Predicting Progestin Therapy Response With PTEN, PAX2, and ß-Catenin in Patients With Endometrioid Precancer.

This study investigates the predictive value of biomarkers PTEN, PAX2, and ß-catenin for therapeutic outcomes in patients with atypical endometrial hyperplasia or endometrioid intraepithelial neoplasia undergoing progestin therapy. In a retrospective study of 128 patients, we analyzed a total of 351 endometrial biopsy samples and categorized outcomes into responders (absence of residual disease) and nonresponders (presence of residual disease). We found aberrant biomarker expression in pretreatment cases: 48% for PTEN, 65% for PAX2, and 36% for ß-catenin. Approximately 77.3% of patients responded to progestin treatment, with nonresponders showing significantly higher initial PTEN loss (75.86% vs 39.79%, P < 0.001). Nonresponders also demonstrated significant PTEN loss (53.33% vs 20.55%, P < 0.001), PAX2 loss (57.33% vs 41.22%, P < 0.05), and ß-catenin nuclear staining (53.45% vs 27.91%, P < 0.01) in follow-up samples. In addition, nonresponders exhibited lower recovery of intact PTEN and PAX2, along with higher ß-catenin aberrancy in cases initially showing normal ß-catenin levels. We conclude that persistent aberrant PTEN and PAX2 expression, coupled with emerging aberrant ß-catenin in follow-ups, indicates a greater likelihood of treatment failure. Conversely, the absence of these aberrations suggests successful progestin therapy. Our findings highlight the utility of this 3-marker panel in assessing residual disease status and predicting progestin treatment outcomes, thus offering critical insights for patient management.

Utility of a PAX2, PTEN, and ß-catenin Panel in the Diagnosis of Atypical Hyperplasia/Endometrioid Intraepithelial Neoplasia in Endometrial Polyps.

The diagnosis of atypical hyperplasia/endometrioid intraepithelial neoplasm (AH/EIN) within endometrial polyps (EMPs) often poses a diagnostic conundrum. Our previous studies demonstrated that a panel of immunohistochemical (IHC) markers consisting of PAX2, PTEN, and ß-catenin can be effectively utilized for the identification of AH/EIN. A total of 105 AH/EIN within EMP were analyzed using the 3-marker panel. We also evaluated these cases for the presence of morules. Benign EMP (n=90) and AH/EIN unassociated with polyp (n=111) served as controls. Aberrant expression of PAX2, PTEN, or ß-catenin was observed in AH/EIN in EMP in 64.8%, 39.0%, and 61.9% of cases, respectively. At least 1 IHC marker was abnormal in 92.4% of cases. Overall, 60% of AH/EIN in EMP demonstrated abnormal results for≥2 IHC markers. The prevalence of PAX2 aberrancy was significantly lower in AH/EIN in EMP than in nonpolyp AH/EIN (64.8% vs. 81.1%, P =0.007), but higher than in benign EMP (64.8% vs. 14.4%, P <0.00001). The prevalence of ß-catenin aberrancy was significantly higher in AH/EIN in EMP than in nonpolyp AH/EIN (61.9% vs. 47.7%, P =0.037). All control benign EMP demonstrated normal expression of PTEN and ß-catenin. Morules were present in 38.1% of AH/EIN in EMP versus 24.3% in nonpolyp AH/EIN, and absent in benign EMP. A strong positive association was found between ß-catenin and morules (Φ=0.64). Overall, 90% cases of atypical polypoid adenomyoma (n=6) and mucinous papillary proliferation (n=4) showed IHC marker aberrancy. In conclusion, the 3-marker IHC panel (PAX2, PTEN, and ß-catenin) is (1) a useful tool in the diagnosis of AH/EIN in EMP; (2) PAX2 loss should be interpreted with caution and in combination with morphology and other markers.

Aggressive High-grade Uterine Sarcoma Harboring MEIS1-NCOA2 Fusion and Amplification of Multiple 12q13-15 Genes: A Case Report With Morphologic, Immunohistochemical, and Molecular Analysis.

