Endometrial carcinomas with ambiguous features

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Endometrial carcinomas are a heterogenous group of tumors that show variable histologies, molecular abnormalities and clinical outcomes. The idea of rigid distinctions between tumor types is appealing to pathologists, gynecologists, researchers and patients, but in a recent study where high grade endometrial carcinomas were reviewed by three experienced gynecologic pathologists, diagnostic agreement about tumor type was reached in only approximately one half of cases. In general, biologically and clinically validated diagnostic criteria are lacking for high grade endometrial carcinomas and for those that appear mixed epithelial. Until such criteria are developed, it remains important to define which morphologic patterns convey accurate clinical and biological information and which do not or might not. “Endometrial carcinomas with ambiguous features,” the focus of this review, are tumors with comparatively uninformative morphologic features. Some publications indicate that gland forming and papillary endometrial carcinomas that appear morphologically low grade or ambiguous are really high grade. There are also indications that high grade endometrial carcinomas are biologically heterogeneous and that the morphologic clues we currently use to distinguish one subtype from another fail to correlate with biological data. Many tumors that appear morphologically mixed are, in fact, not biologically or clinically confused: most represent biologically “pure” tumors with variant morphology. Interesting associations between the presence of Lynch Syndrome (hereditary nonpolyposis colorectal carcinoma syndrome) and ambiguous morphology have been discussed in the literature. An apparent relationship between morphologic ambiguity and malignant mixed Müllerian tumor (MMMT) also exists. The identity of some morphologically ambiguous endometrial carcinoma can be elucidated with immunohistochemistry or other ancillary techniques at present, but the nature of many still remains undefined. This review presents the concept of morphologically ambiguous endometrial carcinomas, proposes morphological gold standard diagnostic criteria for tumors that are not ambiguous (an effort that helps define tumors that are ambiguous), provides a relevant literature review and offers practical guidance for sorting through diagnostically challenging cases.

Section snippets

Background

Several studies performed in the past 5 years have shed some light on the perplexing heterogeneity of endometrial carcinomas and provided insights into the development of valid diagnostic criteria. Two recent studies7, 8 have formally addressed interobserver diagnostic agreement in particular subsets of endometrial carcinoma and described the performance of a single immunohistochemical stain to enhance diagnostic objectivity and, in one instance,7 to provide prognostic information. Although it

Morphologically ambiguous endometrial carcinomas for which biological and clinical data exist

Another study from our group,15 in addition to others,8 examined carcinomas with hyperplastic or low-grade endometrioid architecture and diffusely high nuclear grade. One particular study included cases that had been originally (and mistakenly) diagnosed as complex atypical hyperplasia or FIGO grades 1-2 endometrioid carcinoma. Immunohistochemistry directed at p53, PTEN, and PR distinguished tumors whose clinical course more closely resembled serous carcinoma (overexpressed p53, retained PTEN,

Morphologically ambiguous endometrial carcinomas for which biologically relevant data exist

Tumors resembling CCC, but with columnar or highly pleomorphic cells, tumors resembling serous carcinoma, but with clear cells, and epithelial tumors thought to be “mixed” are examples of interrelated problems about which we have relatively little knowledge. The first two studies discussed below provide insights into the extent to which endometrioid and CCCs and serous carcinomas, can resemble each other, and how immunohistochemistry and molecular typing can distinguish between biologically

Morphologically ambiguous endometrial carcinomas for which little, if any, diagnostically relevant data exist

Despite the fact that tumors in this category are largely biphasic in appearance, there are several biphasic endometrial tumors for which a good deal of relevant data exist: MMMTs with separable, high-grade epithelial and mesenchymal components18; low-grade spindle cell carcinomas, some of which have nonrhabdomyomatous heterologous elements34; combined differentiated and undifferentiated carcinomas (dedifferentiated carcinomas)20; low-grade Müllerian adenosarcomas; and atypical polypoid

Lynch syndrome

Lynch syndrome (LS) is an autosomal dominant, inherited cancer susceptibility syndrome featuring high rate of colorectal, endometrial, ovarian, gastric, urinary, and biliary cancers, among others. A mutation in one, or rarely more, of the DNA MMR genes, hMSH6, hMSH2, hMLH1, hPMS2,37 characterizes the syndrome, with hMSH6 mutations being most common in endometrial cancers. The lifetime cumulative risk of developing an endometrial cancer for an LS patient ranges from 27% to 71%, depending on

Which tumors are morphologically ambiguous

The first part of this discussion centers on which combinations of morphologic features lead to clinically relevant diagnosis in the preponderance of cases. Serous carcinomas can be diagnosed with confidence, provided the tumor shows at least focal papillary and micropapillary architecture and diffusely high grade nuclear features (Figure 6). MMMT can be diagnosed when separable, high-grade epithelial, and pleomorphic spindle cell sarcomatous elements are present (Figure 7). Endometrioid

Acknowledgments

This review is based on an idea suggested by Dr. Karuna Garg. She contributed significantly to the development of the concept of “histologically ambiguous endometrial carcinoma.”

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