Types of Lung Cancer

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Classification of Lung Tumors

The 1999 World Health Organization/International Association for the Study of Lung Cancer Histological Classification of Lung and Pleural Tumours

Epithelial Tumours

Benign

Papillomas
  • Squamous cell papilloma –Exophytic,Inverted
  • Glandular papilloma
  • Mixed squamous cell and glandular papilloma
Adénomas
  • Alveolar adenoma
  • Papillary adenoma
  • Adenomas of salivary-gland type -Mucous gland adenoma, Pleomorphic adenoma, Others
  • Mucinous cystadenoma
Others
  • Preinvasive lesions
  • Squamous dysplasia/Carcinoma in situ
  • Atypical adenomatous hyperplasia
  • Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia

 

Malignant

Squamous cell carcinoma Variants
  • Papillary
  • Clear cell
  • Small cell
  • Basaloid
Small cell carcinoma Variant
  • Combined small cell carcinoma
Adénocarcinoma
  • Acinar
  • Papillary
  • Bronchioloalveolar carcinoma – Non-mucinous (Clara/pneumocyte type II), Mucinous or Mixed mucinous and non-mucinous or intermediate cell type
  • Solid adenocarcinoma with mucin
  • Adenocarcinoma with mixed subtypes
  • Variants – Well-differentiated fetal adenocarcinoma, Mucinous (“colloid”) adenocarcinoma, Mucinous cystadenocarcinoma, Signet-ring adenocarcinoma or Clear cell adernocarcinoma
Large cell carcinoma Variants
  • Large cell neuroendocrine carcinoma
  • Combined large cell neuroendocrine carcinoma
  • Basaloid carcinoma
  • Lymphoepithelioma-like carcinoma
  • Clear cell carcinoma
  • Large cell carcinoma with rhabdoid phenotype
Adenosquamous carcinoma
Carcinomas with pleomorphic, sarcomatoid or sarcomatous elements
  • Carcinomas with spindle and/or giant cells – Pleomorphic carcinoma, Spindle cell carcinoma or Giant cell carcinoma
  • Carcinosarcoma
  • Pulmonary blastoma
  • Others
Carcinoid tumour
  • Typical carcinoid
  • Atypical carcinoid
Carcinomas of salivary-gland type
  • Mucoepidermoid carcinoma
  • Adenoid cystic carcinoma
  • Others
Unclassified carcinoma

Soft Tissue Tumors

  • Localized fibrous tumour
  • Epithelioid hemangioendothelioma
  • Pleuropulmonary blastoma
  • Chondroma
  • Calcifying fibrous pseudotumour of the pleura
  • Congenital peribronchial myofibroblastic tumour
  • Diffuse pulmonary lymphangiomatosis
  • Desmoplastic small round cell tumour
  • Other

Mesothelial Tumours 

Benign

Adenomatoid tumour

Malignant

Epithelioid mesothelioma

Sarcomatoid mesothelioma – Desmoplastic mesothelioma

Biphasic mesothelioma

Other

Miscellaneous Tumors 

  • Hamartoma
  • Sclerosing hemangioma
  • Clear cell tumour
  • Germ cell neoplasms – Teratoma, mature or immature, Malignant germ cell tumour
  • Thymona
  • Melanoma
  • Others

Lymphoproliferative Disease

  • Lymphoid interstitial pneumonia
  • Nodular lymphoid hyperplasia
  • Low-grade marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue
  • Lymphomatoid granulomatosis

Secondary Tumors

Unclassified Tumors

Tumour-like Lesions 

  • Tumourlet
  • Multiple meningothelioid nodules
  • Langerhans cell histiocytosis
  • Inflammatory pseudotumour (Inflammatory myofibroblastic tumour)
  • Organizing pneumonia
  • Amyloid tumour
  • Hyalinizing granuloma
  • Lymphangioleiomyomatosis
  • Multifocal micronodular pneumocyte hyperplasia
  • Endometriosis
  • Bronchial inflammatory polyp
  • Others

Brief description of Various Types of Lung Tumors

Preinvasive Lesions – Squamous Hyperplasia

In hyperplasia, epithelial basal cells proliferate. Then, as a result of chronic exposure and repeated injury by inhaled agents, the columnar hyperplastic epithelium is replaced with stratified squamous epithelium. When the dysplasia involves the full thickness of the epithelium, CIS is present. Invasion of the basement membrane and infiltration of malignant cells into the underlying stroma is the first sign of invasive cancer.