MEIS1-NCOA1/2 fusions are recently described gene rearrangements found in rare sarcomas, mainly involving the genitourinary and gynecologic tracts, with 3 cases reported in the uterine corpus. Although local recurrence was very common, no death has been reported, and some investigators consider these sarcomas low grade. Amplification of genes located at the 12q13-15 locus, especially MDM2 , is the hallmark genetic abnormality in well-differentiated and dedifferentiated liposarcoma of the soft tissue. Some uterine tumors have also been reported to harbor MDM2 amplification, including a proportion of Müllerian adenosarcomas, BCOR fusion-positive high-grade endometrial stromal sarcoma, BCORL1 -altered high-grade endometrial stromal sarcoma, rare JAZF1 fusion-positive low-grade endometrial stromal sarcoma, rare undifferentiated uterine sarcoma, and a single case of MEIS1-NCOA2 fusion sarcoma. Here, we report a case of high-grade MEIS1-NCOA2 fusion uterine sarcoma which also harbored amplification of multiple 12q13-15 genes, including MDM2 , CDK4 , MDM4 , and FRS2 , that exhibited aggressive clinical course leading to patient's death within 2 yr of the initial diagnosis. To the best of our knowledge, this is the first documented case of fatal MEIS1-NCOA2 fusion uterine sarcoma, and the second case of MEIS1-NCOA2 fusion uterine sarcoma that also harbors MDM2 amplification.

Prevalence and prognostic significance of PD-L1, TIM-3 and B7-H3 expression in endometrial serous carcinoma.

Endometrial serous carcinoma (ESC) is an aggressive type of endometrial carcinoma with a poor prognosis. Immune checkpoint blockade has evolved as a novel treatment option for endometrial cancers; however, data on expression of immune checkpoints that may be potential targets for immunotherapy in ESC are limited. We analyzed the prevalence and prognostic significance of PD-L1, TIM-3 and B7-H3 immune checkpoints in 99 ESC and evaluated their correlation with CD8 + tumor infiltrating lymphocytes. Applying the tumor proportion score (TPS) with a cutoff of 1%, PD-L1, TIM-3 and B7-H3 expression was present in 17%, 10% and 93% of cases, respectively. Applying the combined positive score (CPS) with a cutoff of 1, PD-L1, TIM-3 and B7-H3 expression was present in 63%, 67% and 94% of cases, respectively. Expression of these markers was largely independent of one another. PD-L1 correlated with higher CD8 + T-cell density when evaluated by either TPS (p = 0.02) or CPS (p < 0.0001). TIM-3 correlated with CD8 + T-cell density when evaluated by CPS (p < 0.0001). PD-L1 positivity was associated with improved overall survival (p = 0.038) when applying CPS. No association between PD-L1 expression and survival was found using TPS, and there was no association between TIM-3 or B7-H3 positivity and survival by either TPS or CPS. Using TPS, PD-L1 correlated with a higher tumor stage but not with survival, whereas the converse was true when PD-L1 was evaluated by CPS, suggesting that PD-L1 expression in immune cells correlates with prognosis and is independent of tumor stage. In conclusion, PD-L1, TIM-3 and B7-H3 may be potential therapeutic targets in selected patients with ESC. Further investigation of their roles as predictive biomarkers is needed.

Morules But Not Squamous Differentiation are a Reliable Indicator of CTNNB1 (ß-catenin) Mutations in Endometrial Carcinoma and Precancers.

