Small Cell Carcinoma of Ovary, Hypercalcemic Type: A Rare Case Report

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is seen especially in adolescent and young adult women. It is a rare tumor with fewer than 500 cases reported in the literature to date. SCCOHT accounts for less than 0.01% of all ovarian cancers. Most cases are in the 10- to 39-year age range. It is usually seen unilaterally and predominantly in the right ovary. Tumor size greater than 10 cm, age below 30 years, and elevated preoperative calcium levels are poor prognostic factors. Somatic and often germline pathogenic variants of SMARCA4 encoding the SMARCA4 protein (BRG1) are involved in the pathogenesis.^, The literature reported that the long-term survival rate is not more than 30%, even in early-stage cases. Today, multimodal treatments with a multidisciplinary approach constitute the basis of SCCOHT treatment due to the poor prognosis.

Here we present an adolescent girl with SCCOHT without loss of BRG1 and INI1 expression, which are known to be present in 98% and 2% of SCCOHT cases, respectively.

A 16-year-old female initially presented with abdominal pain and weight loss. Clinical examination revealed abdominal distension and a large pelvic mass in the left lower quadrant of the abdomen. Initial laboratory investigations were within normal limits, except for a calcium level of 17.3 mg/dl. Parathyroid hormone (PTH) (< 6 pg/ml) was found to be suppressed. Raised circulating PTH-related peptide (PTHrp) concentration was confirmed in a subsequent blood test. Abdomen ultrasonography and magnetic resonance imaging showed a heterogeneous mass (135 × 124 × 83 mm) with large cystic necrotic components extending from the pelvic region to the umbilicus and free fluid between bowel loops and in the pelvis (Fig. 1). In tumor marker analysis, CA-125 level was significantly increased to 3060.3 U/ml (normal < 35 U/ml). PET-CT scan revealed pathological FDG uptake in the pelvic mass. Tru-cut biopsy from the pelvic mass showed scattered follicle-like spaces consisting of large tumor cells with eosinophilic cytoplasm. In immunohistochemistry staining with WT1, EMA, Cam5.2, BRG1 (Brahma-related gene 1), INI1 (Integrase interactor1), and CD10 were positive, whereas leukocyte common antigen (LCA), cytokeratin7, inhibin, desmin, OCT3, SALL-4, ER, chromogranin, synaptophysin, calretinin, and thyroid transcription factor-1 (TTF1) were negative (Fig. 2). The differential diagnosis includes juvenile granulosa cell tumor with positive WT1, inhibin and calretinin with negative EMA, and dysgerminoma with positive SALLA4 and negative EMA. On the basis of the present morphological and immunohistochemical findings, diagnosis of the large cell variant of SCCOHT was made. Because the tumor size was so large, the tumor board decided to administer preoperative chemotherapy to enable fertility-sparing surgery. Neoadjuvant chemotherapy consisting of cisplatin and etoposide was started. Although good clinical response (improvement of clinical symptoms, normalization in calcium level, decrease in tumor markers) was observed, a slight increase in tumor size was determined radiologically after 3 courses of chemotherapy. At this point, the decision for surgical intervention was made without waiting any longer. Total resection of the mass with left salpingo-oophorectomy was performed. Fertility-sparing surgery was performed by preserving the right ovary and uterus. Histopathologic examination revealed multiple areas of necrosis. The pathological and immunohistological features were the same as those revealed in the examination of tru-cut material. Although the whole left ovary was affected by tumor invasion, no malignant cells were detected in the biopsy of the right ovary lymph nodes, omentum, peritoneum, and peritoneal fluid. After surgery, the VCBA chemotherapy protocol consisting of vinblastine, cisplatin, cyclophosphamide, bleomycin, and adriamycin was started. After 6 cycles of chemotherapy, the patient's Ca-125 level was 8.3 U/ml, her serum calcium level was 9.6 mg/dl, and her PTH was 52.2 pg/ml. She was in clinical and radiological remission, and treatment was discontinued.

