—  SYMPOSIUM #02  —

Simultaneous Carcinomas of the Female Genital Tract
Moderator: Jaime Prat

Section 2 - Simultaneous endometrioid adenocarcinomas of the uterine corpus and ovaries

Julie A. Irving
Department of Pathology, Vancouver General
Hospital, Vancouver , Canada


Simultaneous carcinomas of the uterine corpus and ovary, usually detected as synchronous and less commonly as metachronous tumors, occur in 15 to 20% of ovarian tumors and in approximately 5% of uterine tumors. Both tumors are of endometrioid type in the majority of cases. Accurate diagnosis as separate independent primary tumors, or as primary tumor in one site with metastasis to the other site, has important prognostic implications and is necessary for appropriate staging and treatment. Independent primary tumors of low histologic grade, usually of endometrioid type, and with involvement limited to the endometrium and ovary, are associated with favorable outcome and often require no additional treatment. In contrast, tumors that are metastatic from the uterus to ovary, or from the ovary to uterus, usually carry an adverse prognosis and adjuvant therapy is generally indicated.

This issue has been addressed in daily practice for many years, and the diagnosis has historically relied on assessment of conventional histopathologic parameters. Careful evaluation of these parameters often provides the correct diagnosis, but in a proportion of cases, the features are overlapping or inconclusive, and a definitive diagnosis cannot be rendered. Application of molecular analysis in this setting may facilitate the diagnosis, and has contributed to our understanding of the pathogenesis of this subset of female genital tract tumors. Indeed, specific genetic alterations that are associated with less aggressive biologic behavior have recently been identified in dual primary uterine and ovarian endometrioid carcinomas.

The Distinction of Primary from Metastatic Endometrioid Adenocarcinomas



A. Conventional parameters
Assessment of conventional gross and histologic parameters in simultaneous uterine and ovarian endometrioid adenocarcinomas is, to date, the most practical method for distinguishing independent primary tumors from a primary tumor with metastasis. These parameters include the following:
  • Tumor size

  • Histologic type

  • Tumor grade

  • Myometrial invasion

  • Lymphovascular invasion

  • Unilateral or bilateral ovarian tumor

  • Pattern of ovarian involvement: multinodular growth, ovarian surface implants

  • Fallopian tube involvement

  • Presence or absence of coexistent lesions (ovarian endometriosis or a pre-existing adenofibromatous component in the ovarian tumor, and atypical endometrial hyperplasia)

  • Follow-up
In general, low histological grade of the tumors in both sites, with associated atypical endometrial hyperplasia and ovarian endometriosis, are findings that favour independent primary tumors. In cases of primary endometrioid endometrial carcinoma with ovarian metastasis, typical features include high histological grade in both sites; the ovaries may be normal in size or only minimally enlarged, with bilateral tumor involvement characterized by surface implants, a multinodular growth pattern, lymphovascular invasion, and an absence of endometriosis. Primary ovarian endometrioid carcinomas metastatic to the endometrium are infrequent, and may show direct extension of a high grade ovarian tumor to the serosal aspect of the uterus, with prominent myometrial invasion in the outer half of the myometrial wall. Less often, anterograde tubal migration may result in tumor implantation in the endometrium. In this scenario, clues to the correct diagnosis are a large, unilateral parenchymal ovarian mass, with a small endometrial tumor lacking adjacent atypical hyperplasia.

It is clear that a constellation of histologic features must be taken into account when evaluating simultaneous endometrioid carcinomas, and an accurate diagnosis almost certainly cannot be reached on the basis of a single parameter. Indeed, the presence of certain histologic features, when viewed in isolation, can be misleading. For example, we and others have found that depth of myometrial invasion is not always a reliable discriminator, as some cases with classic morphologic patterns of ovarian metastases are associated with a minimally invasive, or even non-invasive, primary endometrial carcinoma. In such cases, lymphovascular invasion in the myometrium is often absent, supporting the theory that retrograde transtubal migration may be the mechanism of extra-uterine tumor dissemination. According to FIGO, if the site of origin remains in doubt after pathologic examination, assignment of the primary tumor site is based on the initial clinical manifestations.