Although collectively regarded as "squamous differentiation (SD)" in endometrial endometrioid carcinoma (EEC) and atypical hyperplasia/endometrioid intraepithelial neoplasia (AH/EIN), morules (often referred to as "squamous morules") and true SD may represent two distinct phenomena. Here, we explored the distinction between morules versus SD and investigated the association of morules and SD with CTNNB1 mutations. A total of 270 cases of EEC and AH/EIN were studied, including EEC with (n=36) or without (n=36) morules and AH/EIN with (n=80) or without (n=118) morules. Cases were analyzed by immunohistochemistry and selected cases (n=20) by targeted next-generation sequencing panel. Near-perfect agreement was found between morules and glandular ß-catenin nuclear staining in AH/EIN and EEC. A strong positive association was found between morules and glandular ß-catenin nuclear staining ( P <0.0001, Φ=0.59 in AH/EIN; P <0.0001, Φ=0.85 in EEC). There was no association between (1) morules and glandular PAX2 or PTEN aberrant expression or (2) SD and aberrant expression of ß-catenin, PAX2 or PTEN (Φ=0.09, ß-catenin; Φ=0.16, PAX2; Φ=0.13, PTEN). CTNNB1 mutations were identified in all 20 selected morule-containing cases (100%). Next-generation sequencing was performed on 2 (preprogestin and postprogestin treatment) biopsies from 1 patient, revealing identical mutational profile in morules and glands. In conclusion, (1) SD and morules are distinct biological phenomena; (2) the presence of morules, but not SD, is a reliable indicator of CTNNB1 mutations in EEC and AH/EIN. Our findings demonstrate that SD and morules are distinct biological phenomena. Since morules but not SD are associated with ß-catenin mutations, the distinction is clinically relevant and should be included in diagnostic reports.

Reliable Identification of Endometrial Precancers Through Combined Pax2, ß-Catenin, and Pten Immunohistochemistry.

The diagnosis of endometrial atypical hyperplasia/endometrioid intraepithelial neoplasia (AH/EIN) remains challenging and subjective in some cases, with variable histologic criteria and differences of opinion among gynecologic pathologists, potentially leading to under/overtreatment. There has been growing interest in the use of specific immunohistochemical markers as adjuncts in AH/EIN diagnosis. For example, the World Health Organization 2020 Classification specifies that loss of Pten, Pax2, or mismatch repair proteins are desirable diagnostic criteria. Other markers, most notably ß-catenin and Arid1a, are also aberrantly expressed in some AH/EIN. However, the performance of some markers individually-and more importantly as a group-has not been rigorously explored, raising questions as to which marker(s) or combination(s) is the most effective in practice. Formalin-fixed paraffin-embedded tissue sections from AH/EIN cases (n=111) were analyzed by immunohistochemistry for 6 markers: Pax2, Pten, Mlh1, ß-catenin, Arid1a, and p53. Aberrant expression was tabulated for each case and marker. An additional set of normal endometria (n=79) was also analyzed to define optimal diagnostic criteria for marker aberrance. The performance characteristics of each marker, the entire panel, and subsets thereof were quantitatively and statistically analyzed. In order of number of cases detected, the most frequently aberrant markers in AH/EIN were Pax2 (81.1% of cases), Pten (50.5%), ß-catenin (47.7%), Arid1a (7.2%), Mlh1 (4.5%), and p53 (2.7%). The majority of cases showed aberrant expression of ≥2 markers. All 6 markers together identified 92.8% of cases. Arid1a, Mlh1, and p53 were robust and readily scored markers, but all cases showing aberrant expression of these 3 markers were also detected by Pax2, Pten, or ß-catenin. A focused panel of only 3 markers (Pax2, Pten, and ß-catenin) showed optimal performance characteristics as a diagnostic adjunct in the histopathologic diagnosis of AH/EIN. Use of this panel is practicable and robust, with at least 1 of the 3 markers being aberrant in 92.8% of AH/EIN.

Navigating through perplex morphologic changes after exogenous hormone usage.

Clinical application of exogenous hormone as a method of contraception and/or treatment of various gynecologic disorders is exceedingly common. Unfortunately, the concurrent use of these agents also complicates the interpretation of pathology specimens. Various studies have shown that morphologic changes induced by hormonal therapies are present in both non-neoplastic and neoplastic tissues within the women's reproductive tract. It is important to understand the exogenous hormone induced morphologic changes, as it helps the pathologists make the accurate diagnosis, and in turn, guide clinicians to make optimal clinical decisions. In this review, we summarize the morphologic changes in both neoplastic and non-neoplastic endometrial, cervical, and myometrial surgical specimens after hormonal therapies, particularly after progestin treatment. In the endometrium, particularly in the scenario of progestin-treated atypical endometrial hyperplasia/endometrioid intraepithelial neoplasia (AEH/EIN), there is notoriously poor interobserver agreement and difficulty in assessing for the residual disease. We summarize current literature and propose our recommended approach in assessing these challenging endometrial biopsies, including a diagnostic algorism, the use of PAX-2, PTEN, beta-catenin immunohistochemistry panel, as well as consistency in diagnostic wording of the report. In the cervix, progestin makes dysplastic lesions appear metaplastic, thus high-grade squamous dysplastic lesions may be easily missed. Within the myometrium, lesions such as adenomyosis may show various degree of decidualization, while smooth muscle neoplasms may show apoplectic changes, and stromal lesions including endometrial stromal sarcoma may show more eosinophilic cytoplasm. All such changes may pose more or less diagnostic challenges in our daily practice. However, most are readily recognizable when we understand particular hormone related scenarios.

