Gynecologic Cancer Intergroup (Gcig) Consensus Review for Carcinoid Tumors of the Ovary
Neuroendocrine Neoplasms of the Ovary: A Retrospective Written report of the Due north Eastern German Gild of Gynecologic Oncology (NOGGO)
Abstract
Background/Aim: Neuroendocrine neoplasms (NEN) of the female genital tract account for ii% of gynecological cancers. The aim of this written report was to share our experience of 11 primary neuroendocrine neoplasms of the ovary. Patients and Methods: All patients who presented and/or were treated at our Establishment with histologically-confirmed NEN of the ovary were included. Clinical information including tumor stage, diagnostic and therapeutic management and survival were assessed. Pathological specimens were critically reviewed. Results: We identified eleven patients with NEN of the ovary consisting of nine neuroendocrine cancers and two carcinoids. Median age was 55.9 years. NEN were by and large poorly differentiated (72.4%). Primary surgery was performed in all patients. Adjuvant chemotherapy was administered in 5 patients consisting of platinum-based regimens. Median overall survival was xx months. Decision: We propose a diagnostic algorithm for NEN of the ovary and discuss possible treatments according to FIGO stages. Patients should be included in multicenter studies whenever possible.
- Neuroendocrine cancer
- ovarian
- treatment algorithm
Neuroendocrine neoplasms (NEN) are a rare tumor entity arising from the diffuse neuroendocrine cell system. Nigh NEN are located in the gastroenteropancreatic system. Prognosis of this tumor entity is mainly dependent on the histological differentiation and grading, as measured by proliferative activeness. In a big written report performed earlier 5-yr survival was found to be 50.4% if all malignant tumors were included. The cornerstone of treatment is surgical resection. Systemic chemotherapy, employ of radio-nuclides and palliative surgery are effective methods for sure types of advanced neuroendocrine tumors. Cisplatinum in combination with etoposide is a very mutual chemotherapy regimen in poorly differentiated neuroendocrine carcinoma (1, 2). Carcinoids are a sub-grouping of slowly-growing neuroendocrine tumors that may be associated with production of vasoactive substances such every bit serotonin, that can lead to flushing and diarrhea, the then-called carcinoid syndrome. Symptom control in symptomatic carcinoid patients and tumor growth control can be achieved by somatostatin analogues such as octreotide or lanreotide (three, iv).
NEN with the principal in the female person genital tract are extremely rare and business relationship for less than ii% of gynecological cancers (v, vi). Nigh gynecological NEN are located in the uterine cervix and classified as pocket-sized-jail cell neuroendocrine cancer or in the ovary as carcinoids (5, seven). Symptoms observed at initial diagnosis in NEN of the female person genital tract are vaginal bleeding, vaginal discharge, pain, weight loss, constipation, hirsutism, cancerous ascites and sometimes ectopic hormone product such equally serotonin and vasopressin. The diagnosis of NEN mostly relies on histology including immunohistochemistry. Most common markers are chromogranin A, synaptophysin and neuron-specific enolase. Somatostatin receptor scintigraphy tin can help detect the primary in well-differentiated NEN (form I and II). There exist no treatment guidelines for NEN of the female person genital tract. Due to this, many patients are treated according to protocols used for epithelial cancer of the genital tract and non according to recommendations for NEN of eastward.g. the gastrointestinal organization. Neuroendocrine neoplasms of the ovary, for instance, are oft treated with debulking surgery followed by adjuvant chemotherapy with carboplatinum and paclitaxel in line with treatment standards for epithelial ovarian cancer, while neuroendocrine neoplasms of the cervix receive treatment according to guidelines for cervical cancer. The absence of guidelines also as the lack of detailed knowledge on this rare tumor entity of the female genital tract may very well contribute to the poor prognosis of this condition.
Tabular array I.
Patients' overview.
The aim of the present study was to share our experience of neuroendocrine neoplasms arising from the ovary. Eleven patients with NEN of the ovary were analyzed to further enrich clinical knowledge of this very rare disease to guide further therapeutic approaches.
Patients and Methods
In order to identify patients with NEN in the female genital tract a retrospective chart review of all patients with histologically-confirmed NEN of the ovary, treated at the Charité – University Medicine Berlin during the period from 1996 to 2011, was performed. Also patients that were presented to our "second-opinion center" from other institutions were included. Ethical blessing was given past the upstanding committee of the Charité University Berlin (number assigned past ethics board: EA2/075/12). All histological analyses were made past pathologists specialized for both gynecological malignancies and neuroendocrine neoplasms. The diagnosis "neuroendocrine neoplasm" was made if immunhistochemical markers for neuroendocrine differentiation, such as chromogranin A, synaptophysin and/or neurone-speficic enolase, were positive.
