Small cell neuroendocrine carcinoma of the cervix

INTRODUCTION — Cervical cancer encompasses several histologic types, of which the most common is squamous cell (70 percent) (table 1) [1,2]. Adenocarcinoma and its variants account for about 25 percent of cases, while other histologic subtypes are uncommon. Cervical neuroendocrine (mainly small cell) tumors represent only about 2 percent of all cervical malignancies [3-7]. Small cell neuroendocrine carcinoma represents an extrapulmonary variant of small cell lung cancer. (See "Neuroendocrine neoplasms of unknown primary site" and "Extrapulmonary small cell cancer".)

This topic review will cover the epidemiology, clinical presentation, staging, and treatment of small cell neuroendocrine carcinoma of the cervix. Because of the rarity of other neuroendocrine tumors of the cervix, they will not be discussed further.

The management of squamous cell cervical cancer and adenocarcinoma arising in the uterine cervix, as well as the management of other extrapulmonary sites of small cell cancer, are addressed elsewhere. (See "Management of early-stage cervical cancer" and "Management of locally advanced cervical cancer" and "Invasive cervical adenocarcinoma" and "Extrapulmonary small cell cancer".)

EPIDEMIOLOGY AND RISK FACTORS — Small cell neuroendocrine carcinoma of the cervix is a rare disease, accounting for only up to 2 percent of all invasive cervical cancers [3-8]. In a series from the Surveillance, Epidemiology and End Results (SEER) database, the mean annual incidence in the United States from 1977 to 2003 was 0.06 per 100,000 women, compared with 6.6 and 1.2 for squamous cell carcinoma and adenocarcinoma, respectively [9].

Although the disease has been described in women from 22 to 87 years of age, the mean age at diagnosis of small cell neuroendocrine carcinoma of the cervix is about 45 years [10,11].

There had been some uncertainty about whether cervical neuroendocrine cancers are associated with human papillomavirus (HPV). Based on accumulating evidence, the same high-risk HPV strains appear to be an etiology of both small and large cell neuroendocrine cancers [11-15]. This is best supported by a meta-analysis of 143 studies [16]. HPV infection was found in 85 percent of women with small cell cancers; 78 percent were HPV 16 and/or HPV 18 positive. In a subset of five small cell studies (75 cases), 93 percent were positive for p16INK4a. For large cell cancers, 88 percent were HPV positive; 86 percent were positive for HPV 16 or HPV 18.

In contrast to small cell carcinoma of the lung, smoking has not been established as a risk factor for small cell carcinoma of the cervix. However, it has been associated with a poorer prognosis [17]. (See "Pathobiology and staging of small cell carcinoma of the lung", section on 'Epidemiology' and "Clinical manifestations of lung cancer".)

HISTOLOGY — In 1997, a workshop sponsored by the College of American Pathologists and the National Cancer Institute proposed standardized terminology for neuroendocrine tumors of the uterine cervix that was created as a parallel to that used for pulmonary neuroendocrine tumors [7]. (See "Pathology of lung malignancies", section on 'Neuroendocrine tumors'.)

Four categories were identified:

●Small cell neuroendocrine carcinoma

●Large cell neuroendocrine carcinoma

●Typical carcinoid tumor

●Atypical carcinoid tumor

Small cell neuroendocrine carcinoma, first described in 1957, is the most common neuroendocrine tumor [18]. The less common large cell variant, although histologically distinct, shares the same natural history and is treated similarly. The least common type of neuroendocrine cancer that arises in the cervix, a well-differentiated carcinoid tumor, exhibits the typical carcinoid features seen elsewhere in the body (non-existent or minimal cytologic atypia, rare or no mitotic figures, no necrosis), has a different natural history and treatment, and is not discussed further in this review.

CLINICAL PRESENTATION — Patients typically present with abdominopelvic symptoms such as vaginal bleeding or discharge, pelvic pain, or pelvic pressure [19]. Few patients are asymptomatic or present solely after an abnormal Pap smear result.

Often, a pelvic mass is present on clinical exam. Low quality data suggest that the majority have bulky disease at the time of diagnosis. For example, in a review of 188 patients with small cell neuroendocrine carcinoma of the cervix, early (stage I to IIA), advanced (stage IIB to IVA), and metastatic (stage IVB) disease was diagnosed in 135, 45, and 8 women, respectively [19]. Of patients whose tumor size was recorded, 80 percent were ≥2 cm [19].

