Extrapulmonary Small Cell Carcinoma 

Updated: Feb 22, 2018
Author: Irfan Maghfoor, MD; Chief Editor: Nagla Abdel Karim, MD, PhD 

Overview

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 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 extrapulmonary small cell carcinoma 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.

Extrapulmonary small cell carcinoma 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]

Like pulmonary small cell carcinoma (lung cancer), 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 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.[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.[6]  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 tumours more likely to present with localised disease, whereas gastrointestinal EPSCC is most likely metastatic.[6]  

Extrapulmonary small cell carcinoma 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.[7]

 

Presentation

History

Extrapulmonary small cell carcinoma is an aggressive neoplasm that enlarges rapidly and disseminates early in the course of illness. Due to the multiplicity of sites where it can arise, there are no symptoms or signs specifically attributable to extrapulmonary small cell carcinoma. Patients may present with constitutional symptoms of fatigue, weakness, fever, weight loss, and night sweats. They may also have symptoms referable to the organ of origin, such as the following:

  • Hematuria, in cases of bladder tumor
  • Abdominal pain with or without obstruction, with small or large bowel involvement
  • Hoarseness, with laryngeal involvement

Physical Examination

Physical findings are again limited by the organ system involved. Examples include the following:

  • Prostatic enlargement
  • Skin nodules, in cases of Merkel cell carcinoma
  • Enlargement of regional draining lymph nodes

As with pulmonary small cell carcinoma, paraneoplastic syndromes have been described with extrapulmonary small cell carcinoma. Most common of these are hypercalcemia, syndrome of inappropriate secretion of antidiuretic hormone, and secretion of adrenocorticotropic hormone. Patients may present with symptoms and signs of excess calcium, hyponatremia, or corticosteroid excess, depending upon the severity and rate of development of endocrine abnormality.

 

DDx

Diagnostic Considerations

Pathologically, extrapulmonary small cell carcinoma (EPCC) needs to be differentiated from other tumors composed of small round blue cells under light microscopy, including the following:

  • Lymphoma
  • Rhabdomyosarcoma
  • Carcinoids

EPSCC is distinguished from metastatic pulmonary small cell carcinoma with chest imaging. Additional workup with sputum cytology, bronchoscopy, or biopsy should be conducted for indeterminate pulmonary findings.[8]

Differential Diagnoses

 

Workup

Approach Considerations

The diagnostic criteria for extrapulmonary small cell carcinoma (EPSCC) require that the tumor demonstrate histolgic features of small cell carcinoma in the absence of small cell lung cancer (SCLC); thus, biopsy and imaging studies are part of the workup. A paraneoplastic syndrome workup may also be appropriate in certain cases. 

Laboratory Studies

No laboratory investigations aid in the diagnosis of extrapulmonary small cell carcinoma. Most of the laboratory studies done in the workup are to assess end organ function prior to instituting therapy, especially chemotherapy, or to diagnose a suspected paraneoplastic syndrome.

A complete blood count with differential is obtained to assess bone marrow reserve, but it may give clues to bone marrow infiltration by the tumor. Bone marrow infiltration is suspected when peripheral blood displays a leukoerythroblastic picture (ie, red and white blood cell precursors are present).

Blood urea nitrogen and serum creatinine and electrolyte assays are obtained to asses renal function prior to instituting potentially nephrotoxic drugs, as well as to estimate renal clearance of chemotherapeutic agents. In addition, low serum sodium levels and abnormalities in other electrolytes such as potassium may point toward the presence of a paraneoplastic syndrome.

Serum bilirubin and transaminases are measured to assess liver function and to determine appropriate dosing of hepatically cleared chemotherapeutic agents.

Serum calcium is assessed for suspected hypercalcemia and bone metastases.

Imaging Studies

Chest radiography or computed tomography (CT) with or without fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) are required to exclude pulmonary involvement.  

A complete workup should include cross-sectional imaging of the site of origin, as well as of the chest, abdomen, and pelvis for staging. Whole-body imaging with FDG PET/CT may be considered for both staging and assessment of treatment response.[8]

Procedures

Bone marrow aspiration and biopsy are performed to confirm or exclude bone marrow involvement in case of peripheral blood abnormalities. Some authors recommend that bone marrow biopsy should be done in every patient to confirm limited disease.

Sputum cytology, bronchoscopy, or both are performed to exclude pulmonary origin of small cell carcinoma.

