Extrapulmonary Neuroendocrine Carcinomas: Current Management and Future Perspectives.

Neuroendocrine carcinomas (NECs) are poorly differentiated and highly aggressive epithelial neuroendocrine neoplasms. The most common primary site is the lung, but they may arise in every organ. Approximately 37% of extrapulmonary NECs (EP-NECs) occur in the gastroenteropancreatic (GEP) tract, followed by the genitourinary (GU) system and gynecological tract. As a result of their rarity, there is scant evidence to guide treatment recommendations, and a multidisciplinary approach is essential for the management of such patients. Platinum-based chemotherapy currently represents the standard of care for EP-NECs of any site, mirroring the management of small-cell lung cancer (SCLC), but further approaches are still under investigation. Indeed, ongoing trials evaluating targeted therapies, immune checkpoint inhibitors (ICIs), and radionuclide therapy could provide potentially breakthrough therapeutic options. Given the relative dearth of evidence-based literature on these orphan diseases, the aim of this review is to provide an overview of the pathology and current treatment options, as well as to shed light on the most pressing unmet needs in the field.

Primary Vaginal Epithelioid Angiosarcoma: A Case Report and Literature Review of a Rare Neoplasm.

Angiosarcoma is a malignant neoplasm showing morphological or immunophenotypic evidence of endothelial differentiation with either a vascular or lymphatic origin. It has a strong predilection for skin and deep soft tissue. Angiosarcomas of the gynecologic tract are very uncommon, and very few cases have been described in medical literature up to this day. Primary vaginal angiosarcomas with no prior history of radiation are exceedingly rare. The epithelioid subtype of primary vaginal angiosarcomas is even more uncommon. Here we present a rare case of an epithelioid subtype of primary vaginal angiosarcoma in a 47-year-old woman with no prior history of radiation who presented with pelvic pain, malodorous vaginal discharge, and a vaginal mass.

Role of Fine Needle Aspiration Cytology in the Diagnosis of Gynecologic Tumors.

BACKGROUND: The tumors involving the gynecologic tract encompass a wide range of lesions including those of epithelial, mesenchymal, sex cord-stromal, and germ cell origin. Amongst the carcinomas of tubo-ovarian origin, high-grade serous carcinoma is the most common malignancy. The primary role of fine needle aspiration (FNA) cytology in the management of gynecologic tract malignancies is in the diagnosis of their recurrences/metastases. In patients presenting with advanced disease, the cytology specimen may be the initial or the only sampling performed before the initiation of treatment. SUMMARY: This review will discuss the cytologic findings of various gynecologic tract neoplasms with regard to their morphologic features, differential diagnoses, and the ancillary studies that can assist in their recognition. KEY MESSAGES: FNA cytology serves as a valuable tool in the diagnosis and management of gynecologic tract malignancies. However, making an accurate diagnosis of these entities, especially on limited cytology specimens, can be challenging. Awareness regarding the morphologic spectrum of these tumors, their potential mimics, and the ancillary studies that can be employed to refine their characterization, can assist in arriving at the correct diagnosis.

Cytologic features of gynecologic germ cell tumors and carcinomas exhibiting germ cell tumor differentiation.

BACKGROUND: In this study, the authors sought to describe the cytologic features of primary gynecologic germ cell tumors and carcinomas exhibiting germ cell differentiation because little information currently exists. METHODS: An institutional database search was performed to identify histologically confirmed gynecologic germ cell tumors and carcinomas with germ cell tumor differentiation. Available cytologic material was reviewed by three observers, and morphologic features were recorded in addition to patient age at original diagnosis, primary tumor site, site(s) from which the examined cytologic material was obtained, and the type of examined cytologic preparations. RESULTS: In total, 15 cytologic specimens from 12 women (aged 19-82 years) were identified and included touch preparations of core biopsies from various sites (n = 6), fine-needle biopsies (n = 2), pelvic washings (n = 1), ascitic fluids (n = 4), pelvic cyst fluid (n = 1), and endometrial aspirate (n = 1). Of the 12 patients, seven had primary gynecologic germ cell tumors, four had gynecologic (ovarian and endometrial) tumors exhibiting somatic yolk sac tumor-like differentiation, and the remaining patient had an intestinal-type adenocarcinoma arising within an ovarian teratoma. There was morphologic overlap among many of the cases, although cytoplasmic vacuolation/granular cytoplasm was seen in 75% of primary yolk sac tumors or carcinomas with yolk sac tumor differentiation, and dense/squamoid cytoplasm was seen in 100% of teratomatous elements that were sampled. CONCLUSIONS: Germ cell tumors and somatic neoplasms exhibiting germ cell tumor differentiation occurring in adult women share some cytologic features and may be difficult to distinguish from one another, although some tumor types showed characteristic cytomorphologic findings.

