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Objectives The aim of this study was to investigate the value of [18F]fluoro-2-deoxy-D-glucose (18F-FDG) PET/computed tomography (CT) to detect recurrent cervical neuroendocrine carcinoma and its subsequent impact on patient management. Methods A total of 25 patients who had undergone 30 18F-FDG PET/CT studies for suspected recurrent cervical neuroendocrine carcinoma (18 small cells, 2 large cells, 1 atypical carcinoid, and 4 unclassified) were retrospectively analyzed. The findings of the PET/CT images were compared with the histopathologic results in 8 scans and with clinical follow-up in 22 scans. Results Of the 30 PET/CT studies, 63.3% (19/30) were positive for recurrence while 36.7% (11/30) were negative. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 18F-FDG PET/CT for detecting recurrent disease of cervical neuroendocrine carcinomas were 90.0, 90.0, 94.7, 81.8, and 90.0%, respectively. Metastasis to distant organs was the most common (89.4%), followed by lymph node recurrence (52.6%). Lungs were the most frequent site of distant metastasis (63.1%). 18F-FDG PET/CT findings led to the change of the management in 10 out of 25 patients (40%) by introducing the use of previously unplanned therapeutic procedures. Conclusions 18F-FDG PET/CT is an efficient technique for detecting recurrent cervical neuroendocrine carcinoma, and may thus contribute to improving patient management.

Highlights • The coexistence of cervical cancer and pelvic organ prolapse is a rare scenario. • This is the first report of a cervical neuroendocrine cancer in a prolapsed uterus. • A pessary was used to optimize the accuracy and reproducibility of the target volume position during chemoradiation., Background The coexistence of cervical cancer and pelvic organ prolapse represents a rare clinical scenario. Small cell neuroendocrine histology likewise represents only 0.9–1.5% of all invasive cervical cancers. There is no consensus regarding the optimal management of patients with concomitant locally advanced cervical cancer and pelvic organ prolapse. Case summary The patient was a 32-year old woman with an 8-cm fungating cervical mass extruding from the introitus. Biopsy was consistent with small cell neuroendocrine carcinoma. Examination showed stage IIIC1r cervical cancer with stage IV pelvic organ prolapse. After manual reduction, a pessary was used to optimize target volume reproducibility during definitive chemoradiation. The patient was treated using cisplatin and etoposide chemotherapy with intensity modulated radiation therapy followed by intracavitary brachytherapy. The patient had no clinical evidence of disease and recurrence of symptomatic prolapse one year after treatment completion. Conclusion This is the first reported case of a cervical neuroendocrine carcinoma in a prolapsed uterus, and the youngest patient in literature to have concomitant cervical cancer and pelvic organ prolapse. The use of a pessary for optimizing target volume reproducibility during definitive chemoradiation is a viable option in managing this rare case scenario.

Neuroendocrine cervical cancer is a rare subtype of cervical cancer with a highly aggressive malignancy. This study was conducted to analyse the human papillomavirus (HPV) infection and molecular abnormalities in Vietnamese neuroendocrine carcinomas of the uterine cervix. HPV genotyping and p53 mutations were examined using polymerase chain reaction (PCR)-based direct sequencing. Mutations of epidermal growth factor receptor (EGFR), Kirsten rat sarcoma (KRAS), neuroblastoma RAS viral oncogene homolog (NRAS) and v-Raf murine sarcoma viral oncogene homolog B (BRAF) were identified using commercial kits. Four high-risk HPV genotypes were identified in 26 (86.7%) out of a total of 30 tumours. The prevalence of HPV 16, 18, 31 and 45 was 20.0%, 50.0%, 20.0% and 36.7%, respectively. Overexpression of p16INK4a was observed in 93.3% of cases and was significantly correlated with high-risk HPV infections. Furthermore, p53 and NRAS mutations were detected in five (16.7%) and one (3.3%) cases, respectively, whereas no EGFR, KRAS or BRAF mutations were observed. These results demonstrate that high-risk HPV infection may be an important oncogenic factor for the development and progression of cervical neuroendocrine carcinoma.

Neuroendocrine carcinoma is a rare tumor in the uterine cervix with a dismal prognosis. Clinically, it is difficult to differentiate from other cervical malignancies. Clinical presentation varies from vaginal bleeding, discharge per vaginum and cervical mass. For better clinical outcomes, it is vital to diagnose promptly and accurately. We report a 35-year-old female presented with whitish discharge per vaginum and lower abdominal pain for six months. Per speculum reveals an irregular, firm mass measuring 4x3 cm involving both the cervical lips, which turned out to a small cell neuroendocrine carcinoma.

