Academic Editor: Enrique Hernandez
Background: Small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare but highly undifferentiated, aggressive malignancy that primarily affects young women. Most SCCOHT patients present with advanced disease and have a very poor prognosis. Although several therapeutic regimens have been proposed, there is no consensus on the optimal treatment strategy. Case: Herein, we describe three cases of advanced-stage SCCOHT aged from16 to 36 treated with cytoreductive surgery and chemotherapy with or without immune checkpoint blockade treatment. With different strategy, the patients showed utterly different outcomes. Conclusion: The cases highlight the importance of prompt diagnosis as well as early, aggressive, and combined modality treatment of SCCOHT. We believe that improved therapies could result in more young patients surviving SCCOHT.
Small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a rare, highly undifferentiated, aggressive ovarian malignancy of unknown cell origin, which usually occurs in young women. It was first described by Dickersin et al.  in 1982 as paraneoplastic hypercalcemia. Several therapeutic regimens have been proposed for SCCOHT; however, to date, there is no consensus on the optimal treatment strategy. With the development of high-throughput sequencing technology, molecular characteristics of SCCOHT have been gradually revealed, and new molecular targets have been proposed. Herein, we describe three SCCOHT cases with different clinical stages, different treatment approaches, and different outcomes and present an overview of the clinical and pathological features, molecular features, multimodality treatment or therapy, molecular targeting and immunotherapy, genetic counseling, and prevention of SCCOHT.
Patient A was a 36-year-old G2P1 female who was
admitted to the Third Hospital of Peking University in December
2019 with acute abdominal pain, and abdominal distension accompanied by fever.
Bilanual gynecological examination revealed a 9 cm cystic, solid mass in front of
the uterus. Serum calcium and tumor markers were within normal
limits. Pelvic abdominal computerized tomography (CT) indicated
Pelvic abdominal CT, intraoperation view and paraffin
pathological picture of patient A. (A–C) Pelvic abdominal CT.
(A) A plain scan. (B) An arterial phase of enhancement, and (C) is a
venous phase of enhancement. The density of the mass in the plain scan was not
uniform. The lumen was soft tissue density, the extension of the vessels could be
seen at the enhancement stage, the solid components of the mass at the venous
stage were strengthened, the peripheral enhancement was high, suggesting that the
mass could be malignant. (D) Laparoscopic exploration. The right ovary had a
solid but brittle enlargement of 10 cm, a rich blood supply, and a 2 cm incision.
Oozing blood was observed on the surface. (E) Monomorphic round cells with many
After the operation she received, she received three courses of chemotherapy
of TC (paclitaxel 135–175
In August 2020, a 1 cm mass in the right lower abdominal wall was found on the CT, just after the last chemotherapy cycle. The pathology suggested a metastatic lesion of SCCOHT. Considering the disease was not controlled during both the preoperative TC chemotherapy and postoperative EP chemotherapy, cancer-targeted drugs were prescribed. Five courses of anti-PD1 (sintilimab 200 mg injection, the regimen was given every 21 days) were given for 4 months. Ponatinib (protein receptor tyrosine kinase inhibitor) 45 mg qd was used as a maintenance treatment. Follow-up was performed every three months (laboratory tests and ultrasound). At the last follow-up (January 2021), the patient was still alive, showing no signs of recurrence.
Patient B was a 15 years old girl who was admitted to The
Third Hospital of Peking University emergency department in October 2012 due to
epigastric pain and a high fever (38
Pelvic abdominal CT. (A) Huge pelvic mass. (B) A 9 cm mass between the liver, stomach, and pancreas, increased during the chemotherapy.
