Extrapulmonary small cell cancer

INTRODUCTION — Small cell carcinoma is a distinct clinicopathologic entity that usually arises in the lung but can also originate in a wide range of extrapulmonary sites. Small cell carcinoma is the preferred terminology, but these tumors have also been referred to as oat cell carcinoma or sarcoma, small cell neuroendocrine carcinoma, small cell tumor, anaplastic cell carcinoma, microcytoma, reserve cell carcinoma, undifferentiated carcinoma, Kulchitsky cell carcinoma, and carcinoma with amine precursor uptake decarboxylation (APUD) cell differentiation. These tumors are thought to originate from totipotent stem cells present in all tissues, although some small cell carcinomas may arise from more well-differentiated tumors.

Extrapulmonary small cell carcinomas (ESCCs) are extremely rare; these tumors have been described most frequently in the urinary bladder, prostate, esophagus, stomach, colon and rectum, gallbladder, larynx, salivary glands, cervix, and skin. In addition, small cell carcinoma will occasionally present with metastatic disease, and a primary site cannot be identified (small cell carcinoma of unknown primary).

The diverse origin of these ESCCs is illustrated by a study of 120 patients, in which the site of origin was the female genital tract (26 percent), gastrointestinal tract (23 percent), genitourinary tract (19 percent), head and neck (16 percent), unknown primary site (13 percent), and other sites (4.3 percent) [1]. Similar findings have been reported by other groups [2,3].

Although extrapulmonary undifferentiated large cell neuroendocrine carcinomas are distinct histologically, the natural history of such lesions is similar to that of ESCC, and the treatment approach is the same. (See "Pathology of lung malignancies", section on 'Large cell neuroendocrine carcinoma'.)

The key features and general management of ESCCs will be reviewed here, followed by a discussion of ESCCs that arise in relatively more common sites. ESCCs arising in the tubular gastrointestinal tract and the pancreas, cervix, urinary bladder, and with an unknown primary are discussed separately, as is Merkel cell carcinoma of the skin, which is included in the differential diagnosis of these tumors.

●(See "High-grade gastroenteropancreatic neuroendocrine neoplasms".)

●(See "Small cell neuroendocrine carcinoma of the cervix".)

●(See "Small cell carcinoma of the bladder".)

●(See "Neuroendocrine neoplasms of unknown primary site".)

●(See "Pathogenesis, clinical features, and diagnosis of Merkel cell (neuroendocrine) carcinoma".)

OVERVIEW OF ESCC — ESCCs have an aggressive natural history that is characterized by early, widespread metastases. Although some patients who present with locoregional disease may be cured by aggressive therapy, most relapse and the overall prognosis is poor, with less than 15 percent reaching five-year survival [4]. In different studies, the median survival for limited and extensive disease ranges from 1.4 to 3.5 years and 8 to 12 months, respectively [1,2].

Patients may have local relapse or distant metastases at relapse. In one series of 159 patients, 22 patients (13 percent) had local recurrence, 49 (31 percent) had distant metastases, and 20 (13 percent) had both local and distant disease [5]. The liver was the most common site of metastatic disease; only four patients (2.5 percent) had brain metastases at the time of first relapse.

The initial clinical manifestations are often due to locoregional disease, and the presenting symptoms may be indistinguishable from other tumors arising in the same site. ESCCs also can present with symptoms from distant metastases or with paraneoplastic syndromes, as occurs with small cell lung cancer (SCLC). (See "Clinical manifestations of lung cancer", section on 'Paraneoplastic phenomena'.)

A variety of laboratory abnormalities have been reported with ESCC. Immunohistochemistry for thyroid transcription factor 1 (TTF-1) in concert with synaptophysin may help to differentiate ESCC from poorly differentiated carcinomas [6]. As an example, paraneoplastic syndromes can result in hyponatremia, hypokalemia, or hypercalcemia, any of which may require specific treatment. Tumor-associated neuroendocrine markers have been elevated in some cases, although it is generally not useful to measure or monitor these proteins.

ESCCs have the same histologic appearance as SCLC regardless of their site of origin. In most cases, electron microscopy can identify neurosecretory granules that establish the neuroendocrine origin of the tumor, but the absence of such granules does not rule out ESCC. ESCCs are often found in conjunction with other tumor types, and the presence of a small cell component usually determines the biologic aggressiveness of a tumor. The histopathology of SCLC is discussed elsewhere. (See "Pathology of lung malignancies", section on 'Neuroendocrine tumors'.)

Staging — The initial evaluation of a patient with ESCC should include evaluation of the primary tumor and regional lymph nodes to assess the extent of locoregional disease, and computed tomography (CT) of the chest to rule out a primary SCLC.

