Other rare ovarian cancers: Transitional cell carcinoma, malignant Brenner tumor, endometrioid carcinoma, mesothelioma, squamous cell carcinoma, sarcoma

Introduction

Ovarian cancer encompasses a wide variety of tumors, all with different clinical patterns, histologies, and molecular features. Ovarian cancer is typically classified as epithelial (serous, mucinous, endometrioid, clear cell, carcinosarcoma, and mixed) vs nonepithelial (germ cell and sex cord stromal cell). Epithelial ovarian cancers, which comprise 90% to 95% of all ovarian cancer cases, are more common than nonepithelial ovarian cancer. However, there are a group of ultrarare subtypes such as transitional cell carcinoma, endometrioid carcinoma, neuroendocrine tumors (NETs), mesothelioma, squamous cell carcinoma, and ovarian sarcomas. Most of the literature for these subtypes comes from case reports, small case series, and population database resources whose data sources lack the details necessary to make any specific treatment recommendations. In this chapter, we will review these ultrarare subtypes of ovarian malignancies and make recommendations for treatment based on the current literature as well as drawing from similar histologic subtypes from other primary tumor sites.

Transitional cell carcinoma

Transitional cell carcinoma of the ovary is a rare histological type of epithelial ovarian cancer that was first described in 1987 by Austin and Norris ( Table 8.1 ). Similar to other transitional cell tumors such as Brenner tumors of the ovary, transitional cell carcinomas of the ovary contain urothelial-like tissue that closely resembles transitional cell carcinoma of the bladder. Unlike Brenner tumors, however, they lack the dense stromal calcifications and epithelial-type histologic patterns. In fact, molecular and immunohistochemical studies have further distinguished transitional cell carcinoma of the ovary from Brenner tumors by showing a resemblance to high-grade serous carcinomas. Molecular and genetic analysis also demonstrated that ovarian transitional cell carcinomas follow a tumorigenic pathway like that of high-grade serous tumors with frequent TP53 mutations. In the light of new evidence, in the new WHO classification system released in 2014, transitional cell carcinoma of the ovary is no longer considered a separate entity but a variant of high-grade serous (or rarely endometrioid) ovarian carcinoma.

Very few studies have examined the clinical significance of ovarian transitional cell carcinomas. Given the rarity of this tumor, the true incidence of the disease is unknown, but studies have reported incidences ranging from 1% to 2% of cases of ovarian cancer. The clinical presentation is like that of other epithelial ovarian cancers, including symptoms such as abdominal pain, bloating, back pain, and urinary or bowel symptoms. Given the close resemblance to transitional cell carcinomas of the bladder, the differential diagnosis includes metastatic urothelial carcinoma of the urinary tract. Often, it is very difficult to discern the origin of transitional cell carcinomas based on conventional histological stains alone. While Brenner tumors of the ovary and transitional cell carcinomas of urothelial origin express certain cytokeratins and uroplakins, ovarian transitional cell carcinomas usually do not. Therefore, in some cases, immunohistochemistry may be helpful in distinguishing transitional cell carcinomas of ovarian origin from those of urothelial origin. The lack of expression of urothelial markers also supports the idea that transitional cell carcinomas of the ovary originate from Mullerian epithelium rather than being a urothelial neoplasm.

The gross appearance of the tumor is similar to high-grade serous carcinoma, with no specific distinguishing features. Tumors are large and can be solid and cystic with areas of hemorrhage and necrosis.

As mentioned earlier, the 2014 WHO Classification of Female Genital Tumors transitional cell carcinoma was considered a variant of high-grade serous carcinoma. The 2020 WHO Classification of Female Genital Tumors further highlights that high grade serous carcinoma with homologous recombination-deficiency frequently display solid, endometrial-like and transitional patterns. Tumors with transitional pattern are characterized by large papillae lined by multilayered/stratified epithelium, resembling urothelial mucosa ( Fig. 8.1 ). Microcysts or punched out spaces are typically seen with the epithelium ( Fig. 8.2 ). The nuclei are high-grade with significant pleomorphism. Most cases, upon adequate sampling, show areas of more typical high-grade serous carcinoma with papillary, cribriform, slit-like, and glandular patterns. Transitional cell carcinoma and high-grade serous carcinoma share similar immunophenotype. Both tumors are positive for PAX-8, WT-1 ( Fig. 8.3 ), and hormone receptors.

