Other rare uterine cancers: neuroendocrine tumors, yolk sac tumors, choriocarcinoma

Epidemiology

Pathology

Microscopic description

Small-cell neuroendocrine carcinoma (SCNECa) resembles that of pulmonary small-cell carcinoma, with “salt and pepper chromatin” and scant cytoplasm with nuclear molding. Large-cell neuroendocrine carcinoma (LCNECa) typically have neuroendocrine growth pattern, such as organoid/nesting ( Fig. 13.1A ), trabecular or corded. LCNECa characteristically have polygonal cells with abundant cytoplasm and prominent nucleoli ( Fig. 13.1B ). The tumors frequently have central geographic necrosis, numerous mitotic figures and apoptotic bodies. Tumors may show pure SCNECa or LCNECa or may show mixed small and large-cell morphology. NEC can also be mixed with other histotypes, including endometrioid adenocarcinomas, serous carcinomas and carcinosarcomas.

Diagnosis and workup

The differential diagnosis for NEC is broad and includes undifferentiated/dedifferentiated endometrial carcinoma, carcinosarcoma, poorly differentiated endometrioid carcinoma, serous carcinoma with a solid growth pattern and massive necrosis, primitive neuroectodermal tumors (PNETs), and carcinoid tumor. Additionally, NEC is often associated with tumors of other histologic types, including complex atypical hyperplasia, endometrioid carcinoma, carcinosarcoma, or serous carcinoma.

In a 25 patient series, the most common presenting symptom was vaginal bleeding (15 of 25 patients) with other less common presenting symptoms including abdominal pain, symptoms related to metastasis, and abnormal Pap test. Additional common presenting symptoms include postmenopausal bleeding and pelvic pain. Of note, in very rare cases, NEC can also present with signs of paraneoplastic disease and/or Cushing’s syndrome.

Workup begins with a complete physical exam including pelvic and rectovaginal examinations ( Table 13.2 ). The most common physical exam findings include abnormal vaginal bleeding, abdominal pain, and an enlarged uterus and/or a palpable pelvic mass. There is not a typical tumor marker that is elevated in NEC. CA-125 may be elevated in the setting of a mixed tumor, but this marker is not specific to NETs.

Data on the optimal pretreatment imaging are limited. Consideration can be given to obtaining a transvaginal pelvic ultrasound and a chest radiograph. If there is an abnormality on chest radiograph, a chest computed tomography (CT) can be obtained to further evaluate. If there is concern for high-grade carcinoma (e.g., if already diagnosed as high-grade tumor by an endometrial biopsy (EMB)), it is reasonable to obtain a CT of the chest, abdomen, and pelvis to evaluate for metastatic disease. Other initial imaging may be obtained based on symptoms and/or clinical concern for specific metastatic sites.

In some cases, an MRI abdomen and pelvis may be obtained. MRI findings are similar to other poorly differentiated carcinomas, with an ill-defined endometrial-myometrial border and heterogeneity of the mass indicating necrosis and hemorrhage. Consideration can also be given to positron emission tomography (PET).

Similar to other endometrial cancers, the gold standard for initial diagnosis is by pathologic diagnosis obtained from either an EMB or endometrial curettings obtained from a dilation and curettage (D&C).

Staging system

Uterine NEC is surgically staged utilizing the 2017 International Federation of Gynecology and Obstetrics (FIGO)/ Tumor, Node, Metastasis (TNM) system used for endometrial carcinoma ( Table 13.3 ).

Prognostic factors

Factors associated with death in a NCDB series include: diagnosis at 80 years of age or older, stage (diagnosis at stage II or higher compared to stage I), and not receiving adjuvant chemotherapy. Women over the age of 80 have a hazard ratio for death of 2.4 compared to women less than 50 years old and patients who receive chemotherapy have a hazard ratio for death of 0.36 compared to those who do not get chemotherapy. In a smaller study of 42 patients, performance status, FIGO stage, surgery, and histologic subtype (pure type with worse prognosis than mixed type) were significant prognostic factors; in a multivariate analysis, only surgery and histologic subtypes remained significant. There was also a better prognosis in complete surgery cases (versus no surgery or incomplete surgery).

Prognostic factors for small-cell NETs in general (not specific to endometrial origin) include early detection and prompt surgical and adjuvant therapy.