Cellular context determines DNA methylation profiles in SWI/SNF-deficient cancers of the gynecologic tract.

SWI/SNF (SWItch/Sucrose Non-Fermentable) complex deficiency has been reported in a wide variety of cancers and is often associated with an undifferentiated phenotype. In the gynecologic tract SWI/SNF-deficient cancers are diagnostically challenging and little is known about their cellular origins. Here we show that undifferentiated endometrial carcinoma (UDEC), SMARCA4-deficient uterine sarcoma (SDUS), and ovarian small cell carcinoma, hypercalcemic type (SCCOHT) harbor distinct DNA methylation signatures despite shared morphology and SWI/SNF inactivation. Our results indicate that the cellular context is an important determinant of the epigenetic landscape, even in the setting of core SWI/SNF deficiency, and therefore methylation profiling may represent a useful diagnostic tool in undifferentiated, SWI/SNF-deficient cancers. Furthermore, applying copy number analyses and group-wise differential methylation analyses including endometrioid endometrial carcinomas and extracranial malignant rhabdoid tumors, we uncover analogous molecular features in SDUS and SCCOHT in contrast to UDEC. These results suggest that SDUS and SCCOHT represent chromosomally stable SWI/SNF-deficient cancers of the gynecologic tract, which are within the broader spectrum of malignant rhabdoid tumors. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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

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.

Retrospective Analysis of Clinicopathological Features and Prognosis of Gynecological Small-Cell Carcinoma.

PURPOSE: Although rare, small-cell neuroendocrine carcinoma of the gynecologic tract (SCNCGT) is associated with poor prognosis. We analyzed the clinical characteristics, pathological features, treatment strategies, and prognosis in patients with SCNCGT. PATIENTS AND METHODS: We performed a retrospective data analysis of 34 patients with SCNCGT diagnosed and treated at our hospital between 2006 and 2018. Medical records were reviewed for pathological features, treatment methods, and outcomes of this disease. RESULTS: We included 34 patients who had small-cell neuroendocrine carcinoma of the endometrium (SCNCE; 7), ovary (SCNCO; 7), and cervix (SCNCC; 20). All patients with SCNCE underwent comprehensive surgery and six received postoperative chemotherapy. All patients with SCNCO received chemotherapy after surgery; six underwent comprehensive surgery and one underwent treatment only in the pelvic cavity. Sixteen patients with SCNCC underwent radical surgery and received chemotherapy, two of whom received simultaneous radiotherapy. The remaining four patients with SCNCC underwent comprehensive chemotherapy and radiation therapy. Among the 34 patients, 11 had vascular metastases, 15 had lymph node metastases, and seven exhibited positive margins. The median overall survival time among all patients was 23.18 months (range: 3-66 months). Death occurred in 18 cases (52.94%). Recurrence was observed in 13 cases (38.24%). The average time to recurrence was 15.78 months following treatment (range: 2-30 months). All 34 patients were evaluated for neuroendocrine markers. The immunohistochemical positive rates of synaptophysin, CD56, and chromogranin A were 73.5%, 64.7%, and 55.9%, respectively. CONCLUSION: The rates of metastasis and recurrence are high, and prognosis remains poor, even among patients with early-stage SCNCGT. Our data may aid in the development of reference standards for diagnosis and treatment.

The puzzle of gynecologic neuroendocrine carcinomas: State of the art and future directions.

Primary gynecologic neuroendocrine carcinomas (gNECs) are a heterogeneous spectrum of rare and highly aggressive neoplasms, accounting for about 2% of all gynecologic malignancies, which mostly resemble the small cell lung carcinoma (SCLC). Due to the lack of standardized treatment guidelines, their management poses a noteworthy clinical challenge. Currently, cumulative data retrieved from the management of SCLC and from retrospective studies supports a multimodality strategy, based on surgery, chemotherapy, and radiotherapy. Nevertheless, the prognosis remains poor and recurrences are extremely frequent. Hence, there is an urgent need for novel treatment options and promising molecular targets. Recently, there has been an increasing interest on the potential role of immune checkpoint inhibitors, especially in the recurrent setting. However, only scant evidence exists and there is still a long road ahead. A solid collaboration between gynecologists and oncologists worldwide is required to improve the treatment of these puzzling tumors.

