Small cell carcinoma of the ovary, hypercalcemic type complicated by enterocutaneous fistula: a case report

Abstract

Background

Small cell carcinoma of the ovary, hypercalcemic type, is a rare, highly aggressive malignancy that predominantly affects young women and is associated with poor prognosis and limited treatment options.

Case presentation

We report the first documented case of small cell carcinoma of the ovary, hypercalcemic type, in a 30-year-old Pakistani woman who presented with abdominal pain, vomiting, weight loss, and biochemical evidence of hypercalcemia. Imaging revealed a large left adnexal mass measuring 9.3 cm × 10.7 cm × 9.7 cm. Subsequent histopathological and immunohistochemical analysis demonstrated characteristic features of small cell carcinoma of the ovary, hypercalcemic type with complete loss of SMARCA4 (BRG1) expression, confirming the diagnosis. The patient underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, and lymph node dissection, followed by multi-agent chemotherapy. Despite her initial response, she developed widespread metastatic disease with tumor infiltration of the abdominal wall and encasement of ileal loops. This ultimately resulted in a contained ileal perforation and the formation of an enterocutaneous fistula—an uncommon and previously unreported complication of small cell carcinoma of the ovary, hypercalcemic type.

Conclusion

This case highlights the diagnostic and therapeutic challenges associated with small cell carcinoma of the ovary, hypercalcemic type, and underscores the critical role of SMARCA4 immunohistochemistry in confirming the diagnosis, particularly in resource-limited settings where molecular testing may not be widely accessible.

Introduction

Primary small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a rare neoplasm, with fewer than 500 cases reported in literature. According to one study, it has an incidence of 0.12 per 1 million per year [1]. It is an aggressive type of tumor, with poor prognosis and early metastasis. Although the condition may initially be asymptomatic, patients most commonly present with nonspecific symptoms such as lower abdominal pain, abdominal distension, and bloating. Limited data describe a 1-year survival rate of only 50%, with an overall 5-year survival rate of approximately 10% [2]. It predominantly affects young women, with a median age at diagnosis of 24 years, and no authenticated cases have been reported after the age of 56 years [3]. Since 2014, several studies have highlighted the role of germline and somatic mutations of the SMARCA4 gene, which encodes the BRG1 protein, as a significant contributor to the development of this carcinoma, and its involvement has been detected in more than 95% of SCCOHT cases [4, 5].

At present, there is no universally accepted treatment protocol for SCCOHT, presenting a significant challenge in its management; however, a combination of surgery and chemotherapy is most frequently employed. We present the only documented case diagnosed in Pakistan, highlighting its clinical course, surgical management with total abdominal hysterectomy and bilateral salpingo-oophorectomy, and subsequent chemotherapy, which was later complicated by the development of an enterocutaneous fistula (ECF).

Case presentation

A 30-year-old married Pakistani woman presented to the emergency department with complaints of persistent vomiting and bilateral groin pain radiating to the lower abdomen and back for the past 3 days. On further questioning, she reported experiencing generalized fatigue, progressive weight loss, decreased appetite, and intermittent nausea over the preceding 3 months. The patient had no significant past medical or surgical history, apart from a spontaneous vaginal delivery 3 months prior to presentation. She was a nonsmoker and nonalcoholic, with no known comorbidities or family history of gynecological or other cancers. On examination, she was afebrile and vitally stable, but abdominal assessment revealed a palpable irregular pelvic mass corresponding to approximately 14–16 weeks of gestation size.

Initial laboratory investigations are shown in Table 1.

Table 1.

Laboratory investigations

Parameter	Result	Reference range
CA-125	57.50 U/mL	2–30.2 U/mL
Erythrocyte sedimentation rate (ESR)	50 mm/hour	0–20 mm/hour
Platelets	570 × 109/L	150–400 × 109/L
Sodium	134 mmol/L	136–145 mmol/L
Potassium	2.5 mmol/L	3.5–5.1 mmol/L
Chloride	93 mmol/L	98–107 mmol/L
Magnesium	0.9 mg/dL	1.6–2.6 mg/dL
Parathyroid hormone (PTH)	< 3 pg/mL	16–87 pg/mL
Calcium	11.2 mg/dL	8.6–10.2 mg/dL
Hemoglobin	9.9 g/dL	11.1–14.5 g/dL
White blood cell count (WBC)	3.3 × 103/µL	4.0–10.0 × 103/µL
Blood urea nitrogen (BUN)	3 mg/dL	6–20 mg/dL
Bicarbonate (HCO3–)	32.4 mmol/L	20–31 mmol/L

