Pancoast tumor differential diagnosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Mazia Fatima, MBBS [2]

Overview

Pancoast tumor must be differentiated from other causes of mass located in the apical region of the chest which may present with pain in the shoulder region. Differential diagnosis includes most common other conditions that cause hemoptysis, cough, dyspnea, wheeze, chest pain, shoulder pain, unexplained weight loss, unexplained loss of appetite, and fatigue such as superior vena cava syndrome, thoracic outlet syndrome, cervical disk disease, pneumonia/bronchitis, carcinoid tumor, infectious granuloma and thyroid mass.

Differential Diagnosis

Pancoast tumor must be differentiated from other causes of mass located in the apical region of the chest which may present with pain in the shoulder region.The table below summarizes the findings that differentiate apical mass in the chest from the most common other conditions that cause hemoptysis, cough, dyspnea, wheeze, chest pain, shoulder pain, unexplained weight loss, unexplained loss of appetite, and fatigue

Condition/disease	Signs/symptoms	Tests
Pancoast Tumor	The most common symptoms of Pancoast tumor include cough, hemoptysis, dyspnea, chest pain, lack of appetite, weight loss, fatigue. Symptoms of Pancoast's syndrome resulting from Pancoast tumor include shoulder pain along the vertebral border of the scapula, Horner's syndrome and weakness of hand muscles. Less common symptoms of Pancoast's syndrome include paraplegia.	Chest x-ray: Lordotic view on chest x-ray is helpful in visualizing Pancoast tumor because of its characteristic location in the apical portion of the lung. Findings on an x-ray suggestive of Pancoast tumor include opacity at the apex of the lung or in the superior sulcus area, the spread of the tumor can result in rib invasion that is observed as a bone destruction of posterior ribs, vertebral body infiltration, enlargement of the mediastinum. CT scan is diagnostic of Pancoast tumor. CT scan has a limited ability to determine the extent of invasion of the primary tumor into adjoining structures when compared to MRI scan. Subclavian-vessel involvement is assessed by contrast CT scanning. MRI is helpful in the diagnosis of Pancoast tumor. MRI offers greater detail in the evaluation of chest wall invasion, examination of vascular structures and brachial plexus involvement and resectability of the tumor. Other diagnostic studies for evaluating the spread of Pancoast tumor include bone scintigraphy, PET scan, molecular tests and biopsy.
Superior Vena Cava Syndrome	Superior vena cava syndrome patients gradually develop symptoms as the malignancies increase in size. Symptoms occur when obstruction of venous blood flow back to the heart increases gradually,andd may worsen with postural changes. Symptoms are quite varied among benign and malignant superior vena cava syndrome. They can range from sub-clinical presentation to death. The most common symptoms include the following dyspnea, cough, swelling of the face, neck, trunk, and arms. Less common symptoms include the following hoarseness, chest pain, problems swallowing and/or talking, coughing up blood, headache, lightheadedness, decreased alertness, dizziness, fainting, sensation of head or ear "fullness", vision changes.	On chest x-ray, indirect signs such as superior mediastinal widening and right hilar prominence may indicate the presence of a mediastinal mass. On enhanced CT scan, findings include location and severity of the superior vena cava obstruction, superimposed thrombosis, a mediastinal mass or lymphadenopathy, collateral vessels, and associated lung masses. CT scan is the imaging modality of choice. Doppler ultrasound may be valuable in assessing the site and nature of the obstruction in superior vena cava syndrome. Venous patency and the presence of thrombi can also be assessed by using contrast and rapid scanning techniques. Other imaging finding is the radionuclide technetium-99m venography. Invasive contrast venography may be useful on the etiology of obstruction and exact location of the obstruction, also helpful in the surgical management of the obstructed vena cava.
