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Histology of lung cancer

Primary lung cancers are considered to be of two types:

  • Small cell lung cancer (SCLC)
  • Non-small cell lung cancer (NSCLC)

Small cell lung cancer

Small cell lung cancer (SCLC) consists of small cells with a high nucleo-cytoplasmic ratio that proliferate rapidly. Similar to normal neuroendocrine cells, they contain neurosecretory granules that may produce peptide hormones and/or biogenic amines. About 90% of small cell lung cancers stain positive for neuroendocrine markers. Small cell lung cancers usually develop peribronchially and infiltrate the bronchial submucosa. This tumor type can be diagnosed in cytological material such as fine needle aspirations, brush specimens, or lavage. The diagnosis should, if possible, be confirmed in histological specimens before starting therapy.

Photomicrograph demonstrating small cell lung carcinoma in a cytological specimen. Click to enlarge. Photomicrograph showing a small cell lung carcinoma in a histological specimen. Click to enlarge.

Some small cell lung cancers also have areas with squamous cell carcinoma, adenocarcinoma, or large cell carcinoma. They are classified as mixed type.

Non-small cell cancer

Non-small cell lung cancer is divided into four principal subgroups:

  • Adenocarcinoma
  • Squamous cell carcinoma  
  • Large cell carcinoma
  • NSCLC not otherwise specified (NOS). This terminology is used when the NSCLC cannot be clearly diagnosed to be of adenocarcinoma, squamous Cell Carcinoma or large cell carcinoma or some of the other rarer types of carcinoma.

The microscopical subtyping can be difficult, especially in small biopsies or in cytological specimens.


Surgical specimen with a peripheral lung adenocarcinoma. Click to enlarge. Photomicrograph demonstrating lung adenocarcinoma in a cytological specimen. Giemsa stain. Click to enlarge.

Adenocarcinoma consists of glandular tumor cells producing mucous. They usually grow in the peripheral part of the lung. A special variant is adenocarcinoma in situ, previously named bronchoalveolar carcinoma. The immuno histochemical profile can help differentiate between other various types of NSCLC. About 70% of the Adenocarcinomas are positive for the thyroid transcription factor-1 (TTF-1). They also tend to be cytokeratin (CK) 7 positive and CK 20 negative.

Squamous cell carcinoma

Surgical specimen demonstrating a squamous cell carcinoma. Click to enlarge. Photomicrograph showing a squamous cell carcinoma with keratinization. Click to enlarge.

Squamous cell carcinoma consists of cells that can produce keratin in the same way as normal squamous epithelial cells. Histochemically they tend to be TTF-1 negative, but positive for CK 5, 6 and P63 or P40. Squamous cell carcinomas develop from a precancerous lesion proceeded by squamous metaplasia and squamous cell hyperplasia. These tumors generally grow in the central part of the lung in close relation to the large bronchi.

Large cell carcinoma

The tumor cells are large and there is no special differentiation. A variant is the large cell neuroendocrine carcinoma.

Carcinoid  tumor

A carcinoid tumor is an unusual type of lung tumor with neuroendocrine differentiation.

There are two subtypes:

  • typical carcinoid
  • atypical carcinoid

In the typical carcinoid, there are few mitotic figures and no necrosis. This is the more common type of carcinoid tumor and has a good prognosis.
The atypical carcinoid demonstrates many mitotic figures and necrosis. This type has a somewhat worse prognosis compared to the typical carcinoid. 

Assessment of operational preparation

The pathology report should include:

  • tumor type
  • size
  • localization
  • relation to surgical margins

Molecular pathology

All non-small lung cancers should be tested for the presence of mutations in the gene coding for epidermal growth factor receptor (EGFR). Selected cases should be tested by FISH for the ALK-EML4 translocation. Several other actionable and non-actionable molecular aberrations have been identified and they are now a topic of active investigation (10).

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