Sandbox lung cancer differential

• Differentiation of primary and secondary lung tumors is difficult due to overlapping histologic features.
• Topography, size and form of pulmonary growth pattern are important aspects for the differential diagnosis.
• The following table summarizes the differentiation of various lung tumors based on histological and topographical features:

Benign Lung Tumors
			Risk/Epidemiology	Pleuripotent cells	Topography	Gross	Histology	Immunohistochemistry	Imaging	Metastasis
Papilloma	Squamous cell papilloma		HPV 6 and 11 Men Median age of diagnosis is 54 years	Epithelial cells	Endobronchial	Cauliflower-like lesions Tan-white soft to semifirm protrutions	Loose fibrovascular core Stratified squamous epithelium Acanthosis Binucleate forms and perinuclear halos Koilocytosis	N/A	Well circumscribed Homogenous Non-calcified Solitary mass	N/A
	Glandular papilloma		Rare Mean age of diagnosis is 68 years	Goblet cells of respiratory epithelium	Endobronchial	White to tan endobronchial polyps that measure from 0.7-1.5 cm	Thick arborizing stromal stalks Thin-walled blood vessels Non-ciliated or ciliated epithelium	N/A	Well circumscribed Homogenous Non-calcified Solitary mass	N/A
Adenoma	Alveolar adenoma		Mean age of diagnosis is 53 years Female predominance	Alveolar pneumocytes Septal mesenchyme	All lung lobes Lower lobes Hilar	0.7-6.0 cm Well demarcated smooth Lobulated, multicystic Soft to firm Pale yellow to tan cut surfaces	Uncapsulated Multicystic masses Cuboidal cell linning Squamous metaplasia Myxoid and collagenous interstitium	Keratin CEA Surfactant protein TTF-1 Actin	Well circumscribed Homogenous Non-calcified Solitary mass	N/A
	Papillary adenoma		Mean age of diagnosis is 32 years Male predominance	Bronchioloalveolar cell	No lobar predilection Involves alveolar parenchyma	Well defined Encapsulated Soft, spongy to firm mass Granular gray white/ brown 1.0- 4.0 cm	Infiltration Papillary growth pattern Fibrovascular cores Cuboidal to columnar epithelial linning Cilitated and oxyphilic cells Occasional eosinophilic intranuclear inclusions	Cytokeratin Clara cell protein TTF-1 Surfactant apoprotein CEA	Incidental finding	N/A
	Mucinous cystadenoma		No sex predilection Mean age of diagnosis is 52 years	Mucus glands of the bronchus	Central	White-pink to tan Smooth and shiny tumors Gelatinous mucoid solid core 0.7-7.5 cm	Numerous mucin-filled cystic spaces Non-dilated microacini, glands, tubules and papillae	EMA Cytokeratins CEA	Coin lesion Air-meniscus sign	N/A
Malignant Lung Tumors
Variants of lung carcinoma			Risk Factors/Epidemiology	Pleuripotent cell	Topography	Gross	Histology	Immunohistochemistry	Imaging	Metastasis
Squamous cell carcinoma	Papillary		Cigarette smokers Arsenic		Central	White or grey lesions Focal carbon pigment deposits Cavitations. Intraluminal polypoid masses Infiltration	Exophytic Intra-epithelial Without invasion	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		White-tan, soft, friable perihilar masses. Extensive necrosis. 5% peripheral coin lesions	Sheet-like growth Nesting, Trabeculae Peripheral palisading Rosette formation High mitotic rate	CD56 Chromogranin Synaptophysin TTF-1	Hilar or perihilar masses Mediastinal lymphadenopathy Lobar collapse	Bone marrow Liver metastases
Adeno carcinoma	Acinar adenocarcinoma		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.	Irregular-shaped glands Malignant cells Hyperchromatic nuclei Fibroblastic stroma	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
	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	Basaloid large cell carcinoma of the lung		Approximately 10% of lung cancers. Smoking	Neuro endocrine cells Suprabasal bronchial cells.	Peripheral masses Bronchi	Soft, pink-tan tumor Necrosis and occasional hemorrhage Cavitations. Exophytic bronchial growth	Invasive growth pattern Peripheral palisading Small, monomorphic, cuboidal fusiform	Chromogranin Synaptophysin NCAM (CD56)   EBER-1 RNA + Cytokeratin	Large, peripheral masses	Pleura Liver Bone Brain Abdominal lymph nodes Pericardium
	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	> 5 cm Well circumscribed Grey, yellow or tan creamy, gritty, Mucoid and/or hemorrhagic with significant necrosis. Sessile or pedunculated Infiltrative	Biphasic Mixture of carcinomatous and sarcomatous cells	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 tumor	Typical carcinoid Atypical carcinoid			Neuroendocrine cells of lung	Typical carcinoids are throughout the lungs AC is more commonly peripheral	Firm, well demarcated, tan to yellow tumors.	Uniform polygonal cells Nuclear atypia Pleomorphism The most common patterns are the organoid and trabecular Highly vascularized fibrovascular stroma Focal necrosis	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 tumors	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	Ranging in size from 0.5-6 cm Soft, polypoid, and pink-tan in colour High-grade lesions are infiltrative	Exophytic endobronchial growth Surface epithelium lacking changes of insitu carcinoma Absence of individual cell keratinization Transitional areas to low grade mucoepidermoid carcinoma.		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	Gray-white or tan polypoid lesions. Size ranges from 1–4 cm Infiltrative margins.	Invades other cell layers. Heterogeneous cellularity Cribriform pattern Perineural invasion	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	Solid to gelatinous in texture White to gray in colour	Myoepithelial cells Dual layer of cells lining ducts. Low mitotic activity.	MNF116 EMA SMA and S-100	Reflects airway obstruction	Breast
Preinvasive lesions	Squamous carcinoma in situ		Most commonly seen in fifth or sixth decades Mostly seen in women	Basal cells of squamous epithelium	Bronchi	Focal or multi-focal plaque-like greyish lesions Nonspecific erythema Even nodular or polypoid lesions	Goblet cell hyperplasia Basal cell hyperplasia Squamous dysplasia Angiogenic squamous dysplasia Micropapillomatosis	EGFR HER2/neu p53 MCM2 Ki-67 Cytokeratin 5/6 bcl-2 VEGF Folate binding protein p16		Liver Brain Bone Spleen
	Atypical adenomatous hyperplasia			Surfactant apoprotein Clara cell specific 10kDd protein	Pleura Upper lobes	Multiple grey to yellow foci 1mm to 10mm in size.	Intranuclear inclusions Clara cells and type II pneumocytes. Thickened alveolar walls Discontinuous lining of cells Moderate atypia. Pseudopapillae	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			Pulmonary neuroendocrine cells	Endobronchial	Early lesions Small, gray-white nodules Resembling ‘miliary bodies’ Larger carcinoid tumors are Firm Homogeneous Well-defined Grey or yellow-white masses.	Nodular aggregates Fibrosis due to proliferation Invade locally Fibrous stroma aggregates to form ‘tumorlets’. Carcinoids are tumorlets >5cm.		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	0.3-2.0 cm circumscribed mass Gray-white or gray-tan firm tissue Yellow flecks Central calcifications Cut surface has a cartilaginous consistency.	Round to oval-shaped nodules Central sclerosis Hypocellular zone Peripheral cellular zone Calcifications Intranuclear cytoplasmic inclusions	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	Purely cystic Thin-walled Rarely solid Firm to gelatinous Upto 15 cm	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	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	Peripheral Solid lesions Calcified	Capsulated lobules Hypocellular Features of malignancy are absent	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		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	Fascicles of spindle cells. Bronchial invasion Peribronchial distribution Cystic foci of haemorrhage	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.	Prominence of the bronchovascular bundles along Pleura Interlobular pulmonary septa Mediastinum	Anastomosing endothelial-lined cells along lymphatic routes. Spindle cells Intra alveolar siderophages	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	Solitary Round rubbery masses Yellowish-gray discoloration Average size of 3.0 cm Non encapculated Calcifications No local invasion	Mixture of spindle cells Fibroblastic Myofibroblastic Arranged in fascicles Cytologic atypia Touton type giant cells. Plasma cells Lymphoid follicles	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	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	Spindle cells in A myxoid background Collagenized stroma Recanalized thrombi	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	Fleshy-tan tumor Can occlude the lumen of the involved vessel. 3.0- 20.0 cm Invasion of wall of the vein.	Smooth muscle differentiation Moderate to highly cellular spindle cell neoplasms Epithelioid morphology	Vimentin Desmin and actin Keratin		N/A