Thoracic outlet syndrome	Arterial thoracic outlet syndrome can present with pallor, sensation of cold, pain, and paresthesias of the fingers due to severe ischemia. Venous form (aka Paget-Schroetter syndrome, Effort thrombosis and thoracic inlet syndrome) presents with arm swelling and pain.	Chest radiography is helpful to evaluate presence of cervical or first rib, clavicle deformity, pulmonary disease. Color flow duplex scanning, nerve conduction studies, electromyography, or imaging studies are recommended to confirm or rule out a diagnosis of Thoracic outlet syndrome(TOS). Nerve conduction evaluation via root stimulation and F wave is the best direct approach to evaluation of neurologic TOS. CT scan, MRI, Arteriography, while only rarely used to evaluate thoracic outlet syndrome, may be used if a surgery is being planned to correct an arterial TOS. Arteriography is indicated in the presence of evidence of peripheral emboli in the upper extremity, suspected subclavian stenosis or aneurysm (e.g., bruit or abnormal supraclavicular pulsation), blood pressure differential greater than 20 mmHg, Obliteration of radial pulse. Venography indications include persistent or intermittent edema of the hand or arm, peripheral unilateral cyanosis, prominent venous pattern over the arm, shoulder, or chest. Thermography indications are vasomotor or sudomotor instability, weather sensitivity, cold limb in a shawl or C8 distribution. Thermography may be one of the most sensitive tests to objectify the presence of thoracic outlet syndrome, especially if it is felt to be sympathetic in origin
Cervical Disk Disease	With symptomatic degenerative disc disease, chronic shoulder pain sometimes radiates to the arm that may be associated with sporadic tingling or weakness may also be evident. Similar pain may be felt or may increase with range of motion of shoulder joint. While the degeneration of the disc will likely progress as a natural part of the aging process, symptoms such as neck and shoulder pain often decrease over time.
Pneumonia/bronchitis	Typical symptoms include fever, cough, dyspnea, and chest pain; recurrent pneumonia or bronchitis in a smokformerformer smoker should raise the suspicion of lung cancer	Chest X-Ray is the first test performed; CT imaging can be helpful to evaluate pulmonary masses that might not be well visualised with chest x-ray; bronchoscopy can also be used to assess for endobronchial lesions or to biopsy suspicious pulmonary masses
Carcinoid tumor	Often asymptomatic with normal physical examination; may cause cough, dyspnea, hemoptysis, unilateral wheezing, or post-obstructive pneumonia if the tumor is endobronchial or compressing the central bronchi.	CT chest: 80% of carcinoid tumors appear as an endobronchial nodule and 20% as a parenchymal nodule, with smooth, rounded borders and is highly vascularized; flexible bronchoscopy shows raised, pink, vascular, lobulated lesions; endobronchial forceps biopsy is usually required for pathology to be diagnostic; bronchial brushings, sputum specimens, and lavage fluid rarely provide sufficient tissue for a conclusive diagnosis
Metastatic cancer from a non-thoracic primary site	Signs and symptoms depend on the location of the primary tumor and distant disease and may include pain, weight loss, malaise, cough, dyspnea, clubbing, or focal wheezing; physical findings may be present depending on the location and extent of the disease	CT chest shows one or multiple nodules of variable sizes from diffuse micronodular opacities (miliary) to well-defined masses, lesions are often irregular and in the periphery of the lower lung zones; CT/MRI head, CT abdomen and pelvis: extrapulmonary cancers that commonly metastasis to the lung include melanoma, thyroid carcinoma, esophageal cancer; ovarian cancer; sarcomas; and adenocarcinomas of the colon, breast, kidney, and testis; PET-FDG scan shows increased uptake in both primary and distant sites, certain metastatic lesions, such as renal cell carcinoma, have a lower probability of 18-fluorodeoxyglucose (FDG) uptake; CT-guided transthoracic needle aspiration (TTNA) can reveal characteristic malignant cells, pneumothorax complicates 20% to 30% of TTNA procedures, the choice between bronchoscopy and TTNA is based on lesion size, location, risks, and local expertise; biopsy during flexible bronchoscopy and biopsy may show characteristic malignant cells, bronchoscopy has a 100% yield for endobronchial lesions (which are extremely rare in metastatic deposits from other primary tumors)
