invasion	Gray-white or tan polypoid lesions. Size ranges from 1–4 cm Infiltrative margins.	Immunoperoxidase Cytokeratin Vimentin Actin Calponin S-100 protein p63 GFAP		Liver Brain Bone Spleen Kidney Adrenal glands
	Epithelial-myoepithelial carcinoma		Age ranges from 33 to 71 years No association between smoking	Myoepithelial cells	Endobronchia	Myoepithelial cells Dual layer of cells lining ducts. Low mitotic activity.	Solid to gelatinous in texture White to gray in colour	MNF116 EMA SMA and S-100	Reflects airway obstruction
Preinvasive lesions	Squamous carcinoma in situ			Basal cells of squamous epithelium	Bronchi	Goblet cell hyperplasia Basal cell hyperplasia Squamous dysplasia Angiogenic squamous dysplasia Micropapillomatosis	Focal or multi-focal plaque-like greyish lesions Nonspecific erythema Even nodular or polypoid lesions	EGFR HER2/neu p53 MCM2 Ki-67 Cytokeratin 5/6 bcl-2 VEGF Folate binding protein p16
	Atypical adenomatous hyperplasia			Surfactant apoprotein Clara cell specific 10kDd protein	Pleura Upper lobes	Intranuclear inclusions Clara cells and type II pneumocytes. Thickened alveolar walls Discontinuous lining of cells Moderate atypia. Pseudopapillae	Multiple grey to yellow foci 1mm to 10mm in size.	CEA MMPs E-cadherin, ß-catenin, CD44v6 TTF-1 TP53	Typically not visualized on radiographs. Small non-solid nodules Ground glass opacity
	Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia		Most commonly seen in fifth or sixth decades Mostly seen in women	Pulmonary neuroendocrine cells	Endobronchial	Nodular aggregates Fibrosis due to proliferation Invade locally Fibrous stroma aggregates to form ‘tumorlets’. Carcinoids are tumorlets >5cm.	Early lesions Small, gray-white nodules Resembling ‘miliary bodies’ Larger carcinoid tumours are Firm Homogeneous Well-defined Grey or yellow-white masses.		Mosaic pattern of air trapping Sometimes with nodules Thickened bronchial and bronchiolar walls
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
	Pulmonary artery sarcoma		Mean age of diagnosis is 49.3 years Commonly misdiagnosed as PE	Mesenchymal cells of the intima Primitive cells of the bulbus cordi in the trunk of pulmonary artery.	Pulmonary trunk most commonly Right pulmonary artery Left pulmonary artery Pulmonary valve, Right ventricular outflow tract	Spindle cells in A myxoid background Collagenized stroma Recanalized thrombi	Mucoid or gelatinous clots filling vascular lumens The cut surface may show Firm fibrotic areas Bony/gritty or chondromyxoid foci Haemorrhage and necrosis are common in high-grade tumors	Vimentin Osteopontin Factor VIII CD31 CD34	Findings overlap with those of chronic thromboembolic disease Decreased vascularity Heterogeneous soft tissue density Smooth vascular tapering	Lung Mediastinum
	Pulmonary vein sarcoma		Most common in women. Mean age of diagnosis is 49.	Smooth muscle	Pulmonary vein	Smooth muscle differentiation Moderate to highly cellular spindle cell neoplasms Epithelioid morphology	Fleshy-tan tumor Can occlude the lumen of the involved vessel. 3.0- 20.0 cm Invasion of wall of the vein.	Vimentin Desmin and actin Keratin		N/A

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