B. Molecular analysis
In difficult cases where overlapping gross and histologic features are present, ancillary techniques have been used in attempt to reach a more definitive diagnosis. The rationale for this approach is that independent primary tumors will exhibit unique genetic alterations, while a metastatic tumor will have the same genetic alterations as the primary tumor from which it is derived. However, independent primary tumors of the uterus and ovary that have very similar histologic features would be expected to share pathways of tumorigenesis, with field effect resulting in similar genetic alterations. Conversely, metastatic tumors may acquire different molecular profiles from the primary tumor as a consequence of tumor progression. For example, independent tumors can show similar immunohistochemical profiles; metastatic tumors may show distinct profiles for bcl-2, estrogen and progesterone receptors but only in a proportion of cases. Analysis by DNA ploidy also has limited use, since tumor progression can result in different ploidy indexes between primary and metastatic tumors. Loss of heterozygosity (LOH) studies can be useful when the patterns of LOH in both tumor sites are concordant, as this is highly suggestive of a common clonal origin. The finding of discordant LOH patterns is less helpful, because different regions of the same tumor can exhibit tumor heterogeneity.

The most reliable approach to the use of clonal analysis is to examine multiple genetic markers, particularly those that are altered early in tumorigenesis and known to be frequently encountered in endometrioid carcinomas of the uterus and ovary. In endometrioid carcinomas of the uterine corpus, the most common molecular alterations are microsatellite instability (MI) as well as mutations in PTEN, k-ras, and the beta-catenin gene (CTNNB1). Endometrioid carcinomas of the ovary can also exhibit these molecular alterations, characterized by a similar frequency of beta-catenin abnormalities and lower incidence of MI and PTEN mutations.

Microsatellite Instability
Microsatellite instability (MI), a marker of defective DNA mismatch repair, is present in 25-30% of sporadic endometrioid carcinomas of the uterine corpus. In such cases, MI most commonly arises as a result of promoter hypermethylation of the mismatch repair gene hMLH1. This epigenetic phenomenon is likely an early event in endometrial tumorigenesis, as it has been demonstrated in atypical endometrial hyperplasia in the absence of MI, and in the majority of MI-positive endometrial carcinomas. In sporadic ovarian carcinomas of endometrioid type, the reported frequency of MI is variable, but is usually in the range of 15 to 20% of cases.

MI has also been demonstrated with high frequency in simultaneous uterine and ovarian endometrioid carcinomas. In both independent primary and metastatic cases, the vast majority are associated with hMLH1 promoter hypermethylation. Given the common occurrence of MI in simultaneous endometrioid carcinomas, the presence of MI in both sites is insufficient evidence to support a primary tumor with metastasis. The specific patterns of MI must be closely evaluated, with identical patterns of MI suggesting a common clonal origin, and distinct patterns of MI in support of independent primary tumors.

PTEN mutations
Mutations of PTEN, a tumor-suppressor gene isolated from the chromosome 10q23 region, have been reported in a wide range of cancers. PTEN mutations are very common in endometrial tumors and they are almost exclusively limited to those with endometrioid histology. Furthermore, PTEN mutations have been detected in precancerous lesions including atypical endometrial hyperplasia and ovarian endometriotic cysts adjacent to endometrioid carcinomas. In single endometrioid tumors arising in the uterine corpus and ovary, PTEN mutations are present in 30-50% and 20% of cases, respectively. It has been shown that PTEN mutations are also frequently present in simultaneous uterine and ovarian endometrioid carcinomas, in both independent primary and metastatic cases. This is likely in part attributable to the high rate of MI, as approximately 50% of tumors with PTEN mutations demonstrate co-existent MI; conversely, MI-positive endometrial carcinomas are more likely to show mutations in the PTEN tumor suppressor gene.