Differentiation of lung cancer from other diseases with similar presentation

The following table summarizes the differentiation of lung cancer from other disease entities with similar presentation.

Disease	Clinical features Signs & symptoms									Radiological Findings	Characterstic feature
	Fever		Cough		Hemoptysis	Dyspnea	Chest pain	Weight loss	Night sweats
	High-grade	Low grade	Productive	Dry
Acute Lung abscess	+	-	+	-	-	-	+	-	-	Air fluid level	Foul smelling sputum H/o of prior infection or hospitalization Associated with risk factors like aspiration and alcoholism
Malignancy (primary lung cancer)	-	+	-	+	+	-	-	+	+	Coin-shaped lesion Thick wall(>15mm) Ground glass opacities	Long H/o smoking Elderly male or female BAL positive for malignant cells CT guided biopsy is required for confirmation and differnatiation
Pulmonary Tuberculosis	+	-	+	-	+	-	-	-	+	Cavitations in the upper lobe of the lung	People in endemic at high risk Cough >2 weeks with hemoptysis Acid fast stain positive for mycobacteria
Necrotizing Pneumonia	+	-	+		+	-	+	-	-	Multiple cavitary lesions	Acute life threatening condition Complication of pneumonia or lung abscess Multiple organisms responsible prompt treatment with antibiotics is required CBC positive for causative organism
Empyema	+	-	+	-	+	+	+	-	-	Homogeneous consolidations	Blood culture positive for causative agent.
Bronchiectasis	-	-	+	-	+	-	-	-	-	Linear lucencies Tram tracking appearance Clustered cysts Increased pulmonary markings Honeycombing atelectasis	CT confirms the diagnosis .
Wegners granulomatosis	-	-	+		+	+	-	-	-	Pulmonary nodules cavities Infiltrates	Seen mostly in female age group of 40-55 years Traid of Upper , lower respiratory tract and kidney disease Biopsy of involved organ confirms granulomas
Sarcoidosis	+	-	+	-	+	-	-	+	+	Bilateral adenopathy Coarse reticular opacities	More common in African-american females Restrictive lung disease Biposy findings: epithelioid,granulomas, schaumann, asteroid bodies.
Rheumatoid nodule	-	-	-	-	-	+	-	+	-	Pulmonary nodules Cavitations on the upper lobe pf lung.	Rheumatoid arthritis Positive for RF and ACP
Langerhans cell Histiocytosis	-	-	-	-	-	+	+	+	-	Thin-walled cystic cavities	Exclusively afflicts smokers. Musculoskeletal and skin is involved Biopsy of the involved organ
Bronchiolitis obliterans	-	-	+	-	+	+	+	-	-	Patchy consolidation, Ground-glass opacities Nodules.	Biopsy