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Small cell carcinoma of the ovary, hypercalcemic type
Clinical case
A 22-year-old G0 female presents with a newly diagnosed small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). She reported pelvic pain and her physical exam was within normal limits. Pelvic sonography identified a 5 cm complex cystic mass in the left ovary with increased vascularity in multiple nodules ( Fig. 7.1 ). She was thought to have an endometrioma and was taken to the operating room by a gynecologist where she had a left ovarian cystectomy performed. Intraoperative findings did not identify any evidence of disseminated disease. There was cyst rupture during the procedure, and preoperative tumor markers were not sent. Final pathology identified SCCOHT, and the patient underwent completion left oophorectomy with comprehensive minimally invasive surgical staging by a gynecologic oncologist. She was diagnosed with FIGO stage IIIA SCCOHT with disease found in the residual ovary and one aortocaval node, but all other specimens were negative. She is in excellent health and has her contralateral ovary in situ . The patient desires fertility-sparing treatment for her disease. How do you treat this patient?
Epidemiology
Incidence and mortality
SCCOHT unfortunately shares a similar name with small cell neuroendocrine carcinoma of the ovary (sometimes termed pulmonary type), and these two exceedingly rare histologies are often confused. The molecular basis of these two malignancies is distinct, and the cells of origin, though unknown at present, are likely different. This chapter will focus on SCCOHT. SCCOHT is a very rare and aggressive malignancy usually identified in teenage girls and young women. The mean age at diagnosis is 24 years and most cases occur before age 40. The long-term survival for advanced stage cases is extremely dismal; however, more recent reports suggest some anecdotal success with targeted therapeutics, as discussed below. The true incidence of SCCOHT is unknown due to historical difficulty with making a definitive diagnosis and a myriad of histologic mimics, such as poorly differentiated sex cord stromal tumors and various tumors that are metastatic to the ovary. Based on informal discussions with various global experts who have access to registry data, a very rough estimate of SCCOHT incidence of 0.1% of all ovarian cancer cases are SCCOHT, which would translate to ~ 22 cases per year in the United States. The true incidence is unknown; however, as definitive diagnoses are becoming more robust, this estimate may become more precise over the next decade. The ensure the most accurate diagnosis, histologic assessments should be routinely coupled with protein or DNA analyses as discussed below. The largest collective case series to date collated 293 patients to analyze clinical, pathologic, and genetic features. The overall survival for all patients with available data was 39%, and few patients recurred after 5 years as may be expected for an aggressive malignancy. Stage for stage, SCCOHT has a worse prognosis than most ovarian cancers. The collective review reports a five-year survival of 55% for stage I patients, 30 to 40% for stage II and III, and no long-term survival for patients diagnosed at stage IV ( Fig. 7.2 ). The actual survival for patients with available data was 39% and few patients recurred after 5 years as may be expected for an aggressive malignancy.
Etiology and risk factors
The etiology of SCCOHT remains mostly a mystery at this point. A number of laboratories are conducting complex studies to try and identify the cell of origin. The tumor has many molecular and morphologic similarities to malignant rhabdoid tumors suggesting a mesenchymal origin, but details are far from clear. The only well-defined risk factor for SCCOHT is genetic predisposition due to inherited germline mutation in SMARCA4 . These germline mutations should certainly be suspected in any family member with more than one case of SCCOHT, which unfortunately has been reported several times in addition to other known cases that have not been published. The exact frequency of SMARCA4 germline mutations in SCCOHT is estimated to be between 10% and 40% and the penetrance is presently unknown though inheritance patterns are generally paternal. This wide range of estimates is due to ascertainment bias where some cases are collected from genetic testing clinics and others originate from oncologic practices. All patients with SCCOHT should have germline genetic testing for SMARCA4 . If the proband is unavailable for testing, at-risk first-degree family members should have genetic counseling and consider testing. SMARCA4 is a member of the SWI/SNF chromatin-remodeling complexes and has defined roles in transcriptional regulation, DNA-damage repair, and immune surveillance.
Pathology
Gross
Tumors are unilateral, large (mean 15 cm), soft and fleshy, gray-tan, and predominantly solid, but may have a cystic component, and often with areas of hemorrhage and necrosis. The external surface is smooth or nodular. Familial cases may be bilateral.
Histopathologic features
SCCOHT is typically characterized by small monomorphic undifferentiated cells with high nuclear-cytoplasmic ratio and brisk mitotic activity ( Fig. 7.3 A ). The tumor cells are arranged in solid sheets, nests, cords, or trabeculae with little intervening stroma. Follicle-like spaces filled with eosinophilic or basophilic secretions are a characteristic histologic feature ( Fig. 7.3 B). Areas of geographic necrosis and vascular invasion are frequent findings. Approximately half of these tumors exhibit varying proportions of large cells with abundant eosinophilic cytoplasm and are designated as the “large cell variant of small cell carcinoma.” The tumor cells have eccentrically placed nuclei and along with the abundant eosinophilic cytoplasm impart a rhabdoid appearance. Mucinous cysts and glands may be present in a subset of cases. Rarely the mucinous component may be malignant.
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