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.

Survival according to stage at diagnosis (from PMID: 26975901 ).

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.

Signs and symptoms

Women with SCCOHT may present with various symptoms associated with a pelvic mass or advanced ovarian cancer. These commonly would include pelvic pain, frequent urination, bloating, early satiety, nausea, and menstrual irregularities. Increased abdominal girth may be a sign associated with a large abdomino-pelvic mass or large volume ascites.

Physical exam findings

For most women with small ovarian masses, physical exam findings may be within normal limits. A pelvic mass may be appreciated on pelvic exam if the mass is of sufficient size to be differentiated from surrounding soft tissues. Abdominal exam may identify a palpable abdominal mass in women with sizable omental disease, or other related findings. Imaging features are likely to be more useful during the initial evaluation of symptoms than physical findings.

Differential diagnosis

Differential diagnosis for SCCOHT can be wide. There are numerous histologic mimics of SCCOHT discussed previously (see Section “Pathology”). Based on the extreme rarity of this tumor, initial clinical symptoms, and radiographic presentation, it can be very challenging for a reasonable practitioner to include SCCOHT in a preoperative differential diagnosis. Thus, most cases are encountered incidentally and only diagnosed at the time of permanent histologic sectioning. This lack of preoperative suspicion also hampers research efforts that often rely on newly diagnosed, untreated specimens for tissue banking and creation of patient-derived xenograft models.

Tumor markers

There are no clear serum tumor markers for women with SCCOHT. CA125 is often elevated due to involvement of the ovary and/or peritoneum. The increased expression can be variable, but when elevated preoperatively it can be a useful surveillance tool for recurrent disease. Other routine tumor markers such as CEA, CA19–9, inhibin, AFP, LDH, and hCG can be useful in the preoperative differential diagnosis. In some situations, these tumor markers may be elevated, but this would also open the differential to other types of ovarian tumors.

Hypercalcemia is found in up to 60% of cases. Common symptoms of hypercalcemia include dehydration, nausea, vomiting, constipation as well as neurologic symptoms such as confusion, lethargy, and fatigue. Serum calcium levels should be monitored at diagnosis and certainly in the recurrent setting.

Imaging studies

Many women with SCCOHT present with a pelvic mass. Often a pelvis sonogram is ordered based on symptomatology or findings at the time of pelvic exam. If a suspicious pelvic mass is identified, a CT scan of the abdomen and pelvis with oral and nonionic intravenous contrast should be performed. A chest CT should be added if extra-pelvic disease is identified. Common sites for metastatic disease outside the pelvis include the omentum, peritoneum, lymph nodes, and the liver. An MRI of the pelvis can be helpful to further characterize the morphology of a pelvic mass and identify invasion into surrounding structures.

Diagnostic testing

The definitive diagnosis if SCCOHT is made with tissue evaluation. Surgical resection, excisional biopsy, and incisional biopsy are all reasonable approaches to diagnose SCCOHT. Due to the rarity of this entity as well as the presence of histologic mimics, a correct diagnosis of SCCOHT can be quite challenging. In 2014, three independent research groups identified universal SMARCA4 mutations in SCCOHT. Robust antibodies exist for SMARCA4 protein. DNA sequencing or immunohistochemistry protein evaluation should be performed on all suspected cases of SCCOHT. If a mutation or loss of protein expression is not identified in the tumor cells, a diagnosis of SCCOHT should be strongly reconsidered. SMARCA2 protein is also, and uniquely, lost in SCCOHT, which can help with evaluating the differential diagnosis. SMARCA4 is the most useful biomarker for confirming the diagnosis of SCCOHT.