Fourteen days after the operation, an abdominal ultrasound indicated a 7 cm
nodule between the liver, stomach, and pancreas, which was considered a residual
lesion, and a 1 cm lesion on the liver surface, which was considered a metastatic
lesion. Six courses of EP regimen (etoposide 100 mg/m
Patient C was a 33 years old girl who suffered from abdominal distension for two
months. She was diagnosed with myoma or leiomyoma of the uterus and underwent
laparoscopic hysterectomy in another hospital in November 2018. The pathological
findings were initially diagnostic of HGSC of the ovary. Based on this diagnosis,
the patient received three-course chemotherapy of TC (paclitaxel 135–175
The SCCOHT is a rare ovarian tumor with poor prognosis that was first described in 1982 . In the landmark study by Young et al. , the clinical and pathological features of SCCOHT were analyzed. The minimum age of onset was 14 months. The tumor primarily affected young women with a median of 23 years. The clinical signs were nonspecific and mainly included abdominopelvic pain or distension, weight loss, nausea, and vomiting; approximately 60% of SCCOHT cases presented with paraneoplastic hypercalcemia [2,3]. The recurrence rate was 65.1%, and the average recurrence time was 11.5 months [4,5]. The three cases discussed in this report were all PD (progressive disease) after the initial treatment. Most patients are diagnosed at an advanced stage, and the overall long-term survival rate in SCCOHT patients is only 10% to 20% [4,6,7].
The tissue of origin of SCCOHT has been inconclusive. A small cluster of round or oval cells with sparse cytoplasm, hyperchromatic nuclei, prominent nucleoli, and active mitotic figures was found in all three cases presented in this study (Fig. 3). The pathological basis of SCCOHT still remains unclear. SMARCA 4 (SWI/SNF related, matrix associated, actin-dependent regulator of chromatin, subfamily member 4) gene mutation and the relative BRG-1 protein deficiency is the important molecular feature of SCCOHT (Fig. 3) [8,9].
Histological features of SCCOHT. (A,B) The tumor cells were
found to be infiltrating and growing in a flaky, dense nest with small cells and
fibrous cords (
To date, there is no consensus on the optimal strategy for SCCOHT. Among three cases presented in this study, patient B was the youngest but the worst prognosis, which may be related to the lack of experience in the diagnosis and treatment of this rare disease at that time. Pautier et al. , reported a prospective study in which the patients underwent nonconservative debulking surgery, semi-intensive chemotherapy (cisplatin, adriamycin, etoposide and cyclophosphamide), high-dose consolidation chemotherapy (carboplatin, etoposide and cyclophosphamide) followed by autologous hematopoietic stem-cell transplantation, (AHSCT). The outcomes were better for early-stage patients although late-stage diseases remain difficult to manage. The understanding of pathogenesis and development of related targeted drugs has gradually brought certain benefits to the patients. Also, the International SCCOHT Consortium (ISC) presented guidelines for the diagnosis and management of SCCOHT in 2020 which make clinical strategy reasonable . Resect primary ovarian tumor and base diagnosis on expert gynecologic pathology review are needful and chemotherapy should be followed. For recurrent disease, obtain biopsy as clinically indicated and encourage patients to participate in clinical trials. Genetic testing for patient and family members is recommended.
For newly diagnosed cases, primary ovarian tumor resection and diagnosis by gynecologic pathologist are necessary. In this report, cytoreductive surgery was performed in all three cases. Initiate cytotoxic chemotherapy included cisplatin and etoposide regimens (e.g., BEP or similar). For patient A, three courses of TC as neoadjuvant chemotherapy were used. As the disease progressed and tumor mass was found during the second surgery, chemotherapy was changed to EP. Radiation therapy may be considered after chemotherapy for the residual disease, but the efficacy remains uncertain.
For recurrent disease, the principles for recurrent ovarian cancer are applicable. As chemotherapy has limited effectiveness, surgery can be given after the administration of targeted drugs and immunotherapy. Chemotherapy with cisplatin and etoposide regimens or alternative chemotherapy regimens (cyclophosphamide, doxorubicin, vincristine; or carboplatin, paclitaxel; or topotecan; or similar) can be combined with other treatments. SCCOHT patients should be encouraged to participate in clinical trials if available and consider off-label immune checkpoint blockade treatment based on drug availability. In patient A, anti-PD1 and ponatinib were used; In patient C, anti-PD1 and Bevacizumab were used. Both patients benefited from the off-label drugs, which will be discussed in more detail.
