Practice Essentials
Small cell carcinomas (SCC) commonly arise in the respiratory tract; however, it is not uncommon for these cells to arise in nonpulmonary sites, as extrapulmonary small cell carcinoma (EPSCC). [1] Small cell carcinoma is a distinct clinical and pathologic entity that arises from cells of the amine precursor uptake and decarboxylation (APUD) system.
EPSCC is estimated to account for approximately 1000 new cancer cases per year in the United States. This number, however, appears to be an underestimation. Most available literature on this condition exists in the form of case reports and retrospective series.
The etiology of EPSCC is unknown. While some authors have reported an association with tobacco smoking, others have not found a strong causative correlation with tobacco. The diagnostic criteria for EPSCC require that the tumor demonstrate histolgic features of small cell carcinoma in the absence of small cell lung cancer (SCLC).
The role of local and systemic therapies for EPSCC is still not clearly defined. Most reports indicate chemotherapy sensitivity and response rates similar to those seen in SCLC with similar chemotherapeutic regimens. Surgery appears to play a more important role in the management of EPSCC than it does in SCLC.
Pathophysiology
Histologic criteria for diagnosis of extrapulmonary small cell carcinoma (EPSCC) are same as those for pulmonary small cell carcinoma: the presence of uniform small cells with sparse cytoplasm, dense nuclei, and inconspicuous nucleoli. [2] Since EPSCC has been reported in multiple sites, all cases are thought to have an identical cell of origin that derives from those originating in neural crest and then migrates to different epithelial sites within the body. These cells are characterized by the presence of intracytoplasmic neurosecretory granules and positive staining with chromogranin.
EPSCC has been reported to arise in almost all body sites except the central nervous system. [3, 4] Primary sites may include esophagus, salivary glands, gastrointestinal tract (including small intestine and large intestine), pancreas, larynx, cervix uteri, uterus, urinary bladder, prostate, breast, and lacrimal gland in addition to skin, where it is also referred to as Merkel cell carcinoma. [5] One review of 4397 cases from the Surveillance, Epidemiology and End Results (SEER) database found that of 11 primary tumor sites, bladder was most common, while stomach and kidney were rarely affected. [6]
Like pulmonary small cell carcinoma, small cell carcinomas arising from extrapulmonary sites may be associated with paraneoplastic syndromes, notably syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and hypercalcemia. However, deletions of chromosome arm 3p and c-myc amplification described in small cell pulmonary carcinoma have not been reported in extrapulmonary sites.
Epidemiology
Approximately 1000 cases of extrapulmonary small cell carcinoma (EPSCC) are reported annually in the United States, with an overall incidence of 0.1-0.4% of all cancers and 2.5–5% of all small cell carcinomas. [7] A review of the Surveillance, Epidemiology and End Results (SEER) database from 1975 to 2016 found a trend toward an increasing incidence of EPSCC. [6]
Global incidence of extrapulmonary small cell carcinoma is unknown. Most of these malignancies develop after the sixth decade of life and a slight male preponderance has been noted. [7] No predilection for race is in the reported literature.
Prognosis
Because most of the literature is retrospective and in the form of case reports, estimating mortality rates is difficult. In addition, not all reported cases are managed uniformly, thereby making it further difficult to estimate prognosis. These reports suggest differences in patterns of relapse and outcome of EPSCC from differing primary sites, with breast, genitourinary, gynaecological, and head and neck tumors more likely to present as localized disease, whereas gastrointestinal EPSCC is most often metastatic. [7]
EPSCC may have a similar prognosis to that of small cell lung cancer. Those presenting with disseminated disease have a very poor prognosis and short survival time despite management with chemotherapy, radiation therapy, or both. Long-term survival is reported in those presenting with localized disease. [8] In one report, 5-year overall survival in EPSCC ranged from 2.0% to 42.5%, with better survival with breast and cervix EPSCC and worse survival with gastrointestinal (colon, esophagus, pancreas, rectum, and stomach) EPSCC. [6]