Cervical small cell neuroendocrine carcinoma has a particular propensity to spread distantly, which is similar to small cell carcinoma of the lung. As a result, patients can present with systemic symptoms such as weight loss [19]. In addition, patients may present with a paraneoplastic syndrome such as the syndrome of inappropriate antidiuretic hormone secretion (SIADH), Cushing syndrome, hypercalcemia, or a neurologic disorder. The most commonly involved organs include the liver, adrenals, bone, bone marrow, and the brain. (See "Pathobiology and staging of small cell carcinoma of the lung", section on 'Clinical presentation' and "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)" and "Establishing the cause of Cushing syndrome" and "Overview of paraneoplastic syndromes of the nervous system" and "Hypercalcemia of malignancy: Mechanisms".)

DIFFERENTIAL DIAGNOSIS — Small cell carcinoma should be distinguished from other small, round, blue-cell tumors and undifferentiated neoplasms. These include:

Squamous cell carcinoma — Poorly differentiated and basaloid squamous cell carcinomas can be distinguished from small cell neuroendocrine carcinomas because they lack morphologic features on microscopic examination that typically characterize small cell cervical cancer, including nuclear molding and nondiagnostic (or “crush”) artifact. In addition, immunohistochemistry staining for p63 may confirm a squamous histologic origin. In contrast, neuroendocrine markers might not be helpful, as approximately 40 percent of non-keratinizing squamous cell carcinomas can show neuroendocrine differentiation.

Undifferentiated carcinomas of lower uterine segment — Carcinoma of the lower uterine segment (LUS) accounts for approximately 3 to 6 percent of all endometrial cancers [20]. Imaging with magnetic resonance imaging (MRI) may help determine whether the primary emanates from the uterus or the cervix. However, immunohistochemistry may not be useful because undifferentiated carcinomas of the LUS can occasionally show focal positivity for neuroendocrine markers. Therefore, clinicians should rely on clinical findings to differentiate between the two entities.

Embryonal rhabdomyosarcoma — Embryonal rhabdomyosarcoma is positive for muscle markers, including desmin, myogenin, and myo-D1. They typically do not stain for cytokeratin and neuroendocrine markers. (See "Rhabdomyosarcoma in childhood and adolescence: Clinical presentation, diagnostic evaluation, and staging", section on 'Genitourinary tract'.)

Lymphoma — Primary lymphoma of the cervix is exceedingly rare. In one review, only 72 cases were reported in the English literature between 2000 and 2010 [21]. These tumors typically consist of diffuse large B cell lymphoma (DLBCL), present as mass lesions, and respond to combination therapy (chemotherapy plus immunotherapy) [22]. The diagnosis of DLBCL is discussed separately. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma", section on 'Diagnosis'.)

Metastatic disease — For patients with a known neuroendocrine tumor from another primary origin (eg, lung), metastatic disease to the cervix must be excluded. However, isolated metastatic involvement of the cervix appears to be exceedingly rare. As an example, the most common sites of distant metastases from small cell carcinoma of the lung are the liver, adrenal glands, bones, and brain. (See "Clinical manifestations of lung cancer", section on 'Clinical manifestations of extrathoracic metastases'.)

DIAGNOSIS — Biopsy is required for diagnosis. Histologically, pure small cell neuroendocrine carcinoma of the cervix is indistinguishable from small cell carcinoma of the lung and extrapulmonary small cell carcinoma of other sites. (See "Pathobiology and staging of small cell carcinoma of the lung", section on 'Pathology'.)

Microscopy — Microscopic findings on hematoxylin-eosin (H&E) stained sections include a poorly differentiated, diffusely infiltrating tumor composed of small blue cells with scant cytoplasm, hyperchromatic nuclei with finely dispersed chromatin, and absent or inconspicuous nucleoli. The cells of the large cell variant of small cell neuroendocrine carcinoma are distinguished by the presence of prominent nucleoli, vesicular nuclei with a more granular chromatin pattern, and variable amounts of cytoplasm. Neuroendocrine differentiation is demonstrated with pan-neuroendocrine markers such as chromogranin A (CGA), synaptophysin, and neuron-specific enolase.