SMARCA4 is involved in many cellular processes, including transcriptional regulation, DNA damage repair, differentiation, and mitosis. The targeted drug should be focused on several approaches, including exploiting known synthetic lethal interactions of SMARCA4 loss and identifying novel targets through unbiased genetic screens (Table 1).
|Class||Target||Drug||Clinical trial available for SCCOHT|
|Epigenetic||EZH2||Tazemetostat||Phase II NCT02601950|
|therapeutics||LSD1||Seclidemstat||Phase I, NCT03895684|
|CDK4/6||Palbociclib||Phase II, NCT03297606|
|Immunotherapies||PD-1||Pembrolizumab||Phase II, NCT03012620|
Impaired function of the mSWI/SNF complex leads to histone-lysine N-methyltransferase (EZH2) abnormal recruitment to target genes . Selective EZH2 inhibitor tazemetostat has shown an anti-tumor effect in a rat model. Recently, tazemetostat has been approved by the FDA for the treatment of epithelioid sarcoma. The arm accruing patients with SCCOHT in phase II multiarm trial (ClinicalTrials.gov identifier: NCT02601950) was stopped for futility. Of note, 1 patient with SCCOHT was reported to have a PR of 32 weeks [13,14]. One way to improve efficacy may be to combine EZH2 inhibitors with histone deacetylase inhibitors, such as panobinostat or quisinostat, which demonstrated a greater synergistic anti-tumor effect than monotherapy .
A similar approach is used with inhibitors of lysine-specific demethylase-1 (LSD1/KDM1), which is upregulated in SWI/SNF-mutated cancers. The LSD1 inhibitor seclidemstat (SP-2577) demonstrated anti-tumor activity in murine models. A phase I trial (NCT03895684) has been recently designed to investigate the clinical effect of seclidemstat, for patients with SWI/SNF-mutant gynecologic cancers, with an emphasis on SCCOHT, ovarian clear cell carcinomas, and endometrial carcinomas.
Bromodomain and extraterminal motif (BET) inhibitors are other potential drugs for SCCOHT. In vivo studies showed anti-proliferative effects of BET inhibition such as OTX015 in SMARCA4-deficient SCCOHT by downregulating the oncogenic HER3 and other receptor tyrosine kinases . BET inhibitors can also promote an anti-tumor response, decrease regulatory T cells, increase TILs, and synergism in vivo with anti-PD1 therapy .
Targeting other histone modification complexes, HDACi has been clinically approved for the treatment of several hematologic malignancies. Several studies have shown that HDAC is in the context of SCCOHT results in re-expression of SMARCA2, which strongly suppresses the growth of SCCOHT cells . One of these reports also showed in vivo sensitivity of SCCOHT cells to the HDACi Quisinostat.
A previous study showed the SCCOHT cell line’s dependence on a variety of protein receptor tyrosine kinase (RTK) . Ponatinib, an RTK inhibitor approved for clinical use, was found to have a strong inhibitory effect both in vitro and in vivo preclinical models through its inhibition of multiple kinases . Furthermore, inhibition of EGFR2, CSF1R, and VEGFR negatively affect the recruitment and survival of myeloid-derived suppressor cells, thus suggesting ponatinib has a role in modulating the immune microenvironment for anti-tumor effect .
Xue et al.  found that silencing cyclin-dependent kinase4/6 (CDK4/6) may significantly inhibit SCCOHT cell growth by screening short hairpin RNA (shRNA) library. In vitro and in vivo studies suggested that SCCOHT is sensitive to palbociclib, a CDK4/6 inhibitor that has been used in the clinical treatment of ER+ and HER2-breast cancer. The mechanism of action is related to the decrease of cyclin D1 expression and the restriction of CDK4/6 kinase activity due to SMARCA4 deficiency. The Canadian Profiling and Targeted Agent Utilization Trial (NCT03297606), a pan-Canadian phase II basket trial, has recently approved a new match to treat SMARCA4-mutant tumors with the CDK4/6 inhibitor palbociclib based on the findings [20,21].
Although the low mutation burden of SCCOHT would not predict responsiveness to immune checkpoint blockade (ICB), anti-PD1-antibody including pembrolizumab have shown substantial and durable responses in selected patients with recurrent SCCOHT after prior treatment . A French phase II basket trial AcSe program with pembrolizumab (NCT03012620) is currently open for women with rare ovarian tumors, including relapsed SCCOHT. The application of SCCOHT’s immune microenvironment and PD-1/PD-L1 inhibitor needs further study.
