Diagnosis: Combined small cell and squamous carcinoma with minor foci of adenocarcinoma
Follow-up: An abdominal CT in 9/98 showed no metastases or lymphadenopathy. A bone scan and head CT were negative. Clinically, the stage for small cell carcinoma was "limited" and after resection, it was stage 2 (pT2N1MX). Chemotherapy with Cisplatin and VP-16 was begun. No asbestos bodies were found in iron-stained sections of lung away from the tumor, and the unilateral pleural plaque was attributed to collapse therapy for his tuberculosis.
A group of tumors that shows neuroendocrine differentiation occurs in the lung. These tumors are defined by their growth pattern and cytologic features, by the presence of neurosecretory granules ultrastructurally, and by the presence of a number of neuropeptides that can be detected biochemically or by immunohistochemical methods. The individual tumors, although all potentially malignant, vary greatly in their clinical behavior from the low grade carcinoid tumor to the rapidly fatal small cell carcinoma. Classification systems attempt to predict behavior on the basis of morphology.
Small Cell Carcinoma of Lung
Introduction: Small cell carcinoma (SCC) constitutes around 25% of all lung cancers . These tumors used to be confused with lymphomas, but now, when necessary, the distinction can be made by using immunohistochemical markers: leukocyte common antigen for lymphomas and chromogranin or keratin for carcinomas. Diagnosis is based on routine light microscopy of H&E-stained sections or Papanicolaou-stained cytologic preparations, which are usually supplemented by immunoperoxidase stains or electron microscopy. Subclassification of SCC has been attempted, but no prognostic or therapeutic differences have been associated with any subtype, and unanimity of subclassification among pathologists expert in the diagnosis of lung cancer has not been achieved [2-4]. Most SCCs are centrally located; peripheral tumors are rare (~3% of all SCCs). On review, some peripheral tumors diagnosed SCC have had the diagnosis changed to well-differentiated neuroendocrine carcinoma, a lower grade tumor . A current scheme for classifying tumors is shown in the table, but unanimous agreement among pathologists using the scheme hovers around 50%: well-differentiated neuroendocrine carcinoma and large cell neuroendocrine carcinoma are especially difficult to diagnose .
Table: Classification of neuroendocrine tumors 
Clinical features: SCC is a disease of smokers. In one large retrospective study, the M:F ratio was 1566:230 (7:1). This ratio dropped from 14 between '75-'79 to 4 between '90-'94 . Besides the usual symptoms and signs of lung cancer--cough, dyspnea, chest pain, hemoptysis, and weight loss--around 10% of patients will present with a paraneoplastic syndrome--Cushing's, inappropriate antidiuretic hormone secretion, or Eaton-Lambert myasthenia. Other indications include hoarseness, evidence of superior vena caval syndrome, or pleural effusion .
Radiographic findings: Patients often present with mediastinal adenopathy and a hilar mass although sometimes a hilar mass is absent. Even when a central mass is present, lobar collapse is uncommon because the tumor tends not to obstruct the bronchus. Peripheral nodules or masses occur in about 3% of cases .
Diagnosis: Both tissue and cytologic specimens are useful in diagnosing the disease. Endobronchial biopsy and cytologic preparations from bronchial washes, postbronchoscopic sputum samples, fine needle aspirates (FNA), or effusions, if present, complement each other and should be viewed together in making the diagnosis. The diagnosis is less secure when only one modality (e.g., FNA) is available.
Staging: Current therapy depends on whether the disease is "limited" to one lung, the mediastinum, and supraclavicular lymph nodes or is "extensive" with disease outside of these confines. Patients with small cell carcinoma have extensive disease at diagnosis in 2/3 of cases [1,9]. Once a histologic diagnosis of SCC of the lung is made, the extent of tumor spread is determined. For detecting tumor in lymph nodes, CT with a sensitivity of 70-90% and a specificity of 60-90% is used as a guide for mediastinoscopy. Either CT or MR is used for detecting mediastinal or chest wall invasion . Diagnosis of extrathoracic disease depends on clinical signs and symptoms, and may include a radionuclide bone scan, CT of the abdomen, CT of the brain, and bone marrow biopsy . A cost-effective algorithm based on frequency of sites of metastatic involvement and clinical features assumes discontinuation of staging after a distant metastatic site is found . If no metastatic sites outside the thorax are found, limited disease should be staged by the TNM system used for nonsmall cell carcinoma in order to diagnose the small number of patients who may benefit from surgical resection.