Both large and small cell types may be present in the same tumor [12,15]. In either case, the neoplastic cells are typically arranged in clusters, sheets, or trabeculae, separated by a delicate fibrovascular stroma. Nuclear molding is a distinctive and characteristic finding in well-preserved specimens, although "crush" artifact is more frequently observed. Mitotic rates are high, and necrosis of individual tumor cells is common. The natural history and treatment of large cell neuroendocrine carcinoma is similar to small cell neuroendocrine carcinoma and will not be discussed separately. In some cases, there are admixed foci of in situ or invasive adenocarcinoma or squamous cell cancer [11,17,23,24]. In such cases, the small cell neuroendocrine component, even if small, dictates the prognosis as well as the treatment plan.

Immunohistochemistry — Because of their epithelial cellular origin, virtually all small cell neuroendocrine carcinomas are immunoreactive for keratin and epithelial membrane antigen. In addition, at least one marker of neuroendocrine differentiation is expressed in 88 to 100 percent of cases [10,25]. These markers include neuron-specific enolase (NSE), synaptophysin, CGA, and CD56 (neural cell adhesion molecule [NCAM]). The percentage of cases reactive with each varies in different studies. As examples:

●For small cell neuroendocrine carcinomas:

•CGA reactivity is reported in 50 to 76 percent of cases [10,25,26].

•Synaptophysin reactivity is reported in 60 to 90 percent of cases [10,25,26].

•NSE expression is reported in up to 75 percent of cases [25].

•CD56 expression, thought to be the most sensitive marker for the diagnosis of small cell neuroendocrine carcinoma, was reported in 71 to 92 percent of cases [10,26].

●Large cell neuroendocrine carcinomas also express neuroendocrine markers, although only approximately 25 to 38 percent express CGA, and synaptophysin expression is quite variable [26-29].

POSTDIAGNOSIS EVALUATION — Small cell neuroendocrine carcinomas are often not confined to the cervix. Therefore, all patients should undergo a computed tomography (CT) of the chest, abdomen, and pelvis for assessment of the extent of locoregional disease as well as distant spread [30]. Although guidance from the Society of Gynecologic Oncologists supports the role of positron emission tomography/computed tomography (PET/CT) imaging for the evaluation of women with small cell neuroendocrine carcinoma [30], there are no prospective data to suggest that PET/CT provides more information than imaging performed with a multi-detector row CT scanner. Therefore, the use of PET/CT is dependent on institutional standards. (See "Pathobiology and staging of small cell carcinoma of the lung", section on 'Staging workup'.)

Unlike the work-up of small cell carcinoma of the lung, we do not routinely perform bone marrow aspiration and biopsy. In addition, we do not routinely perform imaging of the central nervous system (CNS) to define disease extent. One series found no cranial metastases at initial presentation in a 14-year retrospective experience [31]. Brain imaging is generally only warranted in the presence of lung metastases or symptoms suggestive of CNS involvement (eg, headache, seizures, visual changes) [10].

Further work-up may be necessary if a paraneoplastic syndrome is suspected. The diagnosis and work-up of these syndromes are discussed elsewhere. (See "Overview of paraneoplastic syndromes of the nervous system" and "Clinical manifestations of lung cancer", section on 'Paraneoplastic phenomena' and "Hypercalcemia of malignancy: Mechanisms", section on 'PTH-related protein'.)

Staging system — The outcome of small cell neuroendocrine carcinoma of the cervix depends upon disease extent [10,11,32-34]. Because of the histologic, prognostic, and therapeutic similarities between cervical small cell neuroendocrine carcinoma and small cell lung cancer, the staging of small cell neuroendocrine carcinoma has often been adapted to the two-stage staging system widely used for small cell lung cancer, as originally defined by the Veterans’ Affairs Lung Study Group (see "Pathobiology and staging of small cell carcinoma of the lung", section on 'Staging'):

●Limited-stage disease – This is characterized by disease that can be encompassed within a single radiation therapy (RT) port.

●Extensive-stage disease – This is defined as disease that cannot be encompassed in a single RT port.