Diagnostics included a thorough history taking, clinical and gynecological test, vaginal ultrasound, CT scan and/or somatostatin receptor imaging (Octreotide scintigraphy).
Tabular array II.
Details of immunohistochemistry.
Surgery was always performed by gynecological oncologists. Chief aims were a consummate tumor resection and acceptable staging co-ordinate to FIGO guidelines. Standard procedures included midline laparotomy, peritoneal cytology, extrafascial hysterectomy, adnectomy and omentectomy. When necessary for complete tumor debulking, additional procedures similar pelvic and para-aortic lymph node dissection, appendectomy and bowel resection were performed.
Medical charts were reviewed systematically regarding to demographic and clinical characteristics, including age at primary diagnosis, chance factors, medical history, diagnosis, stage, histological sub-type and grading according to ovarian cancer, surgical procedures and chemotherapy. Follow-upwardly was updated if the final contact was more than than 3 months ago. Patients have been regularly evaluated every 3 months for whatsoever evidence for tumor progression or recurrent disease by clinical examination and ultrasound.
Data were analyzed with the software program PASW 21 (SPSS Inc., Chicago, IL, The states). All results are presented in raw numbers, rates, medians or ranges depending on the underlying distribution. Correlations were performed with the Chi-square examination or the Kendall's tau-b. Survival curves were estimated co-ordinate to the method of Kaplan-Meier.
Results
11 patients with NEN of the ovary were included in the written report: 9 neuroendocrine cancers and ii carcinoids. Two patients with neuroendocrine cancers had a focal neuroendocrine differentiation only within an ovarian cancer. Median age at diagnosis was 55.ix years (range=23-86 years). More than than half of the patients were diagnosed in FIGO stages I/II (6 patients, 54.6%). Ii patients already had distant metastasis at initial diagnosis – ane patient with lung metastasis and the other ane with infiltrates inside the urothelium of the urinary bladder. Well-nigh NEN were poorly differentiated (8 NEN, 72.four%) according to the grading classification of ovarian cancer. Ascites was present in 6 patients (54.five%). Table I shows a summary of all patients.
Histology and immunohistochemistry. Two patients were diagnosed with pocket-size-cell and two with large-cell neuroendocrine cancer of the ovary. Two patients (patient 4 and 9 in Table I) were diagnosed with carcinoids. Ki-67 was positive in seven patients: In five cases it was college than 20% describing G3 tumors according to neuroendocrine nomenclature. Almost common markers in immunohistochemistry were chromogranin A being positive in 62.v%, synaptophysin existence positive in 71.4% and CD56 being positive in 83.3%. Immunohistochemistry details are illustrated in Table Ii. An example of immunohistochemistry tin can be seen in Figure 1.
Surgery. Primary surgery was performed in all cases. Except for i case, all patients received bilateral salpingooophorectomy and hysterectomy. Fertility was preserved in one patient (patient eight) (Table I) by performing unilateral salpingooophorectomy merely. Nonetheless, when she developed recurrent disease two years later on her initial diagnosis salpingooophorectomy of the other side and hysterectomy were and so performed. Systematic pelvic and paraaortic lymphonodectomy was performed in vi patients (54.5%). Bowel resection was necessary in 5 patients (45.v%) and omentectomy in nine patients (81.8%) in order to achieve optimal tumor debulking. Eight patients had no macroscopic tumor residuals left after the performance.
Adjuvant chemotherapy. Adjuvant chemotherapy was administered in five patients later surgery: Carboplatin and paclitaxel was practical in three patients, single-agent carboplatin and single-agent cisplatin in one patient each. Another five patients including the two carcinoid patients did not receive any chemotherapy at all. Patient 8 received cisplatin and etoposide five years later initial diagnosis due to progressive disease. Second-line chemotherapy was necessary in iii patients: Patient 3 developed recurrent disease one yr after initial diagnosis in the pelvis, bone and pulmonary metastasis so that information technology was decided to administer carboplatin in combination with etoposide. She farther received six cycles of FOLFOX equally third-line chemotherapy four calendar month after completion of second-line chemotherapy. She died within ix months after FOLFOX therapy. Patient 11 was treated with half-dozen cycles of paclitaxel as second-line and two cycles of topotecan every bit tertiary-line chemotherapy. She died ane month after the 2nd cycle of topotecan. Patient ane developed recurrent disease inside 6 month afterward adjuvant chemotherapy with carboplatin and paclitaxel and so that a second-line chemotherapy with six cycles of topotecan was administered. Since then she has not suffered from progressive illness.
