Neuroendocrine Tumors of the Female Reproductive Tract: A Literature Review.

The four-category scheme including TC, AC, LCNEC, and SCNEC is still applied to NETs of the female reproductive tract. Ki-67 labeling index is not included in the diagnostic criteria of the 2014 WHO classification of cervical NETs [ 6 ]. The prevalence and biologic behavior of NETs vary along the female reproductive tract. Carcinoid tumors are extremely rare in the cervix and the endometrium, and their clinical behavior is uncertain due to the scarcity of follow-up data. However, in the ovary, carcinoid tumors are the most common NET. Division into four subcategories (insular, trabecular, strumal, and mucinous) instead of TC and AC has obscured the comparison of follow up data from ovarian carcinoids with that of carcinoids in other organs. Both small cell and large cell NECs show highly aggressive clinical behavior, regardless of the site of origin. The uterine cervix is the most common site for NECs, especially SCNECs in the female reproductive tract. Since endometrial NEC is often accompanied by low-grade endometrioid carcinoma, it can be misdiagnosed as FIGO grade 3 endometrioid carcinoma or dedifferentiated carcinoma [ 30 , 33 ]. As NECs are rare and tumors with neuroendocrine differentiation are infrequently found in the endometrium or ovary, various tumors are included in the differential diagnoses. Attention to the histologic features of neuroendocrine differentiation and the immunohistochemical staining of neuroendocrine markers is necessary to reach a correct diagnosis. CD56 is known to be a less specific neuroendocrine marker compared to chromogranin and synaptophysin [ 11 , 20 , 55 ]. The common coexistence of NEC and epithelial tumors along with the monoclonality of the two components implies a common cellular origin of the neuroendocrine and epithelial components [ 17 , 72 ]. Ovarian SCCOPT is a highly aggressive SCNEC and must be distinguished from metastatic small cell carcinoma from other locations. Currently, SCCOHT is considered to be an ovarian malignant rhabdoid tumor, as inactivation of SMARCA4 accompanied by the loss of BRG1 protein and the retention of INI- 1 in immunohistochemistry has been described in this aggressive tumor [ 78 , 82 , 83 ].

Ovarian carcinoid tumors are monodermal teratomas occurring in a pure form (15%) or combined with other teratomatous components (85%), such as a dermoid cyst or a struma ovarii. They can also be a component of mucinous and Brenner tumors. Carcinoid tumors of the ovary can be primary or metastatic; these metastases are usually from gastrointestinal tumors. Primary ovarian carcinoids are mostly confined to a unilateral ovary and behave in an indolent fashion, whereas metastatic tumors tend to be aggressive and associated with poor outcome. Therefore, the distinction between ovarian primary and metastatic carcinoids is critical. In addition to a clinical history of carcinoid tumor in an extraovarian site, such as the gastrointestinal tract or lung, metastatic carcinoids more often show bilateral distribution, multinodular growth, extraovarian tumor nodules, lymphovascular invasion, and absence of teratomatous elements. Ovarian carcinoids can be confused with other primary ovarian tumors, particularly Brenner tumors, granulosa cell tumors, and Sertoli or Sertoli-Leydig cell tumors [ 15 , 46 - 51 ]. Primary carcinoid tumors of the ovary are divided into insular, trabecular, strumal, and mucinous carcinoids. Mixed forms include carcinoid tumors that contain two or more of the aforementioned categories and those that are mixed other types of primary ovarian tumors. Briefly, insular carcinoid, considered to be of midgut derivation, is the most common type of primary ovarian carcinoid tumor. It is composed of small acini and solid nests of round cells with uniform nuclei and abundant eosinophilic cytoplasm. Carcinoid syndrome occurs in about one-third of patients with insular carcinoid, despite the absence of metastasis [ 48 ]. Trabecular carcinoid, considered to be of hindgut or foregut derivation, shows wavy ribbons or a trabecular arrangement of cells in a dense fibrous stroma. The tumors cells are one or two layers thick, and the nuclei are perpendicular to the axis of the ribbon or the trabeculae. Strumal carcinoid is characterized by the coexistence of carcinoid and thyroid tissue. Mucinous carcinoid, the least common type of ovarian carcinoid, resembles a goblet cell carcinoid arising in the appendix. It must be distinguished from a Krukenberg tumor and has been subdivided into well differentiated mucinous carcinoid, atypical mucinous carcinoid, carcinoma arising in mucinous carcinoid, and mixed mucinous carcinoid and other carcinoid types [ 15 , 46 - 51 ]. Primary ovarian carcinoid tumors confined to the ovary and treated with surgery alone are expected to have an excellent overall outcome [ 47 ]. Robboy et al . [ 48 ] reported two recurrences in 48 cases of primary insular carcinoid of the ovary and calculated a survival rate of 95% and 88% at 5 and 10 years, respectively. Mucinous carcinoids might have more aggressive behavior than other types of ovarian carcinoids, particularly if associated with atypical features [ 50 ]. Some ovarian AC cases have been misdiagnosed as ‘carcinoid’ or ‘strumal carcinoid [ 52 , 53 ].’ Kurabayashi et al . [ 53 ] reported a case of stage IA strumal ‘carcinoid’ tumor showing multiple bone and breast metastases 3.5 years postoperatively. Histologic features of the case were consistent with AC. The term ‘AC’ is not included in the past or current WHO classification of ovarian NETs [ 51 , 54 ]. Division into four subcategories (insular, trabecular, strumal, and mucinous) instead of TC and AC has complicated the comparison between follow-up data from ovarian carcinoids and carcinoids from other organs. Further study is clearly necessary to better understand the clinical course of ovarian carcinoids. Carcinoid tumors are immunoreactive to neuroendocrine markers, such as chromogranin, synaptophysin, and CD56. Chromogranin and synaptophysin are excellent discriminatory neuroendocrine markers for a carcinoid tumor. In a study of 42 carcinoid tumors, chromogranin, synaptophysin, and CD56 were expressed in 100%, 98%, and 57% of samples, respectively. CD56 was also positive in 48% of Sertoli cell tumors and in 25% of endometrioid carcinomas. CD56 is neither highly sensitive nor specific enough for neuroendocrine lineage and is of limited value in the identification of ovarian carcinoid tumors [ 55 ]. Various peptide hormones such as serotonin, gastrin, pancreatic polypeptide, glucagon, vasoactive intestinal peptide, prolactin, and somatostatin can be detected in about 25% of cases [ 56 ]. Estrogen receptors and progesterone receptors are usually negative in carcinoid tumors. CDX2, TTF-1, PAX8, and cytokeratins 7 and 20 are used for the discrimination of primary and metastatic carcinoids. As ovarian carcinoid can arise from various teratomatous elements, such as the midgut, hindgut, and respiratory epithelium, the interpretation of immunohistochemical staining should be conducted very prudently [ 57 , 58 ]. Two types of clinically and histologically distinct small cell carcinoma of the ovary have been described: small cell carcinoma, hypercalcemic type (SCCOHT), and small cell carcinoma, pulmonary type (SCCOPT). Clinical features favoring SCCOPT include older age and the absence of hypercalcemia. Histologically, SCCOPT shows characteristic features of SCNEC, such as finely dispersed chromatin, inconspicuous nucleoli, and nuclear molding, whereas SCCOHT has clumped chromatin, prominent nucleoli, and the presence of larger cells in about 50% of cases. Follicle-like spaces are frequently seen in the hypercalcemic type, but are lacking in the pulmonary type. Ovarian surface epithelial tumors are present in more than 50% of pulmonary type tumors, but are absent in the hypercalcemic type [ 59 ]. SCCOPT is a highly aggressive SCNEC and must be distinguished from metastatic small cell carcinoma from other locations, particularly the lung. Usually, bilateral ovarian involvement is a substantial clue for a metastatic tumor, but is also seen in 45% of SCCOPTs. As this tumor shows variable TTF-1 expression, expression of this marker cannot reliably distinguish SCCOPT from pulmonary small cell carcinoma [ 60 ]. These tumors are probably of surface epithelial-stromal origin because they are frequently associated with surface epithelial tumors. In a previous study, eight of 11 SCCOPT cases were associated with surface epithelial tumors [ 59 ]. Rare cases arising in an ovarian teratoma have been reported [ 61 , 62 ]. A diagnosis of SCCOPT can be made in the absence of neuroendocrine marker positivity if the morphologic appearance is typical SCNEC. Perinuclear dot-like cytokeratin 20 staining has been reported in this tumor, as in Merkel cell carcinoma and salivary gland small cell carcinoma [ 63 ]. LCNECs of the ovary have also been reported as non-small cell NEC, undifferentiated non-small cell carcinoma, and NEC, non-small cell type [ 64 - 67 ]. Primary ovarian LCNEC is extremely rare and has a worse prognosis than usual ovarian carcinomas, even when the diagnosis is made at an early stage. In most cases, there are concomitant ovarian surface epithelial tumors, such as mucinous borderline tumor or mucinous carcinoma, endometrioid carcinoma, serous carcinoma, unclassified high-grade carcinoma, or teratoma [ 64 - 67 ]. The NEC component varies from 10% to 90% when it is combined with an epithelial tumor or teratoma. The presence of