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Pulmonary Pathology Online

Pathology of Pulmonary Small Cell Carcinoma

Dr Sampurna Roy MD   




Small cell carcinoma is a distinctive malignant tumour in the field of oncology with characteristic clinical properties, responsiveness to specific chemotherapy, genetic features and highly reliable pathological diagnosis.

Small cell carcinoma usually presents as a central or hilar tumour. 

It is strongly associated with cigarette smoking.

Tumours showing a mixture of small cell carcinoma and large cell carcinomas are more aggressive than pure small cell carcinomas and are less sensitive to irradiation and chemotherapy.

Small-cell carcinoma grows very rapidly, metastasizes early and initially at least is sensitive to chemotherapy.

Long-term disease-free survival is seen in only a minority of patients treated with chemotherapy.

Despite treatment, the patient usually dies with widely disseminated disease within 1-2 years.

Surgeons claim to be able to treat a minority successfully, but these cases are highly selective and some may represent atypical carcinoids rather than small cell carcinoma.

Small cell carcinomas are generally central tumours arising in elderly cigarette smokers but rare cases present as a peripheral nodule and it is these that have the best chances of successful surgical eradication.

The combined subgroup is characterized by the presence of squamous cell carcinoma or adenocarcinoma in addition to small cell carcinoma.

The differences between the oat cell and the intermediate cell types are imprecise and lack clinical relevance, possibly because the described differences are artifactual.

Classic oat cell carcinoma is most often observed in traumatized biopsies or poorly preserved autopsy material, whereas in well-preserved surgical material the intermediate cell type is seen almost exclusively.

Accordingly, it has been recommended by some workers that the terms oat cell and intermediate cell be abandoned.

It has been reported that tumours showing a mixture of small cell carcinoma and large cell carcinoma are even more aggressive than pure small cell carcinomas, and are less sensitive to irradiation and chemotherapy. This lead to a new subdivision of small cell carcinoma in which the distinction between oat-cell and intermediate subtype is discarded, and a new mixed small cell/large cell caterory is recognized.

Mixed small cell/large cell carcinoma is variously estimated as forming from 4 to 19% of all small cell carcinomas.

Microscopic features:

Microscopically, small cell carcinoma is characterized by small, round or oval (oat-like) cells with little cytoplasm and hyperchromatic nuclei, resembling lymphocytes.

The cells are arranged in nests or clusters. The cells may also be arranged in rosettes, pseudorosettes, tubules or ductules.

Rosettes of radially arranged tumour cells may be formed and genuine lumina may also be present and sometimes contain a little mucin.

The edge of the tumour is ill-defined and lacks a capsule.

Necrosis is commonly seen.  

Haematoxyphil, Fuelgen-positive nucleoprotein derived degenerate tumour cells may be deposited in the walls of stromal blood vessels (Azzopardi effect) but this feature is also found on occasion in other cellular tumours, such as lymphoma, seminoma and even other types of lung carcinoma.

Mitoses are numerous and the nuclei of adjacent tumour cells characteristically press on one another, a feature termed nuclear moulding that is especially prominent in cytological specimens.

It is sensitive to chemotherapy and irradiation.

Some small cell carcinomas show scattered tumour cells with hyperchromatic giant nuclei, especially in tumors after radiotherapy or chemotherapy.

Classic oat cells have dense pyknotic nuclei and very sparse cytoplasm.

Intermediate cells are a little larger, have a discernable but still small amount of cytoplasm and a nucleus with a finely divided chromatin pattern. Nucleoli are inconspicuous in paraffin sections but may be quite striking in plastic sections.

In biopsy specimens, the tumour cells are often crushed so that long strands and masses of haematoxyphil material are seen.

This finding should prompt a careful search for viable, non-traumatized tumour cells but by itself does not justify a diagnosis of small cell lung carcinoma because other tumours, and even inflammatory infiltrates, may show the same crush artifact.

A partial change to non-small cell histology during the course of  the disease is encountered in about a fifth of patients. This is relevant to the nature of the mixed small cell/large cell category mentioned above.

In bronchial biopsies, the tumour cells are often seen beneath an intact surface epithelium that shows atypical squamous metaplasia.

Superficial sampling limited to this surface change may lead to erroneous histological classification and, hence, the wrong treatment.