AimsTo explore the expression of secretagogin (SCGN) in neuroendocrine carcinoma of the uterine cervix and analyse its relationship with clinicopathological characteristics and prognosis.MethodsFrom January 2010 to December 2017, 44 patients with cervical neuroendocrine carcinoma undergoing surgery were included in the study group, and 55 patients with cervical non-neuroendocrine carcinoma (including 30 cases of cervical squamous cell carcinoma and 25 cases of cervical adenocarcinoma) undergoing surgery were included in the control group. Immunohistochemical staining of SCGN was performed in both groups and compared with three common neuroendocrine markers, chromogranin A, synaptophysin (Syn) and CD56 in the study group. Detailed clinicopathological data of the two groups were analysed, and the patient survival in the study group was followed up.ResultsThe positive expression of SCGN in cervical neuroendocrine carcinoma, cervical adenocarcinoma and squamous cell carcinoma was 65.9% (29/44), 8% (2/25) and 0%, respectively. The positive expression of SCGN in cervical neuroendocrine carcinoma was significantly higher than that in cervical adenocarcinoma and squamous cell carcinoma (χ2=44.5, p0.05 for all). The intensity of SCGN staining in patients with cervical neuroendocrine carcinoma with lymph node metastasis was significantly higher than that in patients without lymph node metastasis (p=0.020). However, there was no significant association between SCGN expression and survival among patients with cervical neuroendocrine carcinoma (p=0.633).ConclusionsSCGN is a new neuroendocrine marker for cervical neuroendocrine carcinoma, whose expression correlates with lymph node metastasis.

Objective: To present a case of Cushing syndrome caused by a rare, ectopic, adrenocorticotropic hormone (ACTH)-secreting neuroendocrine small cell carcinoma of the cervix.Methods: A differential diagnosis was considered in a young female with ectopic ACTH-dependent Cushing syndrome.Results: A 35-year-old female presented with multiple complications of Cushing syndrome including hypertension, diabetes mellitus, weight gain, and profound lower-extremity weakness. Serum ACTH was elevated and dexamethasone suppression testing with both 1 mg and 8 mg failed to suppress cortisol. Pituitary magnetic resonance imaging and computed tomography of the adrenals were negative. Positron emission tomography and computed tomography revealed a 5.4 × 5.3-cm hypermetabolic pelvic mass with metastases to the lungs. Cervical biopsy confirmed small cell carcinoma of the cervix. The patient underwent1 round of chemotherapy however later passed away due to septic shock and multiple organ failure.Conclusion: Neuroendocrine small cell carcinoma of the cervix is a rare presentation of Cushing syndrome and should be considered in the differential diagnosis of a young female presenting with ACTH-dependent hypercortisolism.Abbreviations: ACTH = adrenocorticotropic hormone;CT = computed tomography

Neuroendocrine carcinoma represents about 1% all cervical cancers accounting for 100-200 diagnoses annually in the USA. Although it is uncommon, it is an aggressive histologic subtype of this otherwise favorable disease. To date, there are no prospective studies or randomized trials specific to this disease to guide standard of care management. Published literature consists of small case series mostly describing single-institution experiences. The Society of Gynecologic Oncology and Gynecologic Cancer InterGroup have issued consensus guidelines about the treatment of this disease based on the existing retrospective literature and expert opinion. Ongoing research is focused on further clarifying the best treatment regimen and defining molecular alterations of these tumors that can be exploited by novel treatment mechanisms. The objective of this manuscript is to describe this entity, review the literature, summarize current treatment recommendations, and propose possible research efforts for women with neuroendocrine cervical cancer.

Reported cases of metastases to the placenta are uncommon, and maternal transmission of tumor to the fetus is even more infrequent. However, vertical transmission of tumor can occur and should be considered as a potential etiology of malignancy in newborns and infants born to mothers with a history of cancer during gestation. Here, we present the imaging findings and clinical course of an unusual case of maternal cervical neuroendocrine carcinoma presenting as bilateral petrous temporal bone lesions in an infant.

Endocervical adenocarcinomas (ECAs) uncommonly metastasize to the ovary; however, when they do they sometimes closely mimic a mucinous/endometrioid ovarian primary tumor. Here, 2 cases of mixed moderately differentiated ECA and high-grade cervical neuroendocrine carcinoma in which the ECA component metastasized to the ovary have been delineated and reported. In both cases, the primary tumor and the metastatic tumor were diffusely positive for p16 and high-risk human papillomavirus. Although similar to previously reported cases of adenocarcinoma in situ and invasive ECAs with ovarian involvement, none of the cases reported to date had concurrent neuroendocrine carcinoma with metastasis of the lower-grade component. In this respect, our cases are unique. The presence of lower uterine segment involvement in both cases and high-risk human papillomavirus positivity in the primary and metastatic tumors suggest a metastatic process, perhaps through transtubal spread, rather than independent primaries.