To the best of our knowledge, this is the first study reporting on the use of ponatinib or combined antiangiogenic therapy bevacizumab and immune checkpoint blockade (ICB) in patients with SCCOHT. Although patient C was misdiagnosed at another hospital and suffered from rectovaginal fistula even progressed during chemotherapy, after full communication with the patient, she was treated with ICB and Bevacizumab, which put the progression of the disease under control, and the second tumor cell reduction was satisfactorily performed. Currently, ICB is performed as maintenance therapy. She is among rare stage IV patients who benefited from the targeted drugs and was still having a good quality of life. Although patient A was timely diagnosed and received standard treatment, despite the change of chemotherapy regimen, the relapse still occurred over a short time, which might be related to the laparoscopic surgery. Considering an uncontrolled condition, five courses of ICB were performed, and Ponatinib was used as a follow-up treatment, as was also reported in previous studies. Although there are some side effects such as low fever, body aches, and leukopenia, the patients still benefited from the targeted drugs.
Owing to the rarity of the tumor and a lack of large series evaluating therapeutic strategies, more case series reports and multicenter analyses are needed to further investigate this rare disease and optimize clinical treatments. Blocking of PD1/PD-L1 is being studied in several malignancies, with good responses, including patients with SCCOHT, and some benefit has been reported, as it is also shown in our cases. Therefore, immunotherapy should be considered in the treatment of these devastating ovarian tumors. We hope that additional viable options will become available as more preclinical and translational studies are being reported and that more SCCOHT patients will benefit from them.
SMARCA4 germline variation is still possible in SCCOHT patients who do not have a family history of SCCOHT . Therefore, patients diagnosed with SCCOHT, with or without a family history of SCCOHT, are advised to seek professional genetic counseling. If SCCOHT patients do not carry the SMARCA4 germline variant, unaffected ovaries’ retention may be considered based on clinical conditions, tumor stage, and other factors. All patient relatives with germline mutations should undergo genetic counseling and mutation detection. Considering the early onset of SCCOHT, poor prognosis, and lack of an effective test, young women with SMARCA4 germline variant, may be considered for prophylactic ovariectomy. In order to achieve fertility preservation and genetic blocking of hereditary tumor families, the carriers may be considered for assisted reproductive technologies before prophylactic ovariectomy .
The SCCOHT is a rare disease with a poor prognosis. Due to the rarity and lack of large series evaluating therapeutic strategies, the clinical diagnosis and treatment experience are worth summarizing as its molecular characteristics are likely to guide the best prevention and treatment. To achieve the most reasonable treatment and genetic tumor prevention, attention should be paid to multidisciplinary cooperation, including gynecological oncology, pathology, genetic counseling, and assisted reproduction. One of the most important things is to pay attention to the mechanism of SMARCA4 driving tumor formation and the development of targeted drugs.
SCCOHT, Small Cell Carcinoma of the Ovary, Hypercalcemic Type; CT, Computerized Tomography; SMARCA4, SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A, Member 4; HRD, Homologous Recombination Deficiency; PD-1, Programmed cell Death 1; PD-L1, Programmed cell Death Ligand 1; PD, Progressive Disease; BEP, Bleomycin Etoposide Platinum; DNA, DeoxyriboNucleic Acid; EZH2, Enhancer of Zeste Homolog 2; LSD1, Lysine-specific Histone Demethylase 1; HDAC, Histone Deacetylase; RTK, Receptor Tyrosine Kinase; CDK, Cyclin-dependent Kinase; HGSC, High-grade Serous Carcinoma.
QH wrote the manuscript and designed the figures. HYG revised the draft. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript.
All subjects or their family members gave their informed consent for inclusion before they participated in the study. The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Institutional Review Board of the Third Hospital of Peking University (approval number: IRB00001052-06058). All patients or their family members have consented to the submission of the case report.
We would like to express our gratitude to all those who helped us during the writing of this manuscript. Thanks to all the peer reviewers for their opinions and suggestions.
This research received no external funding.
The authors declare no conflict of interest.