Recurrent abdominal mass and peritoneal carcinomatosis were demonstrated 14 months after the initial diagnosis. Paraneoplastic hypercalcemia was detected again. Because chemotherapy is preferred in cases where optimal debulking cannot be performed, a second-line chemotherapy protocol consisting of paclitaxel, carboplatin, and cyclophosphamide was started. Next-generation sequencing was done; however, any genomic alteration suitable for targeted therapy could not be identified. At the end of 3 cycles, subtotal excision of the mass was performed. Histopathological findings were the same as for the first tumor specimen. After surgery, 2 more courses of chemotherapy and 30 Gy radiotherapy were applied to the pelvic mass. However, disease progression was observed, and the patient died 17 months after her initial presentation.

The incidence of malignant ovarian neoplasms is 0.1 per 100,000 girls and constitutes approximately 2% of all childhood cancer. Germ cell tumors are the most common and responsible for 60%-70% of ovarian neoplasm in children and adolescents. Surface epithelial-stromal tumors and sex cord-stromal tumors account for 15%-20% and 10%-15% of ovarian malignancies, respectively. The remaining 5% are miscellaneous ovarian neoplasms including small cell carcinoma of the ovary.

Since 1975, this is the first case of SCCOHT in our pediatric oncology clinic. One hundred twenty-four ovarian tumors were diagnosed over a 40-year period in our clinic. The histopathology was germ cell tumors in most of the cases (91.7%), followed by granulosa cell tumor (3.2%), gonadoblastoma (1.6%), Sertoli-Leydig cell tumor (0.8%), and adenocarcinoma (0.8%).

Although the histopathological spectrum of ovarian neoplasms vastly differs according to age group, small cell carcinoma of the ovary accounts for less than 0.01% of all ovarian cancers. Young et al analyzed the clinical and pathological features of patients with SCCOHT. In this study, 97.3% were between the ages of 10 and 39 years. The tumor was almost always unilateral with right-side predominance, and the mean tumor size was 15 cm. A tumor size greater than 10 cm, age under 30 years, and elevated preoperative calcium levels were found to be related to poor prognosis. The age of our patient was compatible with the age range specified in the literature. Patients generally present with symptoms such as nausea, vomiting, abdominal pain, and abdominal distension, similar to other ovarian malignancies, although hypercalcemia was observed in approximately two-thirds of the cases.^, The pathophysiological mechanism of hypercalcemia is considered to be due to the secretion of PTHrp by tumor cells. SCCOHT is the most common ovarian tumor associated with paraneoplastic hypercalcemia. Serum calcium and PTHrp levels can be used as tumor markers. The annual assessment of calcium and Ca-125 levels is advised for SMARCA4 mutation carriers. In cases in which the tumor responds to treatment, serum calcium and PTHrp levels return to normal. Another tumor marker that increased at the time of diagnosis in our case was serum Ca-125 level. It has been suggested that Ca-125 levels can be used as an indicator for the early detection of recurrence. Serum calcium, PTHrp, and Ca-125 levels were high at the time of diagnosis in our case and normalized after treatment. When the disease relapsed, an increase in tumor markers levels was observed again.

The histological examination of SCCOHT generally shows tumor cells mainly consisting of oval hyperchromatic nuclei with minimal cytoplasm; however, in some cases, a glassy eosinophilic cytoplasm and eccentric large pale nuclei are to be seen. This subgroup, namely the large cell variant of SCCOHT, makes up approximately 50% of the SCCOHT cases and is known to be a poor prognosis criterion.^, The histological examination of our patient was consistent with the latter.

