Incidence and mortality

The broad category of NEC accounts for a variety of tumor subtypes. Carcinoid and atypical carcinoid tumors are considered low grade and most frequently found in the gastrointestinal (GI) tracks. Although there are case reports of these low grade tumors arising in the cervix, they are almost always metastatic sites from a GI primary and a full workup in search of a GI site should be undertaken. In the cervix, almost all primary neuroendocrine tumors (NETs) are high grade lesions (see Section “ Pathology ”).

High grade NEC of the cervix account for 1%–2% of cervical cancer diagnoses. The World Health Organization (WHO) further classifies high grade NEC of the cervix into two categories—small cell and large cell carcinomas. As there will be 14,480 cases of cervical cancer in the United States in 2021, a rough calculation will find approximately 150–200 cases/year for the entire country. The median age at diagnosis for patients with high grade NEC of the cervix is 48 years old which is younger than the age for those women diagnosed with squamous or adenocarcinomas of the cervix. Women with high grade NETs are also more likely to present with advanced stage disease than women with squamous or adenocarcinomas of the cervix. Although almost a third of patients will present with clinical stage I disease, an almost equivalent number will have stage IV disease at diagnosis ( Table 14.1 ).

Stage for stage, women with NEC have significantly worse outcomes than those with squamous or adenocarcinomas of the cervix ( Table 14.1 ). Even in those women where disease is clinically limited to the cervix, the 5-year overall survival is only 55% compared to 80%–85% for squamous and adenocarcinomas of the cervix. This speaks to the aggressiveness of the disease as 40% of patients with tumors < 4 cm and clinically limited to the cervix will have metastatic disease to pelvic nodes compared to only 10%–15% of similarly sized tumors that are squamous cell or adenocarcinoma histologies. Women with early disease (stages IA–IIA) high grade NEC of the cervix have a hazard ratio for death of 2.96 when compared to patients with squamous cell carcinoma at the same stage. When comparing women with high grade neuroendocrine and squamous cell carcinomas of the cervix who have locally advanced disease (stages IIB–IVA), the hazard ratio for death is 1.70 if the patient has high grade NEC.

Etiology and risk factors

Risk factors and the etiology of high grade NEC of the cervix continue to be investigated. Whole exome sequencing has compared high grade NEC of the cervix to that same histology in the lung and bladder as well as to cervical squamous cell carcinoma and adenocarcinoma. Investigators found that tumor specimens from women with high grade NEC of the cervix were genetically more similar to the common HPV-associated cervical cancers (squamous and adenocarcinomas) than they were to the high grade NEC of the lung and bladder. The role of HPV in the development of high grade neuroendocrine cervical cancer has been investigated. A meta-analysis found that 85% of patients with small cell neuroendocrine carcinoma (SCNEC) of the cervix were HPV positive with HPV18 being the most common subtype detected. In women with large cell neuroendocrine carcinoma (LCNEC) of the cervix, 88% were found to have HPV with seemingly equal distributions of HPV16 and HPV18 detected. Although HPV may be detected in tumor samples from patients with high grade neuroendocrine cervical cancer, a causative relationship has not been clearly established as it has for squamous cell carcinoma and adenocarcinoma. As many high grade NEC are mixed with squamous and adenocarcinoma and as HPV is commonly found in sexually active women it is unknown whether the virus detected is simply a bystander infection or a causative agent in the disease process.

Gross

The gross appearance of the tumor is variable and can be either small or large involving the entire cervix. The tumors can be polypoid or indurated with tan-white cut surface and necrosis.

Microscopic findings

The 2020 WHO Classification of Female Genital Tumors proposes a standardized nomenclature for all NETs, regardless of the site of involvement. While the etiology may differ at various anatomic sites (i.e., cervix, endometrium, and vulva) the histologic appearance is similar and these tumors should be classified uniformly. Neuroendocrine neoplasms are broadly classified as NET which encompasses low grade (grade 1) and intermediate grade tumors (grade 2), i.e., typical and atypical carcinoid; and high grade NEC that include SCNEC, LCNEC, and mixed carcinomas.

The discussion in this chapter is limited to high grade NEC. SCNEC is characterized by sheets of markedly atypical cells with high nuclear-cytoplasmic ratio, and hyperchromatic nuclei without prominent nucleoli ( Fig. 14.2 ). Nuclei show “salt and pepper” chromatin, nuclear molding with marked crush artifact, numerous apoptotic bodies, geographic necrosis, and frequent mitoses are typical ( Fig. 14.3 ). LCNEC on the other hand is composed of tumor cells that are arranged in a nested pattern, with moderate amounts of cytoplasm and prominent nucleoli ( Fig. 14.4 ). Trabecular, pseudoglandular, and insular patterns are frequent. NEC, either small or large cell type, may be admixed with other components such as adenocarcinoma or squamous carcinoma.