Gross appearance: In contrast to central carcinoid tumors that form polypoid masses in the bronchial lumen, small cell cancers often invade the wall directly, producing only a slight irregularity of the surface mucosa and no luminal stenosis, although obstructive tumors do occur. Peripheral tumors appear as discrete nodules. In either location, tumors are firm and grey-white with variable necrosis.
Histologic features: Histologically, SCC is subclassified into three types. Although no clinical significance of the classification has emerged, it is useful for 2 reasons. First, it defines for the pathologist the histologic features that are expected in these tumors, and second, the existence of combined and mixed categories raises questions about the cell of origin (see below).
The tumor grows in sheets, nests, or trabeculae with delicate stroma containing thin-walled vessels (endocrine or organoid pattern of tumor) . The rare peripheral tumors tend to have nests with more fibrous stroma and inflammatory cells . The tumor cells vary in size, possibly depending on their viability (dying cells are more shrunken and pyknotic than well-preserved ones). Fragile and easily crushed, cells from endobronchial biopsies often show smearing of nuclear material called crush artifact. In well-preserved tissue, cells are medium-sized with angulated nuclei, uniform finely granular chromatin, inconspicuous nucleoli, and scant cytoplasm. Nuclei of adjacent cells indent each other--nuclear molding. Spindling of cells is common just as in carcinoid tumors. There may be scattered, multinucleated tumor giant cells. Minute glands (so-called rosettes), which sometimes contain luminal (but not cellular) PAS-D-positive material, may be present. They do not indicate a combined small cell-adenocarcinoma. Rosettes, a good marker of neuroendocrine differentiation, are found in all types of neuroendocrine tumors from carcinoid to small cell carcinoma . Mitoses are numerous--11 or more per 10 high power fields. Large areas of necrosis, as well as single cell necrosis, are common. Associated with the necrosis there may be staining of vascular walls by bluish DNA debris--the Azzopardi phenomenon.
Variant types of small cell carcinoma: SCCs that show other types of differentiation are a curiosity. Tumors with a substantial component of squamous or gland formation are considered to be "combined" tumors. "Mixed" tumors are defined as typical small cell tumors with "distinct clusters of large-cell carcinoma exhibiting vesicular nuclei with finely dispersed chromatin and prominent nucleoli" . In a study in which these large cells comprised at least 5% of the tumor, there was agreement on the diagnosis by two reviewers for only 11/24 (46%) of the tumors . In 6 studies, comparison of survival of 106 patients with mixed small cell lung cancer and over 1000 patients with pure SCC showed no clear advantage of either type .
Electron microscopy: By electron microscopy, cytoplasmic organelles are sparse. Neurosecretory granules, about 120 nm in diameter, are membrane-bound and have a halo between the granule and the membrane. They are usually located in cell processes. Some tumors have no detectable neurosecretory granules [12,14]. In contrast, granules are larger (100-350 nm diameter) and more plentiful in carcinoid tumors, but variable in number in well-differentiated neuroendocrine carcinomas .
Immunohistochemistry: Like other lung carcinomas, SCCs stain with antibodies to keratin. A more specific antibody to chromogranin A (a granule protein) is the most useful marker of neuroendocrine differentiation, but about half of SCCs do not stain . Antibodies to synaptophysin and Leu-7 are also in common use as markers of neuroendocrine differentiation. If these are all negative in a tumor with the histologic appearance of SCC, electron microscopy can be performed to look for neurosecretory granules.
Interestingly, it has been reported that up to 1/3 of nonsmall cell lung carcinomas also stain with one or more neuroendocrine markers. Further, a study of outcome of patients who were treated with chemotherapy for stage III or IV nonsmall cell lung cancer showed prolonged survival for those who had positively staining tumors compared to those without staining . Thus, given the low specificity and sensitivity of immunohistochemical markers and frequent lack of neurosecretory granules, the diagnosis of SCC rests heavily on routine histology and cytology.
Differential diagnosis: The histologic differential diagnosis includes poorly-differentiated, nonsmall cell carcinomas, lymphoma, other neuroendocrine carcinomas, and metastatic tumors, either neuroendocrine or other . One neuroendocrine carcinoma that should be recognized is the large cell neuroendocrine carcinoma. This tumor behaves in a manner similar to that of SCC, but the large cell size and lower N/C ratio cause it to be mistaken for nonsmall cell carcinoma . Characteristics of this tumor are listed below [7,17].