This two-tiered staging system recognizes the systemic nature of the disease and also serves to define a subset of patients who might benefit from combined modality therapy. (See 'Treatment' below.)

However, routine staging for cervical cancer includes small cell neuroendocrine carcinoma and other neuroendocrine variants, and it is increasingly being used for staging of the disease. While the American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) staging system describes the extent and burden of disease more accurately than does the simple designation of limited- versus extensive-stage disease, there is overlap in prognosis between stage groupings, particularly stages II and III. In most series, patients with stage I to IIA disease fare better than do those with more advanced-stage disease (five-year survival of 37 versus 9 percent in one review of 188 cases [19]), but the value of additional stratification, particularly beyond stage I disease, is unclear.

In one series of 239 cases of small cell neuroendocrine carcinoma, the stage distribution at diagnosis was:

●Stage I – 42 percent

●Stage II – 19 percent

●Stage III – 10 percent

●Stage IV – 23 percent

The International Federation of Gynecology and Obstetrics (FIGO) staging system and the AJCC TNM staging system are shown in the tables (table 2 and table 3).

TREATMENT — Most clinicians favor the use of combined modality therapy (surgery followed by chemotherapy or combined chemoradiotherapy) for limited-stage potentially resectable disease, definitive chemoradiotherapy for locoregionally advanced unresectable but nonmetastatic disease, and palliative chemotherapy alone for those with metastatic disease, using chemotherapy regimens that are typically used for small cell lung cancer [30].

Given the rarity of the condition, there are limited data to guide treatment of small cell neuroendocrine carcinoma. Most published series contain few patients, and there are no prospective trials. In general, survival is poor with radical hysterectomy alone, but there is no consensus as to optimal management [8,10,33]. Treatment considerations generally take into account the treatment options for cervical cancer and particularly for chemotherapy, and have been largely extrapolated from the experience with small cell lung cancer [10,15,19,31,32,34-38]. (See "Extensive-stage small cell lung cancer: Initial management".)

Role of surgery — The role of surgery in small cell neuroendocrine carcinoma is not well studied. In our institution, initial surgery (consisting of hysterectomy and lymphadenectomy) is an appropriate option for patients with small (<4 cm) cervical lesions with no clear parametrial disease and no evidence of metastatic disease. For a tumor >4 cm with known small cell histology, we begin with combined modality therapy (chemotherapy and radiation therapy [RT]). Surgery can then be considered in the adjuvant setting if the patient responds to the primary treatment and there continues to be no evidence of metastatic disease. Our approach is consistent with guidance from the Society of Gynecologic Oncology (SGO) [30].

A role for surgery in patients with apparently early-stage disease is supported by the observation that most series report long-term survival only for those patients who have undergone surgical resection in the context of multimodality treatment [32].

This was shown in a combined analysis of 188 patients derived from both institutional experience and literature review where the major findings consisted of the following [19]:

●A radical hysterectomy was an independent prognostic factor for survival in multivariate analysis (as were early-stage disease and the use of any chemotherapy).

●Among patients with stage I to IIA disease, five-year survival was significantly higher for those undergoing versus not undergoing radical hysterectomy (38 versus 24 percent).

However, because of the retrospective nature of the study, the contribution of the surgical procedure may have been overestimated because patients who were fit to undergo and selected for radical hysterectomy may have a better prognosis than those patients who were not selected to undergo surgery.

On the other hand, other small series suggest that surgery plays little role among patients receiving definitive chemoradiation. For example, among 31 patients who were treated on chemoradiation protocols (29 of whom had a cervical biopsy alone), the three-year disease-free rate was 80 and 38 percent among those with early-stage versus advanced-stage disease, respectively [31].

Fertility-sparing surgery — Due to the early propensity for hematogenous spread despite locally negative resection margins and due to the limited prognosis, fertility-sparing surgery is not a recommended treatment option for young patients with small cell neuroendocrine carcinoma.

Concerns about fertility preservation are particularly common among women with gynecologic malignancies. Unfortunately, for young women with small cell neuroendocrine carcinoma, the desire to preserve fertility must be taken in the context of the aggressive behavior of this tumor, including its rapid growth characteristics and the propensity for early metastases. While small cell neuroendocrine carcinoma is extremely sensitive to both chemotherapy and RT, the majority of patients relapse within two years.