Survival. Median overall survival was 20 months (range=2-213 months) and median progression-gratuitous survival was 12 months. Table I shows overall survival for each patient. Patients who were diagnosed with advanced stages had a significant shorter overall survival (p=0.003) and a significant shorter progression-free survival (p=0.006). When comparing the overall survival of patients with distant metastasis (M1) versus patients without afar metastasis overall survival was significantly meliorate in patients without metastasis (p=0.027). However, there was no significant difference regarding the progression-gratuitous survival of patients with M1 and M0 (p=0.066).
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Figure 1.
Example of a neuroendocrine cancer. (a): Tumor below a corpus albicans. (b): Morphology of the tumor. Magnification ×400. Tumor cells have enlarged basophilic nuclei with granular to vesicular chromatin. Mitoses are easily detectable (arrows). (c): Neuroendocrine marker synaptophysin shows strong immunohistochemical cytoplasmatic reactivity. Magnification ×400. (d): Neuroendocrine marker CD56 shows strong immunohistochemical cytoplasmatic reactivity. Magnification ×400.
Give-and-take
In the present article we summarized 11 cases of NEN of the ovary. Most NEN of the ovary are associated with an epithelial ovarian cancer in terms of a focal neuroendocrine differentiation. Pure ovarian NEN are extremely rare (viii). In our analyses there were 7 pure NEN - the largest corporeality reported then far.
Due to the rarity of the illness no diagnostic and no treatment guidelines be. Then far 36 cases with ovarian non-small prison cell neuroendocrine carcinoma (LCNEC) accept been reported in the literature (9-12). Most ovarian NEN are treated according to ovarian cancer handling guidelines. However, ovarian NEN are – despite their oft early diagnosis – more aggressive with a median Os of 20 months in our study. Median OS for all poorly-differentiated tumors was 10.nine months. The 5-yr survival charge per unit in the study of Oshita et al. who summarizes all 33 reported LCNEC, was 34.nine% (9).
The most important pathological tool for the diagnosis of neuroendocrine neoplasms is immunohistochemistry. In club to diagnose a neuroendocrine neoplasm of the female gynecological tract there should be at least 2 positive neuroendocrine markers. Rekhi et al. reported that 88% of their collective with cervical NEN existence positive for at least one neuroendocrine marker (13). The marker most often used in the analysis of Rekhi et al. was synaptophysin. They proposed an immunohistochemistry panel of synaptophysin, chromogranin and CD56. In our collective these iii markers were positive in 71.four%, 62.5% and 83.3% respectively. The nearly common markers in our study were CK7 with a positivity in 87.5%, followed by CD56 with a positivity in 83.3%.
The protein Ki-67 is a marking for the aggressiveness of a tumor and strictly associated with jail cell proliferation. It is the essential component in the WHO classification of gastro-entero-pancreatic neuroendocrine neoplasms, and should be evaluated when diagnosing a neuroendocrine tumour. The grading of neuroendocrine tumors of the gastroenteropancreatic system is based on the pct of Ki-67. In contrast to this fact, it is frequently non evaluated in neuroendocrine tumors of the gynecological tract. However, it is not simply helpful in guiding us with regard to treatment but information technology likewise determines the use of diagnostic tools. That is considering if Ki-67 is beneath 30% a somatostatin receptor imaging (either as octreotide scintrgraphy or 68Ga-DOTATOC.PET/CT) can provide additional data to a conventional CT scan for staging and therapy selection. Tumors expressing somatostatin receptors can be detected with the somatostatin receptor scintigraphy (14). In Figure 2 we propose a potential diagnostic algorithm for ovarian NEN.
In nigh patients ovarian NEN surgery was performed with the aim of complete macroscopic tumor resection. Bilateral salpingo-oophorectomy and total abdominal hysterectomy are the most common procedures in the literature, which was also the example in our study. In early-stage carcinoid tumors confined to i ovary unilateral salpingo-oophorectomy with a fertility-sparing arroyo with thorough follow-ups is possible (15). Oshita et al. reported that 29 out of 33 patients received adjuvant chemotherapy that was platinum-based in all reported cases by Veras et al. (viii, 9). Platinum-based chemotherapy seems to be the adjuvant treatment-of-choice in poorly-differentiated NEC, and should always be administered in stages III and IV (Figure iv). In small cell NEC cisplatin and etoposide - according to the treatment of neuroendocrine cancers of the gastroenteropancreatic organization and pocket-sized cell lung cancer - is an adequate option. In large prison cell NEC the therapeutic choice might be unlike although sufficient clinical information are lacking to back up an culling approach to minor cell NEC. Nosotros propose a platinum-based chemotherapy e.1000. with cisplatin. Information technology should exist emphasized that all patients should exist treated within a clinical report setting whenever possible and treatment should be discussed in interdisciplinary tumor conferences.
