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Neuroendocrine carcinoma of ovary: Hitherto rare entity in primary ovarian tumors


1 Department of Pathology, Lady Hardinge Medical College, New Delhi, India
2 Department of Histopathology, Sir Gangaram Hospital, New Delhi, India
3 Obstetrics and Gynaecology, Sir Gangaram Hospital, New Delhi, India

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Date of Submission26-Sep-2021
Date of Decision22-Feb-2022
Date of Acceptance23-Feb-2022
Date of Web Publication27-Sep-2022
 

   Abstract 


Neuroendocrine neoplasms (NEN) of the female genital tract are extremely uncommon. These tumors can be broadly divided into well differentiated (carcinoid) and poorly differentiated NEN (small cell and large cell carcinomas). Occurrence of neuroendocrine carcinomas (NECs) in ovary has rarely been reported. These high-grade malignant tumors have a fulminant clinical course with a short period of survival, even when diagnosed at an early stage. We hereby report two cases of primary neuroendocrine carcinoma of the ovary.

Keywords: Neuroendocrine carcinoma, Neuroendocrine neoplasm, ovary


How to cite this URL:
Osama MA, Rao S, Bhardwaj P, Mediratta G, Bhalla S, Badwal S. Neuroendocrine carcinoma of ovary: Hitherto rare entity in primary ovarian tumors. Indian J Pathol Microbiol [Epub ahead of print] [cited 2022 Dec 7]. Available from: https://www.ijpmonline.org/preprintarticle.asp?id=357287





   Introduction Top


Neuroendocrine neoplasms (NEN) of the female genital tract are uncommon and account for only 2% of gynecological cancers.[1],[2] Most of these gynecological NEN are located in the cervix or ovary. NEN have a dichotomous morphological division into neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs). Low-grade NETs exhibit characteristic organoid architecture and include grade 1 tumors (carcinoids) and grade 2 tumors (atypical carcinoids). NECs are composed of high-grade malignant cells, which could either be small cell or large cell type. However, before making a diagnosis of primary ovarian NEN, it is important to exclude possibility of metastatic tumors from other organs, such as lung and gastrointestinal tract. The prognosis of this category of tumors is entirely dependent on the histological differentiation and grading (measured by proliferative index).[3]


   Case History Top


Case 1: A 26-year-old female patient, with no previous comorbidities, presented with complaints of severe back pain on February 2021. On per abdominal examination, a mobile mass measuring 10 × 8 cm with varying consistency was palpated. Laboratory investigation showed hypercalcemia (15.5 mg/dl). CA-125 levels were elevated (100 U/ml). Intravenous contrast enhanced computed tomography (CT) scan of the pelvis showed a bulky right ovary with heterogeneous signal intensity measuring 7.7 × 5.2 cm while the other ovary was normal [Figure 1]a. In view of radiological findings and elevated CA-125 levels in a young patient, the patient underwent surgical excision of the mass. Peritoneal biopsy, omental biopsy, and peritoneal fluid were also sent for evaluation. Frozen section of the ovarian mass revealed poorly differentiated malignant neoplasm. Hematoxylin and eosin (H&E) stained sections showed a malignant tumor arranged in nests, lobules, and trabecular configuration separated by fibrocollagenous septae [Figure 1]b. The tumor was partially surrounded by pseudocapsule, at places showing normal ovarian stroma at periphery. The tumor cells were round to polygonal with scant cytoplasm and hyperchromatic nuclei with coarse chromatin and inconspicuous to small nucleoli. Tumor cells focally showed fine stippled chromatin. Foci of tumor necrosis along with apoptosis were noted [Figure 1]c. Mitotic activity was about 10–12/10 hpf. Tumor deposits were also seen in the peritoneum and omentum. On immunohistochemistry (IHC), tumor cells were positive for synaptophysin [Figure 1]d, chromogranin [Figure 1]e, CK-7, TTF-1 [Figure 1]f, and p53 (mutant type); and were negative for CK20, CDX2, inhibin, and PLAP. Ki67 proliferative index was 30–40%. Similar atypical cells were observed in peritoneal fluid as well. Considering the tumor morphology and IHC findings, a final diagnosis of small-cell NEC was rendered. Further, positron emission tomography (PET) scan was done and showed no lesions in lungs or elsewhere in body. The patient had received three cycles of peptide receptor radionuclide therapy [(177)Lu-DOTATATE] on her last follow-up.
Figure 1: (a) Intravenous contrast enhanced axial CT scan of the pelvis showing bulky right ovary with heterogeneous signal enhancement of the solid area; (b) tumor arranged in nests and lobules separated by thin fibrocollagenous septae (H&E 100×); (c) tumor nest with central necrosis (H&E 200×); (d) synaptophysin positivity (100×); (e) chromogranin positivity (200×); (f) TTF-1 positivity (100×)

