Emerging Therapeutic Concepts and Latest Diagnostic Advancements Regarding Neuroendocrine Tumors of the Gynecologic Tract

Abstract

Neuroendocrine neoplasms (NENs) are particularly rare in all sites of the gynecological tract and include a variety of neoplasms with variable prognosis, dependent on histologic subtype and site of origin. Following the expert consensus proposal of the International Agency for Research on Cancer (IARC), the approach in the latest World Health Organization (WHO) Classification System of the Female Genital Tumours is to use the same terminology for NENs at all body sites. The main concept of this novel classification framework is to align it to all other body sites and make a clear distinction between well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). The previous WHO Classification System of the Female Genital Tumours featured more or less the same principle, but used the terms ‘low-grade neuroendocrine tumor’ and ‘high-grade neuroendocrine carcinoma’. Regardless of the terminology used, each of these two main categories include two distinct morphological subtypes: NETs are represented by typical and atypical carcinoid and NEC are represented by small cell neuroendocrine carcinoma (SCNEC) and large cell neuroendocrine carcinoma (LCNEC). High-grade NECs, especially small cell neuroendocrine carcinoma tends to be more frequent in the uterine cervix, followed by the endometrium, while low-grade NETs usually occur in the ovary. NENs of the vulva, vagina and fallopian tube are exceptionally rare, with scattered case reports in the scientific literature.

Neuroendocrine Neoplasms of the Gynecologic Tract

“…NENs of the ovary are classified into ovarian carcinoids (grade 1) and ovarian NEC (grade 3). Except for the ovaries, the terms carcinoid and atypical carcinoid were removed from the nomenclature; instead, these correspond to NETs in the updated classification [ 8 , 19 ].…”

“…Elevated neuron-specific enolase ranging from 154–370 U/l has been observed in the literature depending on the stage of the disease and the tested subjects [ 22 , 23 ]. Studies have reported that the levels of neuron-specific enolase were decreased with treatment, yet recurrences were observed within a year [ 19 , 24 , 25 ]. The sensitivity and specificity of neuron-specific enolase in differentiating neuroendocrine from non-neuroendocrine tumors are 39–43% and 65–73%, respectively [ 26 ].…”

Extrapulmonary Neuroendocrine Carcinomas: Current Management and Future Perspectives

“…According to the updated fifth edition of the WHO classification of gynecologic NENs, grade 3 tumors are poorly differentiated high-grade NECs that are further classified into SCNECs and LCNECs [64].…”

Positive clinical outcomes following therapy with programmed cell death protein 1/programmed cell death ligand 1 inhibitors in neuroendocrine carcinoma of the cervix

“…Furthermore, there are mixed neuroendocrine-non neuroendocrine neoplasms (MiNENs). Among these, SCNEC is the most frequent type of NECC ( Georgescu et al, 2021 ).…”

“…In the future, extensive studies are needed to demonstrate this viewpoint. Most NECC are strongly and diffusely positive for p16 because of high-risk HPV, particularly HPV16 and HPV18 ( Castle et al, 2018 ; Georgescu et al, 2021 ). Xing et al (2018) performed an immunohistochemical evaluation of 10 SCNEC cases and found that all tumors exhibited diffuse/strong p16 expression.…”