Seminars in Oncology
Volume 30, Issue 1 , Pages 3-8, February 2003

Pathology of small cell carcinoma of the lung☆

Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY.

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Abstract 

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. Semin Oncol 30:3-8. Copyright 2003, Elsevier Science (USA). All rights reserved.

 

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Primary small cell carcinoma of the lung 

Small cell carcinoma of the lung (SCLC) is one of the major subtypes of primary lung carcinoma that exists within a spectrum of other neuroendocrine (NE) lung tumors. It is probably more closely related to large cell neuroendocrine carcinoma (LCNEC) of the lung than to carcinoid tumors and shares clinical, morphological, and immunohistochemical features with LCNEC, a less common but highly aggressive NE malignancy.

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World Health Organization classification of small cell carcinoma 

The World Health Organization (WHO) classification of 19991 defines small cell carcinoma as “a malignant epithelial tumor consisting of small cells with scant cytoplasm, ill-defined cell borders, finely granular nuclear chromatin, and absent or inconspicuous nucleoli. The cells are round, oval, and spindle-shaped and nuclear molding is prominent. The mitotic count is high.”

This definition recognizes SCLC within the spectrum of morphologically identifiable NE tumors that also includes LCNEC, typical carcinoid, and atypical carcinoid. This group of tumors shares morphologic, ultrastructural, immunohistochemical, and molecular characteristics, but because of differences in incidence, and in clinical, epidemiologic, histologic, survival, and molecular characteristics, the WHO chose to categorize these malignancies separately in the classification of lung tumors.2

Small cell lung cancer is maintained as a separate histologic type within the latest WHO classification scheme because of its relatively common occurrence (compared with typical and atypical carcinoid) and because of its clinical distinction among lung cancers. The biologic features of this tumor and its response to chemotherapy make it unique among bronchogenic carcinomas and help distinguish it from non–small cell carcinoma even before pathology specimens are obtained.

The classification of SCLC by histologic appearance has evolved through the 1962 categorization by Kreyberg into two subtypes, oat cell and polygonal, to the 1967 WHO listing of four subtypes of lymphocyte-like, polygonal, fusiform, and other, on to the 1981 WHO classification that included oat cell, intermediate, and combined oat cell carcinoma, finally to the classification of small cell carcinoma and a variant known as combined small cell carcinoma.3 This latest variant is defined as “a small cell carcinoma combined with an additional component that consists of any of the histological types of non–small cell carcinoma, usually adenocarcinoma, squamous cell carcinoma, or large cell carcinoma, but less commonly spindle cell or giant cell carcinoma.”1 The histologic types of non–small cell carcinoma present in combined small cell carcinoma may also include LCNEC. Heterologous elements such as sarcoma may rarely be found combined with small cell carcinoma; in this case the tumor would be called a combined small cell carcinoma and sarcoma and is considered a variant of small cell carcinoma and not a carcinosarcoma.

It was in 1988 that the International Association for the Study of Lung Cancer recommended that the terms “oat cell carcinoma” and “intermediate cell type” be dropped and proposed that three subtypes of small cell carcinoma be used: small cell carcinoma, mixed small cell/large cell carcinoma, and combined small cell carcinoma. The mixed small cell/large cell carcinoma category, defined as a tumor with components of both small cell carcinoma and large cell carcinoma, did not show clinical significance or histologic reproducibility. This category of mixed small cell/large cell carcinoma is narrower than the currently recommended variant of combined small cell carcinoma, where there is a mixture of small cell carcinoma and any other non–small cell carcinoma including LCNEC.1

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Pathology of small cell carcinoma 

Small cell lung cancer is an aggressive neoplasm, which is reflected in its high-grade morphology, evident in both cytologic and histologic preparations. The diagnosis should be made on light microscopy findings, but may be supported by immunohistochemical or electron microscopy (EM) studies.

The gross pathology features are rarely appreciated in detail because the majority of patients with SCLC do not undergo surgical resection and the macroscopic findings of this tumor are mostly limited to autopsy findings, where the appearance may be altered by therapy. More than half of the tumors present as perihilar masses with extensive lymph node involvement. The cut surface is gray to tan or white and shows a large amount of necrosis. Involvement of the mucosal surface is not common because the tumor is predominately submucosal in location. It is unusual to find an endobronchial component and for this reason the tumor cells are unlikely to be found in cytologic brushes or washes or in sputum specimens. In rare instances a peripheral coin lesion may be present. The tumor also may surround or grow in a circumferential fashion along the bronchial submucosal tissue and cause bronchial lumen narrowing or obstruction because of extrinsic compression.

The microscopic features of SCLC are often limited and distorted because the specimens examined in pathology are usually small biopsy fragments that are obtained via bronchoscopy or fine needle aspiration biopsy. The surgical pathology biopsy or resection specimens are often mechanically distorted because of the nuclear fragility of the cells and slide preparations can show crush artifact and fragmentation (Fig 1).

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  • Fig. 1. 