Undifferentiated and dedifferentiated neoplasms of the female genital tract.

Undifferentiated neoplasms in the female gynecologic tract comprise two main groups-undifferentiated carcinoma, most common in the endometrium and ovary, and undifferentiated uterine sarcoma, although tumors with an undifferentiated appearance may occur in all gynecologic organs. Their differential diagnosis is broad and generous sampling, careful morphological evaluation, judicious use of immunohistochemistry, and in many cases, molecular testing is often essential in the diagnostic work-up. As some of these neoplasms fail to respond to conventional chemotherapy regimens and/or radiation therapy, targeted therapy may be valuable in treating these highly aggressive tumors, thus the importance of precise diagnosis. In this review we discuss the clinicopathological features of undifferentiated carcinoma, dedifferentiated carcinoma, and undifferentiated uterine sarcoma, followed by a comprehensive analysis of morphological mimickers. Finally, we briefly review ovarian and lower genital tract tumors with an undifferentiated histological appearance.

DICER1-associated embryonal rhabdomyosarcoma and adenosarcoma of the gynecologic tract: Pathology, molecular genetics, and indications for molecular testing.

Gynecologic sarcomas are uncommon neoplasms, the majority occurring in the uterus. Due to the diverse nature of these, the description of "new" morphological types and the rarity of some of them, pathological diagnosis and treatment is often challenging. Finding genetic alterations specific to, and frequently occurring, in a certain type can aid in the diagnosis. DICER1 is a highly conserved ribonuclease crucial in the biogenesis of microRNAs and mutations in DICER1 (either somatic or germline) have been detected in a wide range of sarcomas including genitourinary embryonal rhabdomyosarcomas (ERMS) and adenosarcomas. Importantly, DICER1-associated sarcomas share morphological features irrespective of the site of origin such that the pathologist can strongly suspect a DICER1 association. A review of the literature shows that almost all gynecologic ERMS reported (outside of the vagina) harbor DICER1 alterations, while approximately 20% of adenosarcomas also do so. These two tumor types exhibit significant morphological overlap and DICER1 tumor testing may be helpful in distinguishing between them, because a negative result makes ERMS unlikely. Given that germline pathogenic DICER1 variants are frequent in uterine (corpus and cervix) ERMS and pathogenic germline variants in this gene cause a hereditary cancer predisposition syndrome (DICER1 syndrome), patients diagnosed with these neoplasms should be referred to medical genetic services. Cooperation between pathologists and geneticists is crucial and will help in improving the diagnosis and management of these uncommon sarcomas.

A Study of Prognostic Factors of Chinese Patients with Gynecologic Tract Carcinosarcomas Prognosis of Gynecologic Carcinosarcomas.

BACKGROUND: Thinking of the rarity and malignancy of gynecologic tract carcinosarcomas (GTCS), the aim of the study was to investigate the possible predictors of relapse-free survival (RFS) and overall survival (OS) for GTCS patients. METHODS: We performed a retrospective cohort study of women with GTCS at our hospital between January 2009 and December 2013. We used the Kaplan-Meier method to calculate RFS and OS, and Cox regression analysis to define the survival effects of risk factors. RESULTS: A total of 45 GTCS patients were included in the study. The median follow-up time was 46 months. Cox regression analysis showed that lymph node metastasis was significantly associated with worse RFS (HR: 3.145; 95%CI: 1.181-8.378; P=0.022) and OS (HR: 4.065; 95%CI: 1.57-10.524; P=0.004). Pelvic lymphadenectomy had a favorable RFS (HR: 0.213; 95%CI: 0.057-0.796; P= 0.021). CONCLUSION: Lymph node metastasis significantly affected the prognosis of uterine carcinosarcoma. Pelvic lymphadenectomy could reduce the relapse rate of GTCS patients.

A clinical analysis of small-cell neuroendocrine carcinoma of the gynecologic tract: report of 20 cases.