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Case 2: A 65-year-old postmenopausal female patient presented with complaints of pain in the lower abdomen on January 2018. The patient also had complaints of abdominal distension, increased frequency of micturition, and constipation of 1 month duration. Per vaginal examination revealed a large, lobulated firm mass arising from the right fornix and extending till the umbilical region. Laboratory investigation showed increased serum calcium levels (13.8 mg/dl). Non-contrast axial CT scan of the pelvis showed a right adnexal mass measuring 7.9 × 7.4 × 9 cm [Figure 2]a. Intraoperatively, large solid mass lesion with increased vascularity was observed in the right adnexal region [Figure 2]b. Right ovary was not clearly demarcated. The left ovary was relatively normal in size. Diagnostic laparotomy with debulking of the right ovarian mass with total abdominal hysterectomy and bilateral salpingo-oophorectomy was done. Per-operative frozen section of the ovarian mass revealed poorly differentiated malignant tumor of ovary. Paraffin sections from ovarian mass exhibited a high-grade malignant tumor [Figure 2]c. The cells were arranged in dyscohesive sheets with large areas of necrosis and peritheliomatous survival pattern [Figure 2]d. The tumor cells were small, having high nucleus–cytoplasm ratio (N/C ratio) and mildly pleomorphic hyperchromatic nuclei. Brisk mitotic activity was observed. No glandular architecture was noted. Prominent lymphovascular invasion was seen. The tumor was diffusely infiltrating the ovarian stroma, surrounding fibroadipose tissue, ipsilateral fallopian tube, and mesosalpinx. On IHC, the tumor cells were positive for synaptophysin [Figure 3]a, neuron-specific enolase (NSE), Vimentin and focally positive for chromogranin and TTF-1 [Figure 3]b. Placental alkaline phosphatase (PLAP), inhibin, epithelial membrane antigen (EMA), LCA, and CD99 were negative. Ki67 proliferative index was 80% [Figure 3]c. Peritoneal washings, omental biopsy, and peritoneal biopsy showed similar tumor cells. Taking into account these morphological and IHC features, possibility of a poorly differentiated NEC/NET was suggested. The patient was asked to be re-evaluated for any focus of tumor in the abdomen and lungs, which was found to be negative. Hence, a final diagnosis of primary NEC of ovary was given. The patient refused for further treatment/chemotherapy and expired within few months.
Figure 2: (a) Non-contrast axial CT scan of the pelvis showing a large right adnexal mass; (b) intraoperative image of the ovarian mass with increased vascularity; (c) poorly differentiated cellular malignant tumor with focal areas of necrosis (H&E 200×); (d) cells arranged in dyscohesive sheets with large areas of necrosis and peritheliomatous survival pattern (H&E 100×)

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Figure 3: IHC (a) Synaptophysin positivity (200×); (b) focal TTF-1 positivity (200×); (c) high Ki67 proliferative index (80%) (200×)

