Investigation of Uterine Carcinosarcoma: Case Report and Cohort Analysis

Timothy N. Hembree, DO, PhD, Jamie K. Teer, PhD, Ardeshir Hakam, MD, and Alberto A. Chiappori, MD

Disclosures

Cancer Control. 2016;23(1):61-66. 

In This Article

Abstract and Introduction

Abstract

Background: Uterine carcinosarcoma, a rare gynecological malignancy, often presents at the advanced stage with a poor prognosis because current therapies have not improved rates of survival. Genetic characterization of this tumor may lead to novel, specifically targeted drug targets to provide better treatment options for patients with this malignancy.

Methods: We present a case of a woman aged 61 years with uterine carcinosarcoma and retrospectively analyzed 100 study patients with uterine carcinosarcoma. From this group, 9 study patients underwent targeted sequencing of 1,321 genes.

Results: All 9 study patients had at least 1 mutation in JAK2, KRAS, PIK3CA, CTNNB1, PTEN, FBXW7, TP53, and ERBB2; of these, TP53 was the most frequently mutated gene (6/9). In addition, ARID1A and KMT2C, which have been described and identified as part of a set of chromatin-remodeling genes, were also found in our analyses. From our 100-person cohort clinical analyses, study patients with stage 1 cancer had a median survival rate of 33 months (95% confidence interval, 19–109) compared with a median survival rate of 6 months (95% confidence interval, 3–12) in those with stage 4 disease.

Conclusions: Disease stage alone predicted the rate of clinical survival. Up to 50% in the study group were identified at having early stage disease (stage 1/2), indicating improved rates of overall detection compared with previously reported data. Our mutational analysis findings add to the number of tumors in which these mutations have been found and suggest that chromatin-remodeling dysregulation may play a role in the tumorigenesis of carcinosarcoma.

Introduction

Uterine carcinosarcomas are rare gynecological tumors that make up fewer than 5% of all uterine malignancies; however rare, these tumors account for a disproportionate percentage of associated mortality.[1,2] Their classic presentation has been described as a triad of symptoms: pain, severe vaginal bleeding, and the passage of necrotic tissue through the vagina.[1] More than one-half of patients (53%) present with advanced stage disease, and 20% of patients with localized disease at presentation are upstaged during laparotomy.[3,4]

Staging is the most significant prognostic indicator and reflects a poor overall, 5-year, disease-specific survival rate (36.4% for all stages; 62.3% for stage 1 and 0% for stages 2 to 4).[5] Risk factors are similar to those seen in endometrial carcinoma and include nulliparity, advanced age, obesity, exposure to exogenous estrogens, history of pelvic irradiation, and the long-term use of tamoxifen.[2,6]

The histology of the tumor is mixed with epithelial and mesenchymal elements, thus designating it a carcinosarcoma. The tumor is classified based on the sarcomatous portion as either homologous (consisting of mesenchymal elements found in the female genital tract) or heterologous (consisting of mesenchymal elements foreign to the female genital tract). Within the uterus, carcinosarcomas commonly arise from the posterior wall of the uterine body near the fundus. The mass usually grows to fill and distend the uterus, and most carcinosarcomas are visualized as exophytic lesions. The extent of myometrial invasion of these tumors is sometimes controversial, but it is generally accepted that the degree of myometrial invasion is a poor prognostic indicator and likely a predictor of metastasis.[7]

The origin of the tumor is thought to follow the embryological development path of the Müllerian ducts and is most likely derived from a pluripotent stem cell that differentiates into both epithelial and mesenchymal cell types. Further characterization of the tumor histology supports the "conversion" theory, which states that an epithelial-to-mesenchymal transition occurs because the sarcomatous portion of the tumor exhibits markers consistent with an epithelial origin.[8]

Historically, this tumor was considered to be uterine sarcoma, and treatment was directed at the sarcomatous element. However, the carcinoma portion of the tumor is now favored as the primary determinant of tumor aggressiveness, with recent advances in treatment directed toward those elements.[9] Regardless, standards of therapy (surgical debulking, lymphadenectomy, and adjuvant chemotherapy) have not improved overall survival rates, particularly in those with advanced disease. Therefore, improving our understanding of tumor biology (molecular profile and oncogenic drivers) should be a priority.

In that regard, somatic mutations (eg, KRAS, PI3KCA) known to be carcinogenic drivers in other tumors (eg, lung adenocarcinomas, colon adenocarcinomas) have been demonstrated in carcinosarcomas.[10] This increased our curiosity on a more detailed molecular analysis of these tumors. Thus, we present a case patient with uterine carcinosarcoma and report on our clinical and molecular analysis findings for a cohort of patients with this disease.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....