Given the constellation of symptoms and abnormal findings, a contrast-enhanced computed tomography (CT) scan of the abdomen and pelvis was performed. Imaging revealed a large, centrally necrotic mass in the left adnexa measuring 9.3 cm × 10.7 cm × 9.7 cm, causing anterior displacement of the urinary bladder (Fig. 1). A transvaginal ultrasound confirmed these findings and revealed a small intramural fibroid in the uterine fundus.

Fig. 1.

Arrows pointing to the large heterogeneous mass in the pelvis

Owing to the suspicion of malignancy, the patient underwent exploratory laparotomy. Intraoperatively, a large left adnexal mass was identified and surgically excised. Total abdominal hysterectomy with bilateral salpingo-oophorectomy, omentectomy, and para-aortic and pelvic lymph nodes dissection was performed to ensure complete staging and cytoreduction. Frozen section analysis of the excised mass suggested a malignant undifferentiated neoplasm.

Gross pathological examination of the left ovarian mass revealed a large, multinodular cystic tumor measuring 13 cm × 11.5 cm × 9 cm and weighing 660 g. The cut surface was tan-brown with extensive central necrosis and hemorrhage. Microscopic examination revealed sheets and nests of small, round blue cells with scant cytoplasm and hyperchromatic nuclei embedded in a myxoid background. Pseudoglandular spaces and high mitotic activity were also observed (Fig. 2A–D).

Fig. 2.

A Nests and sheets of tumor cells in a myxoid stroma within ovarian parenchyma seen at the periphery. B Cords of tumor cells with foci of necrosis. C Nests of monomorphic tumor cells with increased mitotic figures. D Pseudoglandular arrangement of tumor cells

Immunohistochemical staining showed diffuse positivity for Cam 5.2, CD56, WT-1, and CD99, with focal staining for synaptophysin. The tumor was negative for chromogranin, EMA, calretinin, CD117, CD34, and desmin. Notably, SMARCB1 (INI-1) expression was retained, whereas SMARCA4 (BRG1) expression was lost—a finding supportive of a diagnosis of SCCOHT (Fig. 3).

Fig. 3.

SMARCA4 immunohistochemical stain with loss of expression in tumor cells and positive internal control of endothelial cells

Histological evaluation of the uterus, contralateral ovary, fallopian tubes, and lymph nodes showed no evidence of malignancy. The omentum contained a single microscopic tumor deposit, and all 33 lymph nodes examined were negative. CT imaging of the chest and peritoneal cytology showed no distant metastasis. On the basis of these findings, the disease was staged as FIGO stage IIIa (pT3a).

The patient was initiated on adjuvant chemotherapy with cisplatin (80 mg/m², day 1) and etoposide (100 mg/m², days 1–3). She completed three cycles over a 3-month period, during which she experienced nausea and vomiting that were managed symptomatically, without other major adverse effects. Although her serum calcium levels remained mildly elevated during follow-up, her initial response to treatment was stable.

However, 18 months later, a surveillance CT scan revealed extensive pelvic–abdominal recurrence. The recurrent tumor appeared as multiple lobulated, heterogeneously enhancing masses forming a conglomerate lesion measuring 12.9 cm × 14.5 cm × 14.3 cm. The lesion infiltrated the anterior abdominal wall, bladder dome, and encased the surrounding bowel loops (Fig. 4).

Fig. 4.

The superior (long) arrow highlights the involvement of bowel loops from the tumor. The central (short) arrow highlights the displacement of adjacent bowel loops

Despite five further cycles of chemotherapy (regimen not specified in the available records), the tumor continued to progress. The patient subsequently declined additional treatment because of poor tolerance and disease burden. Several weeks later she presented to the hospital with an ECF. CT Imaging confirmed extensive intra-abdominal disease with tumor infiltration of the anterior and lateral abdominal walls and encasement of the ileal loops. A contained perforation of the distal ileum was identified, with contrast leakage through the incisional scar, confirming the development of an ECF. The lesion also encased mesenteric vessels and abutted the dome of the urinary bladder, consistent with advanced tumor infiltration. Histopathological confirmation was not feasible, but the CT findings were considered diagnostic.