However, information technology is unclear if adjuvant chemotherapy should exist e'er administered in early stages. There are two patients (patient 7 and 8) in our collective who were diagnosed with an ovarian NEC FIGO stage I N0 M0 with a Ki-67 of 5-10%. They both did not receive adjuvant chemotherapy after their surgery. Patient seven is still complimentary of disease 37 months after initial diagnosis while patient 8 developed progressive disease five years afterward initial diagnosis and and so chemotherapy was administered. In our opinion it is feasible to perform debulking surgery lonely in patients with Ki-67 ≤5% and FIGO Ia. This should be especially taken into business relationship in younger patients with unfulfilled wish for a child, FIGO Ia and Ki-67 ≤5%, where a unilateral salpingo-oophorectomy might exist sufficient. In full general, at that place is limited evidence to utilise systemic chemotherapy in slowly growing low proliferative NET, and alternative approaches such equally somatostatin receptor targeted therapies should be considered.
In few cases in the literature somatostatin analogues such every bit octreotide were administered to slow tumor growth and to ameliorate carcinoid symptoms (16-18). Octreotide was even shown to induce a remission in a patient with an endometrial NEN refractory to chemotherapy (17). We have not administered these substances, equally in that location is not plenty evidence of their efficacy in neuroendocrine neoplasms of the female genital tract. This therapeutic direction is in contrast to neuroendocrine neoplasms in the gastroenteropancreatic organisation where octreotide and lanreotide are established and canonical therapies and thus frequently used in lodge to ameliorate symptoms and to slow tumor growth (2). In Figures 2 and 3 we suggest handling algorithms for well and poorly differentiated NEN.
Pros and cons of electric current therapy. The existing therapy options for ovarian NEN remain on a foundation of footling testify. Surgical resection is unquestionable the cornerstone of therapy, with undoubted benefit for the patient (fifteen). Whether radical surgery including safe omentectomy and hysterectomie provides an added benefit is unclear at this point. It is routinely performed, equally an adaption from ovarian cancer surgery, but might very well be unnecessary. Systemic therapy options are likewise associated with pros and cons. Somatostatin analogues or peptide-radioreceptor therapy represent a therapy option with a rather indolent side outcome profile. But since they are bound to the existence of somatostatin receptors, a positive receptor scan prior the therapy is obligatory. Likewise the efficacy of this option seems to be express to well-differentiated neoplasms and should only be discussed in poorly differentiated tumors, when the Ki-67 alphabetize remains beneath thirty%. In cases of poorly differentiated neoplasms with loftier proliferation alphabetize (Ki-67 >30%) chemotherapy remains the only pick. The major point of controversy with chemotherapy remains the fact, that the benefit of adjuvant chemotherapy after surgical resection is not proven due to the rarity of this entity and the lack of study data. The con for this therapy option, could exist the hypothesis, that it brings no benefit to the patient while being associated to substantial side effects like nausea, pilus-loss and hemotoxicity
Neuroendocrine neoplasms of the ovary are a very rare tumor entity in gynecological oncology. Treatment guidelines do not exist and it remains unclear if this tumor entity should be treated according to handling guidelines of NEN of the gastroenteropancreatic system or according to the guidelines of ovarian cancer. Information technology is known, even so, that surgery is the cornerstone of therapy and should be performed in any case. Larger, multicenter studies are warranted to shed more light on this rare tumor entity and to optimize treatment.
Acknowledgements
No funding was received. Dr. Hannah Woopen, MSc is participant in the Charité Clinical Scientist Program funded past the Charité Universitätsmedizin Berlin and the Berlin Institute of Health.
Footnotes
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↵§ These authors contributed equally to this report.
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↵* This paper was presented at the 5th International Charité-Mayo Conference, fifteen-18 April 2015, Berlin, Germany.
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Conflicts of Interest
The Authors declare that they have no competing interests.
- Received Dec 9, 2015.
- Revision received January 25, 2016.
- Accepted February 1, 2016.
- Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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Source: https://ar.iiarjournals.org/content/36/3/1003
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