Papillary mucinous metaplasia of the endometrium as a possible precursor of endometrial mucinous adenocarcinoma

Abstract

Mucinous adenocarcinoma is an uncommon type of endometrial adenocarcinoma for which precursor lesions have yet to be clarified. During a review of noncancerous endometrial lesions in postmenopausal women, we found that mucinous endometrial glands showed variable degrees of epithelial changes that ranged from the formation of simple tubular glands to the formation of complex glands with papillary tufts, and some of the glands with papillary tufts were architecturally similar to low-grade mucinous adenocarcinomas. Based on histological similarities, we have postulated that mucinous metaplasia could be a precursor lesion of mucinous adenocarcinoma. To explain the pathogenetic significance of endometrial mucinous metaplasia, we analyzed the immunohistochemical expression of ER, PR, MKI67, PTEN, b-catenin, P16 INK4A , TP53, and PAX2 in 21 endometrial mucinous metaplasias, screened for KRAS (n ¼ 16) and PTEN (n ¼ 14) mutations, and compared expression patterns between samples with simple mucinous glands, those with complex glands having intraglandular papillary tufts, and endometrioid adenocarcinomas. Compared with the surrounding flat mucinous epithelium and simple mucinous metaplasia, the intraglandular papillary tufts associated with papillary mucinous metaplasia were characterized by selectively decreased expression of PAX2 (P ¼ 0.029) and PR (Po0.001), and overexpression of P16 INK4A (P ¼ 0.014). There were no significant differences in the levels of expression of ER, PTEN, b-catenin, TP53, and MKI67 between the two groups. In contrast with endometrioid adenocarcinomas, rates of MKI67 proliferation were very low in both groups. Mutations in KRAS were identified in 89% of cases with papillary mucinous metaplasia, in contrast to 14% in simple mucinous metaplasia (P ¼ 0.001). No PTEN mutations were observed in either of the two groups. In conclusions, immunohistochemical and molecular genetic profiling suggest that papillary mucinous metaplasia is a possible precancerous lesion in a subset of endometrial carcinomas. Modern Pathology (2012Pathology ( ) 25, 1496Pathology ( -1507 doi:10.1038/modpathol.2012; published online 6 July 2012Keywords: endometrium; mucinous; mucinous metaplasia; papillary metaplasia; PAX2; P16 INK4A ; senescence Endometrial carcinoma is classified into two major groups, types I and II, according to clinicopathological features and molecular pathogenetic mechanisms. Most type I tumors are characterized by an endometrioid histology and are frequently associated with PTEN mutations, whereas type II tumors show a serous histology and are frequently associated with the altered expression of TP53 tumor-suppressor genes. Endometrial hyperplasia and endometrial intraepithelial carcinoma are thought to be precursor lesions of type I and II endometrial carcinomas, respectively. However, this simplified classification and their precursor lesions cannot explain the pathogenesis of all endometrial carcinomas.Mucinous adenocarcinoma, an uncommon type of endometrial adenocarcinoma comprising o10% of endometr...

Frequent KRAS mutation in complex mucinous epithelial lesions of the endometrium

“…14 More recently, KRAS mutation was found in a high proportion of a small, highly selected cohort of complex, papillary mucinous lesions of the endometrium. 11 Similar to the latter, the current study also identifies a significant difference in the prevalence of KRAS mutation between simple and complex mucinous lesions (0% vs 55%). Patients with KRAS mutation had a PPV of 88% (7 of 8 cases) of having atypical complex hyperplasia or carcinoma in their follow-up hysterectomy specimens, although this value dropped to 67% (10 of 15 cases) if all types of follow-up specimens including curettage and hysterectomy were considered.…”

“…We did not further subclassify complex mucinous lesions, as recent immunohistochemical and molecular genetic investigations indicated that complex mucinous lesions with varying complexity and cytological abnormalities share similar oncogenic profiles as possible precancerous lesions at least for a subset of endometrial adenocarcinomas. 11 In our study, 54% (14/35) of patients with complex mucinous changes were found to have complex atypical hyperplasia or adenocarcinoma in their follow-up curettage or hysterectomy specimens. In a study by Nucci et al, 3 the majority of complex mucinous lesions were found to have endometrial carcinoma in the follow-up hysterectomy.…”

“…However, such high frequency of subsequent malignancy was not seen in this current investigation and in others. 11 The reason for this disparity is unclear but possible explanations include varying histological criteria for case inclusion in different studies, 8,11 for instance, endometrial mucinous lesions with more extensive architectural complexity and/or severe cytological atypia leading to a significant suspicion for carcinoma were excluded from the complex mucinous category and classified as carcinoma in our study. KRAS mutation has been linked to epithelial tumors with mucinous differentiation of various organs including pancreas, colon and lung.…”

“…The lesions within the latter group showed a high incidence of KRAS mutation in association with overexpression of P16, PAX2 and PR, suggesting that they may be precursor lesions of mucinous endometrial adenocarcinoma. 11 KRAS is a key oncogene in the EGFR signaling cascade (RAS-MAPK pathway) and its mutation is an early oncogenic event in the development of human cancers. 12 Nearly all KRAS mutations occur in codon 12 or 13 of exon 2 of the gene leading to a mutant oncoprotein that is locked in its activation conformation, resulting in constant activation of the signaling pathway in the absence of ligand activation.…”

“…12 KRAS is frequently mutated in ovarian mucinous neoplasms and endometrial mucinous carcinoma as well. 14 Prompted by the recent report of a high frequency of KRAS mutations found in a small cohort of endometrial papillary mucinous lesions, 11 we investigated various mucinous lesions for the presence of KRAS mutation in endometrial biopsy or curettage specimens in correlation with clinical progression.…”