A separate 1.6 cm × 1.6 cm presacral mass was also identified at the S2 vertebral level. Her serum calcium level at this time was critically elevated at 17.2 mg/dL.

Given the poor prognosis and lack of further curative options, palliative care was discussed with the patient and her family. She chose to leave the hospital against medical advice. Follow-up communication confirmed that she passed away at home within a week of discharge, with an overall survival of 26 months from the time of initial diagnosis. The patient was lost to follow-up on multiple occasions, which contributed to gaps in interim data and may have affected treatment outcomes. The timeline for the clinical course of the patient has been described in Table 2.

Table 2.

Timeline of the diagnosis and treatment

Time (relative to initial presentation in months)	Clinical event
0	The patient presented to the emergency room (ER) with symptoms, and all the relevant investigations were done
0.5	Total abdominal hysterectomy with bilateral salpingo-oophorectomy, omentectomy, and para-aortic and pelvic lymph nodes dissection was performed
4	Three cycles of cisplatin (80 mg/m2, day 1) and etoposide (100 mg/m2, days 1–3) were completed
7	CT scan indicated stable disease
11	Surgery was recommended, but the patient declined
18	Extensive pelvic–abdominal recurrence was noted; chemotherapy was advised
24	Five additional cycles were completed (total of nine cycles overall); the patient was subsequently lost to follow-up
26	Patient presented to the ER with enterocutaneous fistula. Palliative care was discussed. The patient passed away within a week

Discussion

SCCOHT constitutes less than 0.01% of all ovarian tumors. It predominantly occurs in young adults, typically between the ages of 9 and 55 years, with a median age of around 24 years [1, 3, 6]. It was initially recognized in 1979 by Scully, and then described in more detail by Dickersin et al. in 1982. Since 2014, the World Health Organization (WHO) has officially classified it in the category of miscellaneous ovarian tumors [7].

There are two main types of SCCOHT, namely, pulmonary and hypercalcemic. The distinguishing features of the hypercalcemic type include affecting younger women and the presence of hypercalcemia. The pulmonary type also resembles small cell carcinoma of the lung owing to its neuroendocrine differentiation [8].

Pathologists often encounter challenges in diagnosing tumors within this broad group owing to their overlapping morphological features and immunohistochemistry profiles, leading to difficulties in distinguishing between them [9]. Older studies regarding other immunohistochemical stains for this cancer are inconclusive. In some instances, neoplastic cells show focal positivity for epithelial membrane antigen (EMA), broad-spectrum cytokeratin, calretinin, and CD10, while consistently testing negative for desmin, S100, and inhibin. Occasionally, neoplasms display focal positivity with neuroendocrine markers. Furthermore, most cases demonstrate diffuse nuclear positivity when tested with an antibody targeting the N-terminal of WT1 [10]. Thus, these tests alone are not enough for a differential diagnosis of SCCOHT, as it needs to be distinguished from a variety of primary or metastatic ovarian tumors, including adult and juvenile granulosa cell tumors, small cell neuroendocrine carcinoma (metastatic or pulmonary type), and germ cell tumors.

Recent advancements in technology and genome sequencing have enabled the examination of genomic alterations in ovarian cancers. Several tumors are associated with mutations in SMARC genes, but SMARCA4 mutations have a strong correlation with SCCOHT, and these mutations can be germline or somatic [11]. The SMARCA4 (BRG1) gene is located on chromosome 19p, and its product is part of the SWI/SNF chromatin-remodeling complex. The loss of SMARCA4 is believed to create a reliance on SMARCA2-containing SWI/SNF complexes, which drive oncogenic pro-survival and anti-apoptotic signaling through changes in gene expression [12] . Owing to the high frequency of SMARCA4 gene mutations in SCCOHT, the lack of SMARCA4 protein could be an important diagnostic marker for this highly deadly disease affecting women, and even play a potential role in treatment. Our case showed complete loss of SMARCA4 with retained expression of the SMARCAB1 gene, as observed through immunohistochemical staining. Although the association of SMARCA4 was discovered in 2014, not all cases tested for it in their diagnoses. Tischkowitz et al. [3] highly recommend performing SMARCA4 IHC staining to aid in diagnosing ovarian neoplasms when SCCOHT is a differential consideration, and when a definitive diagnosis of another neoplasm is not possible. Currently, SMARCA4 IHC is not routinely available in many pathology laboratories. As a result, the actual number of women affected globally is still unclear, posing challenges in identifying suitable candidates for new treatments or clinical trials.