Atypical Adenomatous Hyperplasia (AAH)

Adenocarcinomas may be preceded by AAH in peripheral airway cells. AAH is a discrete parenchymal lesion arising in the alveoli close to terminal and respiratory bronchioles. The frequency and rate of progression from AAH to cancer is considered to be quite low, in the range of 1% to 5% over a period of years.

Adenocarcinoma

This tumor type accounts for nearly 40% of all lung cancers. Adenocarcinoma is the most common type of lung cancer in women and nonsmokers.

According to the 2004 WHO classification, adenocarcinoma can be sub-classified into five major subtypes

  • acinar,
  • papillary,
  • solid with mucin production,
  • bronchioloalveolar, and
  • mixed adenocarcinomas – Most (80%) adenocarcinomas fall into the mixed subtype.

When tumor cells grow in a purely lepidic fashion without evidence of invasion, they are regarded as BAC. On histologic examination mucus production shows positivity to mucicarmine or periodic acid-Schiff staining. Lung adenocarcinomas typically immuno stain for thyroid transcription factor-1.

The lesions are usually more peripherally located, and tend to be smaller. Despite the tendancy for earlier metastasis, adenocarcinomas grow slower than squamous cell carcinomas. Smoking history is less frequent with adenocarcinoma as compared to squamous or small cell carcinomas.

KRAS mutations occur primarily in adenocarcinoma, and are seen less frequently in nonsmokers (5%) than in smokers (30%). Rest are p53, RB1, and p16 mutations ,c MET amplification. Mutations and amplifications in the epidermal growth factor receptor gene (EGFR) occur in patients with adenocarcinoma (mostly women, nonsmokers, and those of Asian origin).

They usually originate within the periphery of the lung ,therefore not readily amenable to detection by sputum cytology. Lymphatics and blood are the primary routes of spread of adenocarcinoma, and BAC mainly spreads through aerogenous route.

Brochoalveolar Carcinoma

BAC is defined as an adenocarcinoma of the lung, which grows in a lepidic fashion along the alveolar septae without invasion of stroma, blood vessels, or pleura, which presents a barrier to gas exchange in the affected alveolar sac, leading to right to left intrapulmonary shunt.

BAC has been sub-classified in three types-

  • non-mucinous,
  • mucinous, and
  • mixed mucinous and non-mucinous. Mucinous BAC has a tendency to be multifocal and fatal
  • Histologically pure BAC is uncommon, comprising only 3% of all lung cancers.

It has been shown that while patients with small peripheral lung adenocarcinomas with a pure BAC pattern and no invasion had 100% 5-year survivals, those with mixed BAC with invasive components and BAC with purely invasive growth patterns demonstrated 5-year survivals of 75% and 52%, respectively.

Adenosquamous Carcinoma

Adenosquamous carcinoma of the lung is characterized by the presence of squamous cell carcinoma and adenocarcinoma with each comprising at least 10% of the tumor.

They account for 1% to 2% of lung cancers and are usually located in the periphery of the lung and may contain a central scar. The routes of dissemination and metastasis are similar to the other NSCLCs.

Squamous Cell Carcinoma

This tumor type accounts for approximately 30% of all lung cancers. Squamous differentiation is characterised by squamous pearl formation, intercellular bridges and individual cell keratinization. There are no squamous cells normally present in the respiratory mucosa, and they develop from metaplastic cells that usually arise as a result of tobacco exposure.

The histologic subtypes described include basaloid, small cell, papillary and clear cell types. Most of the squamous cell carcinomas of lung (70%) are present in central location, with central cavitation (due to necrosis) being a common finding.

Due to exfoliation of the malignant cells from the bronchial surface, squamous cell carcinoma can be detected by cytologic examination at its earliest stage. They spread primarily by lymphatic and hematogenous routes and direct invasion.