OBJECTIVE: The aim of this retrospective observational study was to analyze the clinical and pathological characteristics of small-cell neuroendocrine carcinoma of the gynecologic tract (SCNCGT). METHODS: Twenty patients with SCNCGT were enrolled and their clinic-pathological features were analyzed. All patients were treated at the Beijing Obstetrics and Gynecology Hospital, Capital Medical University, China, and were followed up until December 31, 2017. RESULTS: (1) Patient characteristics: The incidence of SCNCGT was 0.3% (20/6578) of gynecologic cancer in our hospital from January 1, 2007, to December 31, 2017. The average age of the patients was 42.0 ± 11.8 (23-63 years). Out of 20 patients enrolled, seven (35.0%) had lymph node metastasis. Out of 17 patients treated with complete surgery, 14 (82.4%) had lymph-vascular space invasion. (2) Treatment: Eleven out of the 14 patients with small-cell neuroendocrine carcinoma of the cervix (SCNCC) were treated with radical surgery; all the 11 patients received chemotherapy and radiotherapy postoperatively. The remaining three patients received comprehensive chemotherapy and/or radiotherapy instead of radical surgery. The six patients who had one or the other type of SCNCGT (involving the ovary, endometrium, or vagina) were all treated with comprehensive surgery. (3) Prognosis: The follow-up time for the study ranged from 8 to 87 months. Three (15.0%) of the 20 patients were diagnosed with distant metastasis at the beginning of the study. Eight (40.0%) patients died as of December 31, 2017, while the other 12 patients were in follow-up. The average survival time was 43.6 months (16-77 months). CONCLUSION: SCNCGT is a highly malignant tumor characterized by rare morbidity, a propensity for metastasis, and poor prognosis. Comprehensive treatment may be a good approach to prolong survival in some patients.

Small Cell Carcinoma of the Vulva: Case Report.

Neuroendocrine tumours are rare in the gynaecologic tract, comprising approximately 2% of all gynaecological tumours. They have an aggressive behaviour and are a diagnostic and clinical challenge, due to their rarity and the lack of standardized therapeutic approaches. There are a few case reports. It is defined as a high-grade carcinoma exhibiting neuroendocrine differentiation. The authors describe the case of a 70-year-old woman, with vulvar neuroendocrine small cell carcinoma after superficial vulvectomy. The patient was submitted to a surgery with wide local excision and adjuvant radiation therapy. A review of the literature on this topic is also presented.

Vaginal fine-needle aspiration: A useful alternative to biopsy.

BACKGROUND: Vaginal fine-needle aspiration (FNA) is infrequently performed to assess palpable lesions. We perform the first multi-institutional study to evaluate this procedure. METHODS: We retrospectively reviewed vaginal FNAs performed at two institutions for the past 27 years. Clinical, cytological and histological data were reviewed and tabulated. RESULTS: We identified 43 specimens from 39 patients (mean age 56 years, range 18-86 years). Twenty four patients (62%) had prior malignancies from the following sites: gynecologic tract (22), bladder (1), and breast (1). Twenty four specimens were malignant, 18 were benign (including eight cases from patients with prior malignancy) and one was unsatisfactory. Of 28 FNA specimens from patients with a malignant history, 18 (64%) were positive for malignancy. The most common malignancies were metastatic ovarian carcinoma (50%), squamous cell carcinoma (25%), and uterine cancer (17%). Mean time to metastasis/recurrence was 16 months and was longest in patients with ovarian metastasis (26 months) compared to other malignancies (P = 0.002). The most common benign diagnoses were cysts (33%) and inflammation (22%). In 27 cases with histological correlation, there were 20 true positives, six true negatives and one false negative (sensitivity =95%, specificity =100%). Seven patients had a recent Pap test with two true positives, two true negatives, and three false negatives (sensitivity = 40%, specificity = 100%). CONCLUSION: Vaginal FNA is usually performed to rule out a secondary malignancy, often of ovarian origin. Vaginal metastases from extra-gynecologic sites are rare. FNA is both highly sensitive and specific and may be a safe and effective alternative to biopsy. Diagn. Cytopathol. 2016;44:665-669. © 2016 Wiley Periodicals, Inc.

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

Neuroendocrine tumors of the female reproductive tract are a heterogeneous group of neoplasms that display various histologic findings and biologic behaviors. In this review, the classification and clinicopathologic characteristics of neuroendocrine tumors of the female reproductive tract are described. Differential diagnoses are discussed, especially for non-neuroendocrine tumors showing high-grade nuclei with neuroendocrine differentiation. This review also discusses recent advances in our pathogenetic understanding of these disorders.

Neuroendocrine Tumors of the Female Reproductive Tract: A Literature Review

Neuroendocrine tumors of the female reproductive tract are a heterogeneous group of neoplasms that display various histologic findings and biologic behaviors. In this review, the classification and clinicopathologic characteristics of neuroendocrine tumors of the female reproductive tract are described. Differential diagnoses are discussed, especially for non-neuroendocrine tumors showing high-grade nuclei with neuroendocrine differentiation. This review also discusses recent advances in our pathogenetic understanding of these disorders.