It is essential that invasive tumour be examined.

There may be infiltration of  the overlying epithelium by small groups of tumour cells, similar to that seen in Pagetís disease of the nipple.

Differential Diagnosis:

- Small cell carcinoma is liable to be mistaken for large cell carcinoma if attention is concentrated on cell size and the presence of sufficient  amounts of cytoplasm.  These two tumours are best separated on their nuclear characteristics. The finely divided, evenly dispersed chromatin of a small cell carcinoma contrasts greatly with the clumped chromatin and prominent nucleolus set in an otherwise vesicular nucleus of a large cell carcinoma.

- Lymphocytes, either reactive or neoplastic may also be mistaken for small cell carcinoma, especially if the tissue is at all traumatized.

The carcinoma cells are larger than reactive lymphocytes and may be distinguished from lymphoma cells by immunocytochemistry, using antibodies against leucocytes (CD45) and cytokeratin.

- Some squamous cell and adenocarcinomas are composed small tumour cells but these lack the nuclear features of small cell carcinoma and show no immunohistochemical or ultrastructural evidence of neuroendocrine differentiation.

Wider sampling generally reveals their true nature.

If adequate, non-traumatized tissue is provided, small cell carcinomas are relatively easily distinguished from other histological types. It may be difficult to diagnose some cases, particularly in small biopsies.

Classification of small cell carcinoma: (International Association for the Study of Lung Cancer):

- Small cell (Pure form)

- Mixed cell small cell/large cell

- Combined (small cell and adenocarcinoma or squamous carcinoma)

Classification of small cell carcinoma:  (WHO)

- Oat cell

- Intermediate

- Combined         


Electron microscopy:

Electron microscopy shows the characteristic 50-200 nm dense-core cytoplasmic granules but they are far fewer than in a carcinoid.

They have to be distinguished from bristle-coated vesicles, small lysosomes and small exocrine granules.

Bristle-coated vesicles have a fuzzy surrounding membrane whilst lysosomes and exocrine granules lack the halo separating the central core from the outer membrane.

Exocrine granules are also usually more pleomorphic.

Minority of small cell carcinomas show undoubted ultrastuctural evidence of squamous or mucous cell differentiation, alone or in combination with dense-core granules. 

Note:  A variety of non-small cell carcinomas are sometimes found to contain dense-core granules on electron microscopy.


Immunohistochemistry shows that in line with their epithelial nature, a range of cytokeratins may be demonstrated in small cell lung carcinoma, often with a perinuclear or dot-like paranuclear distribution.

Immunohistochemistry has been widely used in attempts to distinguish small cell and non-small cell lung carcinoma, but no completely satisfactory markers of neuroendocrine differentiation is available.

At present, chromogranin A and synaptophysin probably represent the best combination to establish the diagnosis.

Chromogranin A is a fairly specific protein component of endocrine granules but is usually difficult to detect because small cell lung carcinomas are only sparsely granulated.

In situ hybridization may be useful here for it demonstrates high levels of chromogranin A mRNA in these tumours.

Gastrin releasing peptide (GRP ; human bombesin) is an autocrine growth factor for both normal and neoplastic neuroendocrine cells and can be readily demonstrated in carcinoids, but in only a minority of small cell carcinomas.

GRP mRNA can be consistently demonstrated in small cell carcinomas.

Leu-7, a surface antigen present in human natural killer cells and neuroendocrine cells, has also been used to identify a neuroendocrine subtype but its specificity is not very high.

In contrast to these neuroendocrine markers, CD44 is reported to be expressed only by non-small cell carcinomas.

 Further reading:

Small-cell lung cancer: an update on targeted therapies.

Update on small cell carcinoma and its differentiation from squamous cell carcinoma and other non-small cell carcinomas.

Pathology of small cell carcinoma of the lung.

Typical and atypical pulmonary carcinoid tumor overdiagnosed as small-cell carcinoma on biopsy specimens: a major pitfall in the management of lung cancer patients.

Small cell lung carcinoma in the form of multiple lung nodules

Peripheral small-cell carcinoma of the lung resembling carcinoid tumor. A clinical and pathologic study of 14 cases.

The unusual spectrum of neuroendocrine lung neoplasms.


Dr Sampurna Roy  MD

Consultant  Histopathologist (Kolkata - India)






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