Several studies have shown that loss of SMARCA4 protein expression is highly sensitive and specific for the diagnosis of SCCOHT. Loss of nuclear immunoreactivity with this marker was demonstrated in more than 95% of patients with SCCOHT. It is an important marker in distinguishing malignant differentiated ovarian tumors from their histological counterparts. Alternatively, an intact BRG1 could indicate a deficiency in other subunits of the SWI/SNF complex. In the study of Ramos et al, it was noted that 1 case did not show SMARCA4 mutation and instead showed loss of SMARCB1/INI-1. Karnezis et al showed that 3 out of 4 SCCOHT cases had a loss of INI-1. Although it was stated in the studies in the literature that loss of BRG1 and INI1 expression could play a role in the pathogenesis of SCCOHT, BRG1 and INI1 expressions were found to be preserved in our case. It appears that there are exceptional cases with hitherto undescribed genetic abnormalities. The impact of different genetic abnormalities on prognosis might be the subject of future research.

Since its first description, management of SCCOHT has varied widely. With the advance in molecular, diagnostic, and treatment approaches, the Gynecologic Cancer Inter Group (GCIG) in 2014 and International SCCOHT Consortium (ISC) in 2020 developed guidelines for management. Surgery plays an important role in the treatment of SCCOHT, and if necessary, recurrent excisions are recommended. Today, fertility-preserving surgery is advised because the disease is more common among young women. In our patient, fertility-preserving surgery was performed. Three to six cycles of neoadjuvant chemotherapy are recommended when primary total excision is not possible.^, Cisplatin and etoposide combination regimens are preferred in most cases. It has been reported that the best survival results have been achieved with a semi-intense cisplatin-based VPCBAE (vinblastine, cisplatin, cyclophosphamide, bleomycin, adriamycin, etoposide) chemotherapy regimen.^, There were some reports on the use of carboplatin and paclitaxel regimens. Radiotherapy is increasingly being incorporated into the multimodal therapeutic approach for SCCOHT. Pautier et al showed that disease recurrence was reduced in patients receiving radiotherapy. Callegaro-Filho et al also showed that adjuvant radiotherapy is effective in prolonging the survival of SCCOHT patients. However, there are not enough studies to systematically recommend pelvic radiotherapy. Despite the aggressive treatment, there is a significant risk of relapse, and mean survival times are not more than 35 months at stage I and only 3.3 months at stage IV.^,

The link between SCCOHT and inactivating mutations of SMARCA4 could enable the development of a diagnostic genetic test or targeted molecular therapies. Preliminary studies show that inhibitors targeting EZH2 (enhancer of zeste homolog 2) and receptor tyrosine kinase and anti-PD-1 immunotherapy could potentially be effective for SCCOHT patients. Genetic counseling is recommended for women affected by SCCOHT. Annual control with ultrasonography and Ca/PTHrp levels is recommended. Prophylactic oophorectomy can be considered for elderly SMARCA4 mutation carriers.

Although only 1 case was reported, we believe that sharing our experience with this rare case will contribute to drawing attention to the issue and facilitating the identification of cases. The strengths of the case were genetically analyzed in detail by NGS and immunohistochemical staining. Our case is a rare subtype of this rare tumor with loss of neither BRG1 nor INI1 expression. Because of the rarity of SCCOHT, we believe that every reported case is important and will contribute to guiding clinical practice.

Patient consent was not required because no personal information or details are included.

Çağrı Coşkun: Conception and design, Data collection, Analysis and interpretation of results, Draft manuscript preparation

Nilgun Kurucu: Conception and design, Data collection, Analysis and interpretation of results, Draft manuscript preparation

Alp Usubutun: Conception and design, Pathological evaluation of the biopsy specimens

Tutku Soyer: Conception and design, Data collection, Analysis and interpretation of results, Draft manuscript preparation

H. Nursun Ozcan: Conception and design, Evaluation of the radiological images

Nur Berna Çelik Ertaş: Conception and design, Data collection, Analysis and interpretation of results, Draft manuscript preparation

Tezer Kutluk: Conception and design, Data collection, Analysis and interpretation of results, Draft manuscript preparation