The most important differential diagnoses are metastatic urothelial carcinoma to the ovary and malignant Brenner tumor (MBT). Clinical history of bladder cancer is essential to exclude metastatic urothelial carcinoma. Histologically, the two tumors are very similar; however, the presence of more typical areas of high-grade serous carcinoma would support an ovarian primary. Immunohistochemically, unlike ovarian transitional cell carcinoma, urothelial carcinomas are positive for CK20, GATA3, and uroplakin (~ 50% of cases), while negative for WT-1 and hormone receptors. PAX-8 can be positive in both tumors.

MBTs usually have infiltrating nests of tumor cells with urothelial-like appearance. The hallmark of the diagnosis is the presence of benign or borderline Brenner tumor, and sometimes extensive sampling is necessary to find these components. MBTs are usually negative for WT-1 and hormone receptors, though the latter may be weakly expressed. The expression of markers of urothelial differentiation such as GATA3 is not well studied currently, limiting its use.

The molecular profile of transitional cell carcinomas is not well-studied due to the lack of consistency in reporting and accurately diagnosing these tumors. A recent study has shown that proteins associated with cell death, apoptosis and necrosis were highly expressed in transitional cell carcinomas (defined as tumors having > 50% of said morphology). Conversely, proteins with reduced expression included those associated with DNA homologous recombination, cell mitosis, proliferation and survival, and cell cycle progression pathways. Proteomic analysis revealed three biomarkers including Claudin-4 (CLDN4), ubiquitin carboxyl-terminal esterase L1 (UCHL1), and minichromosome maintenance protein 7 (MCM7) that were enriched in transitional cell carcinoma over high-grade serous carcinoma, but were not able to distinguish the two tumors with 100% sensitivity and specificity. Additional studies are necessary to confirm these differences and determine their clinical significance.

Like epithelial ovarian cancers, ovarian transitional cell carcinomas are staged according to International Federation of Gynecology and Obstetrics (FIGO) staging ( Table 8.2 ). As there have been so few reported cases of these tumors, there is not much data on overall prognosis and survival. Kommoss et al. found that ovarian transitional cell carcinomas had a significantly better prognosis as compared to all other types of ovarian carcinomas after standardized chemotherapy (5-year survival was 57% as compared to 31% for patients with ovarian carcinomas of other types, P = 0.03). In addition, the authors found that even among patients with postoperative residual tumor < 1 cm, there was still a trend toward better survival. It has also been suggested by other researchers that ovarian transitional cell carcinomas are more chemosensitive than epithelial ovarian cancers and this may explain the better prognosis compared to other more common serous carcinomas. Guseh et al. found that patients with these tumors are less likely to demonstrate resistance to platinum chemotherapy and have improved overall survival when compared to patients with papillary serous ovarian cancer. The authors suggested that a propensity for micronodular rather than macronodular extraovarian spread and better surgical resectability due to lesser degree of diffuse infiltrative growth may also be factors contributing to the overall improved survival and prognosis.

Patients with transitional cell carcinoma of the ovary appear to benefit from optimal surgical resection, followed by adjuvant platinum-based chemotherapy. Given the scarcity of reported cases, there are no current recommendations for surveillance and treatment of recurrence. Because transitional cell carcinomas of the ovary follow a similar tumorigenic pathway to high-grade serous ovarian cancer and have been shown to be associated with better prognosis after following a similar treatment paradigm, surveillance for recurrence and treatment of recurrent disease should be the same as that for epithelial ovarian cancers ( Fig. 8.4 ).