Infectious granuloma	History may include travel to endemic areas, pet/animal exposures, and specific leisure activities (e.g., caving); may feature cough, dyspnea, hemoptysis, weight loss, fever, joint aches, skin lesions, and night sweats, or no symptoms; many possible causes: Histoplasma capsulatum, Mycobacterium tuberculosis, Coccidioides immitis, Cryptococcus neoformans, Aspergillus, Pseudallescheria boydii, Fusarium species, zygomycetes, and others; non-specific skin findings may be seen in atypical mycobacteria and cryptococcosis; lymphadenopathy may be present with active disease	CT-guided TTNA can be used for diagnostic sampling, pneumothorax complicates 20% to 30% of TTNA procedures, the choice between bronchoscopy and TTNA is based on lesion size, location, risks, and local expertise; CT chest typically shows lesions <2 cm diameter and round with smooth borders, old granulomatous disease may feature central, laminated, or diffuse calcification pattern, mediastinal lymphadenopathy without calcifications is sometimes present, nodules from angioinvasive fungi (e.g., Aspergillus, Pseudallescheria boydii, Fusarium species, and zygomycetes) may demonstrate the "halo sign" (ground-glass opacity surrounding the nodule), occasionally, calcifications can be seen in the spleen or liver; fungal serologies: positive during active infection; flexible bronchoscopy and biopsy can sometimes provide sample for identification and culture and sensitivity of organism; PET: usually negative (<2.5 standardised uptake values), may be positive in active infectious processes
Sarcoidosis	Cough, dyspnea, fatigue, weight loss, fever, night sweats, rash, eye pain, photophobia, blurred vision, and red eye; pulmonary examination is usually unrevealing; can affect any organ, so physical findings depend on specific organs affected; skin lesions including maculopapular eruptions, subcutaneous nodular lesions, and red-purple skin lesions	CT chest: mediastinal adenopathy often present with sarcoid. Sarcoid nodules have predilection for upper zones, although can be located throughout the lung; flexible bronchoscopy and biopsy can demonstrate presence of non-caseating granulomas; CT-guided TTNA can provide access to material from some lesions inaccessible to flexible bronchoscopy; laboratory markers: ACE elevation may be seen in sarcoidosis but is non-specific.
Rheumatoid arthritis	Arthralgias, pain, skin nodules, pleural effusions, pleuritis, joint pain, and deformity	CT chest typically shows lung nodule 3 mm to 7 cm, predominantly in peripheral upper and mid-lung zones, may show cavitation; flexible bronchoscopy and biopsy shows rheumatoid necrobiotic nodule, necrobiotic nodules demonstrate a central zone of eosinophilic fibrinoid necrosis surrounded by palisading fibroblasts, the nodule often centered on necrotic inflamed blood vessels; laboratory markers: patients with lung nodules due to rheumatoid arthritis frequently have high levels of rheumatoid factor, although seronegative cases have been reported.
Wegener's granulomatosis	Cough, chest pain, dyspnea, hemoptysis, rhinorrhoea, epistaxis, ear/sinus pain, hoarseness, fever, fatigue, anorexia, weight loss, palpable purpura, painful ulcers, uveitis, upper airway inflammation, and sinus pain	CT chest shows solitary or multiple lung nodules, airways are frequently affected; Flexible bronchoscopy or CT-guided TTNA may show necrotising granulomatous inflammation; laboratory markers: anti-neutrophil cytoplasmic antibody (ANCA), ANCA testing results depend on the extent and severity of the disease.
Arteriovenous malformation	Dyspnea is uncommon, may cause hemoptysis, pulmonary bruit, arteriovenous communications, or hemorrhagic telangiectasia in the skin, mucous membranes, and other organs, cyanosis and finger clubbing may be present, neurological symptoms from cerebral aneurysms, cerebral emboli	CT chest shows round or oval nodule(s) with feeding artery and draining vein often identified, most common in lower lobes, multiple lesions in 30% of cases, usually round or oval, ranging from 1 cm to several cm in diameter; pulmonary angiography confirms presence and location of AVMs, identifies feeding arterial and venous structures, in cases of significant hemoptysis, pulmonary angiogram is combined with bronchial artery embolisation; ABG analysis may show decreased pO2 and decreased oxygen saturation when AV flow is severe., in cases of severe systemic AVMs, chronic hypoxemia may cause polycythemia
Amyloidosis	Weight loss, paresthesias, dyspnea, and fatigue are the most common symptoms associated with amyloidosis and are common to all systemic forms; weight loss of >9 kg is common; small vessel involvement can cause jaw or limb claudication, and rarely angina; amyloid purpura is present in about 1 in 6 patients, typically peri-orbital; eyelid petechiae are common; hepatomegaly >5 cm below the right costal margin is seen in 10% of patients and splenomegaly is usually of modest degree.	CT chest shows lung involvement characterised by focal pulmonary nodules, tracheobronchial lesions, or diffuse alveolar deposits; serum immunofixation shows presence of monoclonal protein; urine immunofixation shows presence of monoclonal protein; immunoglobulin free light chain assay shows abnormal kappa to lambda ratio.
