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CASE PRESENTATION
An adolescent female with no significant past medical history and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 presented with acute onset left lower quadrant abdominal pain. Her physical exam was significant for a palpable (approximately 10 cm) left adnexal mass with associated left lower quadrant pelvic pain with positive peritoneal sign. An ultrasonography scan revealed an 8.4×10.9×10.0 cm left ovary with absent Doppler waveforms suspicious for ovarian torsion (Figure 1). She underwent emergent left salpingo-oophorectomy performed by the hospital on-call obstetrician-gynecologist, at which time a 10×12 cm necrotic ovary was found. The decision to proceed with an exploratory laparotomy approach was made based on the comfort level and discretion of the surgeon. The final pathology returned as ovarian infarct and small cell carcinoma of the ovary hypercalcemic type.
(A) Sagittal ultrasound: 11.5×9.8×6.5 cm heterogenous lower pelvic mass. (B) Transverse ultrasound read: ‘May represent a left ovarian neoplasm or a torsed and edematous left ovary’. (C) Coronal CT: left adnexal/pelvic mass lesion measuring up to 11.0 cm with marked vascularity. (D) Sagittal CT.
Dr Korangy: What are the hallmark features of small cell carcinoma of the ovary hypercalcemic type that distinguish this diagnosis?
On gross evaluation, the left ovary was an enlarged, flesh-like mass with portions of necrosis. On microscopic evaluation, there are predominantly diffuse arrangements of cells with follicle-like structures ( Figure 2 ). Tumor cells in particular had hyperchromatic nuclei and scant cytoplasm.
(A) Low power field microscopy, 10 x magnification. (B) Medium power field microscopy, 20 x magnification. (C) High power field microscopy, 40 x magnification. (D) Predominantly diffuse arrangement of cells with follicle-like structures. Tumor cells have hyperchromatic nuclei and scant cytoplasm. (E) Immunostain Claudin-4: negative. (F) Immunostain SMARCA4 (BRG1): positive lesional cells.
The histogenesis and cell lineage of small cell carcinoma of the ovary hypercalcemic type remains under investigation. Recent studies discuss that small cell carcinoma of the ovary hypercalcemic type is characterized by germline or somatic mutations in SMARCA4 and other subunits in the SWI/SNF (switch/sucrose non-fermenting) chromatin remodeling complex. This mutation then causes a loss of the BRG1 protein. SMARCA4 (BRG1) and SMARCA2 (BRM) are components of the SWI-SNF chromatin remodeling complex that are both highly sensitive and specific for small cell carcinoma of the ovary hypercalcemic type. 1 The discovery of SMARCA4 mutations that characterize these tumors was as recent as 2014. 2 This has since served as a durable feature for anticipated targeted therapy.
Most notably in this patient, on immunohistochemical staining Claudin-4 is negative, and specifically SMARCA4 is positive in lesional cells which support the diagnosis ( Figure 2 ). Multiple other immunohistochemical stains were performed and were all negative. These findings were reviewed by a second pathologist who confirmed the diagnosis.
Diagnosis by cytopathology may be challenging and is especially difficult when discovered under the presentation of ovarian torsion. 3 This typically requires collaboration and confirmation together with multiple expert pathologists specializing in gynecologic malignancy. Initial differential diagnoses include germ cell tumors, specifically granulosa cell tumors and dysgerminomas. The histologic appearance may also be similar to that of Burkitt’s lymphoma, and small cell carcinoma of the ovary, pulmonary type. It can be challenging to differentiate small cell carcinoma of the ovary hypercalcemic type from juvenile granulosa cell tumors, even when performed by gynecological pathologists. This is a result of the many overlapping morphological and immunohistochemical features specifically between these two tumors. Claudin-4 is also used for differentiation of adenocarcinoma, as well as a predictor of overall survival in those with ovarian cancer. 4 Additionally, juvenile granulosa cell tumors may clinically manifest with hypercalcemia, which further complicates the diagnosis. 5
Dr Reyes: What would be your approach to counseling a patient and her family with this diagnosis?