According to a study conducted by Young et al. [6], favorable prognostic factors for SCCOHT include localized stage of the tumor, size less than 10 cm, patient age above 30 years, and absence of large cells. Our 30-year-old patient presented with a 13 cm × 11.5 cm × 9.5 cm tumor and a microscopic omental deposit, with a survival duration of 26 months. Survival is poor, with six out of seven patients dying of complications within 27 months of diagnosis [1]. Our case was further complicated by multiple lapses in follow-up, a factor that may have influenced disease progression and outcomes, and which highlights the challenges of continuity of care in such settings.

There have been some previous reports similar to our case. Keikha et al. [13] reported the case of a 22-year-old woman who presented with SCCOHT, which caused ovarian torsion. The patient opted for unilateral salpingo-oophorectomy and chemotherapy, but unfortunately, she experienced relapse and passed away 6 months after the initial diagnosis. Bruno et al. [14] reported a recent case of SCCOHT in a 20-year-old woman who, following surgical resection, received chemotherapy combined with autologous stem cell transplantation, resulting in a relapse-free survival of 28 months. Unlike these reports, our case was complicated by the development of an ECF secondary to tumor infiltration—a progression pattern that, to our knowledge, has not been previously documented in SCCOHT. This highlights a rare manifestation of local tumor aggressiveness and expands the spectrum of complications associated with this malignancy.

An ECF is defined as abnormal communications between the bowel and skin [15]. Almost 90% of ECFs arise as postoperative complications, while other important etiologies, either alone or in combination with prior surgery, include inflammatory bowel disease, trauma, and malignancy [16]. ECFs in the setting of malignancy are particularly challenging, as they rarely close spontaneously and often hinder the administration of further oncologic therapy, thereby worsening prognosis and quality of life [17].

At present, there exists no universal consensus on the best course of action for the treatment of SCCOHT owing to its poor prognosis. The current adjuvant treatment only results in modest improvements in survival, highlighting the critical need for novel therapies [18]. SCCOHT serves as an excellent prototype for developing novel therapies targeting driver genes and related pathways. Recent advancements in molecular genetics can guide optimal management and enhance our understanding of pathogenesis. However, the rarity of SCCOHT limits the feasibility of prospective clinical trials [11].

Conclusion

The above case involves a 30-year-old woman who underwent bilateral salpingo-oophorectomy, hysterectomy, and lymph node dissection upon diagnosis of SCCOHT but ultimately succumbed to disease progression despite chemotherapy. The recent identification of SMARCA4 mutations as key drivers of SCCOHT offers promising opportunities for diagnosis and targeted therapies. However, many cases may go undiagnosed or misclassified, especially in low- and middle-income countries, where access to molecular testing is limited. Making SMARCA4 IHC more widely available in such settings is essential—not only to ensure accurate diagnosis but also to lay the groundwork for future research and more effective, individualized treatment strategies.

Abbreviations

SCCOHT

Small cell carcinoma of the ovary, hypercalcemic type

CT

Computed tomography

WHO

World Health Organization

EMA

Epithelial membrane antigen

ECF

Enterocutaneous fistula

Author contributions

EF, NK, and NUD performed the histological and immunohistochemical evaluation and literature review. EF drafted the manuscript. JA-G participated with correspondences, reviewing, and editing the drafted manuscript as per journal policy, as well as the submission of the article. All authors read and approved the final manuscript.

Funding

No financial support was provided for this study.

Availability of data and materials

Data and materials of this work are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

This study was granted an exemption from full ethical review, since clinical pictures of the patient or any information that could directly identify the patient were not used.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Competing interests

It is declared that all authors have no conflict of interest.