Cancer Intergroup (Gcig) Consensus Review for Carcinoid Tumors of the Ovary I
Neuroendocrine Neoplasms of the Ovary: A Retrospective Written report of the Due north Eastern High german Society of Gynecologic Oncology (NOGGO)
Abstract
Background/Aim: Neuroendocrine neoplasms (NEN) of the female genital tract business relationship for two% of gynecological cancers. The aim of this study was to share our feel of 11 principal 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 direction and survival were assessed. Pathological specimens were critically reviewed. Results: We identified eleven patients with NEN of the ovary consisting of ix neuroendocrine cancers and ii carcinoids. Median age was 55.nine years. NEN were mostly poorly differentiated (72.4%). Primary surgery was performed in all patients. Adjuvant chemotherapy was administered in five patients consisting of platinum-based regimens. Median overall survival was 20 months. Determination: 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
- handling algorithm
Neuroendocrine neoplasms (NEN) are a rare tumor entity arising from the diffuse neuroendocrine cell system. Most NEN are located in the gastroenteropancreatic organisation. Prognosis of this tumor entity is mainly dependent on the histological differentiation and grading, as measured by proliferative activity. In a large study performed earlier 5-yr survival was institute to be l.4% if all cancerous tumors were included. The cornerstone of treatment is surgical resection. Systemic chemotherapy, utilise of radio-nuclides and palliative surgery are effective methods for certain types of avant-garde neuroendocrine tumors. Cisplatinum in combination with etoposide is a very common chemotherapy regimen in poorly differentiated neuroendocrine carcinoma (one, two). Carcinoids are a sub-group of slowly-growing neuroendocrine tumors that may exist associated with production of vasoactive substances such every bit serotonin, that can lead to flushing and diarrhea, the and then-called carcinoid syndrome. Symptom control in symptomatic carcinoid patients and tumor growth control can be accomplished past somatostatin analogues such as octreotide or lanreotide (3, 4).
NEN with the primary in the female genital tract are extremely rare and business relationship for less than 2% of gynecological cancers (v, vi). Most gynecological NEN are located in the uterine neck and classified as pocket-size-jail cell neuroendocrine cancer or in the ovary equally carcinoids (5, vii). Symptoms observed at initial diagnosis in NEN of the female genital tract are vaginal bleeding, vaginal discharge, pain, weight loss, constipation, hirsutism, cancerous ascites and sometimes ectopic hormone production such as serotonin and vasopressin. The diagnosis of NEN generally relies on histology including immunohistochemistry. Almost common markers are chromogranin A, synaptophysin and neuron-specific enolase. Somatostatin receptor scintigraphy can help notice the primary in well-differentiated NEN (grade 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 not according to recommendations for NEN of e.g. the gastrointestinal system. Neuroendocrine neoplasms of the ovary, for example, are often treated with debulking surgery followed by adjuvant chemotherapy with carboplatinum and paclitaxel in line with handling standards for epithelial ovarian cancer, while neuroendocrine neoplasms of the cervix receive handling according to guidelines for cervical cancer. The absenteeism of guidelines as well as the lack of detailed noesis on this rare tumor entity of the female genital tract may very well contribute to the poor prognosis of this condition.
Table 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 cognition of this very rare disease to guide further therapeutic approaches.
Patients and Methods
In lodge 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 – Academy Medicine Berlin during the period from 1996 to 2011, was performed. Too patients that were presented to our "second-opinion center" from other institutions were included. Upstanding approval was given by the ethical committee of the Charité University Berlin (number assigned by ideals board: EA2/075/12). All histological analyses were fabricated 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 examination, vaginal ultrasound, CT scan and/or somatostatin receptor imaging (Octreotide scintigraphy).
Table II.
Details of immunohistochemistry.
Surgery was always performed by gynecological oncologists. Principal aims were a complete tumor resection and adequate 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 like 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 historic period at principal diagnosis, risk factors, medical history, diagnosis, stage, histological sub-type and grading co-ordinate to ovarian cancer, surgical procedures and chemotherapy. Follow-up was updated if the last contact was more than three months ago. Patients have been regularly evaluated every three months for whatever evidence for tumor progression or recurrent affliction by clinical examination and ultrasound.
Data were analyzed with the software plan PASW 21 (SPSS Inc., Chicago, IL, USA). All results are presented in raw numbers, rates, medians or ranges depending on the underlying distribution. Correlations were performed with the Chi-foursquare test or the Kendall'southward tau-b. Survival curves were estimated according to the method of Kaplan-Meier.
Results
Eleven patients with NEN of the ovary were included in the study: nine neuroendocrine cancers and 2 carcinoids. Ii patients with neuroendocrine cancers had a focal neuroendocrine differentiation but within an ovarian cancer. Median historic period at diagnosis was 55.9 years (range=23-86 years). More than than one-half of the patients were diagnosed in FIGO stages I/II (6 patients, 54.half-dozen%). 2 patients already had distant metastasis at initial diagnosis – one patient with lung metastasis and the other one with infiltrates inside the urothelium of the urinary float. Virtually NEN were poorly differentiated (8 NEN, 72.4%) according to the grading classification of ovarian cancer. Ascites was present in 6 patients (54.v%). Tabular array I shows a summary of all patients.