Small cell carcinoma of the gynecologic tract: a multifaceted spectrum of lesions.

OBJECTIVE: Small cell carcinoma (SmCC) of the female genital tract constitutes a diagnostic and clinical challenge given its rarity and the lack of standardized therapeutic approaches. Here we review the morphological, clinical and molecular features of gynecologic SmCCs and discuss potential areas for future research. METHODS: Data for this review article were identified by searches of PubMed, EMBASE and the Internet using the search terms "small cell carcinoma" or "neuroendocrine carcinoma" and "gynecologic", "uterine cervix", "cervix", "uterus", "endometrium", "ovary", "vagina", "fallopian tube" or "vulva", and research articles published in English between 1972 and February 2014 were included. RESULTS: SmCCs arising from different organs within the gynecologic tract share the same histopathologic characteristics, which closely resemble those of small cell lung carcinoma. The expression of at least one immunohistochemical neuroendocrine marker is a common finding. The uterine cervix is the most frequent site of SmCC in the female genital tract. HPV infection seems to play a role in the development of cervical SmCC but not in cancers of other gynecologic sites. FIGO stage is an established prognostic factor, in particular in SCCs of the cervix. Irrespective of the site, SmCCs of the gynecologic tract display an aggressive clinical behavior with few reported long-term survivors. The therapeutic management includes surgery, radiotherapy and chemotherapy. CONCLUSIONS: Despite the potential differences in etiology and risk factors, SmCCs from different sites of the gynecologic tract have similar morphologic appearances and clinical behavior. Recent genomic analyses of small cell carcinoma of the lung have revealed potential driver genomic alterations. We posit that the comprehensive genomic characterization of gynecologic SmCCs may lead to the identification of markers that result in an improvement of diagnostic reproducibility of SmCCs of the gynecologic tract, and of molecular aberrations that may be exploited therapeutically in subgroups of the disease.

Neuroendocrine tumors of the gynecologic tract: select topics.

Tumors of the diffuse neuroendocrine cell system (DNES) may arise in any component of the gynecologic tract, including the vulva, vagina, cervix, endometrium, and ovary. Overall such tumors in the gynecologic tract are rare, constituting only 2% of gynecologic cancers, comprising a spectrum of tumors of variable biologic potential. Due to the rarity of such tumors, pathologists experience may be limited and these may present diagnostic challenges. Currently the nomenclature employed is still that of the pulmonary classification systems, carcinoid, atypical carcinoid, small and large cell neuroendocrine carcinoma that broadly correlates to low/grade 1, intermediate/grade 2, and high grade/grade 3 of the WHO gastroenteropancreatic neuroendocrine tumors classification. Furthermore in keeping with the lung, proliferative rate is assessed based on mitotic index rather than Ki-67 staining. In this review we cover select neuroendocrine tumors of the gynecologic tract.

Rabdomiosarcoma embrionario de cérvix uterino en mujer adulta / Embryonal rhabdomyosarcoma of uterine cervix in adult female

El rabdomiosarcoma (RMS) del tracto genital inferior es una patología maligna relativamente frecuente en la infancia aunque muy poco prevalente en la edad adulta. Tan solo suponen el 2-4 por ciento de todos los sarcomas de partes blandas. Se trata de una neoplasia derivada de células progenitoras de miocitos de músculo estriado en distinto grado de diferenciación. En un elevado número de casos, el cuadro se presenta como un pólipo endocervical de apariencia benigna, lo cual retrasa el diagnóstico. El correcto manejo del RMS de tracto genital es controvertido. Un esquema agresivo de tratamiento con cirugía, poliquimioterapia y radioterapia en pacientes seleccionadas, ha demostrado aumentar la supervivencia e incluso conseguir la curación en estadios precoces.

Rhabdomyosarcoma (RMS) of the lower genital tract is a common childhood malignancy but a rare tumor in female adults. It accounting for around 2-4 percent of soft-tissue sarcomas. It is a malignant neoplasm originating from myogenic progenitors cells that shows variable stages of skeletal muscle differentiation. In many cases, the tumor appears as a benign endocervical polyp and this delays the correct diagnosis. Optimal management of adult genital tract RMS is uncertain. Aggressive primary therapy with local excition, poliche-motherapy and radiotherapy in selected patients may result in prolonged survival and cure in early stages.