Squamous cell carcinoma of the lung differential diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2]

Overview

Squamous cell carcinoma of the lung must be differentiated from other diseases that cause chronic cough, weight loss, hemoptysis, and dyspnea among adults such as pulmonary tuberculosis, sarcoidosis, pneumonia, pulmonary fungal infection, and secondary metastases.

Differentiating Squamous Cell Carcinoma of the Lung from other Diseases

The following table summarizes the differentiation of various lung tumors based on histological and topographical features:

Abrevations: HPV: human papillomavirus; CEA: Carcino embryogenic antigen; TTF1: Thyroid transcription factor-1; EMA: Epithelial membrane antigen; CK: Cyto keratin; CD: Cluster differentiation; NCAM: Neural Cell Differentiation Molecule; MMP's: Mettaloprotineases matrix ; GFAP: Glial fibrocilliary acid protein
Benign Lung Tumors
Benign lung tumor			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	Non-encapsulated 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 (SCC)	Papillary		Cigarette smokers Arsenic	Epithelial cells	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	Liver Breast Bone
	Clear cell						Cells with clear cytoplasm
	Basaloid						Peripheral palisading of nuclei. Poor differentiation
Small cell carcinoma			Smoking Radon exposure	Bronchial precursor cell	Peripheral	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
Adenocarcinoma	Acinar adenocarcinoma		Smoking	Columnar cells of bronchioles	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 CEA 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 Kidney Gastrointestinal Tract
	Papillary adenocarcinoma						Papillae Necrosis Surrounding invasion Cuboidal to columnar epithelial 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					Mixed type of cells Low to high grade differentiated cells.
	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					Focal Cells with nuclei displaced to sides Components of other cells are present.
		Clear cell adenocarcinoma					Clear cells with no nuclei
Variants of lung carcinoma			Risk Factors/Epidemiology	Pleuripotent cell	Topography	Gross	Histology	Immunohistochemistry	Imaging	Metastasis
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 CD56  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
Variants of lung carcinoma			Risk Factors/Epidemiology	Pleuripotent cell	Topography	Gross	Histology	Immunohistochemistry	Imaging	Metastasis
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, and 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
Variants of lung carcinoma			Risk Factors/Epidemiology	Pleuripotent cell	Topography	Gross	Histology	Immunohistochemistry	Imaging	Metastasis
Carcinoid tumor	Typical carcinoid Atypical carcinoid		Most common in males Mean age of diagnosis 45	Neuroendocrine cells of lung	Typical carcinoids are throughout the lungs Atypical carcinoid 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 CD57 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 in-situ carcinoma Absence of individual cell keratinization Transitional areas to low grade mucoepidermoid carcinoma	GFAP	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 p53 GFAP	Well circumscribed Nodule	Liver Brain Bone Spleen Kidney Adrenal glands
	Epithelial-myoepithelial carcinoma		Age ranges from 33 to 71 years No association with smoking	Myoepithelial cells	Endobronchial	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
Variants of lung carcinoma			Risk Factors/Epidemiology	Pleuripotent cell	Topography	Gross	Histology	Immunohistochemistry	Imaging	Metastasis
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	Cauliflower like Mosaic pattern	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 are: 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.	Keratin CEA	Mosaic pattern of air trapping Sometimes with nodules Thickened bronchial and bronchiolar walls
Variants of lung carcinoma			Risk Factors/Epidemiology	Pleuripotent cell	Topography	Gross	Histology	Immunohistochemistry	Imaging	Metastasis
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) 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 Primary lesion 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 in nature
	Congenital peribronchial myofibroblastic tumor		Rare Sporadic Complicated by Polyhydramnios Non-immune hydrops fetalis	Spindle cells	Along the bronchi	5-10 cm Well-circumscribed Non-encapsulated Smooth or multinodular surface The cut surface has a tann-grey to yellow-tan fleshy appearance Hemorrhage Necrosis	Fascicles of spindle cells Bronchial invasion Peribronchial distribution Cystic foci of hemorrhage	Vimentin	Well circumscribed Opaque hemithorax Heterogeneous mass	Rare
	Diffuse pulmonary lymphangiomatosis		Children Young adults of both sexes	Smooth muscle 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	Vimentin	Increased interstitial markings Thickening of the: Interlobular septa Fissures Central airways Pleura	Skin Bone
	Inflammatory myofibroblastic tumor		Previous viral infections HHV8 Children	Myofibroblastic cells	Localized to bronchi	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 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 pulmonary embolism	Mesenchymal cells of the intima Primitive cells of the bulbus cordi in the trunk of pulmonary artery	Pulmonary trunk most commonly involving: 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 Hemorrhage 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 parenchyma 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 Actin Keratin		N/A

• The table below summarizes the findings that differentiate squamous cell carcinoma of the lung from other conditions that cause chronic cough, weight loss, hemoptysis, and dyspnea.

