Adenocarcinoma of the lung differential diagnosis

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

Overview

Adenocarcinoma of the lung must be differentiated from atypical adenomatous hyperplasia of the lung, adenocarcinoma in situ, squamous cell carcinoma of the lung, small cell carcinoma of the lung, malignant mesothelioma, and metastatic adenocarcinoma.

Differentiating Adenocarcinoma of the Lung from other Diseases

Adenocarcinoma of the lung must be differentiated from:[1]

  • Colorectal adenocarcinoma
  • Breast adenocarcinoma
  • Invasive ductal carcinoma of the breast
  • Invasive lobular carcinoma

Differentiating Lung Cancer from Other Diseases

Lung cancer must be differentiated from other cavitary lung lesions. The table below summarizes the differentiation:

Causes of

lung cavities

Differentiating Features Differentiating radiological findings Diagnosis

confirmation

  • CXR and CT demonstrates cavities in the upper lobe of the lung
  • Sputum smear positive for acid-fast bacilli and nucleic acid amplification tests (NAAT) is used on sputum or any sterile fluid for rapid diagnosis and is positive for mycobacteria.
  • Any age group
  • Acute, fulminant life threating complication of prior infection
  • >100.4 °F fever, with hemodynamic instability
  • Worsening pneumonia-like symptoms
  • CBC is positive for causative organism
  • Children and elderly are at risk
  • Empyema appears lenticular in shape and has a thin wall with smooth luminal margins
  • Pulmonary nodules with cavities and infiltrates are a frequent manifestation on CXR
  • Elderly females of 40-50 age group
  • Manifestation of rheumatoid arthritis
  • Presents with other systemic symptoms including symmetric arthritis of the small joints of the hands and feet with morning stiffness are common manifestations
  • Pulmonary nodules with cavitation are located in the upper lobe (Caplan syndrome) on X-ray
  • On CXR bilateral adenopathy and coarse reticular opacities are seen
  • CT of the chest demonstrates extensive hilar and mediastinal adenopathy
  • Additional findings on CT include fibrosis (honeycomb, linear, or associated with bronchial distortion), pleural thickening, and ground-glass opacities.[10]
  • Common appearance on CT is patchy consolidation,often accompanied by ground-glass opacities and nodules.[14]
  • Exclusively afflicts smokers, with a peak age of onset of between 20 and 40 years
  • Clinical presentation varies, but symptoms generally include months of dry cough, fever, night sweats, and weight loss
  • Skin is involved in 80% of the cases, scaly erythematous rash is typical
  • Thin-walled cystic cavities are the usual radiographic manifestation, observed in over 50% of patients by either CXR or CT scans.[16]
  • Biopsy of the lung

The following table summarizes the differentiation of various lung tumors based on histological and topographical features:[17]

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[18]
Benign lung tumor Risk/Epidemiology Pleuripotent cells Topography Gross Histology Immunohistochemistry Imaging Metastasis
Papilloma[19] Squamous cell papilloma
  • HPV 6 and 11
  • Men
  • Median age of diagnosis is 54 years
  • 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
  • Endobronchial
  • White to tan endobronchial polyps that measure from 0.7-1.5 cm
  • N/A
  • Well circumscribed
  • Homogenous
  • Non-calcified
  • Solitary mass
  • N/A
Adenoma[20] Alveolar adenoma
  • Mean age of diagnosis is 53 years
  • Female predominance
  • 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
  • Well circumscribed
  • Homogenous
  • Non-calcified
  • Solitary mass
  • N/A
Papillary adenoma[21]
  • 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
  • Incidental finding
  • N/A
Mucinous cystadenoma
  • No sex predilection
  • Mean age of diagnosis is 52 years
  • 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
  • Coin lesion
  • Air-meniscus sign
  • N/A
Malignant Lung Tumors[22]
Variants of lung carcinoma Risk Factors/Epidemiology Pleuripotent cell Topography Gross Histology Immunohistochemistry Imaging Metastasis
Squamous cell carcinoma (SCC)[23] Papillary
  • Epithelial cells
  • Central
  • Exophytic
  • Intra-epithelial
  • Without invasion
Clear cell
Basaloid
  • Peripheral palisading of nuclei.
  • Poor differentiation
Small cell carcinoma[24]
  • 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
  • Bone marrow
  • Liver
Adenocarcinoma[25][26][27] Acinar adenocarcinoma
  • Columnar cells of bronchioles
  • Peripheral
  • Single or multiple lesions
  • Different in size
  • Peripheral distribution
  • Gray-white central fibrosis
  • Pleural puckering
  • Anthracotic pigmentation
  • Lobulated or ill defined edges
  • Irregular-shaped glands
  • Malignant cells:
    • Hyperchromatic nuclei
    • Fibroblastic stroma
  • 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
Bronchio-alveolar carcinoma Non-mucinous
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
Mucinous (“colloid”) carcinoma
Mucinous cystadenocarcinoma
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[28] Basaloid large cell carcinoma of the lung
  • Approximately 10% of lung cancers
  • Smoking
  • Soft, pink-tan tumor
  • Invasive growth pattern
  • Peripheral palisading
  • Small, monomorphic, cuboidal fusiform
  • Large, peripheral masses
Clear cell carcinoma of the lung
Lymphoepithelioma-like carcinoma of the lung
Large-cell lung carcinoma with rhabdoid phenotype
Mixed type
Variants of lung carcinoma Risk Factors/Epidemiology Pleuripotent cell Topography Gross Histology Immunohistochemistry Imaging Metastasis
Sarcomatoid carcinoma[29] Carcinosarcoma
  • Central or peripheral
  • Upper lobes
  • No specific imaging features 
Spindle cell carcinoma
  • Only spindle shaped tumor cells
  • Lymphoplasmacytic infiltrates
Giant cell carcinoma
Pleomorphic carcinoma
Pulmonary blastoma
Variants of lung carcinoma Risk Factors/Epidemiology Pleuripotent cell Topography Gross Histology Immunohistochemistry Imaging Metastasis
Carcinoid tumor[30] Typical carcinoid