Pulmonary tuberculosis	Cough longer than 2 to 3 weeks, discolored or bloody sputum, night sweats, weight loss, loss of appetite, and/or pleuritic chest pain.	Chest x-ray: primary disease commonly presents as middle and lower lung zone infiltrates, ipsilateral adenopathy, atelectasis from airway compression, and pleural effusion can be seen, reactivation-type (post-primary) pulmonary TB usually involves apical and/or posterior segment of right upper lobe, apicoposterior segment of left upper lobe, or superior segment of either lower lobe, with or without cavitation, as disease progresses it spreads to other segments/lobes; sputum smear: positive for acid-fast bacilli (AFB), sputum may be spontaneously expectorated or induced, and at least 3 specimens should be collected (minimum 8 hours apart, including an early morning specimen, which is the best way to detect Mycobacterium tuberculosis, organisms other than M. tuberculosis, especially on-tuberculous mycobacteria (e.g., M. kansasii and M. avium , may be positive for AFB stain; nucleic acid amplification tests (NAAT): positive for M. tuberculosis DNA or RNA amplification tests for rapid diagnosis, may be used on sputum or any sterile body fluid.
Non-Hodgkin's lymphoma (NHL)	Aggressive NHL may present with fever, drenching night sweats, malaise, weight loss, cough, shortness of breath, abdominal discomfort, headache, change in mental status, dizziness, ataxia, pleural effusion, lymphadenopathy, pallor, purpura, jaundice, hepatomegaly, splenomegaly, skin nodules, and abnormal neurological examination, low-grade NHL patients often minimally symptomatic or asymptomatic.	CT chest: frequently anterior mediastinum, can determine if mass is cystic or solid and whether it contains calcium or fat, contrast enhancement provides information concerning vascularisation of the mass and relationship to adjacent structures; FBC with differential: shows thrombocytopenia, pancytopenia; Blood smear: shows nucleated red blood cells, giant platelets; lymph node biopsy with immunohistochemistry: shows characteristic cells, preferably obtain excisional or core biopsy to provide information on lymph node architecture; mediastinoscopy: used to sample mediastinal nodes.
Hodgkin's lymphoma	Predominantly a disease of young adults; most patients present with a several-month history of persistent adenopathy, most commonly of the cervical chain.	Plain chest x-ray: typically shows mediastinal mass/large mediastinal adenopathy; PET scan: involved sites appear fluorodeoxyglucose (FDG)-avid (bright) with PET imaging; lymph node biopsy with immunohistochemistry: the Hodgkin's cell can be a characteristic Reed-Sternberg cell, or one of its variants, such as the lacunar cell in the nodular sclerosis subtype; in nodular lymphocyte-predominant Hodgkin's lymphoma, the characteristic cell is the lymphocytic and histiocytic (L&H) cell, also referred to as a popcorn cell.
Thymoma/Thymic carcinoma	Approximately 30% of patients with thymoma are asymptomatic at the time of diagnosis; may also present with cough, chest pain, signs of upper airway congestion, superior vena cava syndrome, dysphagia, or hoarseness; may have features of paraneoplastic syndromes associated with thymoma including myasthenia gravis, polymyositis, lupus erythematosus, rheumatoid arthritis, thyroiditis, and Sjogren's syndrome; about 30% of patients have symptoms suggestive of myasthenia gravis (e.g., ptosis, double vision)	Plain chest x-ray: in 50% of the patients, thymomas are detected by chance with plain-film chest radiography; CT chest: 90% occur in anterior mediastinum; Positron emission tomography (PET): may be of value in determining malignancy and extramediastinal involvement; pre-operative biopsy: indicated if there are atypical features or if imaging suggests invasive tumor and patient is under consideration for induction therapy
Bronchogenic cyst	Usually diagnosed in infancy and childhood, although 50% are diagnosed after 15 years of age; Approximately 50% of patients are asymptomatic; in adults, chest pain (often pleuritic) and dysphagia (due to esophageal compression) are the most common symptoms; may also feature recurrent cough and chest infection/pneumonia, superior vena cava syndrome, tracheal compression, and pneumothorax	Two-view chest radiography: typically shows a sharply demarcated spherical mass of variable size, most commonly located in the middle mediastinum around the carina, can appear as a solid tumor or show air-fluid level if cyst is infected or contains secretions; CT chest: frequently middle mediastinum, typically at level of the mediastinum, calcifications may also be seen; MRI: frequently middle mediastinum, typically at level of the mediastinum, T2-weighted images show a homogeneous mass of moderate-to-bright intensity, on T1-weighted images, lesions may vary in intensity depending on protein content of the cyst.