Large Cell Neuroendocrine Carcinoma [7,17]
Cell of origin: It is commonly believed that SCCs arise from neuroendocrine cells normally present in the airway epithelium. However, when SCCs are studied by electron microscopy, features of adenocarcinoma or squamous carcinoma may be present. In one study, only 19 of 29 cases classified as SCC showed neurosecretory granules: most of the others were classified as adenocarcinoma or squamous carcinoma based on ultrastructural findings . Further, histologic examination of autopsy material from patients with SCC shows that 10-25% of tumors show either complete or partial change to squamous, glandular, or large cell types [19-21]. While some of the changes might be related to therapy, in some cases no therapy was given. In the present case, squamous and glandular differentiation were found in the initial resected specimen. The phenomenon of mixed differentiation in a single tumor suggests a common endodermal origin for both small cell and nonsmall cell lung cancers [1,21]. Phenotypic differentiation by light microscopy, not cell of origin, is the defining feature of the tumor.
Genetic basis for neuroendocrine differentiation: The achaete-scute gene, which is present in Drosophila as well as in vertebrates, and which is important in neuronal differentiation, apparently plays a role in differentiation of pulmonary (but not other organ) neuroendocrine cells and also in neuroendocrine differentiation in all members of the group of neuroendocrine tumors. Mice lacking the gene develop no neuroendocrine cells in the respiratory tract. Further, treatment of cultured SCC cell lines with a missense version of the gene results in loss of some neuroendocrine features. The factors regulating this gene are not yet known .
Treatment: Patients with tumors that are staged by the TNM system as I or II sometimes undergo surgical resection, in combination with chemotherapy [23-25]. Other limited tumors are treated with chemotherapy and thoracic radiation, which confers a small benefit compared to chemotherapy alone . Patients with extensive disease, including the elderly and unfit, usually receive combination chemotherapy .
Prognosis: The few patients who undergo resection for stage I or II disease may do well (7/10 disease-free at five years in one series) . For others, the prognosis has changed little in the past 25 years. With treatment, median survival is 14-18 mo for limited disease and 9-11 mo for extensive disease. Adverse prognostic features include male sex, age >70 y, and poor performance status . A retrospective study of survival in 3681 patients with SCC in the UK showed a two-year survival of 8.5% for limited disease and 2.2% for extensive disease. Deaths from SCC continued until 7 years after diagnosis . A retrospective study of 594 patients (NCI) from 4/73 to 4/93 showed no difference in survival for either limited or extensive disease during the second decade (cisplatin-based therapy) compared to the first decade (cytoxan-based therapy). In both decades, adverse prognostic signs with extensive disease were poor performance status (3 or 4) or metastases to liver or CNS, whereas adverse signs for limited disease were performance status 3 or 4. Etoposide-cisplatin plus chest radiation significantly prolonged survival in limited disease in both decades .
1. Hinson J, Perry M. Small cell lung cancer. CA Cancer J Clin 1993; 43:216-225.
2. Hirsch F, Matthews M, Yesner R. Histopathologic classification of small cell carcinoma of the lung. Comments based on an interobserver examination. Cancer 1982; 50:1360-1366.
3. Aisner S, Finkelstein D, Ettinger D, Abeloff M, Ruckdeschel J, Eggleston J. The clinical significance of variant-morphology small-cell carcinoma of the lung. J Clin Oncol 1990; 8:402-408.
4. Fraire A, Johnson E, Yesner R, Zhang X, Spjut H, Greenberg S. Prognostic significance of histopathologic subtype and stage in small cell lung cancer. Hum Pathol 1992; 23:520-528.
5. Warren W, Memoli V, Jordan A, Gould V. Reevaluation of pulmonary neoplasms resected as small cell carcinomas. Significance of distinguishing between well-differentiated and small cell neuroendocrine carcinomas. Cancer 1990; 65:1003-1010.
6. Travis W, Gal A, Colby T, Klimstra D, Falk R, Koss M. Reproducibility of neuroendocrine lung tumor classification. Hum Pathol 1998; 29:272-279.
7. Travis W, Linnoila R, Tsokos M, Hitchcock C, Cutler G, Nieman L, Chrousos G, et al. Neuroendocrine tumors of the lung with proposed criteria for large-cell neuroendrocrine carcinoma. An ultrastructural, immunohistochemical, and flow cytometric study of 35 cases. Am J Surg Pathol 1991; 15:529-553.
8. Janssen-Heijnen M, Schipper R, Klinkhamer P, Crommelin M, Coebergh J-W. Improvement and plateau in survival of small-cell lung cancer since 1975: a population-based study. Ann Oncol 1998; 9:543-547.