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   Discussion Top


NEN/NETs are quite heterogeneous as they display a spectrum of histological findings and biological behavior.[4] In the female genital tract, ovaries, and cervix are the main site of involvement, albeit quite rare as such. In cervix, small cell neuroendocrine carcinoma (SCNEC) is the most common NEN followed by large cell neuroendocrine carcinoma (LCNEC). On the contrary, the terminology of “neuroendocrine” in ovary is mainly referred to low-grade NETs (namely carcinoids); however, NEC of small and large cell type are also infrequently encountered.[5],[6],[7],[8]

The histogenesis of NENs of ovary is still unclear. Carcinoids in ovary are hypothesized to develop from indigenous neuroendocrine cells as pure forms (called as monodermal teratomas), or in association with mature cystic teratomas. According to another hypothesis, NEN is believed to arise from surface epithelial tumors expressing endocrine pathway of differentiation. In a study by Eichhorn et al.,[5] out of the total 11 SCNEC cases, 8 were associated with surface epithelial tumors. In neither of our cases, any mixed epithelial differentiation could be appreciated. Carcinoid tumors could be either primary or metastatic. Primary ones generally behave in an indolent manner and are treated by surgery only, but the metastatic ones are aggressive in nature and associated with poor outcome.[6]

SCNEC is a highly aggressive NEN, and distinguishing primary tumor from metastatic small cell carcinoma from other possible locations (most commonly lung) is of paramount importance. The foremost clue for a metastatic tumor is the bilateral ovarian involvement. Clinico-radiological evaluation is necessary to make this distinction with certainty in most cases.

LCNEC of ovary is an exceedingly rare neoplasm and is mostly associated with surface epithelial tumors or germ cell tumors. Veras et al.,[7] in their cases series of 11 non-small cell NECs, showed co-occurrence of mucinous tumors in 5 cases and teratomas in 3 cases. Incidence of primary pure LCNEC of the ovary is very infrequent.[7],[8] LCNEC has larger tumor cells with abundant cytoplasm, higher nuclear grade, and geographic areas of necrosis.

The presence of any neuroendocrine carcinomatous component in an epithelial tumor needs to be reported as it has a negative prognostic significance. Possible differentials NENs ovary may include desmoplastic small round cell tumor, Ewing sarcoma/primitive neuroectodermal tumor, high-grade endometrial stromal sarcoma, lymphoma, and rarely melanoma. IHC is crucial to diagnose NEN of ovary and to differentiate it from other morphological mimickers. To confirm the lineage, IHC markers for neuroendocrine differentiation such as chromogranin A, synaptophysin, NSE, CD56, and cytokeratins are usually put as baseline markers. To differentiate it from other ovarian tumors, markers like ER, PR, p53, WT-1, inhibin, PLAP, LCA, CD99, CDX2, TTF-1, PAX8, CK7, and CK20 are used. In both of our cases, tumors were positive for a minimum of two neuroendocrine immunomarkers and were negative for markers for other possible differentials. Seidman studied 15 cases of small cell carcinoma of ovary and found p53 positivity in 80% of the cases.[9] Verset et al.,[10] reviewed TTF-1 expression of NEC in pulmonary and extrapulmonary endocrine tumors by 16 authors and concluded that >90% of small cell carcinoma lung and 39% cases of NEC of other organs showed TTF-1 expression. Thus, IHC is not of much use in differentiating primary vs metastatic NECs. Both our cases showed TTF-1 positivity, varying from diffuse expression in one case to focal in other.

Both SCNEC and LCNEC of the gynecological tract are aggressive tumors, with a high propensity for lymphatic and hematogenous spread.[5],[7] Distant metastasis at presentation is common. Patients diagnosed with NECs of ovary have shown a poor survival outcome as compared to various epithelial ovarian cancers likes serous, endometrioid, mucinous, or clear cell carcinomas.[7],[11] Due to rarity of this disease, the treatment guidelines are not clearly defined, however, these neoplasms are often treated with debulking surgery followed by adjuvant chemotherapy with carboplatinum and paclitaxel.[12] With the advancement of medical genetics, new potential target therapies against SMARCA4 variants have been discovered.[13],[14] Correct diagnosis at an early clinical stage and a low tumor grade morphology can predict a favorable survival outcome.