Objectives: To evaluate the clinicopathologic correlation and prognostic value of HPV18 DNA viral load in patients with early-stage cervical neuroendocrine carcinoma (NECA). Methods: Formalin-fixed, paraffinembedded tissue of cervical NECA patients with known HPV18 infection and clinicopathologic data including follow-up results were collected. The HPV18 DNA load was assessed with quantitative PCR targeting the HPV18 E6E7 region. Results: Twenty-one patients with early-stage (IB-IIA) cervical NECA were identified. HPV18 DNA viral load ranged from 0.83 to 55,174 copies/cell (median 5.90). Disease progression, observed in 10 cases (48%), was not significantly associated with any clinicopathologic variables. However, the group of patients with progressive disease tended to have a higher rate of pelvic lymph node metastasis (50% versus 9%, p=0.063) and a lower median value of HPV18 DNA viral load (4.37 versus 8.17 copies/cell, p=0.198) compared to the non-recurrent group. When stratified by a cut-off viral load value of 5.00 copies/cell, the group of patients with viral load ≤5.00 copies/cell had a significantly shorter disease-free survival than the group with viral load >5.00 copies/cell (p=0.028). The group with a lower viral load also tended to have a higher rate of disease progression (75% versus 31%, p=0.080). No significant difference in the other clinicopathologic variables between the lower and higher viral load groups was identified. Conclusion: HPV18 DNA viral load may have a prognostic value in patients with early-stage NECA of the cervix. A low viral load may be predictive of shortened disease-free survival in these patients.

Carcinoma meningitis with uterine cervical cancer is an extremely rare event. We present the clinicopathologic characteristics and diagnostic imaging findings of a patient with advanced small-cell neuroendocrine carcinoma of the cervix who had developed carcinoma meningitis during systematic chemotherapy.

Objective: To evaluate the expression and prognostic significance of survivin, CD117, and C-erbB-2 in neuroendocrine carcinoma of the uterine cervix. Materials and Methods: Immunohistochemical stains of survivin, CD117, and C-erbB-2 were evaluated in 100 cases of cervical neuroendocrine carcinoma. The findings were correlated with clinicopathologic variables and disease-free survival. Results: Expressions of survivin, CD117, and C-erbB-2 were detected in 27.0%, 12.0%, and 2.0% of the cases, respectively. Survivin-positive patients had a significantly younger mean age than the survivin-negative group (P = 0.033). In early-stage cases, tumor recurrence was significantly associated with lymph node metastasis (P = 0.005), depth of invasion (P = 0.028), and the presence of lymphovascular space invasion (P = 0.031) but not with the expression of survivin or CD117. Subgroup analysis in early-stage cases without lymph node metastasis (n = 32) showed that only survivin expression had a significant association with decreased disease-free survival (P = 0.041). Conclusions: Survivin expression may be a prognostic indicator for survival in early-stage neuroendocrine carcinoma of the uterine cervix without lymph node metastasis. Adjuvant survivin-targeted therapy may have potential benefit in patients with this tumor.

Cervical small cell neuroendocrine carcinoma (SCNEC) and large cell neuroendocrine carcinoma (LCNEC) are uncommon but highly aggressive neoplasms. From a diagnostic point of view, there may be problems both in distinguishing these from other neoplasms and in confirming a cervical origin. This is important as management is critically dependent on the correct histologic diagnosis. We undertook a detailed immunohistochemical analysis of a relatively large series of primary cervical SCNEC (n=13) and LCNEC (n=8). Cases were stained with AE1/3, chromogranin, CD56, synaptophysin, PGP9.5, TTF1, p16, p63, CK7, CK20, neurofilament, and CD99. CK20 and neurofilament staining was undertaken to investigate whether some of these neoplasms might exhibit a Merkel cell immunophenotype and CD99 staining to assess whether there is immunohistochemical overlap with neoplasms in the Ewing family of tumors (EFT). For all markers, staining was classified as negative, 1+ (10% cells immunoreactive), 2+ (10 to 50% cells immunoreactive), or 3+ (50% cells immunoreactive). Eleven and 6 SCNEC and LCNEC, respectively were positive with AE1/3. Chromogranin, CD56, synaptophysin, and PGP9.5 were positive in 11, 19, 19, and 9 cases, respectively. Altogether 15 cases (71%) (11 SCNEC, 4 LCNEC) exhibited nuclear positivity, often diffuse, with TTF1. All but 1 case was diffusely positive with p16. p63 was positive in 9 cases, including 5 with diffuse nuclear immunoreactivity. Ten and 4 neoplasms were positive with CK7 and CK20, respectively. Neurofilament was positive in 7 tumors. The 4 neoplasms that were CK20 positive were stained with the monoclonal antibody CM2B4, generated against an antigenic epitope on the Merkel cell polyomavirus T antigen; all were negative. CD99 was positive in 6 cases. In 2 cases, adjacent foci of adenocarcinoma in situ (AIS) contained scattered individual chromogranin positive cells, raising the possibility that some cervical neuroendocrine carcinomas arise from neuroendocrine cells in AIS. Four of 13 cases of pure AIS also contained scattered chromogranin positive cells. Our results illustrate that a proportion of cervical neuroendocrine carcinomas are negative with broad spectrum cytokeratins and some of the commonly used neuroendocrine markers. TTF1 positivity is extremely common and may be a useful marker of a neuroendocrine carcinoma. It is of no value in exclusion of a pulmonary primary. p16 is almost always positive in cervical neuroendocrine carcinomas, possibly owing to an association with oncogenic human papillomavirus, although other mechanisms of expression are also possible. Cervical neuroendocrine carcinomas may be p63 positive, illustrating that this marker is not specific for squamous differentiation. CK20 and neurofilament positivity in some cervical neuroendocrine carcinomas is in keeping with a Merkel cell immunophenotype, similar to that described in SCNECs in other organs. However, the absence of staining with CM2B4 argues against a true Merkel cell tumor. CD99 staining in a cervical neuroendocrine carcinoma should not result in misdiagnosis as a neoplasm in the Ewing family of tumors.