an NEC component in an otherwise usual epithelial tumor should be reported because of the potential negative prognostic impact of NEC histology. Generally speaking, a neuroendocrine component might have a prognostic impact when it reaches a certain proportion of the overall tumor. The percentage of NEC component that is necessary to confer a prognosis worse than that of the accompanying epithelial tumor is not clear [ 67 ]. Primary pure LCNEC of the ovary is very rare [ 68 , 69 ]. LCNECs probably arise from the neuroendocrine cells present in surface epithelial-stromal tumors or germ cell tumors [ 70 ]. In a case of mixed LCNEC and mucinous borderline ovarian tumor, clonality analysis using the human androgen receptor gene showed monoclonality in both components, suggesting that the LCNEC might have arisen from the mucinous epithelial tumor [ 71 ]. The common coexistence of NEC and epithelial tumors, along with the monoclonality of the two components, implies a common cellular origin of the neuroendocrine and epithelial components [ 17 , 72 ]. A case of LCNEC associated with serous carcinoma revealed a different pattern of microsatellite instability in both components. A dual origin with concomitant transformation of epithelial cells and neuroendocrine cells might be possible in that case [ 65 ]. In one previous study, ovarian LCNECs were misdiagnosed as dysgerminoma, sex cord tumor, or other types of carcinoma in eight of 11 cases [ 64 ]. Attention to the histologic features of neuroendocrine differentiation and the use of immunohistochemical stains are necessary to resolve this potential underrecognition [ 64 ]. CD56 is known to be a less specific neuroendocrine marker compared to chromogranin and synaptophysin [ 11 , 20 , 55 ]. However, chromogranin and synaptophysin can be detected in ovarian Sertoli cell tumors, Sertoli-Leydig cell tumors, and endometrioid tumors, which could be a potential pitfall resulting in the misdiagnosis of NETs [ 55 , 73 ]. LCNEC associated with serous carcinoma has rarely been reported in the ovary, as in the endometrium [ 65 , 74 ]. Immunohistochemical evidence of neuroendocrine differentiation in ovarian serous carcinoma is more frequent than morphological evidence. Taube et al . [ 75 ] reported synaptophysin and chromogranin expression in 6.7% and 20.7% of high-grade ovarian serous carcinomas, respectively, and found that patients with synaptophysin expression in more than 20% of tumor cells had a significantly shorter survival time than those with 0% to 20% positive cells. SCCOHT of the ovary is a highly aggressive neoplasm affecting young females and is associated with paraneoplastic hypercalcemia in two-thirds of cases. Microscopic findings show a sheet-like arrangement of cells punctured by follicle-like spaces. The tumor cells are typically small and round with hyperchromatic nuclei and brisk mitotic activity. A large cell component with moderate to abundant eosinophilic cytoplasm is seen in about 50% of cases. Tumors composed exclusively of large cells are designated the ‘large cell variant’ of SCCOHT. The large cells can have a rhabdoid appearance. Differential diagnoses include juvenile and adult granulosa cell tumors, high-grade serous carcinoma, desmoplastic small round cell tumor, dysgerminoma, Ewing sarcoma, primitive neuroectodermal tumor, neuroblastoma, round cell sarcoma, high-grade endometrial stromal sarcoma, undifferentiated carcinoma, lymphoma, melanoma, and SCNEC [ 76 ]. Ovarian SCCOHT is often misunderstood or confused with a subtype of NEC due to the usage of the term ‘small cell carcinoma’. This tumor is included in a miscellaneous category in the 2014 WHO classification of female reproductive organs [ 77 ]. Recently, somatic and germline SMARCA4 mutations accompanied by the loss of BRG1 protein expression in immunohistochemistry have been described in SCCOHTs [ 78 - 81 ]. To date, the diagnosis of SCCOHT has been made on the basis of microscopic findings without any specific immunohistochemical markers. The loss of BRG1 protein expression is confirmed to be a useful marker for diagnosing SCCOHT, although the interpretation should be conducted carefully due to the possible heterogeneity and variable intensity of this immunostaining [ 82 ]. BRG1 and INI-1 are members of the SWI/SNF complex and are involved in chromatin remodeling. The alternative expression of INI-1 and BRG1 is regarded as a molecular hallmark of malignant rhabdoid tumor. The histological resemblance between SCCOHT and malignant rhabdoid tumor became a trigger to evaluate INI-1 and BRG1 immunostaining in SCCOHT. In addition to the lack of BRG1 immunoreactivity, SCCOHT cases also showed retained INI-1 expression [ 78 , 82 , 83 ]. Currently, SCCOHT is considered to be an ovarian malignant rhabdoid tumor [ 78 , 82 , 83 ].