   Conclusion Top


There is a paucity of published literature on NEN of ovary. These tumors have an incongruous presentation and response to therapy (including surgery, chemo, and radiotherapy). Hence, more number of studies with close follow-up of patients are required to predict the efficacy of treatment protocols which in long run, may improve the survival rates of this rare tumor.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Dasari A, Shen C, Halperin D, Zhao B, Zhou S, Xu Y, et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol 2017;3:1335-42.  Back to cited text no. 1
    
2.
Chun YK. Neuroendocrine tumors of the female reproductive tract: A literature review. J Pathol Transl Med 2015;49:450-61.  Back to cited text no. 2
    
3.
Colgan TJ, Kim I, Hirschowitz L, McCluggage WG. Neuroendocrine tumours. In: Kurman RJ, Carcangiu ML, Herrington CS, Young RH, editors. WHO Classification of Tumours of Female Reproductive Organs. 4th ed. Lyon: IARC Press; 2014. p. 196-8.  Back to cited text no. 3
    
4.
Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, et al. One hundred years after “carcinoid”: Epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 2008;26:3063-72.  Back to cited text no. 4
    
5.
Eichhorn JH, Young RH, Scully RE. Primary ovarian small cell carcinoma of pulmonary type. A clinicopathologic, immunohistologic, and flow cytometric analysis of 11 cases. Am J Surg Pathol 1992;16:926-38.  Back to cited text no. 5
    
6.
Davis KP, Hartmann LK, Keeney GL, Shapiro H. Primary ovarian carcinoid tumors. Gynecol Oncol 1996;61:259-65.  Back to cited text no. 6
    
7.
Veras E, Deavers MT, Silva EG, Malpica A. Ovarian nonsmall cell neuroendocrine carcinoma: A clinicopathologic and immunohistochemical study of 11 cases. Am J Surg Pathol 2007;31:774-82.  Back to cited text no. 7
    
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Shakuntala PN, Uma Devi K, Shobha K, Bafna UD, Geetashree M. Pure large cell neuroendocrine carcinoma of ovary: A rare clinical entity and review of literature. Case Rep Oncol Med 2012;2012:120727. doi: 10.1155/2012/120727.  Back to cited text no. 8
    
9.
Seidman JD. Small cell carcinoma of the ovary of the hypercalcemic type: p53 protein accumulation and clinicopathologic features. Gynecol Oncol 1995;59:283-7.  Back to cited text no. 9
    
10.
Verset L, Arvanitakis M, Loi P, Closset J, Delhaye M, Remmelink M, et al. TTF-1 positive small cell cancers: Don't think they're always primary pulmonary!. World J Gastrointest Oncol 2011;3:144-7.  Back to cited text no. 10
    
11.
Eichhorn JH, Lawrence WD, Young RH, Scully RE. Ovarian neuroendocrine carcinomas of non-small-cell type associated with surface epithelial adenocarcinomas. A study of five cases and review of the literature. Int J Gynecol Pathol 1996;15:303-14.  Back to cited text no. 11
    
12.
Zhu Y, Meng F, Fang H, Zhang Z, Wang L, Zheng W. Clinicopathologic characteristics and survival outcomes in neuroendocrine carcinoma of the ovary. Int J Gynecol Cancer 2020;30:207-12.  Back to cited text no. 12
    
13.
Lu B, Shi H. An in-depth look at small cell carcinoma of the ovary, hypercalcemic type (SCCOHT): Clinical implications from recent molecular findings. J Cancer 2019;10:223-37.  Back to cited text no. 13
    
14.
Tischkowitz M, Huang S, Banerjee S, Hague J, Hendricks WPD, Huntsman DG, et al. Small-cell carcinoma of the ovary, hypercalcemic type-genetics, new treatment targets, and current management guidelines. Clin Cancer Res 2020;26:3908-17.  Back to cited text no. 14
    

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Correspondence Address:
Seema Rao,
Department of Histopathology, Sir Gangaram Hospital, New Delhi - 110 060
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijpm.ijpm_954_21



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