Small cell neuroendocrine carcinoma showing tumor cells with high nuclear-cytoplasmic ratio and crush artifact (arrow).

Small cell neuroendocrine carcinoma showing tumor cells with high N/C ratio, salt and pepper chromatin, frequent mitoses ( black arrows ), and apoptotic bodies ( red arrows ).

Large cell neuroendocrine carcinoma showing nested and trabecular pattern composed of cells with moderate amounts of cytoplasm and prominent nucleoli.

Ancillary testing

The diagnosis of NEC is made based on a combination of morphology and immunohistochemical stains. Markers of NEC include synaptophysin ( Fig. 14.5A ), chromogranin ( Fig. 14.5B ), CD56, neuron-specific enolase (NSE), and insulinoma-associated protein 1 (INSM1). CD56 and NSE are not very specific, and if they are the only positive markers a diagnosis of NEC should not be made in the absence of characteristic morphology. NEC are variably positive for cytokeratins and sometimes use of more than one keratin marker is necessary to confirm epithelial differentiation. NEC usually display block-like staining for p16, and the majority are positive for high-risk HPV. The latter supports a diagnosis of NEC, when epithelial markers are negative.

Small cell neuroendocrine carcinoma showing diffuse staining for synaptophysin (A) and chromogranin (B).

Differential diagnosis

NEC can mimic poorly differentiated squamous carcinoma with small cell morphology, and the pseudoglandular pattern may be mistaken for adenocarcinoma. In curettage specimens they can also mimic high grade squamous intraepithelial lesion (HSIL). Making the distinction between squamous carcinomas with basaloid/small cell features and NEC can be challenging, and a low threshold to perform neuroendocrine stains is prudent when frequent mitoses and apoptotic bodies are seen, to ensure the correct diagnosis. Squamous carcinomas are diffusely positive for p40 and p63 and negative for neuroendocrine markers. Adenocarcinomas are more diffusely positive for keratin markers and negative for neuroendocrine marker expression. Another important differential diagnosis is primitive neuroectodermal tumor (PNET) as they have histologic overlap with NEC and express neuroendocrine markers. In such cases positivity for epithelial markers and high-risk HPV would support a diagnosis of NEC over PNET.

Molecular alterations

A subset of SCNEC can have recurrent genetic alterations in TP53/BRCA, PI3K/AKT/mTOR, and MAPK pathways. Loss of heterozygosity in the short arm of chromosome 3 (3p) has been reported.

Signs and symptoms

Women with high grade NEC of the cervix may have their disease detected by routine Pap screening or gynecologic exam. In these patients, disease is typically asymptomatic. As this disease tends to effect younger women, some may have diagnosis made during pregnancy (see Section “ Special considerations ”). In those women who present with grossly evident disease, symptoms are similar to those found in patients with other large cervical tumors. These include postcoital bleeding, irregular bleeding, or discharge. Women with metastatic disease may experience pain or weight loss. Common sites for metastatic disease outside the pelvis include the liver, lung, and brain. Disease metastatic to these sites are typically asymptomatic but obviously large volume disease in the brain can cause significant neurologic symptoms.

Physical exam findings

For the minority of women with lesions found on screening cytology, physical exam may not reveal obvious abnormalities. However, most women will have grossly evident tumor on pelvic examination. In fact, over 80% of women will have a tumor > 2 cm at time of presentation. A thorough pelvic exam including a rectovaginal examination is important to determine extent of disease within the pelvis ( Table 14.2 ). Physical exam findings are similar to those found in women with more common squamous cell or adenocarcinomas and largely related to extent of disease spread. For example, women with large, bulky tumors may have unilateral leg swelling/lymphedema if tumor has spread to pelvic lymph nodes or compresses the pelvic sidewall. As mentioned, common sites for metastatic disease outside the pelvis include the liver, lung, and brain. Disease in these sites may cause symptoms but are unlikely to present with findings on physical exam.

Differential diagnosis

Accurate diagnosis of high grade NEC of the cervix is exceedingly important as therapeutic approaches are different than those for more common squamous cell and adenocarcinomas (see Section “ Treatment of primary disease ”). Most times the diagnosis will be made on pathologic review of cervical specimens (see Section “ Pathology ”). High grade NETs are frequently mixed with squamous cell or adenocarcinoma. When both subtypes of cervix cancer are present, treatment recommendations should follow algorithms for the neuroendocrine component as opposed to the squamous cell or adenocarcinoma components of the mixed tumor. Clinicians should have a high level of suspicion for high grade NEC of the cervix in patients who present with widely metastatic disease particularly with multiple tumors in the liver and/or lung.