Endocervical neoplasia: Pathologic updates in diagnosis and prognosis.

The diagnosis of adenocarcinoma of the uterine cervix can be challenging due to the varied histologic types different etiologies and their associated biologic behaviors and corresponding clinical management implications. To address these issues a new classification system has been developed and is introduced in the most recent edition of the WHO Classification of Female Genital Tumors. This system is based on morphology and the relationship with human papillomavirus (HPV). All the tumors are now classified into HPV-associated (HPVA) and HPV-independent (HPVI). In addition there are diagnostic pathology related advancements which are able to predict prognosis such as the incidence of lymph node metastasis and the tumor recurrence. These advances include cancer invasive patterns tumor nuclear grade and the status of necrotic tumor debris. This review will discuss endocervical adenocarcinomas (EAC) including their precursors in association with HPV. Instead of discussing each histologic type of ECA individually we group all EACs into four categories based on their dominant growth patterns including glandular papillary mucin producing and solid microscopic appearances. Differential diagnosis and diagnostic pitfalls are addressed in each category. The glandular growth pattern is the most common. In this category location is important to be considered for the differential. The mucin-producing group is comprised by HPVA and HPVI tumors and the differential diagnosis should include metastatic mucinous carcinomas. Serous carcinoma of the uterine cervix no longer exists; however the terminology serous-like adenocarcinoma has been designated to tumors with the serous morphology that are HPV positive. We include this tumor in the papillary architecture category. A solid growth pattern can be found in multiple histologic types of EAC and most of them behave aggressively. Histopathologic parameters with prognostic relevance are also briefly discussed.

PD-L1 Expression in Endocervical Adenocarcinoma: Correlation With Patterns of Tumor Invasion, CD8+ Tumor-infiltrating Lymphocytes, and Clinical Outcomes.

Programmed death-1 ligand (PD-L1) expression has been used as a predictive marker for response to immune checkpoint inhibitors and has been reported to have prognostic value. Its prevalence and significance in endocervical adenocarcinoma (ECA) remain underinvestigated. We evaluated PD-L1 expression and CD8+ tumor-infiltrating lymphocyte density in whole tissue sections of 89 ECAs. PD-L1 expression was observed in 68% of ECAs by combined positive score (CPS, cutoff 1) and 29% of ECAs by tumor proportion score (TPS, cutoff 1%). Using CPS, PD-L1 expression was seen in 11%, 78%, and 72% of pattern A, B, and C tumors, respectively, with significantly higher expression in tumors with destructive-type invasion (B and C) (P=0.001 [A vs. B], 0.0006 [A vs. C], 0.0002 [A vs. B+C]). Using TPS, no significant difference in PD-L1 expression was seen between tumors with different invasion patterns (0%, 22%, and 32% in tumors with pattern A, B, and C, respectively; P=0.27 [A vs. B], 0.053 [A vs. C], 0.11 [A vs. B+C]). PD-L1-positive ECAs demonstrated significantly higher CD8+ tumor-infiltrating lymphocyte density (CPS: P=0.028; TPS: P=0.013) and worse progression-free survival when compared with PD-L1-negative ECAs (CPS: hazard ratio [HR]=4.253 vs. 0.235, P=0.025; TPS: HR=4.98 vs. 0.2; P=0.004). When invasion patterns were separately assessed, pattern C tumors similarly showed worse progression-free survival in PD-L1-positive tumors (CPS: HR=6.15 vs. 0.16, P=0.045; TPS: HR=3.78 vs. 0.26, P=0.027). In conclusion, our data show frequent PD-L1 expression in ECA with destructive-type invasion, supporting the role of the PD-1/PD-L1 pathway as a therapeutic target for these tumors. Our data also support PD-L1 as a negative prognostic marker associated with a potentially unfavorable outcome.