    Cytologic preparation of SCLC. Notice the high nuclear-to-cytoplasmic ratio, the hyperchromatic blue color of the nuclei, and overall poor preservation with crush artifact.

In the case of cytology specimens extensive air-drying may occur. These artifactual changes can make a definitive diagnosis difficult and may result in frequent under-diagnosis, requiring additional sampling. Cytology is a superior method for the recognition of the cells of SCLC because of fewer artifacts and better preservation.

Small cell lung cancer falls into the category of “small round blue cell” tumors. The light microscopic appearance of SCLC usually shows a monotonous population of “blue” cells with hyperchromatic nuclei and foci of necrosis. The individual tumor cell size is called small, but is nonetheless at least twice the size of a lymphocyte nucleus. At higher magnification, individual cell atypia or pleomorphism can be appreciated in the form of irregular nuclear contours and a high nuclear-to-cytoplasmic ratio with barely visible cytoplasm. The cell shape is round to oval with occasional spindle cell morphology. The cellular arrangement may include rosette formations and individual cell necrosis or karyorrhexis is frequent. The number of mitotic figures can be very high, exceeding 10 mitotic figures per single high power field.4 Nuclear chromatin is finely to coarsely granular and is often described as having a “salt and pepper” chromatin pattern (Fig 2).

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  • Fig. 2. 

    Low-power view of small cell carcinoma on cytology. Note the monomorphic appearance of a “small round blue” cell tumor and the “salt and pepper” chromatin pattern.

This description of the chromatin appearance is also applied to other NE tumors. Molding of the nuclei, one against the other, may be seen and this is observed most often in cytology preparations. The fragile nuclei may break down, leading to streaks of blue nuclear material coursing throughout the specimen or the deposition of the nuclear DNA along blood vessels. Pathologic grading of this tumor is not necessary because all SCLCs are high-grade tumors.

The differential diagnosis of SCLC includes the members of the small round blue cell tumor family: non–small cell lung carcinoma, lymphoma, poorly differentiated carcinoma metastatic from other sites, sarcomas, other NE tumors of the lung such as carcinoids and LCNEC, chronic inflammation, and reserve cell hyperplasia, which can be present on a cytology specimen.

Once a tumor is pathologically determined to be malignant and is consistent with a lung primary, the major task facing the pathologist is the distinction between SCLC and non–small cell lung carcinoma because of the great difference in treatment options. This can be difficult and much attention in the literature has been given to the morphologic separation of these two entities.5

At the ultrastructural (US) level, the characteristic EM finding in SCLC is the presence of dense core granules in the cytoplasm. These granules, however, may be absent in up to 35% of cases.6 Additional EM findings include little cytoplasm with few organelles and moderately to uniformly dense nuclear chromatin. Differentiation along three lines with US evidence of squamous, adeno and small cell carcinoma features has been described in the same cell.7

There is a long list of the immunohistochemical antibodies that may show positive staining in SCLC (as well as in other NE tumors). The most useful markers are chromogranin, synaptophysin, and CD56. Neuron specific enolase is commonly positive, but has proven to be a less specific marker. Most immunohistochemical studies have been performed on formalin-fixed, paraffin-embedded tissue, but immunochemistry may be applied to cytology material as well. Because the differential diagnosis of SCLC includes lymphoma, keratin markers to identify epithelial origin are often used. The reported frequency of keratin positivity varies, but is almost always negative in lymphoma. There are a number of hormonal markers that may be positive in SCLC. These include calcitonin, glucagon, corticotropin, insulin, and VIP, among others. This positivity relates to the fact that SCLC is the most common tumor associated with ectopic hormone production.

Treatment effects that can be seen in small cell carcinoma include the appearance of a different morphology from the original tumor, such as small cell/large cell carcinoma (Fig 3) or the addition of non–small cell carcinoma, particularly squamous cell, to the microscopic features.

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  • Fig. 3. 

    Fine needle aspirate of small cell carcinoma showing areas of squamous differentiation in the form of very large eosinophilic cells with generous amounts of cytoplasm.

The reasons for this phenomenon are not clearly understood.

It is not possible to discuss the pathology of SCLC without including the other NE lung tumors. Small cell lung cancer exists on the most aggressive end of a spectrum of primary lung tumors showing varying degrees of NE differentiation. The well-differentiated end of this spectrum starts with carcinoid tumor. Such a spectrum would contain carcinoid tumorlet, carcinoid, atypical carcinoid, LCNEC, and small cell carcinoma. Carcinoid tumorlet is usually an incidental finding at autopsy, and consists of small collections of NE cells and is rarely clinically important. Tumorlets have been called by a number of names including peripheral adenomas and atypical hyperplasia of bronchiolar epithelium.8, 9 They stain similarly to other NE tumors and share EM features. Carcinoid tumors are low-grade malignant tumors of NE cells that occur infrequently (Fig 4).

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  • Fig. 4. 

    Tissue section of carcinoid tumor demonstrating bland nuclear morphology, but note the neuroendocrine similarity to small cell carcinoma and the trabecular arrangement.