Neuroendocrine carcinomas of the uterine cervix are rare tumors with early metastases, highly aggressive clinical behavior, and poor clinical outcome. Several adhesion molecules like cadherins have been tested in an attempt to explain their unique characteristics. Cluster differentiation 44 (CD44) is a widely expressed cell surface glycoprotein that serves as an adhesion molecule in cell-to-substrate and cell-to-cell interaction. We have examined the expression of the standard CD44 (CD44s) by immunohistochemical stains in the paraffin-embedded cervical neoplasm tissue of 17 cases of primary cervical neuroendocrine carcinoma, 28 cases of cervical adenocarcinoma, and 50 cases of cervical squamous cell carcinoma. Loss of CD44s expression was found in 16 of 17 neuroendocrine carcinomas, 14 of 28 adenocarcinomas, and three of 50 squamous cell carcinomas. The differences were statistically significant. We also examined immunohistochemically the expression of the BRG-1 subunit of the SWI-SNF complex, which has been reported to regulate the expression of CD44 in all cases. Loss of BRG-1 expression was observed in 12/16, 6/14, and 1/3 CD44s-negative neuroendocrine carcinomas, adenocarcinomas, and squamous cell carcinomas, respectively. This study suggests that loss of the CD44s molecule may imply special biological behaviors of cervical neuroendocrine carcinomas, and loss of expression of BRG-1 may contribute to this.

Fourteen primary cervical neoplasms with light microscopic features of neuroendocrine carcinoma were studied. Two were of intermediate cell type (IC), resembling the pulmonary atypical carcinoid; seven were small cell type (SC), analogous to pulmonary oat cell carcinoma; two were SC with foci of IC; three were SC with foci of squamous or adenocarcinoma. Four patients were Stage I, five were Stage II, two were Stage III, and three were Stage IV. One patient (Stage I) underwent hysterectomy and has completed radiation therapy. Two patients underwent radical hysterectomy and chemotherapy. One received radiation and chemotherapy; one received only chemotherapy; nine received radical radiation therapy. One patient (Stage I) is alive and well 10.5 years later; one (Stage II) died of other causes 24 months after diagnosis. One other is alive with the disease 12 months postdiagnosis. Eleven died secondary to tumor, four to 33 months (mean 14, median 12.5 months) after diagnosis. There was no significant difference in survival between IC and SC types, either mixed or pure. Cervical neuroendocrine carcinomas are biologically aggressive neoplasms, regardless of histologic type.

Somatostatin and its analogues inhibit the growth of various kinds of endocrine and exocrine cells via the somatostatin receptor (SSTR). Expression of SSTR2A has been reported in many well-differentiated neuroendocrine tumors and small numbers of poorly differentiated neuroendocrine carcinomas. SSTR2A-positive neuroendocrine tumors may be treatable by SS analogues. Uterine cervical neuroendocrine carcinoma is generally associated with poor prognosis. We examined the expression of SSTR2A and other neuroendocrine markers [neural cell adhesion molecule (NCAM), chromogranin A, and synaptophysin] by immunohistochemical methods in seven neuroendocrine tumors of the uterine cervix: five small cell carcinomas and two large cell neuroendocrine carcinomas. SSTR2A was expressed in one small cell carcinoma and two neuroendocrine large cell carcinomas. The cell membrane of cells in these carcinomas showed strong immunohistochemical reactivity for SSTR2A. SSTR2A-positive cases are also frequently positive for the expression of chromogranin A. Treatment with SSTR2A may be effective for endocrine tumors. The results indicate the usefulness of SSTR2A analogs for the treatment of some uterine neuroendocrine carcinomas.