Prior to treatment, patients should be evaluated to determine whether or not distant metastases are present. Positron emission tomography (PET) is useful in the staging and treatment response of ESCC and should be considered in the initial staging of such patients [7]. As an example, in one study of 33 patients with ESCC, PET scans influenced management in 19 percent of 43 imaging studies. Other imaging procedures that can be useful include abdominal and pelvic CT scans and bone scan.

Magnetic resonance imaging (MRI) of the brain is recommended if neurologic symptoms are present. Bone marrow biopsy is indicated only if there are abnormal blood counts or findings on the peripheral smear, without other evidence of disseminated disease. Based on the results of such evaluation, patients with disease confined to a primary site and/or regional nodes are classified as having limited disease, while all others are considered to have extensive disease.

Treatment — The initial management of patients with locoregional disease is patterned after that for other tumor types arising in the same extrapulmonary site. In general, this includes surgery and/or radiation therapy (RT) and chemotherapy. Despite aggressive locoregional treatment, relapse is common and adjuvant systemic chemotherapy is generally recommended. There are no randomized clinical trials or prospective clinical studies, and this approach is based upon case reports and extrapolation from the experience with SCLC. Most patients develop metastatic disease despite adjuvant therapy, and the prognosis is poor.

The treatment of systemic disease with chemotherapy is based upon that used in SCLC, typically a platinum-based regimen with etoposide. Objective responses are common, but most are partial and of short duration [8-10]. Amrubicin monotherapy has been noted to be effective as salvage therapy after platinum-based chemotherapy [11]. However, topotecan shows only modest activity in pretreated ESCC [12]. However, immunotherapy has expanded the treatment for SCLC both in the front-line and relapse settings [13-16]. Anecdotal cases of immunotherapy in ESCC have been noted [17-19], and thus the role of immunotherapy in these rare tumors warrants further investigation. (See "Extensive-stage small cell lung cancer: Initial management" and "Treatment of refractory and relapsed small cell lung cancer".)

The prognosis for patients with disseminated disease is poor despite chemotherapy and, in general, is similar to that for patients with extensive SCLC. However, two reports noted that patients with ESCC had a worse response rate, medial survival, and prognosis compared with patients with SCLC [20]. This may be especially true for patients with ESCC of the hepatobiliary tract and pancreas [21] and those with poor performance status and liver involvement [20]. By contrast, in another series patients with ESCC had a better three-year survival than those with SCLC (19 versus 5 percent) [3]. Breast ESCC had the best three-year survival (60 percent) and gastrointestinal the worst (7 percent). The choice of chemotherapy regimen, duration of treatment, role of maintenance therapy, and retreatment following relapse in patients are discussed elsewhere.

In general, prophylactic cranial irradiation is not recommended because there appears to be a decreased incidence of brain metastases in ESCC compared with SCLC [1,4]. In a review of 280 patients with ESCC treated over a 12-year period, only 18 patients (6 percent) developed brain metastases [22]. However, prostate and head and neck ESCC have been reported to have a higher frequency of brain metastases; 16 to 19 percent and 41 percent, respectively. Thus, prophylactic cranial radiation can be considered in such patients [23,24].

PROSTATE ESCC — Pure ESCC arising in the prostate is a rare disorder that is distinct from the far more common prostatic adenocarcinoma. Guidelines from the National Comprehensive Cancer Network (NCCN) suggest a combination of etoposide with either cisplatin or carboplatin in patients with pure small cell carcinoma of the prostate; or the combination of docetaxel and carboplatin [25].

Prostate cancer with neuroendocrine features (termed aggressive-variant prostate cancer) may also emerge during the progression of prostate cancer. The optimal way to manage men with castration-resistant, metastatic prostate cancer and neuroendocrine differentiation is not established. However, patients may be sensitive to chemotherapy regimens containing a taxane and platinum agent, which is discussed in more detail elsewhere. Immunotherapy has also been used for platinum-resistant ESCC of the prostate [19]. (See "Chemotherapy in advanced castration-resistant prostate cancer", section on 'Aggressive prostate cancer variants'.)

GALLBLADDER ESCC — ESCC accounts for between 1 and 5 percent of malignancies arising in the gallbladder [26]. The epidemiology of gallbladder ESCC is similar to that of adenocarcinoma, suggesting common etiologic factors [27-29]. In a series of 53 patients, small cell carcinoma was twice as common in women, the median age at diagnosis was 64 years, and two-thirds had coexisting cholelithiasis [27]. (See "Gallbladder cancer: Epidemiology, risk factors, clinical features, and diagnosis".)

Patients typically present with a large tumor mass that is indistinguishable from other tumors arising in the gallbladder. The symptoms and findings on physical examination are secondary to the presence of a mass or obstruction of the biliary tract [27,30]. In addition, gallbladder ESCC may be associated with paraneoplastic syndromes. Laboratory features are nonspecific and reflect obstruction of the biliary tract. (See "Gallbladder cancer: Epidemiology, risk factors, clinical features, and diagnosis".)