Treatment of primary disease

Standard treatment guidelines do not exist given the rarity of NEC and lack of prospective data to guide therapy. Treatment regimens are largely based on traditional treatments of endometrial cancer and small-cell lung cancer. The majority of reported treatment regimens in the literature include surgical resection and adjuvant therapy with platinum-based chemotherapy with or without radiation therapy. Treatment usually begins with surgery for women without metastatic disease ( Fig. 13.2 ). Surgery generally includes hysterectomy, bilateral salpingo-oophorectomy (BSO), and lymph node assessment. For younger women, fertility preserving surgery can be considered on an individual basis but most patients should undergo BSO.

Adjuvant treatment is reasonable to consider given aggressive nature of this cancer type with high risk of recurrence and metastasis. In the largest reported series of cases, all patients underwent surgery, 60% received chemotherapy, and 28% received radiation. Compared to women with poorly differentiated endometrial carcinoma, those with NEC were more likely to receive adjuvant chemotherapy, likely owing to the tendency to present with later stage disease. In another series, all patients underwent surgery and 80% received adjuvant therapy. All patients undergoing surgery with the majority also receiving adjuvant chemotherapy is consistent with smaller series and case studies.

The most common reported chemotherapy regimens include cisplatin and etoposide. The following dosage regimen has been reported in the literature and is reasonable to consider for adjuvant treatment: cisplatin (80 mg/m ² on day 1) and etoposide (80–120 mg/m ² on days 1–3) over a 3-week interval. Of note, adjuvant treatment regimens used for NEC are largely based on data from small-cell lung cancer and neuroendocrine cervical cancer. A case series of SCNECa of the cervix demonstrated 83% recurrence-free survival (RFS) at 3 years with use of adjuvant etoposide and cisplatin. Indications for neoadjuvant chemotherapy are similar to those in other endometrial cancer types, and may be considered in the setting of advanced stage disease, though its use is rare in the reported literature.

In conclusion, there are no evidence-based therapeutic regimens for NEC due to its rarity, but surgery followed by adjuvant chemotherapy (most commonly cisplatin and etoposide) has been used with several patients obtaining long-term survival in case reports.

Surveillance for recurrence

Based on recommendations for surveillance of endometrial carcinoma, it is reasonable to consider physical exam every 3–6 months for 2–3 years and then every 6 months or annually with thorough review of systems and tumor markers (if initially elevated) at each visit, as well as imaging if clinically indicated. Evidence-based recommendations for surveillance are lacking.

Survival and patterns of failure

A large case series reports 5-year progression-free survival (PFS) and overall survival (OS). Five-year PFS is 81.8%, 50%, 32.5%, and 14.3% for FIGO stages I, II, III, and IV, respectively. OS is 88.9%, 100%, 46.7%, and 21.4% for FIGO stages I, II, III, and IV, respectively. Recurrence occurred in 50% of cases with a higher rate of hematogenous recurrence compared to lymphogenous or local recurrence.

Treatment of recurrent disease

There are no standard regimens due to rarity of the disease ( Table 13.4 ). One report in the literature describes the use of salvage chemotherapy with cisplatin (75 mg/m ² ) and ifosfamide (5 g/m ² ). Second-line therapies can be considered based on cervical and lung cancer data: cyclophosphamide/doxorubicin/vincristine (CAV), irinotecan/platinum (IP), or topotecan.

Based on preliminary data from NEC of the cervix, PI3K and MEK inhibitors are targeted therapies that may have therapeutic potential for treatment of endometrial NEC. One study looked at a newly established neuroendocrine cervical carcinoma cell line and found that when etoposide and cisplatin were combined with a PI3K inhibitor (which functions in the mTOR pathway), the growth of tumor cells was significantly reduced. Another study examined a MEK inhibitor, trametinib, which functions in the RAS pathway and is FDA-approved for treatment of unresectable or metastatic melanoma in patients with BRAF mutations, in the treatment of a patient with recurrent cervical neuroendocrine carcinoma with a KRAS mutation; she has been on trametinib for 8 cycles and is without evidence of disease. Based on data from pulmonary small-cell tumors, a number of other targeted therapies have been studied including angiogenesis inhibitors, mTOR inhibitors, and PARP inhibitors.

There is a case report evaluating the use of a programmed cell death 1 (PD-1) receptor inhibitor, nivolumab, in the treatment of a patient with recurrent, metastatic SCNECa of the cervix. The patient experienced a complete response and remained free of disease 4 months after stopping treatment. Further research is needed to see if immunotherapy is a reasonable approach to recurrent NEC of the cervix and/or endometrium.