Pulmonary Small Cell Carcinoma

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

Image of Small Cell Carcinoma (intermediate cell type)

Small cell carcinoma is the most malignant of lung cancers and usually presents as a central or hilar tumour. Visit: Lung Tumour-Online

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.

Image of Small Cell Carcinoma (pathweb.uchc.edu ): Image Link1 ; Image Link2 ; Image Link3 ; Image Link 4 ; Image Link5

Microscopic features:

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

Image1 ; Image2 ; Image3

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 Paget’s 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.

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:

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.

Visit: Neuroendocrine Tumours of the Lung ; Central Carcinoid Tumour ; Peripheral Carcinoid Tumour ; Atypical Carcinoid ; Large Cell Neuroendocrine Tumour ; Diffuse idiopathic neuroendocrine cell hyperplasia (DIPNECH) ; Pulmonary Tumorlet .

Pathology of small cell carcinoma of the lung.Semin Oncol. 2003 Feb;30 (1):3-8.

Small cell carcinoma of the lung is one of the major subtypes of primary lung cancer. It is a highly aggressive lethal neuroendocrine carcinoma. It is closely related to other neuroendocrine carcinomas of the lung, including carcinoid, atypical carcinoid, and large cell neuroendocrine carcinoma. This article discusses the classification of small cell carcinoma of the lung, identifies its cytologic and histologic characteristics, and places it in context with the other neuroendocrine carcinomas 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. Am J Surg Pathol. 2005 Feb;29(2):179-87.

Seven patients with typical or atypical pulmonary carcinoid tumors overdiagnosed as small-cell carcinoma on bronchoscopic biopsies are described. Bronchial biopsies from 9 consecutive small-cell lung carcinoma patients were used as control group for histologic and immunohistochemical studies (cytokeratins, chromogranin A, synaptophysin, Ki-67 [MIB-1], and TTF-1). The carcinoid tumors presented as either central or peripheral lesions composed of tumor cells with granular, sometimes coarse chromatin pattern, high levels of chromogranin A/synaptophysin immunoreactivity, and low (<20%) Ki-67 (MIB-1) labeling index. The tumor stroma contained thin-walled blood vessels. Small-cell carcinomas always showed central tumor location, finely dispersed nuclear chromatin, lower levels of chromogranin A/synaptophysin, and high (>50%) Ki-67 (MIB-1) labeling index. The stroma contained thick-walled blood vessels with glomeruloid configuration. Judging from this study, overdiagnosis of carcinoid tumor as small-cell carcinoma in small crushed bronchial biopsies remains a significant potential problem in a worldwide sample of hospital settings. Careful evaluation of hematoxylin and eosin sections remains the most important tool for the differential diagnosis, with evaluation of tumor cell proliferation by Ki-67 (MIB-1) labeling index emerging from our review as the most useful ancillary technique for the distinction.

Small cell lung carcinoma in the form of multiple lung nodules. Arch Bronconeumol. 1997 Jan;33(1):52-4.

Small cell carcinoma of the lung occasionally presents as a single pulmonary nodule, but its expression in the form of multiple pulmonary nodules has not been reported in the literature. We describe a single case of small cell carcinoma of the lung presenting as multiple pulmonary nodules that seems to have been cured by chemotherapy.

Peripheral small-cell carcinoma of the lung resembling carcinoid tumor. A clinical and pathologic study of 14 cases.Arch Pathol Lab Med. 1985 Mar; 109(3):263-9.

We studied 14 small-cell, epithelial tumors of the lung with histologic features intermediate between typical carcinoid tumor and undifferentiated small-cell carcinoma. All of the tumors arose in the periphery of the lung beyond a segmental bronchus and were excised. Histologically, three of the tumors were low grade and 11 were high grade. The low-grade tumors had an organoid pattern comprising more than half of the area examined histologically, less than five mitoses per 10 high-power fields, individual cell necrosis, and nuclear pleomorphism of less than half of the cells. The high-grade tumors had the opposite characteristics. Distinction of these peripheral tumors from typical carcinoid tumors and from undifferentiated small-cell carcinomas is established after excision and cannot be made reliably on the findings of a transbronchial or needle biopsy. Prognosis was worse than that for typical carcinoid tumors but better than that for undifferentiated small-cell carcinomas.

The unusual spectrum of neuroendocrine lung neoplasms. Ultrastruct Pathol. 1989 Sep-Dec;13(5-6):515-60.

Neoplasms of the lungs showing neuroendocrine differentiation are classified histologically into the following groups: (1) carcinoid, (2) atypical carcinoid (well-differentiated neuroendocrine carcinoma and malignant carcinoid, (3) small cell neuroendocrine carcinoma (small cell undifferentiated carcinoma and oat cell carcinoma), and (4) large cell neuroendocrine carcinoma (atypical endocrine tumor of the lung and intermediate neuroendocrine carcinoma). Nine examples of neuroendocrine lung carcinomas are discussed that have unusual histologic features that make it difficult to assign them to one of the above groups, have unusual immunohistochemical features, have unusual ultrastructural features, or exhibit a biologic behavior different from what one would have predicted from their morphologic appearance. The findings in these nine cases suggest that the present classification of neuroendocrine lung neoplasms may be too precise and that these neoplasms, like other nonneuroendocrine pulmonary tumors, exhibit a wider morphologic and biologic spectrum than previously appreciated.

June 2007