Adenocarcinoma of Mullerian origin: review of pathogenesis, molecular biology, and emerging treatment paradigms

 Note: changes in staging classifications (eg. stage 11C deleted; expanded sub-categories...)

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 Recent data regarding the genetics and histopathology of epithelial ovarian cancer (EOC) has improved our understanding of ovarian carcinogenesis. These results and current hypotheses indicate that epithelial ovarian, peritoneal, and tubal cancers are not distinct entities but represent a spectrum of disease that originates in the Mullerian compartment. Due to this new information, the FIGO staging classification for ovarian, tubal, and peritoneal cancers was revised (Table 1) [2]. Tubal and peritoneal cancers are now included in the ovarian cancer staging classification, and the primary site designated when possible [2,3]. This new staging exemplifies our current understanding of the relationship between these disease entities and challenges our previous classification of ovarian, peritoneal, and tubal cancers. We and others assert that this group of gynecologic cancers should be collectively designated as adenocarcinomas of Mullerian origin. In this review, we will focus on the incidence, classification, and origin of Mullerian adenocarcinomas. We will also review the molecular and pathologic profiling that support the concept of adenocarcinomas of Mullerian origin as a unified entity and will assist in diagnostic and treatment paradigms......

Table 1

Ovarian cancer staging (FIGO 2013 vs. FIGO 1988)

Review

Incidence

It is difficult to discern how many annual deaths occur due to adenocarcinomas of Mullerian origin. While EOC caused approximately 14,030 deaths in the United States in 2013 [4] and 151,905 deaths worldwide in 2012 [5], it is unclear exactly how many deaths were caused by peritoneal and tubal cancers. Peritoneal and tubal carcinomas have been considered rare malignancies and separate entities from ovarian carcinomas; thus, epidemiologic studies have proven difficult [6]. Tubal carcinomas account for only 0.14-1.8% of gynecologic malignancies [7,8]. In the United States, from 1995–2004, the age adjusted incidence rates for tubal and peritoneal carcinomas were 3.7 and 6.8 per million, respectively [6]. Newer theories indicate that the number of peritoneal and tubal cancers may be grossly underestimated.

Additionally, CUP (cancer of unknown primary) accounts for 3-5% of malignant epithelial cancers [9] and in 2012, there were an estimated 31,000 new cases of CUP in the United States [10]. Potentially 5% of CUP may originate in the female reproductive system based on data from post mortem autopsy studies [9,11]. It is important to recognize the adenocarcinoma of Mullerian origin subset of CUP when it occurs, because these cancers will typically have a more favorable prognosis and sensitivity to platinum-based chemotherapeutic regimens [12].....

 

Current classification

Epithelial ovarian cancer classification

  EOC classification has changed significantly over the past decade. The most recent proposed division of EOC includes two distinct histologic groups: type I and type II cancers. It should be noted that the type I and type II classification is generally used to broadly classify ovarian neoplasms for research purposes based on their unique clinical and molecular genetic features [13]. The classification was not meant to be used for clinical purposes. Type I tumors include low-grade serous and low-grade endometrioid cancers, as well as mucinous, clear cell, and transitional cell carcinomas......

 

Peritoneal cancer classification

Peritoneal carcinomas have been called multiple names including peritoneal papillary serous carcinoma, peritoneal mesothelioma, primary peritoneal carcinoma, and normal-sized ovary carcinoma syndrome. In 1993, the Gynecologic Oncology Group established specific guidelines for the diagnosis of peritoneal carcinoma....