Squamous cell carcinomas show the highest frequency of p53 mutations of all histologic types of lung carcinoma. Overexpression of EGFR has been detected in 80% of squamous cell carcinomas, but it is rarely mutated.

Large Cell Carcinoma

In this undifferentiated epithelial tumor, the characteristic cytologic features of squamous or small cell differentiation are lacking. Typical presentation for this tumor is large nuclei, moderate amount of cytoplasm and prominent nucleoli.

World Health Organization classification recognizes neuroendocrine differentiation type, basaloid, lymphoepithelioma like,rhabdoid type and clear cell types, they differ little clinically. LCNEC (large cell neuroendocrine carcinoma) is considered an aggressive malignancy with a prognosis similar to SCLC.

Sarcomatoid Carcinoma

These are poorly differentiated NSCLCs in which sarcoma or sarcoma like (giant and spindle cell) component is present. The five variants identified are-

  • Spindle Cell Carcinoma – Spindle cell carcinoma is a NSCLC consisting exclusively of spindle-shaped tumor cells, which resemble spindle cells found in sarcomas.
  • Carcinosarcoma – Carcinosarcoma is defined as a tumor with a mixture of usual NSCLC and sarcomatous elements, such as malignant cartilage (chondrosarcoma), bone (osteosarcoma), and muscle (rhabdomyosarcoma).
  • Giant Cell Carcinoma – Giant cell carcinomas are composed entirely of highly pleomorphic and multinucleated giant cells.
  • Pleomorphic Carcinoma – Pleomorphic carcinoma is a poorly differentiated type of NSCLC  containing at least 10% spindle or giant cells.
  • Pulmonary Blastoma – Pulmonary blastoma is a mixed tumor containing a primitive epithelial component that may resemble well-differentiated fetal adenocarcinoma and a primitive mesenchymal stroma, with some sarcomatous components.

Sarcomatoid carcinomas are rare tumors (0.3-1.3%). They can arise in the central or peripheral lung. Peripheral tumors are usually large masses, and they invade the chest wall.

Small Cell Carcinoma

This tumor type accounts for approximately 15% of all lung cancers. They characteristically consist of small epithelial tumor cells with finely granular chromatin and absent or inconspicuous nucleoli. Necrosis is frequent and extensive and the mitotic count is high.

While SCLC represents a light microscopic diagnosis, electron microscopy shows neuroendocrine granules in at least two-thirds of cases and immunohistochemistry for neuroendocrine markers (chromogranin and synaptophysin) is positive in most (~90%) cases.

Most SCLCs present as a perihilar mass. Approximately 5% of SCLCs present as peripheral small lesions. The tumors are large masses with extensive necrosis. Extensive lymph node metastases are common.  Ectopic hormone production is most commonly seen in this lung tumor. Most cases are seen in smokers, with only about 1% in nonsmokers. Their high propensity of metastasis makes them most aggressive lung tumor, virtually incurable by surgical means.

Carcinoid Tumors

Lung tumors with neuroendocrine morphology and differentiation include the low-grade typical carcinoid, intermediate-grade atypical carcinoid, high-grade LCNEC, and SCLC.

Carcinoid tumors are characterized by organoid growth pattern, uniform cytologic features, and immunohistochemical expression of neuroendocrine markers, such as chromogranin and synaptophysin.

Carcinoid tumors have been divided into two categories, typical and atypical types, based on their clinical behavior and pathologic features. Atypical carinoids having more malignant histologic and clinical features.

TYPICAL CARCINOID ATYPICAL CARCINOID
 low  grade neuroendocrine carcinomas intermediate grade neuroendocrine carcinomas
fewer than 2 mitoses per 2 mm2 field and lack necrosis 2-10 mitosis per 2 mm2 field and/or foci of necrosis
uniformly distributed throughout the lungs commonly peripheral tumors.
Smaller tumor sizes larger tumor sizes
Lower rates of metastasis higher rate of metastases
Better survival survival is significantly reduced
10-15% of typical 40-50% of atypical

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