Primary NEC from other sites metastatic to the cervix should also be ruled out. As mentioned, primary carcinoid or atypical carcinoid tumors of the cervix are very rare, and a complete GI workup should be performed to rule out a GI source before assigning the cervix as primary site. For high grade NEC, isolated metastases from other primary sites to the cervix are equally rare. Therefore, high grade NEC found on just the cervix and in the lungs is likely a primary cervical lesion as opposed to a primary lung cancer. Small cell lung cancer will almost always spread to the liver, adrenal glands, bone, and brain before the cervix; however, small cell cervical cancer may metastasize to the lung before other sites of disease are evident.

Tumor markers

There are no validated serum tumor markers for women with high grade NEC of the cervix. However, as high grade NEC of the cervix are histologically similar to small cell lung cancer, some have suggested utilizing serum NSE as a tumor marker for these patients. NSE is a neuro- and neuroendocrine-specific isoenzyme of enolase which localizes to neurons and neuroendocrine cells. This serum marker can be found elevated in people with several types of tumors of neuronal or neuroendocrine origin including small cell lung cancer. In patients with small cell lung cancer, serum NSE is frequently elevated at diagnosis, normalizes with response to primary therapy, and may rise again with recurrence. Small cell lung cancer patients with elevated serum NSE at diagnosis have worse progression free and overall survival compared to those with normal levels.

Imaging studies

As a large percentage of women with high grade NEC of the cervix will have metastatic disease outside the pelvis at time of diagnosis, it is important to perform comprehensive imaging to determine disease stage and appropriate treatment recommendations (see Section “ Treatment of primary disease ”). As part of initial workup, all women with newly diagnosed disease should undergo either computed tomography (CT scan) of the chest, abdomen, and pelvis, positron emission tomography (PET scan) from skull to thigh, or a combined PET/CT scan. Although combination PET/CT scan is preferred by most, there are no studies showing that it is superior to CT scan in patients with high grade NEC of the cervix.

For patients with disease limited to the cervix, magnetic resonance imaging (MRI) of the pelvis should be performed to evaluate tumor size and to rule out parametrial involvement. In women with cervical cancer, this modality has been shown to be the more accurate in assessing tumor size and parametrial involvement than CT or PET scans. Transrectal ultrasonography is another option for determining these factors; however, this approach requires technical experience and expertise not common at most centers. Confirming that tumors are < 4 cm in size without parametrial invasion, and no suspicious lymph nodes is important in determining who might be a surgical candidate (see Section “ Treatment of primary disease ”).

Routine MRI of the brain at time of diagnosis is not necessary. Metastatic disease at initial diagnosis is a rare event with one retrospective study showing no occurrences in 31 patients. However, it should be performed if the patient is having neurologic symptoms or if PET and/or CT scans detect metastatic disease in the liver and/or lung. Oligometastatic disease to the brain in the absence of disease spread to the liver, lung, or other sites is a rare event occurring in only 3% of patients.

DOTATATE scans are frequently used to detect disease in patients with well and moderately differentiated NEC of the GI track. These scans utilize DOTA-peptides (DOTATAC, DOTANOC, and DOTATATE) that specifically bind to somatostatin receptors on the surface of GI NETs. In patients with somatostatin expressing tumors, DOTATATE scans have with a sensitivity of 97% in detection of metastatic disease and are more sensitive than CT scans. Although there are no studies in the ability of DOTATATE to detect disease in women with high grade NEC of the cervix, it is unlikely that this type of scan would be of use in these patients as these tumors are almost always negative for the somatostatin receptor.

Diagnostic testing

Similar to squamous cell and adenocarcinoma of the cervix, diagnosis of high grade NEC of the cervix is made pathologically with a biopsy. This is commonly a biopsy of grossly evident tumor on the cervix but may also require colposcope directed biopsies if an abnormality was detected on screening cytology. Occasionally a LEEP or cone specimen for what was thought to be squamous cell or adenocarcinoma will return with a high grade neuroendocrine component as almost 50% of women with high grade NEC will have a mixed tumor. When this occurs, patients should be treated with the therapeutic approaches for high grade NEC as opposed to those for squamous cell or adenocarcinoma as the neuroendocrine component is significantly more aggressive and drives prognosis (see Section “ Treatment of primary disease ”).