The microscopic findings are similar to those of small cell lung cancer (SCLC). In some cases, ESCC is found in conjunction with adenocarcinoma or other histologic types of gallbladder cancer [26]. Tumors with mixed histology are consistent with the hypothesis that ESCC arises either from a totipotent stem cell or within foci of more differentiated tumors. (See "Pathology of lung malignancies", section on 'Neuroendocrine tumors'.)

Abdominal ultrasound is the preferred imaging modality for biliary tract disease. The mass may obstruct the biliary tree as well as the vessels of porta hepatis [27]. Computed tomography (CT), endoscopic retrograde cholangiopancreatography (ERCP), and angiography can also be useful in staging and treatment planning, although laparotomy is often required to obtain tissue for a diagnosis and define the extent of disease [27].

Prior to treatment, patients should be evaluated to rule out a primary SCLC or evidence of distant metastases (see 'Overview of ESCC' above). There is no specific staging system for gallbladder ESCC; tumors should be staged according to the Tumor, Node, Metastasis (TNM) system (table 1). (See "Gallbladder cancer: Epidemiology, risk factors, clinical features, and diagnosis", section on 'TNM staging system'.).

Treatment and prognosis — Almost all gallbladder ESCCs are either locally advanced or metastatic at diagnosis, and the prognosis is poor [26-29]. In a series of 53 cases from the literature, those with disseminated disease had a median survival of eight months, and one- and two-year survival rates of 28 and 0 percent, respectively [27].

In patients with localized disease, surgical resection may result in prolonged survival in occasional patients [31]. However, the development of distant metastases in most patients has led to the use of systemic chemotherapy as adjuvant therapy in this setting [27].

Chemotherapy is also used in the treatment for disseminated disease. Although there are no clinical trials of different regimens, the choice of systemic therapy is based upon the experience in SCLC. (See "Extensive-stage small cell lung cancer: Initial management".)

LARYNGEAL ESCC — ESCC can arise anywhere in the head-neck region and occurs most frequently in the larynx [32-35]. The epidemiology and risk factors for laryngeal ESCC are similar to that for other laryngeal tumors. Most patients are between the ages of 60 and 80, and there is a slight male predominance [32]. Smoking, chewing tobacco, and excess alcohol intake have been associated with ESCC of the larynx [32]. (See "Epidemiology and risk factors for head and neck cancer", section on 'Risk factors'.)

The clinical features of laryngeal ESCC are similar to those of other laryngeal tumors and are due to the presence of a laryngeal mass [32]. Cervical lymph node metastases are often the initial site of tumor spread, and the origin of the tumor in the larynx only becomes apparent when the patient later presents with hoarseness [36]. In a review of 66 cases, cervical lymph node involvement was present in 35 (53 percent) at presentation [32]. In addition, some patients have symptoms from paraneoplastic syndromes. (See "Overview of the diagnosis and staging of head and neck cancer".)

ESCC of the larynx grossly is indistinguishable from other tumors [32], while its histopathologic appearance is the same as that of small cell lung cancer (SCLC). In addition to small cell carcinoma, large cell poorly differentiated neuroendocrine tumors have been described [32]. (See "Pathology of lung malignancies", section on 'Neuroendocrine tumors'.)

Although most tumors are composed of pure ESCC, some have elements of squamous cell carcinoma or adenocarcinoma [36-39]. These composite tumors are thought to arise in a common totipotent stem cell that can differentiate into various cell types.

The differentiation of ESCC from other laryngeal tumors requires biopsy and histologic examination of the tumor. Tissue may be obtained from the tumor itself or from a cervical lymph node.

Before treatment, patients should be evaluated to rule out primary SCLC or evidence of distant metastases, which are often present at diagnosis (see 'Overview of ESCC' above). Laryngeal small cell carcinoma is staged according to the Tumor, Node, Metastasis (TNM) staging classification used for squamous cell carcinoma of the larynx (table 2). (See 'Staging' above.)

Treatment and prognosis — The overall prognosis of ESCC of the larynx is poor due to early spread of disease, with a five-year disease-specific survival rate of less than 20 percent [35].

In patients without distant metastases, management of local and regional disease has relied upon surgery, radiation therapy (RT), or a combined-modality approach [36,38]. Although occasional long-term survivors have been reported [33], the local recurrence rate is high, especially when disease is present in the cervical lymph nodes, and distant metastases are almost always seen. (See "Treatment of locoregionally advanced (stage III and IV) head and neck cancer: The larynx and hypopharynx".)