Histology and immunohistochemistry. Ii patients were diagnosed with small-jail cell and two with large-prison cell neuroendocrine cancer of the ovary. Two patients (patient 4 and ix in Table I) were diagnosed with carcinoids. Ki-67 was positive in 7 patients: In five cases information technology was higher than xx% describing G3 tumors according to neuroendocrine classification. Almost mutual markers in immunohistochemistry were chromogranin A being positive in 62.5%, synaptophysin being positive in 71.4% and CD56 being positive in 83.3%. Immunohistochemistry details are illustrated in Table 2. An example of immunohistochemistry can exist seen in Figure 1.
Surgery. Primary surgery was performed in all cases. Except for one case, all patients received bilateral salpingooophorectomy and hysterectomy. Fertility was preserved in one patient (patient 8) (Table I) by performing unilateral salpingooophorectomy only. However, when she adult recurrent disease ii years after her initial diagnosis salpingooophorectomy of the other side and hysterectomy were then performed. Systematic pelvic and paraaortic lymphonodectomy was performed in six patients (54.5%). Bowel resection was necessary in five patients (45.5%) and omentectomy in nine patients (81.8%) in gild to achieve optimal tumor debulking. 8 patients had no macroscopic tumor residuals left after the operation.
Adjuvant chemotherapy. Adjuvant chemotherapy was administered in five patients after surgery: Carboplatin and paclitaxel was applied in iii patients, single-amanuensis carboplatin and single-amanuensis cisplatin in one patient each. Another five patients including the 2 carcinoid patients did not receive whatever chemotherapy at all. Patient 8 received cisplatin and etoposide five years after 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 administrate carboplatin in combination with etoposide. She farther received six cycles of FOLFOX as third-line chemotherapy four calendar month afterward completion of 2nd-line chemotherapy. She died inside nine months later FOLFOX therapy. Patient 11 was treated with six cycles of paclitaxel equally second-line and two cycles of topotecan as third-line chemotherapy. She died one calendar month afterwards the 2nd bike of topotecan. Patient 1 developed recurrent disease inside six month subsequently adjuvant chemotherapy with carboplatin and paclitaxel so that a second-line chemotherapy with six cycles of topotecan was administered. Since then she has non suffered from progressive disease.
Survival. Median overall survival was 20 months (range=ii-213 months) and median progression-free 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 distant metastasis overall survival was significantly amend in patients without metastasis (p=0.027). All the same, there was no meaning deviation regarding the progression-gratis 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 hands detectable (arrows). (c): Neuroendocrine marker synaptophysin shows strong immunohistochemical cytoplasmatic reactivity. Magnification ×400. (d): Neuroendocrine mark CD56 shows stiff immunohistochemical cytoplasmatic reactivity. Magnification ×400.
Discussion
In the nowadays 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 (8). In our analyses in that location were seven pure NEN - the largest corporeality reported so far.
Due to the rarity of the disease no diagnostic and no treatment guidelines exist. So far 36 cases with ovarian not-small cell neuroendocrine carcinoma (LCNEC) accept been reported in the literature (nine-12). Most ovarian NEN are treated co-ordinate to ovarian cancer treatment guidelines. However, ovarian NEN are – despite their often early diagnosis – more aggressive with a median Os of 20 months in our study. Median OS for all poorly-differentiated tumors was x.ix months. The 5-year survival rate in the report of Oshita et al. who summarizes all 33 reported LCNEC, was 34.nine% (9).
The nearly of import pathological tool for the diagnosis of neuroendocrine neoplasms is immunohistochemistry. In order to diagnose a neuroendocrine neoplasm of the female gynecological tract there should be at least two positive neuroendocrine markers. Rekhi et al. reported that 88% of their collective with cervical NEN beingness positive for at least one neuroendocrine mark (13). The mark most oftentimes used in the analysis of Rekhi et al. was synaptophysin. They proposed an immunohistochemistry console of synaptophysin, chromogranin and CD56. In our commonage these three markers were positive in 71.4%, 62.v% and 83.3% respectively. The most common markers in our study were CK7 with a positivity in 87.v%, followed by CD56 with a positivity in 83.3%.
The protein Ki-67 is a marker for the aggressiveness of a tumor and strictly associated with cell proliferation. It is the essential component in the WHO nomenclature of gastro-entero-pancreatic neuroendocrine neoplasms, and should be evaluated when diagnosing a neuroendocrine neoplasm. The grading of neuroendocrine tumors of the gastroenteropancreatic organisation is based on the per centum of Ki-67. In dissimilarity to this fact, information technology is often not evaluated in neuroendocrine tumors of the gynecological tract. Nevertheless, information technology is not but helpful in guiding united states with regard to treatment but it as well determines the employ of diagnostic tools. That is because if Ki-67 is below 30% a somatostatin receptor imaging (either as octreotide scintrgraphy or 68Ga-DOTATOC.PET/CT) can provide additional information to a conventional CT scan for staging and therapy pick. Tumors expressing somatostatin receptors can be detected with the somatostatin receptor scintigraphy (xiv). In Figure two we propose a potential diagnostic algorithm for ovarian NEN.
