Hereditary Syndromes Manifesting as Endometrial Carcinoma: How Can Pathological Features Aid Risk Assessment?

Table 1

A summary of the epidemiological, mutational, clinical, and pathological characteristics and features encountered in hereditary syndromes manifesting as endometrial carcinoma. The indicators noted by pathologists to augur a need to notify clinicians on the possible need for referral to a geneticist for further clinical assessment and confirmatory gene mutational testing. Highlighted in the extreme right column are the histological features seen on microscopy and ancillary tests including immunohistochemistry and polymerase chain reaction- (PCR-) based tests such as microsatellite instability analysis and MLH-1 methylation study.

Syndrome	Incidence in general population	Lifetime risk of developing endometrial carcinoma	Most common sentinel tumor in women (%)	Germline gene mutation	Associated malignancies	Indicators to prompt pathologist to alert clinician on the possible need for referral to a geneticist
Lynch syndrome or hereditary nonpolyposis syndrome (HNPCC)	1 in 300 to 1 in 500	40%–60%	Endometrial carcinoma (50%)	MLH1, MSH2, MSH6, PSM2, EPCAM	Endometrial, ovarian, gastric, breast,; intestinal, pancreatic, urinary tract, renal, and bile duct carcinoma	Microscopic findings: Mixed carcinoma.; Undifferentiated or differentiated carcinomas.; Significant peritumoral and/or intratumoral lymphocytic infiltrate.; Tumors arising from lower uterine segment.; Synchronous endometrial and ovarian carcinomas.; Ancillary investigations: Immunohistochemistry: Loss of MMR protein staining for MLH1, MSH2, MSH6 or PSM2.; Methylation study: Absence of promoter methylation of MLH1 in cases with loss of IHC staining.; Microsatellite instability analysis: Instability of >1 (MSI-H) or instability in 1 locus (MSI-L)
Muir-Torre syndrome	Variant of Lynch syndrome with an incidence of 9% among Lynch syndrome patients	20%–60%	Colorectal carcinoma (47%); #if benign lesions also taken into account, the most common sentinel tumor is sebaceous neoplasms (50%)	Similar to Lynch syndrome	Similar to Lynch syndrome	Microscopic findings: Sebaceous neoplasm: sebaceous adenoma, sebaceoma, sebaceous carcinoma. (sebaceous hyperplasia not shown to be associated with Muir-Torre syndrome).; Ancillary investigations: (1) Immunohistochemistry: loss of MIHC staining for MLH1, MSH2, MSH6 or PSM2. (Poor positive predictive value without proper clinical assessment for syndrome).
Cowden syndrome	Estimated at 1 in 200,000 (likely underestimated due to difficulty in identifying such patients)	~28%	Breast carcinoma (48%); #if benign lesions are also taken into account, the most common sentinel tumor are mucocuteneous lesions (~85%)	PTEN	Breast, thyroid, and endometrial; carcinoma	Microscopic findings: Trichilemmommas, particularly if multiple; Breast hamartoma, especially if prominent hyalinised stroma.; Breast carcinoma with dense hyalinised collagenous stroma.; Multiple hamartomatous gastrointestinal polyp.; Oesophageal glycogenic acanthosis.; Histologic confirmation of radiological suspicion of Lhermitte-Duclos.; Ancillary investigation: Immunohistochemistry: PTEN IHC loss in trichilemmommas has not been shown to be particularly helpful in identifying cases as it is also commonly lost in sporadic cases as well.

MSI-L, microsatellite low; MSI, microsatellite high; and MMR, mismatch repair genes (i.e., MLH1, MSH2, MSH6, and PMS2).