Chemotherapy — In the absence of high quality data, we administer a similar treatment program as the one used for small cell lung cancer regardless of stage and whether surgery was performed. The specifics of the cisplatin/etoposide chemotherapy regimen are outlined in the table (table 4).

For patients who undergo RT, the first two cycles of chemotherapy can be given concurrently with RT (on days 1 and 22). The subsequent two cycles are given after RT. Substitution of carboplatin for cisplatin is appropriate for patients with preexisting renal dysfunction or peripheral neuropathy (table 5). (See 'Chemotherapy alone versus chemoradiotherapy' below.)

Some patients with early-stage disease will not have metastases at presentation and are potentially curable with local therapies [6,39]. However, given the propensity for early dissemination and patterns of treatment failure (with distant metastases predominating [19]) and the sensitivity of small cell neuroendocrine cancers to platinum-based chemotherapy, systemic chemotherapy is considered a critical component of standard therapy for all stages of disease [30].

Benefit of chemotherapy — The benefit of systemic chemotherapy as a component of multimodality treatment for small cell neuroendocrine carcinoma can be illustrated by the following observations:

●In a series of 17 patients with small cell neuroendocrine carcinoma, treatment consisted of primary surgery with or without individualized adjuvant treatment (eg, RT, concurrent chemoradiation therapy, or chemotherapy alone) [40]. The main results were as follows:

•Median overall survival (OS) was significantly better for patients with early-stage (IA1 to IB2) compared with those with advanced-stage disease (stage IIB to IV, 31 versus 6 months, respectively).

•Among women with stage IA1 to IB2 disease, the three-year distant recurrence-free survival rate was significantly better for those patients who received chemotherapy as a component of treatment compared with those who did not (83 versus 0 percent).

●In another series of 23 women, adjuvant chemotherapy with either cisplatin, vinblastine, and bleomycin (PVB) or vincristine, doxorubicin, cyclophosphamide, alternating with cisplatin and etoposide (VAC/PE) was administered after radical hysterectomy [38]. At a median follow-up of 41 months, 10 of 14 patients receiving VAC/PE were alive compared with only three of nine receiving PVB.

Chemotherapy alone versus chemoradiotherapy — Despite the lack of data, most clinicians favor the use of combined chemotherapy and RT because of the strong evidence supporting concurrent chemoradiotherapy in other subtypes of cervical cancer.

There are no randomized trials comparing chemotherapy alone versus chemoradiotherapy either as primary therapy or in the adjuvant setting following radical hysterectomy. The available retrospective series addressing the benefits of chemoradiotherapy versus chemotherapy alone are of limited utility [17,32]. As an example, one retrospective study compared the outcomes of 68 patients with stage IB to IIA small cell neuroendocrine carcinoma of the cervix who were treated with radical surgery alone (n = 7), neoadjuvant chemotherapy followed by surgery with or without adjuvant RT (n = 11), radical surgery and adjuvant chemotherapy (n = 24), and radical surgery followed by RT or chemoradiation (n = 26) [17]. The main findings were:

●For the entire cohort, the estimated two- and five-year survival rates were 65 and 47 percent, respectively.

●In multivariate analysis, International Federation of Gynecology and Obstetrics (FIGO) stage was the only independent predictor of outcome; patients with stage IB1 disease had significantly better five-year survival than did those with IB2 or IIA disease (55 versus 32 percent).

●Although there was a trend toward better survival with adjuvant chemotherapy, it was not statistically significant (five-year survival 49 versus 42 percent with and without adjuvant chemotherapy, respectively).

Role of prophylactic cranial irradiation — There are no prospective data to inform the role of prophylactic cranial irradiation (PCI) for these patients, and in many institutions, including our own, it is not performed.

The limited information suggests that PCI may not play as crucial a role in the management of small cell carcinoma of the cervix as it plays in small cell carcinoma of the lung. For example, in one series of 21 patients, the majority of recurrences were systemic, and none occurred in the central nervous system (CNS) as the first site of metastases [10]. Two patients developed simultaneous brain and lung metastases, suggesting that lung involvement might predict a cohort at risk for brain metastases, although the data are far too small to be conclusive.