Most patients are asymptomatic and the tumors are equally distributed between men and women. There appears to be no association with smoking. Paraneoplastic syndromes may occur with carcinoid tumors.10 Atypical carcinoid is similar histologically to carcinoid, but atypical carcinoids are usually larger tumors and have a higher rate of metastasis with reduced survival.11 They are separated from carcinoid essentially by their increased mitotic count, but other features such as nuclear pleomorphism and necrosis have been considered (Fig 5).

Large cell neuroendocrine carcinoma, a category of lung tumor that is a high-grade malignancy with findings of NE differentiation that are visible by light microscopy (Fig 6).

While this most often refers to the nuclear chromatin pattern (Fig 7), included in the description of NE features are organoid appearance and palisading of nuclei and trabecular or rosette arrangements. These light microscopic features should be confirmed by US analysis or immunohistochemical staining. There is much confusion in the literature as to the appropriate classification of LCNECs. According to Colby et al,3 they correspond most closely to tumors called “intermediate-cell differentiated NE carcinomas” by Gould et al12 in the mid 1980s. They also may have been classified as atypical carcinoids and intermediate oat cell tumors, among others. Large cell NE carcinomas are less common and more difficult to diagnose than the other NE tumors. They may been seen as a pure population or in association with other lung cancers, both NE and non-NE, such as squamous or adenocarcinomas. Ectopic hormone production is not found with these tumors. The dense core granules seen by EM in this tumor are fewer in number than in atypical carcinoid and are not observed within cytoplasmic processes. Other features usually associated with squamous differentiation may also be present.3 Frequent mitosis and much necrosis are common. The immunohistochemical staining pattern, while focal, resembles that seen in SCLC (Fig 8), but neuron specific enolase is considered too unreliable here. Large cell neuroendocrine carcinoma should be distinguished from other NE tumors, although it may not be easy to do so, particularly on limited material.

The criteria for the diagnosis of NE tumors of the lung are delineated in Table 1 (modified from the WHO classification).

Table 1. Criteria for diagnosis of neuroendocrine lung tumors
Typical carcinoidA tumor with carcinoid morphology and less than two mitoses per 10 HPF.
No necrosis and ≥0.5 cm.
Atypical carcinoidA tumor with carcinoid morphology with 2-10 mitoses per 10 HPF or necrosis.
Large cell neuroendocrine carcinoma(1) A tumor with neuroendocrine morphology (organoid nesting, palisading, rosettes, trabeculae).
(2) High mitotic rate: 11 or greater per 10 HPF.
(3) Necrosis, often large.
(4) Cytologic features of a NSCLC: large cell size, low nuclear to cytoplasmic ratio, vesicular or fine chromatin, and/or frequent nucleoli. Some tumors have fine nuclear chromatin and lack nucleoli.
(5) Positive immunohistochemical staining for one or more NE markers (other than neuron specific enolase) and/or NE granules by electron microscopy.
Small cell carcinoma(1) Small size.
(2) Scant cytoplasm.
(3) Nuclei: finely granular nuclear chromatin, absent or faint nucleoli.
(4) High mitotic rate, 11 or greater per 10 HPF.
(5) Frequent necrosis.

Abbreviations: HPF, high-power field; NSCLC, non–small cell lung cancer; NE, neuroendocrine.

If a non–small cell carcinoma of the lung does not demonstrate a NE appearance by light microscopy, but is shown to have NE features by immunohistochemistry or EM, the tumor is classified as a large cell carcinoma with NE differentiation.13 This is in distinction from LCNEC, where the endocrine features should be apparent by light microscopy alone. These tumors are similar to the other non–small cell (adeno, squamous, or large cell) lung carcinomas where NE differentiation, not seen microscopically, can be found using additional studies.

According to the International Association for the Study of Lung Cancer, mixed small cell/large cell carcinoma is defined histologically as a tumor with a mixture of small and large cells. They may coexist interspersed or sharply demarcated. This subtype is not uniformly accepted, and studies have not confirmed the clinical significance or interobserver reproducibility for this category.1

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Conclusion 

The mainstay of the diagnosis of SCLC remains light microscopy, either cytologic or histologic. The use of immunostains, EM, and molecular genetics has increased our understanding of these lesions, but they have not as yet replaced the use of routine microscopy in the diagnosis and separation of these highly aggressive neoplasms from other tumor, either primary or metastatic, to the lung.

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References 

  1. In: ed 3.  Travis WD,  Colby TV,  Corrin B, et al. editor. Epithelial tumors, in Histological Typing of Lung and Pleural Tumours. Washington, DC: Armed Forces Institute of Pathology; 1999;p. 32
  2. In: ed 3.  Travis WD,  Colby TV,  Corrin B, et al. editor. Introduction, in Histological Typing of Lung and Pleural Tumours. Washington, DC: Armed Forces Institute of Pathology; 1999;p. 1
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☆ Address reprint requests to Maureen F. Zakowski, MD, Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021.

PII: S0093-7754(03)70038-4

doi:10.1053/sonc.2003.50015

Seminars in Oncology
Volume 30, Issue 1 , Pages 3-8, February 2003

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