August 2018 Case

John Paul Govindavari, MD (Resident) and Shivani Kandukuri, MD (Faculty)

67 year-old female with several years' history of an adnexal mass, sonographically consistent with a dermoid tumor, presented with a chief complaint of several months of worsening abdominal distension, urinary frequency, and pelvic pressure. She underwent a laparoscopic bilateral salpingo-oophorectomy which revealed a 10 cm ruptured cyst. Intraoperative frozen section findings were consistent with mature teratoma.

13 cm unilocular pink-tan cystic structure filled with viscous tan-white fluid. Internal lining was generally smooth but had focal shagginess.

• Ki-67: 30%
• P53: Diffusely positive
  

Cystic sebaceous tumor, consistent with well-differentiated sebaceous carcinoma

Malignant Teratomas
Benign mature teratomas are quite common, with malignant transformation occurring rarely in less than 2% of cases. Mature teratomas with malignant transformation are often larger than benign tumors, with >90% of them measuring 10-20 cm with a gross cauliflower-like mass, mural nodule or plaque protruding into the cyst cavity. Currently only 9 cases of sebaceous carcinoma arising within a mature teratoma have been reported, with the estimated incidence rate of 1 to 2 per 1,000,000 per year.

Sebaceous carcinoma is a malignancy derived from the adnexal epithelium of sebaceous glands, and most commonly arises from the Meibomian glands of the eye. Although the exact pathogenesis is unclear, some believe that sebaceous carcinomas arise from pluripotent stem cells, while others suggest that they develop from malignant transformation of differentiated sebaceous cells.

Histologically, sebaceous carcinomas have basaloid cells arranged in sheets with cytologic atypia and central areas of necrosis. Immunohistochemistry reveals overexpression of P53 and ki67, as seen in some reported cases, like in our case. Sebaceous carcinomas arising in mature teratomas are grossly and microscopically similar to those arising from other sites, but are more frequently large, with a squamoid appearance and occasional squamous pearls. It is important to remember these tumors must be distinguished from basal cell carcinomas with sebaceous differentiation and sebaceous adenomas.

Given the paucity of data directing the management of patients with extraocular sebaceous carcinoma, the optimal treatment plan for these patients remains unclear. None of the patients diagnosed with sebaceous carcinomas arising from a mature teratoma have developed recurrent disease, with follow up durations ranging from 4-72 months. In reviewing the literature, 3 patients with stage IA-IIIC disease were treated with adjuvant chemotherapy, regimens including Cyclophosphamide and Adriamycin or Cisplatin, Bleomycin and Vinblastine. Compared to those with expectantly managed disease, there was no overall survival advantage. Although ocular sebaceous carcinomas are aggressive, often recurring locally after surgical resection and metastasizing via lymphatics, the prognosis of extraocular sebaceous carcinoma is thought to be far better.

In our case, the tumor was localized to the ovary until immediate pre-operative incidental rupture occurred, thus upstaging from stage IA to stage IC disease. Research indicates that malignant dermoid cysts confined to the ovary have good overall 5-year survival rates approaching 75%. In general, capsular rupture and tumor extension are strong poor prognostic factors in cases of mature teratomas with malignant transformation (these conclusions are based on pooled data of all histologic types of malignant transformation within a mature dermoid, and are not specific to sebaceous carcinoma). However given this data, we opted to complete surgical staging via a second procedure, which confirmed only localized disease. Considering the additional morbidity of adjuvant therapy with no clear evidence of survival benefit, the patient has chosen to proceed with frequent surveillance.

This is a rare genetic condition with autosomal dominant inheritance that is clinically characterized by the presence of at least one sebaceous skin tumor and at least one visceral malignancy, typically of the gastrointestinal or genitourinary tract. Muir-Torre syndrome is a phenotypic variant of Lynch Syndrome and results from mutations in DNA mismatch repair genes. Screening for mismatch repair defects or microsatellite instability with IHC reveals have shown high positive predictive value for detecting Muir-Torre syndrome. Therefore, most experts recommend screening all sebaceous neoplasms, ocular, cutaneous or visceral, for mismatch repair defects.

In our case, no germline mutation (Muir Torre or Lynch syndrome) was detected. But she is microsatellite instability high which is clinically significant in terms of future treatment options, as the FDA has now approved the use of PD1 checkpoint inhibitors for patients with metastatic or unresectable solid tumors with evidence of mismatch repair deficiency or microsatellite instability.

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