9. Richardson G, Venzon D, Phelps R, Edison M, Brown M, Frame J, Ihde D, et al. Application of an algorithm for staging small-cell lung cancer can save one third of the initial evaluation costs. Arch Intern Med 1993; 153:329-337.
10. Shaffer K. Radiologic evaluation in lung cancer. Diagnosis and staging. Chest 1997; 112:235S-238S.
11. Colby T, Koss M, Travis W. Atlas of Tumor Pathology. Tumors of the Lower Respiratory Tract. Third Series, Fascicle 13, Washington, DC, Armed Forces Institute of Pathology 1995: 235-257.
12. Nomori H, Shimosato Y, Kodama T, Morinaga S, Nakajima T, Watanabe S. Subtypes of small cell carcinoma of the lung: Morphometric, ultrastructural, and immunohistochemical analyses. Hum Pathol 1986; 17:604-613.
13. Jiang S-X, Kameya T, Shoji M, Dobashi Y, Shinada J, Yoshimura H. Large cell neuroendocrine carcinoma of the lung. A histologic and immunohistochemical study of 22 cases. Am J Surg Pathol 1998; 22:526-537.
14. Mackay B, Ordoñez N, Bennington J, Dugan C. Ultrastructural and morphometric features of poorly differentiated and undifferentiated lung tumors. Ultrastruct Pathol 1989; 13:561-571.
15. Tötsch M, Müller L, Hittmair A, Öfner D, Gibbs A, Schmid K. Immunohistochemical demonstration of chromogranins A and B in neuroendocrine tumors of the lung. Hum Pathol 1992; 23:312-316.
16. Schleusener J, Tazelaar H, Jung S, Cha S, Cera P, Myers J, Creagan E, et al. Neuroendocrine differentiation is an independent prognostic factor in chemotherapy-treated nonsmall cell lung carcinoma. Cancer 1996; 77:1284-1291.
17. Travis W, Rush W, Flieder D, Falk R, Fleming M, Gal A, Koss M. Survival analysis of 200 pulmonary neuroendocrine tumors with clarification of criteria for atypical carcinoid and its separation from typical carcinoid. Am J Surg Pathol 1998; 22:934-944.
18. Li W, Hammar S, Jolly P, Hill L, Anderson R. Unpredictable course of small cell undifferentiated lung carcinoma. J Thorac Cardiovasc Surg 1981; 81:34-43.
19. Abeloff M, Eggleston J, Mendelsohn G, Ettinger D, Baylin S. Changes in morphologic and biochemical characteristics of small cell carcinoma of the lung. A clinicopathologic study. Am J Med 1979; 66:757-764.
20. Brereton H, Mathews M, Costa J, Kent C, Johnson R. Mixed anaplastic small-cell and squamous-cell carcinoma of the lung. Ann Intern Med 1978; 88:805-806.
21. Adelstein D, Tomashefski Jr J, Snow N, Horrigan T, Hines J. Mixed small cell and non-small cell lung cancer. Chest 1986; 89:699-703.
22. Borges M, Linnoila R, van de Velde H, Chen H, Nelkin B, Mabry M, Baylin S, et al. An achaete-scute homologue essential for neuroendocrine differentiation in the lung. Nature 1997; 386:852-855.
23. Meyer J. Five-year survival in treated stage I and II small cell carcinoma of the lung. Ann Thorac Surg 1986; 42:668-669.
24. Mountain C. Operation for small-cell carcinoma revisited. J Clin Oncol 1987; 5:687-688.
25. Baker R, Ettinger D, Ruckdeschel J, Eggleston J, McKneally M, Abeloff M, Woll J, et al. The role of surgery in the management of selected patients with small-cell carcinoma of the lung. J Clin Oncol 1987; 5:697-702.
26. Pignon J-P, Arriagada R, Ihde D, Johnson D, Perry M, Souhami R, Brodin O, et al. A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 1992; 327:1618-1624.
27. Bunn Jr P, Carney D. Overview of chemotherapy for small cell lung cancer. Semin Oncol 1997; 24 (suppl 7):S7-69-S7-74.
28. Souhami R, Law K. Longevity in small cell lung cancer. A report to the Lung Cancer Subcommittee of the United Kingdom Coordinating Committee for Cancer Research. Br J Cancer 1990; 61:584-589.
29. Chute J, Venzon D, Hankins L, Okunieff P, Frame J, Ihde D, Johnson B. Outcome of patients with small-cell lung cancer during 20 years of clinical research at the US National Cancer Institute. Mayo Clin Proc 1997; 72:901-912.
Table of Contents
Last revised 1/19/99
Copyright 1999 by Martha L. Warnock. All rights reserved.