In nigh patients ovarian NEN surgery was performed with the aim of consummate macroscopic tumor resection. Bilateral salpingo-oophorectomy and total abdominal hysterectomy are the about common procedures in the literature, which was as well the instance in our study. In early-phase carcinoid tumors confined to ane ovary unilateral salpingo-oophorectomy with a fertility-sparing approach with thorough follow-ups is possible (xv). 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. (eight, 9). Platinum-based chemotherapy seems to exist the adjuvant treatment-of-choice in poorly-differentiated NEC, and should always exist administered in stages III and IV (Figure 4). In small cell NEC cisplatin and etoposide - according to the handling of neuroendocrine cancers of the gastroenteropancreatic system and pocket-sized cell lung cancer - is an acceptable option. In large jail cell NEC the therapeutic selection might be unlike although sufficient clinical data are defective to support an alternative approach to small cell NEC. Nosotros advise a platinum-based chemotherapy e.chiliad. with cisplatin. It should be emphasized that all patients should be treated inside a clinical study setting whenever possible and treatment should be discussed in interdisciplinary tumor conferences.
However, it is unclear if adjuvant chemotherapy should exist always administered in early stages. In that location are ii patients (patient seven and 8) in our collective who were diagnosed with an ovarian NEC FIGO stage I N0 M0 with a Ki-67 of v-10%. They both did not receive adjuvant chemotherapy after their surgery. Patient 7 is notwithstanding complimentary of illness 37 months later on initial diagnosis while patient eight adult progressive disease five years after initial diagnosis then 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 account in younger patients with unfulfilled wish for a child, FIGO Ia and Ki-67 ≤5%, where a unilateral salpingo-oophorectomy might be sufficient. In general, there is limited evidence to utilize systemic chemotherapy in slowly growing low proliferative Net, and culling approaches such as somatostatin receptor targeted therapies should be considered.
In few cases in the literature somatostatin analogues such equally octreotide were administered to slow tumor growth and to ameliorate carcinoid symptoms (16-18). Octreotide was fifty-fifty shown to induce a remission in a patient with an endometrial NEN refractory to chemotherapy (17). Nosotros take not administered these substances, every bit there is not enough evidence of their efficacy in neuroendocrine neoplasms of the female genital tract. This therapeutic management is in contrast to neuroendocrine neoplasms in the gastroenteropancreatic system where octreotide and lanreotide are established and approved therapies and thus oftentimes used in order to improve symptoms and to ho-hum tumor growth (2). In Figures ii and 3 nosotros propose treatment algorithms for well and poorly differentiated NEN.
Pros and cons of current therapy. The existing therapy options for ovarian NEN remain on a foundation of little evidence. Surgical resection is unquestionable the cornerstone of therapy, with undoubted benefit for the patient (xv). Whether radical surgery including prophylactic omentectomy and hysterectomie provides an added do good is unclear at this signal. Information technology is routinely performed, every bit 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 effect profile. Merely since they are bound to the existence of somatostatin receptors, a positive receptor scan prior the therapy is obligatory. Too the efficacy of this option seems to be limited to well-differentiated neoplasms and should only be discussed in poorly differentiated tumors, when the Ki-67 alphabetize remains beneath xxx%. In cases of poorly differentiated neoplasms with high proliferation index (Ki-67 >30%) chemotherapy remains the merely option. The major bespeak of controversy with chemotherapy remains the fact, that the benefit of adjuvant chemotherapy later surgical resection is non proven due to the rarity of this entity and the lack of study data. The con for this therapy selection, could be the hypothesis, that it brings no benefit to the patient while being associated to substantial side effects like nausea, hair-loss and hemotoxicity
Neuroendocrine neoplasms of the ovary are a very rare tumor entity in gynecological oncology. Treatment guidelines practise non exist and information technology remains unclear if this tumor entity should be treated according to treatment guidelines of NEN of the gastroenteropancreatic system or according to the guidelines of ovarian cancer. Information technology is known, all the same, that surgery is the cornerstone of therapy and should exist performed in any example. 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 Programme funded by the Charité Universitätsmedizin Berlin and the Berlin Institute of Wellness.
Footnotes
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↵§ These authors contributed equally to this report.
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↵* This paper was presented at the fifth International Charité-Mayo Conference, xv-eighteen April 2015, Berlin, Deutschland.
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Conflicts of Interest
The Authors declare that they have no competing interests.
- Received December 9, 2015.
- Revision received Jan 25, 2016.
- Accepted February 1, 2016.
- Copyright© 2016 International Institute of Anticancer Enquiry (Dr. John G. Delinassios), All rights reserved
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Source: https://ar.iiarjournals.org/content/36/3/1003
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