Special tests that may be performed, depending on primary site of origin, include the following:

  • Upper endoscopy: Esophagus

  • Direct laryngoscopy, bronchoscopy, and upper endoscopy: Origin in head and neck region

  • Cystoscopy: Urinary bladder

  • Lower endoscopy: Rectum and large bowel

  • Pelvic examination: Cervix and uterus

Histologic Findings

Extrapulmonary small cell carcinoma histologically consists of sheets of uniform small round cells with scant cytoplasm, dense nuclei, and indistinct nucleoli.

Immunohistochemical stains with silver impregnated stains usually have positive results; however, EPSCC cannot be diagnosed on the basis of immunoreactivity alone. Neural cell adhesion molecule (NCAM or CD56) is the most sensitive neuroendocrine marker.[8]

Staging

There is no American Joint Committee on Cancer (AJCC) staging classification for extrapulmonary small cell carcinoma. In the reported literature, extrapulmonary small cell carcinoma is universally staged similarly to small cell carcinoma of lung as limited stage or extensive stage, as follows:

  • Limited stage: Tumor is confined to the organ of origin, with or without regional lymph node involvement. Alternatively, limited stage has also been defined as that encompassed within one radiation port.

  • Extensive stage: Disease has spread to distant organs or beyond regional lymph nodes.

 

Treatment

Approach Considerations

The care of patients with limited extrapulmonary small cell carcinoma should involve a multidisciplinary approach that includes initial consultations with surgical, medical, and radiation oncologists to devise the most appropriate management plan.

No randomized studies exist to guide decisions regarding management of extrapulmonary small cell carcinoma. The organ and site of involvement, as well as extent of disease, are important in management. Based on experience published in the form of retrospective reviews, combination chemotherapy appears to form the mainstay of treatment, similar to that for small cell carcinoma of the lung.[9, 10]  A study by Grossman et al found that surgery and radiation significantly improve median, 5-year, and 10-year survival rates, although outcomes remain poor.[11]

Tumor lysis syndrome can occur rapidly in patients with small cell carcinomas on institution of therapy.

Medical Care

Patients with extrapulmonary small cell carcinoma who present with localized disease may be treated with chemotherapy and local therapy in the form of surgery or radiation therapy. The active regimens include those containing platinum (cisplatin or carboplatin) or anthracyclines. Combination chemotherapy with a platinum-based combination has produced response rates similar to those seen in small cell lung cancer, and long-term survival has been reported.[12]

Patients with extrapulmonary small cell carcinoma and extensive stage disease should be treated initially with combination chemotherapy. The role of surgery and radiation therapy in this situation is not defined, but surgery may be used for palliative purposes. Patients who achieve complete remission may have prolonged survival despite presenting with advanced-stage disease. Survival in excess of 120 months has been reported.

The optimum therapy for limited-stage extrapulmonary small cell carcinoma is less clearly defined, but the principles of management of limited-stage small cell carcinoma have been frequently applied in the management of limited-stage extrapulmonary small cell carcinoma. Surgery, radiation, and chemotherapy may play a role in the management. In contrast to small cell lung cancer, surgery is often the primary therapy in such individuals since the presentation in organs such as esophagus, thyroid, and female genitourinary tract may lead to initial surgical resection. In some of these patients, initial surgical resection may result in complete removal of malignancy. However, due to propensity for systemic spread, all such patients should be considered for combination chemotherapy after surgical resection.

The role of radiation therapy is not clear; however, prolonged survival after radiation therapy alone has been reported in limited numbers of patients who presented with very-limited-stage disease.

Estimates of brain metastasis in the literature range from 1.7% up to 40%.[13, 14] Frequency varies by site. Esophageal small cell cancer has a low incidence of brain metastasis, as do genitourinary, colorectal, small bowel, and appendix small cell cancers, and prophylactic cranial irradiation is not recommended in these patients. The frequency of brain metastasis is much higher in prostate small cell carcinoma, with estimates ranging from 16% to 19%, and in head and neck small cell cancer, with a frequency of up to 41%. Prophylactic cranial irradiation should be considered in these patients.[15, 16]

 

Prevention

Data linking extrapulmonary small cell carcinoma to tobacco smoking are inconclusive; however, at least one study has reported that most patients with extrapulmonary small cell carcinoma in the study were former or current smokers. Since smoking is implicated as an etiologic agent in several different kinds of malignancies, smoking cessation education and programs with a concerted efforts form health care providers and government agencies are needed.