Small cell carcinoma of the ovary hypercalcemic type was first described in the medical literature in 1994 by Young et al and portends an aggressive course of progression. 6 In this retrospective cohort, the median age reported was 23 years, with an overall survival rate of 50% at 1 year, and less than 10% at 5 years. Although it is exceedingly rare, small cell carcinoma of the ovary hypercalcemic type is the most common undifferentiated ovarian malignant tumor in women under 40 years of age. 5 There currently exists no standard protocol for treatment; however, the main tenets rest on optimal cytoreductive surgery and platinum-based chemotherapeutic regimens.
Familial small cell carcinoma of the ovary hypercalcemic type specifically is associated with a younger age at the time of diagnosis. If suspected based on germline mutations of SMARCA4 with loss of BRG1 expression, genetic testing should be offered to the patient’s family members. There are no formal recommendations for surveillance of affected family members and unfortunately the patient described in this Tumor Board was adopted during early childhood and has since lost established contact with her original birth parents. Literature has proposed that affected family members may also be offered a risk-reducing bilateral oophorectomy; however, with the low aforementioned median age of diagnosis for small cell carcinoma of the ovary hypercalcemic type and no clear consensus opinion, many patients will find this option unacceptable to perform early enough in life for it to provide potential benefit.5
Dr Reyes: What would be your recommendation at this time for treatment?
When feasible and appropriate, upfront surgical tumor removal and chemotherapy serves as therapy for patients with small cell carcinoma of the ovary hypercalcemic type. 4 Even so, survival is described to be only 33% in stage IA disease. 6 Complete and adequate treatment typically follows with chemotherapy, whereas radiotherapy has not been routinely used as part of treatment.7
Due to the rarity and rapid progression of small cell carcinoma of the ovary hypercalcemic type, there has been limited ability to complete clinical trials and establish a standard treatment regimen. 2 It is commonly considered a systemic disease with presumed presence of regional or distant micrometastases, regardless of the presence of overt extra-ovarian disease. 2 As such, adjuvant chemotherapy is recommended for all stages. This is generally a cisplatin and etoposide-based combination of six cycles including vinblastine (6 mg/m2 intravenous (IV) over 30 min on day 1), cisplatin (90 mg/m2 IV over 4 hours on day 1), cyclophosphamide (1000 mg/m2 IV over 60 min on day 2), bleomycin (15 units/m 2 IV over 24 hours on day 2), doxorubicin (45 mg/m2 IV over 30 min on day 3), and etoposide (200 mg/m2 IV over 2 hours on day 3).8 9
Following the initial diagnosis, the patient opted for completion staging 6 weeks later via a total laparoscopic hysterectomy, right salpingo-oophorectomy, complete omentectomy, and staging peritoneal biopsies, with concomitant cystoscopy, and rigid sigmoidoscopy for assessment of bowel integrity after extensive enterolysis. Lymphadenectomy was omitted after discussion during pre-operative counseling with the patient. Final pathology review was without residual tissue pathologic changes—thus confirming stage IC1.
Dr Reyes: Please provide your opinion regarding the indication for lymphadenectomy in the setting of this diagnosis, and how you would counsel the patient regarding her fertility options
In the largest retrospective review containing 47 cases of small cell carcinoma of the ovary hypercalcemic type, surgical management consisted of 55% undergoing unilateral salpingo-oophorectomy, whereas the remaining 45% underwent total hysterectomy with bilateral salpingo-oophorectomy. A total of 85% of all cases underwent additional procedures and this includes omentectomy, debulking of extra-ovarian tumor, lymph node dissection, and peritoneal biopsies. 8
The NCCN [National Comprehensive Cancer Network] guidelines for principles of surgery includes para-aortic and pelvic lymphadenectomy in addition to a total hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and peritoneal biopsies as part of the staging procedure in newly diagnosed ovarian cancer, specifically those with epithelial histology. Additionally, peritoneal surfaces suspicious for harboring metastasis should be selectively excised. Appropriate staging is important to determine prognosis and treatment options after initial surgery.
The patient has an aggressive and rare form of ovarian cancer that is notorious for having an extremely poor prognosis and thus necessitating adjuvant therapy. Since determination of stage would not have affected the decision to proceed with adjuvant therapy or not, along with the risk of lymphedema following lymphadenectomy, the patient decided to forego the lymphadenectomy portion of the staging procedure in the setting of non-enlarged and non-suspicious nodes previously identified on imaging.