Specific Biomarker Expression Patterns in the Diagnosis of Residual and Recurrent Endometrial Precancers After Progestin Treatment: A Longitudinal Study.

BACKGROUND: Conservative management with progestin is a treatment option for atypical hyperplasia (AH). However, pathologic diagnosis of residual/recurrent lesions is often problematic because of the profound morphologic changes induced by progestin and the lack of established diagnostic criteria for progestin-treated residual AH. METHODS: We conducted a longitudinal study of 265 endometrial biopsies from 54 patients with a history of AH on progestin therapy. Patient outcomes were divided into 3 categories after morphologic review and immunohistochemical staining with phosphatase and tensin homolog (PTEN) and paired box 2 (PAX2): (1) persistent or residual disease; (2) recurrent disease; (3) complete response. All specimens were classified into 3 categories based on morphology: (1) persistent/recurrent disease (nonresponse), (2) morphologically uncertain response, (3) optimally treated (complete response). The staining patterns of PTEN/PAX2 were tracked over time in individual patients and correlated with morphologic findings before and after progestin therapy. RESULTS: Our data showed that aberrant expression patterns of PTEN and/or PAX2 were identified in 48 (88.9%) of the 54 primary biopsies and persisted in persistent/recurrent AH across serial endometrial biopsies (n=99, P<0.00001), while normal PTEN and PAX2 expressions were consistently observed in optimally treated cases (n=84, P<0.00001). More importantly, follow-up biopsies that showed a morphologically uncertain response but a PTEN/PAX2 expression pattern identical to the initial biopsy were significantly correlated with persistent or recurrent disease (n=18, P=0.000182), as evidenced by areas with morphologic features diagnostic of AH on subsequent biopsy. CONCLUSIONS: Biomarker PTEN/PAX2 signatures offer a valuable diagnostic aid to identify residual AH in progestin-treated endometrial samples for which the biomarker status from preprogestin treated AH is known. The findings of this study are promising for a possible future change of diagnostic practice.

Multimodality Imaging of Uterine Cervical Malignancies.

OBJECTIVE. In this article, we provide an updated review on the role of imaging in initial staging, treatment monitoring, and follow-up of cervical cancer with a focus on the role of MRI and FDG PET/CT. In addition, the 2018 International Federation of Gynecology and Obstetrics staging system and its implication on management of cervical cancer are explored. CONCLUSION. Imaging plays a major role in treatment planning and as a prognostic indicator in patients with cervical cancer. MRI and PET/CT have complementary roles: MRI is essential for the local staging of the primary tumor, and PET/CT is the most useful modality for detecting regional nodal and distant metastases.

PD-L1 Expression and CD8+ Tumor-infiltrating Lymphocytes in Different Types of Tubo-ovarian Carcinoma and Their Prognostic Value in High-grade Serous Carcinoma.

The prevalence and significance of programmed death-1 ligand (PD-L1) expression in different types of tubo-ovarian carcinoma have not been well defined. We evaluated PD-L1 expression and CD8 tumor-infiltrating lymphocyte (TIL) density in whole tissue sections of 189 cases of tubo-ovarian carcinoma, including high-grade serous carcinoma (HGSC, n=100), clear cell carcinoma (CCC, n=24), endometrioid carcinoma (EmC, n=40), and mucinous carcinomas (MC, n=25). Using the tumor proportion score (TPS) with a 1% cutoff, PD-L1 expression was present in 21% of HGSC, 16.7% of CCC, 2.5% of EmC, and 4% of MC. Using the combined positive score (CPS) with a cutoff of 1, PD-L1 expression was present in 48% of HGSC, 25% of CCC, 20% of EmC, and 24% of MC. HGSC demonstrated significantly higher CD8 TIL density than CCC (P=0.013238), EmC (P=0.01341), or MC (P=0.004556). In HGSC, CD8 TIL density was directly correlated with PD-L1 positivity using either TPS (P=0.0008) or CPS (P=0.00011). Survival analysis of patients with high stage (stage III to IV) HGSC revealed PD-L1 positivity by TPS to be associated with improved progression-free survival (adjusted hazard ratio: 0.4912 vs. 2.036, P=0.0378). Although not statistically significant, a similar trend was observed in overall survival (adjusted hazard ratio: 0.3387 vs. 2.953, P=0.0548). In contrast, with CPS, no significant difference was identified between PD-L1-positive and negative groups in either progression-free survival (P=0.5086) or overall survival (P=0.7823). Neoadjuvant chemotherapy was associated with higher PD-L1 expression by TPS (P=0.00407) but not CPS. No significant difference in PD-L1 expression was detected in tumors from patients with germline BRCA1/2 mutations compared with germline mutation-negative tumors by either TPS or CPS. In conclusion, the prevalence of PD-L1 expression is variable in different types of tubo-ovarian carcinoma and is highest in HGSC. In high-stage HGSC, PD-L1 positivity in tumor cells is associated with an increased immune response and improved survival.