Long-Term Monitoring

Patients with extrapulmonary small cell carcinoma require close monitoring for adverse effects of chemotherapy. Complete blood counts with differential counts should be checked prior to each cycle of chemotherapy to ensure adequate hematologic recovery. Liver and renal function should be monitored to detect toxicity from chemotherapy as well as to assess if adjustment of chemotherapy doses is needed.

Response to therapy is monitored by obtaining CT scans after 2 cycles of chemotherapy before chemotherapy is continued.

If elevated prior to therapy, serum lactate dehydrogenase is a good marker and should be monitored.

 

Medication

Medication Summary

Medication used in the management of extrapulmonary small cell carcinoma includes chemotherapeutic agents to effect tumor shrinkage and induce remission as well as medication to reduce morbidity from treatment, malignancy, or both.

Antiemetic agents

Class Summary

Nausea and vomiting caused by antineoplastic agents is induced by stimulation of chemoreceptor trigger zone. This effect is mediated by central neurotransmitters (ie, dopamine and acetylcholine).

The severity of nausea and vomiting caused by antineoplastic agents varies with the agent or combination used, but it may be so disabling that patients occasionally decline continuation of chemotherapy. Appropriate prophylaxis and treatment of nausea and vomiting are therefore critical for administration of chemotherapy.

Metoclopramide (Clopra, Reglan, Maxolon, Octamide PFS)

Metoclopramide has central and peripheral antiemetic activity. In the CNS it acts on the chemoreceptor trigger zone while in the GI tract it stimulates acetylcholine release in the myenteric plexus.

Dexamethasone (Decadron)

Dexamethasone is a synthetic corticosteroid commonly used in combination with serotonin receptor antagonists or metoclopramide in prevention and treatment of chemotherapy-induced nausea and vomiting.

Ondansetron (Zofran)

Selective 5-HT3-receptor antagonist. Unclear whether effect is centrally and/or peripherally mediated. Used to prevent chemotherapy-induced nausea and vomiting.

Granisetron (Kytril)

Selective 5-HT3-receptor antagonist. Unclear whether effect is centrally and/or peripherally mediated. Used to prevent chemotherapy-induced nausea and vomiting.

Dolasetron (Anzemet)

Binds to 5-HT3 receptors located on vagal neurons in GI tract, blocking signal to VC, thus preventing nausea and vomiting.

Palonosetron (Aloxi)

Selective 5-HT3 receptor antagonist with long half-life (40 h). Indicated for prevention and treatment of chemotherapy-induced nausea and vomiting. Blocks 5-HT3 receptors peripherally and centrally in chemoreceptor trigger zone.

Antineoplastic agents

Class Summary

Chemotherapy forms the mainstay of management of extrapulmonary small cell carcinoma. Antineoplastic agents are used in potentially curative therapy in limited extrapulmonary small cell carcinoma in combination with radiation therapy, surgery, or both. In extensive extrapulmonary small cell carcinoma, chemotherapy is used for prolongation of survival or palliation of symptoms.

Antineoplastic agents interfere with cell division and growth. Some antineoplastic agents are cell-cycle dependent and phase specific, such as antimetabolites (cytosine arabinoside, methotrexate), while others, like alkylating agents (cyclophosphamide), are not.

Etoposide (Toposar, VePesid)

Inhibits topoisomerase II enzyme leading to breakage of DNA strands. Etoposide is cell cycle specific and causes cell cycle arrest in late S and early G2 phase of cell cycle.

Cisplatin (Platinol)

Alkylating agent causing intrastrand and interstrand cross-linking of DNA, leading to strand breakage. Has broad range of antitumor activity. Use in testicular, ovarian, and transitional cell carcinomas.

Carboplatin (Paraplatin)

Analog of cisplatin (ie, platinum-salt alkylating agent). Has similar efficacy as cisplatin but with lower toxicity profile. Carboplatin is associated with less renal toxicity but enhanced myelosuppression compared to cisplatin. Mechanism of action for carboplatin is production of cross-links within and between strands of DNA.

Cyclophosphamide (Cytoxan, Neosar)

Chemically related to nitrogen mustards. As alkylating agent, mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.

Doxorubicin (Adriamycin, Rubex)

Inhibits topoisomerase II and produces free radicals, which may cause destruction of DNA. The combination of these 2 events can in turn inhibit growth of neoplastic cells.

Vincristine (Oncovin)

Inhibits tubulin polymerization during mitosis. G2 phase specific.