As PTEN mutations are so common in these tumors, the presence of a PTEN mutation in both tumor sites is not necessarily indicative of a clonal origin; additional molecular data and correlation with clinicopathologic findings is essential to the correct interpretation.

CTNNB1 mutations
The Wnt signaling pathway involves a highly conserved family of growth factors that bind transmembrane receptors and modulate many cellular processes including cell adhesion, proliferation, and differentiation. Endometrioid carcinomas of the uterus and ovary are often characterized by mutations of CTNNB1, the gene encoding beta-catenin, which is a critical component of Wnt signaling. Mutations in CTNNB1 and other genes involved in the same pathway are associated with abnormal nuclear accumulation of beta-catenin, which can be visualized by immunohistochemistry.

CTTNB1 mutations occur in approximately 25% of endometrioid carcinomas of the uterine corpus and from 16% to 54% of ovarian endometrioid carcinomas; these are characteristically early stage tumors associated with a favorable prognosis. In a recent study, CTNNB1 mutations were identified in approximately 50% of simultaneous independent primary uterine and ovarian endometrioid carcinomas, but were absent in all metastatic tumors examined. This finding has provided evidence that nuclear expression of beta-catenin and/or detection of a CTNNB1 mutation is more likely to be associated with an independent primary tumor and, as all patients had favorable outcomes, is a potential prognostic marker.

Nuclear accumulation of beta-catenin in endometrioid carcinomas of the uterine corpus and ovary tends to be most prominent in squamous morules. The significance of this finding is not clear, but it has been suggested that activation of the APC/beta-catenin pathway may be responsible for driving the tumor cells toward a more differentiated phenotype. Simultaneous endometrioid carcinomas often show squamous differentiation, and this finding may prompt determination of immunohistochemical expression of nuclear beta-catenin. If conventional histopathologic findings are in favour of separate primary tumors, positive nuclear beta-catenin lends additional support to the interpretation.

Conclusions and Future Directions

The issue of accurate diagnosis and prognostication of simultaneous endometrioid tumors of the uterus and ovary has been a challenging area of surgical pathology for many years. At present, the diagnosis relies on thorough histopathologic examination. Ancillary molecular analysis can provide very useful information to assist in the diagnosis, particularly as potential biomarkers of endometrioid tumorigenesis are now recognized. Specifically, at least 3 mutator pathways (MI, PTEN, and beta-catenin/CTNNB1 abnormalities) are associated with the development of simultaneous endometrioid tumors. In the appropriate histologic context, nuclear immunoreactivity for beta-catenin and/or CTTNB1 mutations is evidence for independent primary tumors, whereas a membranous pattern of beta-catenin immunoreactivity and an absence of CTTNB1 mutation is more likely to occur in metastatic tumors. It must be emphasized that molecular data should be interpreted in the context of conventional clinicopathologic findings, particularly when only one or two markers have been evaluated.

Global Genetic Profiling
Conventional histopathologic examination with ancillary molecular testing of one or two biomarkers can still result in an equivocal diagnosis. Endometrioid carcinomas of the uterine corpus and ovary exhibit similar phenotypes, and not surprisingly, similar genotypes as a consequence of shared pathways of tumorigenesis. Recently developed techniques, such as array comparative genomic hybridization, allow high throughput analysis of DNA copy number changes throughout the genome. By analyzing copy number for thousands of genes, a genetic "fingerprint" results unique to that tumor. This technique has been shown to discriminate between a primary tumor and a metastasis of this tumor, compared to independent tumors of similar histological type. In the future, global genetic profiling of this subset of female genital tract tumors should expand and refine our ability to accurately diagnose these tumors as independent primaries or metastases and determine the potential prognostic relevance of specific molecular alterations (i.e beta-catenin) by correlation of profiling data with patient outcome.

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