Fertility-sparing is not typically recommended and completion surgery with or without staging for all patients remains the standard surgical component of treatment. In patients without germline SMARCA4 pathogenic variants, fertility-sparing surgery may be considered in comprehensively staged 1A patients with appropriate counseling and shared decision making if family planning desires have not yet been fulfilled. 9 In juxtaposition, some gynecologists maintain that a less aggressive fertility sparing treatment may be justified due to the poor survival rates despite radical surgery. 5 There are available reproductive endocrinology options such as oocyte cryopreservation, although this treatment requires ovarian hyperstimulation prior to oocyte collection, and therefore delays surgical management and chemotherapy in the timespan of typically weeks. 2
Dr Reyes: How would you counsel the patient regarding her adjuvant chemotherapeutic options?
There have been numerous case reports that report success with this chemotherapeutic regimen, including a patient with FIGO [International Federation of Gynecology and Obstetrics] stage IIIC who was effectively treated. The largest study of vinblastine, cisplatin, cyclophosphamide, bleomycin, doxorubicin, and etoposide included six patients with FIGO stage I disease, and only one of six was noted to have recurrent disease after prolonged follow-up. 2 Cisplatin (80 mg/m2), doxorubicin (40 mg/m2), etoposide (75 mg/m2), and cyclophosphamide (300 mg/m2 × 3 days) is an alternative regimen that has been shown to have promising results for some patients. 2 The added benefits of bleomycin and vincristine make the previously described regimen more favorable, with cisplatin, doxorubicin, etoposide, and cyclophosphamide being favored in those patients with pulmonary toxicity as a viable alternative. There have been minimal reports that suggest utility of high dose chemotherapy with autologous stem cell transplant and heated intraperitoneal chemotherapy and is infrequently used. 2
In consideration of the above studies and the available medical literature, along with the poor clinical outcomes from the traditional management of small cell ovarian cancer, the treatment for small cell lung cancer was discussed as well, specifically for the hypercalcemic variant with the patient. This treatment per NCCN guidelines is a combination of platinum therapy, etoposide, and the use of novel immunotherapy. Immunotherapy for small cell lung cancer consists of either atezolizumab or durvalumab.10 Due to the higher level of success, as well as the overall poor response rate to the current standard chemotherapy treatment, with shared medical decision-making, the patient decided to proceed with an immunotherapy regimen. As both were not approved currently for treatment of small cell ovarian cancer at the time of this patient’s care, authorization was discussed and eventually approved for the use of pembrolizumab for this indication.
Four weeks postoperatively, the patient began and completed two cycles of carboplatin AUC 5, etoposide 100 mg/m2, and pembrolizumab 200 mg. Two weeks after cycle 2, however, her course was complicated by a hospital admission for lethargy and electrolyte abnormalities, where a repeat CT scan at that time revealed a 10 cm pelvic soft tissue mass consistent with platinum-refractory progression of disease.
Dr McGrath
In the radiographic images, her interval imaging showed a new 9×10 cm left large lobular anterolateral pelvic soft tissue mass. There was also a 3.5×2 cm right anterior pelvic soft tissue nodule ( Figure 3 ). Both were considered new findings and, taking into account her oncologic course and the timing, this would be considered platinum refractory recurrence of disease.
(A) Coronal CT: new 9×10 cm left large lobular anterolateral pelvic soft tissue mass. New 3.5×2 cm right anterior pelvic soft tissue nodule. (B) Sagittal CT: new findings compatible with recurrent malignancy.
Dr Reyes: What would be your discussion with the patient at this time, with the imaging findings raising concern for disease recurrence?