PROGNOSIS — For women with small cell carcinoma of the cervix, the prognosis is worse compared with cervical squamous cell carcinomas or adenocarcinomas [8,9], though somewhat better than for small cell lung cancer. Like small cell lung cancer (and its large cell variant), the outcome of small cell neuroendocrine carcinoma of the cervix is associated with disease extent [10,11,32-34]. The five-year survival rate is approximately 30 percent for patients with limited-stage disease. However, few patients with more extensive disease survive beyond two years. (See "Pathobiology and staging of small cell carcinoma of the lung", section on 'Staging'.)

The major adverse prognostic factors are advanced tumor stage, larger tumor size, pure small cell histology, and smoking [32,38,41,42]. In one study, the only survivors were those with tumors <4 cm and no clinical evidence of nodal metastases [10].

The natural history of small cell neuroendocrine carcinoma is significantly worse than that of the more common squamous cell cancer or adenocarcinoma [8,9]. Small cell neuroendocrine carcinomas are more likely to have lymph node metastases and lymphovascular space invasion, and their clinical course is marked by early hematogenous dissemination [6,19,43,44].

POST-TREATMENT SURVEILLANCE — All patients who complete treatment for this disease should undergo routine post-treatment surveillance using a similar follow-up schedule as with other forms of cervical cancer. Although these patients appear to be at greater risk for distant metastases compared with other histologic types of cervical cancer, the role of routine imaging, including periodic computed tomography (CT) or positron emission tomography (PET/CT) scans, is unclear. (See "Invasive cervical cancer: Patterns of recurrence and post-treatment surveillance".)

However, given the high risk of distant relapse, it is our approach to offer periodic imaging every three to six months following curative intent treatment. In addition, imaging should be performed if there is suspicion of recurrence based on symptoms or physical exam findings, especially if the patient would be considered a candidate for additional therapy. (See "Treatment of refractory and relapsed small cell lung cancer".)

APPROACH TO RECURRENT OR METASTATIC DISEASE — Patients with widespread metastatic or recurrent disease are treated with chemotherapy regimens similar to those used for treatment of small cell lung cancer such as etoposide plus cisplatin (table 4) [30] (see "Extensive-stage small cell lung cancer: Initial management" and "Treatment of refractory and relapsed small cell lung cancer"). A subsequent retrospective report evaluated the combination of topotecan, paclitaxel, and bevacizumab in recurrent small cell carcinoma of the cervix which was superior to other chemotherapy regimens [45].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Treatment of cervical cancer".)

SUMMARY AND RECOMMENDATIONS

●Small cell neuroendocrine carcinoma of the uterine cervix is a rare, aggressive subtype of cervical cancer that is characterized by a high frequency of lymph node metastases and early hematogenous dissemination. Human papillomavirus appears to be an etiology of these cancers. (See 'Introduction' above and 'Epidemiology and risk factors' above.)

●Prior to treatment, patients should be evaluated to determine whether distant metastases are present and to rule out a primary small cell lung cancer. Brain imaging is only warranted in the presence of lung metastases or symptoms. (See 'Postdiagnosis evaluation' above.)

●For patients with early-stage disease (International Federation of Gynecology and Obstetrics [FIGO] stage I to IIA, (table 2)), tumor size ≤4 cm, and no metastatic disease, we suggest initial surgery rather than platinum-based combination chemotherapy (Grade 2C). (See 'Role of surgery' above.)

●For all patients, regardless of whether surgery is performed, we recommend chemotherapy with or without radiation therapy (RT) (Grade 1B). We administer a cisplatin/etoposide chemotherapy regimen (table 4). For patients who are candidates for RT, we administer chemotherapy concurrently during RT. (See 'Chemotherapy' above.)

●In contrast to small cell lung cancer, we suggest not pursuing prophylactic cranial irradiation (PCI) outside of the context of a clinical trial (Grade 2C). (See 'Role of prophylactic cranial irradiation' above and "Prophylactic cranial irradiation for patients with small cell lung cancer".)

●Post-treatment surveillance should include symptom review and pelvic examination; periodic full body imaging is reasonable given the high risk of distant relapse. (See 'Post-treatment surveillance' above.)