Systemic chemotherapy, used as an adjuvant following local treatment and for the management of patients who present with metastatic disease, may induce remissions and prolong survival [35]. The chemotherapy approach is the same as that used for extensive SCLC (see "Extensive-stage small cell lung cancer: Initial management"). However, because of the low incidence of central nervous system (CNS) metastases in patients with ESCC of the larynx, prophylactic cranial radiation is not recommended [40].

In patients with metastatic disease, control of laryngeal disease can take precedence over systemic treatment if there is an imminent risk of respiratory obstruction. In such situations, RT is preferred followed by systemic chemotherapy [41].

SALIVARY GLAND ESCC — ESCCs of the parotid, submandibular, and minor salivary glands account for 1 to 2 percent of all salivary gland tumors [42]. There are no known risk factors for ESCC of the salivary glands. Most tumors occur between the ages of 50 and 70 years.

The typical patient presents with a rapidly growing, painless mass in a salivary gland [43]. Less often, pain may be noted and some patients may present with symptoms due to a paraneoplastic syndrome.

The histologic appearance of salivary gland ESCC is similar to that of small cell lung cancer (SCLC). In addition to pure ESCC, tumors with concurrent features of squamous or ductal differentiation have been described [44,45]. Salivary gland ESCC appears to arise from stem cells of the salivary duct system capable of differentiation to ductal or neuroendocrine-like cells [44]. (See "Salivary gland tumors: Epidemiology, diagnosis, evaluation, and staging".)

The diagnosis is based upon histologic examination of a biopsy sample, from either a fine-needle aspirate or a surgical resection specimen. Before treatment, patients should be evaluated to rule out a primary SCLC or evidence of distant metastases (see 'Overview of ESCC' above). There is no separate staging classification for ESCC of the salivary glands, and these tumors are staged according to the Tumor, Node, Metastasis (TNM) system (table 3 and table 4) [46].

Treatment and prognosis — Decisions regarding therapy are largely based upon experience with other salivary gland tumors and anecdotal case reports. For patients who present without evidence of metastatic disease, surgical resection of the tumor, along with regional lymph node dissection, is the preferred treatment. Postoperative radiation therapy (RT) has been used to improve local control, although there are no trials documenting its efficacy.

Despite local treatment, most patients relapse with distant disease. Adjuvant systemic chemotherapy has been used with platinum-based regimens. Metastatic disease, whether present at diagnosis or developing after treatment of the primary tumor, is managed with systemic therapy. Systemic therapy regimens are based upon those used for patients with SCLC. (See "Extensive-stage small cell lung cancer: Initial management".)

When compared with ESCCs arising in the larynx and other sites, those originating in salivary glands appear to have a better prognosis. In a retrospective analysis of 20 patients, the two- and five-year survival rates were 70 and 46 percent, respectively, compared with 16 and 5 percent for laryngeal small cell carcinoma [44]. This may be due to early recognition of salivary gland abnormalities because of their superficial location, thereby permitting earlier diagnosis.

SUMMARY

●Introduction – Small cell carcinoma is a distinct clinicopathologic entity that usually arises in the lung but can also originate in a wide range of extrapulmonary sites. These tumors are thought to originate from totipotent stem cells present in all tissues, although some small cell carcinomas may arise from more well-differentiated tumors. (See 'Introduction' above.)

●Overview – Extrapulmonary small cell carcinomas (ESCCs) are extremely rare; these tumors have been described most frequently in the urinary bladder, prostate, esophagus, stomach, colon and rectum, gallbladder, larynx, salivary glands, cervix, and skin. (See 'Overview of ESCC' above.)

Although the initial clinical manifestations are often due to locoregional disease, ESCCs have an aggressive natural history that is characterized by early, widespread metastases. Although some patients who present with locoregional disease may be cured by aggressive therapy, most relapse and the overall prognosis is poor. (See 'Overview of ESCC' above.)

●Staging – The initial evaluation of patients with ESCCs should include evaluation of the primary tumor and regional lymph nodes to assess the extent of locoregional disease and computed tomography (CT) of the chest to rule out a primary small cell lung cancer (SCLC). Prior to treatment, patients should be evaluated to determine whether or not distant metastases are present. (See 'Staging' above.)

●Treatment – The initial management of patients with locoregional disease is patterned after that for other tumor types arising in the same extrapulmonary site. Despite aggressive locoregional treatment, relapse is common and adjuvant systemic chemotherapy is generally recommended, although all data are derived from case reports and no randomized clinical trials have been conducted. Despite adjuvant therapy, most patients develop metastatic disease. (See 'Treatment' above.)

The management of systemic disease with chemotherapy is patterned after the approach used in SCLC and generally utilizes a combination of a platinum compound and etoposide. Although objective responses are commonly observed, most are partial and of short duration. (See "Extensive-stage small cell lung cancer: Initial management".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Nasir Shahab, MD, who contributed to an earlier version of this topic review.