Small cell carcinoma of the ovary hypercalcemic type is often initially responsive to chemotherapy, but presents with short intervals of recurrence, and there are very limited data regarding therapeutic options for management in the recurrent setting. Treatment for recurrences may include a combination of cyclophosphamide, doxorubicin, vincristine or carboplatin in combination with topotecan. 9
When reviewing the literature to determine an appropriate chemotherapy regimen for this patient, a clinical trial was identified assessing the efficacy of pembrolizumab in platinum-sensitive or platinum-resistant ovarian cancer. 11 Zsiros et al demonstrated an objective response rate of 47.5% using a combination of intravenous pembrolizumab 200 mg, bevacizumab 15 mg/kg every 3 weeks, and cyclophosphamide 50 mg once daily for the treatment of recurrent disease. Of the 40 patients involved, three achieved a complete response and 16 achieved a partial response. In addition, 38 of the 40 patients had clinical benefit from this regimen. 11
Ovarian cancer is associated with statistically longer survival when there is increased infiltration of T cells in tumor islets. However, immunotherapy is successful at depleting these T cells through the use of programmed cell death (PD-L1) and VEGF (vascular endothelial growth factor). VEGF is highly expressed in most ovarian cancers, which serves as a major driver for ovarian tumor neovascularization which is also targeted. Bevacizumab is a humanized monoclonal antibody that targets VEGF. Cyclophosphamide is a cytotoxic agent that selectively depletes regulatory T cells, and pembrolizumab is a PD-L1 inhibitor. Therefore, it is theorized that in combination, these three medications can decrease a tumor’s immunosuppressive response and help the body’s immune system to infiltrate ovarian cancer and cause cytotoxicity. 11
In wanting to continue immunotherapy, the patient’s treatment plan was then transitioned to pembrolizumab, bevacizumab, and oral cyclophosphamide. Within three cycles on this triple chemotherapeutic regimen, the patient showed radiographic improvement with resolution of the previously identified mass (Figure 4). To date, the patient has experienced a clinical and radiographic response with the PD-1/PD-L1 immune checkpoint inhibitor, pembrolizumab. She maintains a durable response 24 months after the index completion surgery, and is status post 22 rounds of maintenance chemotherapy with bevacizumab, cyclophosphamide, and pembrolizumab.
(A) Prior coronal CT with recurrence of malignancy. (B) Recent coronal CT: previously identified mass is no longer identified. (C) Thin nodular left anterior soft tissue 3.3×0.7 cm, representing scarring versus residual tissue.
Dr Reyes: What would be your recommended oncologic surveillance?
Recommendations for surveillance are not well established due to the rare nature of small cell carcinoma of the ovary hypercalcemic type and its low associated survival rate. Current recommendations are adaptations from other distinct germ cell tumors per the NCCN guidelines and include a CT chest, MRI or CT abdomen pelvis and positron emission tomography (PET) scan every 3 months for the first 2 years after treatment. This subsequently is spaced in interval to 4 months for the third year off of treatment, and every 6–12 months for the fourth and fifth year. Yearly visits should be continued thereafter, and a pelvic US [ultrasound] should be completed every 6–12 months. Blood work such as serum complete blood counts and chemistries are repeated at each monitoring visit. Other organs should be monitored yearly with an echocardiogram, pulmonary function tests, audiology, and renal assessment as warranted.
The patient has had interval imaging scans and tumor marker surveillance with cancer antigen 125 (CA125), and has shown sustained remission for the past 24 months to date. She continues to do well, and currently continues on maintenance chemotherapy of bevacizumab, cyclophosphamide, and pembrolizumab.
CONCLUSION
Small cell carcinoma of the ovary hypercalcemic type is a rare and aggressive malignancy that is difficult to diagnose and manage. The cell lineage of this tumor is undetermined; however, characteristics such as age distribution and the discovery of the SMARCA4 mutation are similar in nature to germ cell tumors. Due to the rapid pattern of progression, it is extremely difficult to develop protocols for primary and recurrent treatment, as well as surveillance for remission and that of family members. This case presentation demonstrates successful treatment of recurrent small cell carcinoma of the ovary hypercalcemic type, using pembrolizumab, cyclophosphamide, and bevacizumab, adapted from the clinical trial performed by Zsiros et al for ovarian cancer recurrence. Thus far, this treatment regimen has proven effective and the patient is currently on continued triple chemotherapeutic maintenance, without any current evidence of recurrence after 24 months. Combination pembrolizumab, cyclophosphamide, and bevacizumab may be beneficial not only for ovarian cancer recurrence, but specifically for small cell carcinoma of the ovary hypercalcemic type as well.
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Footnotes
Presented at Western Association of Gynecologic Oncology (WAGO) Annual Meeting Tumor Board, Jun 17, 2022, Coeur d'Alene, Idaho.
Contributors All authors have contributed to the writing of this manuscript. MS is the co-presenter. EM is the co-presenter. EK is the pathologist. JM is the radiologist. HR is the discussant.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; internally peer reviewed.