Atypical carcinoid

  • Most common in males
  • Mean age of diagnosis 45
  • 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
Salivary gland tumors[31] 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
  • Well-circumscribed oval or lobulated mass
  • Calcifications
  • Post-obstructive pneumonic infiltrates
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
  • Gray-white or tan polypoid lesions
  • Size ranges from 1–4 cm
  • Infiltrative margins
  • Invades other cell layers
  • Heterogeneous cellularity
  • Cribriform pattern
  • Perineural invasion
  • Well circumscribed
  • Nodule
Epithelial-myoepithelial carcinoma
  • Age ranges from 33 to 71 years
  • No association with smoking
  • Endobronchial
  • Solid to gelatinous in texture
  • White to gray in colour
Variants of lung carcinoma Risk Factors/Epidemiology Pleuripotent cell Topography Gross Histology Immunohistochemistry Imaging Metastasis
Preinvasive lesions[32] Squamous carcinoma in situ
  • Most commonly seen in fifth or sixth decades
  • Mostly seen in women
  • Basal cells of squamous epithelium
  • Focal or multi-focal plaque-like greyish lesions
  • Nonspecific erythema
  • Even nodular or polypoid lesions
  • Micropapillomatosis
  • Cauliflower like
  • Mosaic pattern
Atypical adenomatous hyperplasia
  • Multiple grey to yellow foci
  • 1mm to 10mm in size
  • Typically not visualized on radiographs
  • Small non-solid nodules
  • Ground-glass opacity
Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia
  • Endobronchial
  • Early lesions are:
    • Small, gray-white nodules
    • Resembling ‘miliary bodies’
  • Larger carcinoid tumors are:
    • Firm
    • Homogeneous
    • Well-defined
    • Grey or yellow-white masses
  • 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[33] Epithelioid haemangioendothelioma / Angiosarcoma
  • Caucasian
  • 80% are women
  • Endothelial cells
  • 0.3-2.0 cm circumscribed mass
  • Gray-white or gray-tan firm tissue
  • Yellow flecks
  • Central calcifications
  • Cut surface has a cartilaginous consistency
Pleuropulmonary blastoma
  • Most common in children
  • Median age of diagnosis is 2 years
  • Purely cystic
  • Thin-walled
  • Rarely solid
  • Firm to gelatinous
  • Upto 15 cm
  • Unilateral
  • Localized airfilled cysts
  • Septal thickening or an intracystic mass
Chondroma
  • Young women
  • Capsulated lobules
  • Hypocellular
  • Features of malignancy are absent
  • N/A
  • Multiple
  • Well circumscribed lesions
  • “Pop-corn” calcifications
Congenital peribronchial myofibroblastic tumor
  • 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
  • Well circumscribed
  • Opaque hemithorax
  • Heterogeneous mass
  • Rare
Diffuse pulmonary lymphangiomatosis
  • Children
  • Young adults of both sexes
  • Prominence of the bronchovascular bundles along
  • Anastomosing endothelial-lined cells along lymphatic routes
  • Increased interstitial markings
  • Skin
  • Bone
Inflammatory myofibroblastic tumor
  • Localized to bronchi
  • Solitary
  • Round rubbery masses
  • Yellowish-gray discoloration
  • Average size of 3.0 cm
  • Non-encapculated
  • Calcifications
  • No local invasion
  • Solitary mass
  • Regular borders
  • Spiculated appearance
  • Accompanied by
  • Rare
Pulmonary artery sarcoma
  • 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
Pulmonary vein sarcoma
  • Most common in women
  • Mean age of diagnosis is 49
  • Fleshy-tan tumor
  • Can occlude the lumen of the involved vessel
  • 3.0- 20.0 cm
  • Invasion of wall of the vein
  • N/A

The following table summarizes the differentiation of lung cancer from other disease entities with similar presentation.[4][5][7][34][15]

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
Malignancy

(primary lung cancer)

- + - + + - - + +
  • Coin-shaped lesion
  • Thick wall(>15mm)
  • Ground glass opacities 
Pulmonary Tuberculosis + - + - + - - - +
Necrotizing Pneumonia + - + + - + - -
  • Multiple cavitary lesions
Empyema + - + - + + + - -
Bronchiectasis - - + - + - - - -
  • Linear lucencies
  • Tram tracking appearance
  • Clustered cysts
  • CT confirms the diagnosis
Wegners granulomatosis - - + + + - - -
  • 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 + - + - + - - + +
Rheumatoid nodule - - - - - + - + -
Langerhans cell Histiocytosis - - - - - + + + -
  • Thin-walled cystic cavities
Bronchiolitis obliterans - - + - + + + - -
  • Ground-glass opacities
  • Biopsy

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