Organ system		Diseases	Clinical manifestations								Diagnosis				Other features
			Symptoms							Physical exam
			Onset	Duration	Productive cough	Hemoptysis	Weight lost	Fever	Dyspnea	Ascultation	Lab findings	Imaging	PFT	Gold standard
Respiratory	Parenchyma	Lung cancer	Chronic	Years	+	+	+	+/−	+	Hoarseness	The following investigations may be helpful: Complete blood count (CBC) ALT, AST Calcium Alkaline phosphatase LDH Creatinine	Contrast−enhanced CT of chest and upper abdomen	Not specific	Tissue biopsy (sample should be sufficient for molecular testing)	Risk factor: Cigarette smoking Types Small cell lung cancer (SCLC) Non−small cell lung cancer (NSCLC)
		Interstitial lung disease	Chronic	Variable	−	+	+	−	+	Wheezing Crackles or velcro rales Inspiratory high−pitched rhonchi	The following investigations may be helpful: Hepatic function test Renal function test CBC Serological testing	Nodular, reticular or both pattern in chest X−ray CT in patients with diffuse pulmonary lung disease	Reduction in FVC, RV, FRC, TLC and FEV1 on spirometry FEV1/FVC normal or increase Lung volumes Diffusion capacity (DLCO reduced)	Lung biopsy when lab, imaging, and PFT has indeterminate result	Clubbing is common in asbestosis and idiopathic pulmonary fibrosis
		Tuberculosis (TB)	Chronic	More than 2 or 3 weeks	+	+	+	+	+	Pleural effusion Crackles Whispered pectoriloquy Decreased fremitus Rhonchi	Sputum acid−fast bacilli (AFB) smear may be positive Mycobacterial culture may be positive Molecular testing may be helpful	Reactivation of TB is observed as infiltration in the upper lobe in chest X−Ray In patients with HIV, Tb is observed as lobar infiltration, adenopathy, lung mass named tuberculoma, small fibronodular lesions, and/or pleural effusion on chest X−Ray CT can detect early nodal process	Decreased FEV1 Reduced FVC	Isolation of Mycobacterium tuberculosis from some secretion	Etiology: Mycobacterium tuberculosis Complications: Pneumothorax, bronchiectasis, pulmonary destruction and chronic pulmonary aspergillosis
Cardiac		Pulmonary hypertension	Chronic	More than 2 years	−	+	+	−	+	Hoarseness	The following investigations may be helpful: HIV serology Antinuclear antibody (ANA) Rheumatoid factor (RF) Anti−neutrophil cytoplasmic antibody (ANCA)	Enlargement of the central pulmonary artery and right heart in chest X−Ray Pulmonary artery systolic pressure can be estimated in echocardiography	Low levels of FEV1 Decreased FVC DLCO reduced	Mean pulmonary artery pressure more than 25 mmHg at rest	Chest pain Ascites Syncope Peripherial edema
Organ system		Diseases	Clinical manifestations								Diagnosis				Other features
			Symptoms							Physical exam
			Onset	Duration	Productive cough	Hemoptysis	Weight lost	Fever	Dyspnea	Ascultation	Lab findings	Imaging	PFT	Gold standard
Autoimmune		Wegener's disease (GPA)	Chronic	Months	+	+	+	+	+	Hoarseness Stridor Wheezing	The following investigations may be helpful: ANCA, P−ANCA, C−ANCA BUN Creatinine Complete blood count Urinalysis Lung biopsy	Nodules, pulmonary infiltrates, reticular margins, pleural opacities and cavities in chest X−Ray Nodules, cavities and stellate−shaped peripherial pulmonary in chest CT Bronchoscopy may be helpful	Low levels of DLCO Reduce lung volumes	Tissue biopsy	Nasal crusting, sinus pain, chronic rhinosinusitis, nasal obstruction and discharge in upper airway Saddle nose deformity Purpura in lower extremities
		Microscopic polyangitis (MPA)	Chronic	Variable	+	+	+	+	+	Hoarseness Stridor Wheezing	The following investigations may be helpful: ANCA positive BUN Creatinine Complete blood count Urinalysis	Cavitation, nodules, and alveolar opacities in chest X−ray Head and chest CT may be helpful Electromyography/nerve conduction study may also be helpful	Reduced lung volumes	Tissue biopsy	Nerve damage Rhinosinusitis Purpura involving lower extremities
		Churg−Strauss	Chronic	Variable	+	+	+	+	+	Wheezing Rales Rhonchi Expiratory sounds(related to asthma)	Peripherial eosinophilia In active phase CRP and erytrocyte sedimentation rate high Elevated IgE ANCA positive	Infiltrates in chest X−Ray Ground glass opacities, tree−in−bud sign and small nodules in chest CT	Lung volumes decreased FVC reduced FEV1/FVC ratio <70%	Tissue biopsy	Asthma Eosinophilia Rhinosinusitis

References

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