Tracheal tumors	Common symptoms include dyspnea, cough, hemoptysis, wheeze, and stridor; less commonly, hoarseness and dysphagia may be present	Plain chest radiographs are generally insensitive for detection of tracheal tumors, clues that may indicate the presence of a tracheal tumour include abnormal calcification, tracheal narrowing, post-obstructive pneumonia, and/or atelectasis; helical CT enables accurate calculation of tumor volumes and can help differentiate mucosal lesions from submucosal lesions; MRI can be useful in assessing extension into surrounding tissue and vascular anatomy; bronchoscopy allows direct visualisation, opportunity for biopsy, and potential for laser treatment.
Thyroid mass	Symptoms and signs depend on size of mass; may be visible/palpable as lump on anterior aspect of neck; may present with dysphagia, hoarseness, difficulty breathing, and pain in neck or throat; may also be signs and symptoms of hyper- or hypothyroidism depending on the nature of the mass.	Laboratory testing should include thyroid function panel, with TSH, free T4, free T3; I-123 thyroid scan is ordered for patients with overt or subclinical hyperthyroidism a hyperfunctioning (hot) nodule is almost always benign, most nodules are hypofunctioning (cold) (most of these are benign, but malignant nodules are also cold); ultrasound and doppler can be used to define dimensions of thyroid nodules and solid/cystic component(s), features suspicious of malignancy include microcalcifications, a more tall-than-wide shape, hypervascularity, marked hypoechogenicity, or irregular margins, it can also guide fine-needle aspiration, which can reveal malignant cells or cyst fluid; CT neck can evaluate cervical lymph nodes in cases of medullary thyroid cancer, and extension of the scan into the chest can help evaluate a retrosternal thyroid mass

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
Pancoast Tumor			Asbestos exposure for prolonged period of time Exposure to gold, nickel Smoking Men	Columnar cells of bronchioles Epithelial cells Neuro endocrine cells Suprabasal bronchial cells	Peripheral Bronchi	White or grey lesions Focal carbon pigment deposits Cavitations Intraluminal polypoid masses Infiltration Peripheral distribution Gray-white central fibrosis Pleural puckering Anthracotic pigmentation Necrosis Cavitation Hemorrhage Lobulated or ill defined edges		Keratin Cytokeratins CEA Thyroid transcription factor-1 (TTF-1) CD56 Chromogranin Synaptophysin Cytokeratin	Chest x-ray: Lordotic view on chest x-ray is helpful in visualizing Pancoast tumor because of its characteristic location in the apical portion of the lung. opacity at the apex of the lung or in the superior sulcus area, the spread of the tumor can result in rib invasion that is observed as a bone destruction of posterior ribs, vertebral body infiltration. enlargement of the mediastinum. CT scan is diagnostic of Pancoast tumor. CT scan has a limited ability to determine the extent of invasion of the primary tumor into adjoining structures when compared to MRI scan. Subclavian-vessel involvement is assessed by contrast CT scanning. MRI is helpful in the diagnosis of Pancoast tumor. MRI offers greater detail in the evaluation of chest wall invasion, examination of vascular structures and brachial plexus involvement and resectability of the tumor. Other diagnostic studies for evaluating the spread of Pancoast tumor include bone scintigraphy, PET scan, molecular tests and biopsy.	Liver Breast Bone Bone marrow Adrenal glands Kidney Gastrointestinal Tract Pleura Abdominal lymph nodes Pericardium
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