Cervical Adenocarcinoma: Histopathologic Features From Biopsies to Predict Tumor Behavior.

The pattern-based classification system of endocervical adenocarcinoma correlates with nodal metastasis and clinical outcomes, but its application in biopsies is challenging. The aim of this study was the correlation of additional histologic features with patterns of invasion as well as prognosis. A total of 103 specimens from 71 cervical adenocarcinoma cases were studied. Among the 71 cases, all had resection specimens including hysterectomy, cold knife cone excision or loop electrosurgical excision procedure excision, and 32 of these had prior cervical biopsies. We applied the pattern-based classification system to all the specimens and evaluated histopathologic features microscopically. Findings in biopsies were compared with their corresponding resections and correlated with nodal status and disease stage. In 71 resection specimens, pattern A was present in 10 (14.1%), pattern B in 12 (16.9%), and pattern C in 49 (69%) cases. Of the 32 cervical biopsies, pattern of invasion could be classified in only 16 (50%) cases, including 1 (6%) with pattern A, 4 (25%) with pattern B, and 11 (69%) with pattern C. Of the 32 cervical biopsies, 30 could be evaluated for intraluminal necrotic/tumor debris and/or grade 3 nuclei, which correlated with pattern C as well as with lymph node metastasis in the subsequent staging specimens. No tumor with patterns A or B had intraluminal necrotic/tumor debris or grade 3 nuclei in either biopsy or resection specimens. Therefore, intraluminal necrotic/tumor debris and grade 3 nuclei are highly predictive histologic features for cervical adenocarcinomas with pattern C invasion and nodal metastasis.

Challenges in the Pap diagnosis of endocervical adenocarcinoma in situ.

INTRODUCTION: Recognition of adenocarcinoma in situ (AIS) in cervical cytology is challenging. MATERIALS AND METHODS: We calculated the sensitivity and accuracy of Papanicolaou (Pap) tests obtained within 1 year of a histologic diagnosis of AIS from 2007 to 2016. We also correlated it with the coexistence of squamous lesions, calculated the interobserver agreement, and compared these measures with those of endocervical adenocarcinoma (ECCA). We correlated AIS detection with high-risk human papillomavirus (hrHPV) status. RESULTS: Of 72 patients with histologic AIS and 48 patients with ECCA, 92% and 87.5%, respectively, had abnormal Pap test results. A glandular abnormality was detected in 44.4% of the AIS and 77.1% of the ECCA cases. Complete cytohistologic concordance was reached in 8.3% of AIS and 22.9% of ECCA cases. In addition, 27.8% of AIS and 6.3% of ECCA cases were diagnosed on Pap as a high-risk squamous abnormality. Concurrent squamous lesions were present in 79.2% of patients with AIS and 29.2% of patients with ECCA. The Paps from the AIS and ECCA cases were diagnosed as pure squamous abnormalities in 47.2% and 10.4% of cases, respectively. In the AIS cases, interobserver agreement was substantial for detection of any high-risk cytologic abnormality (kappa = 0.67) and fair for detection of any glandular abnormality (kappa = 0.34). Among the 26 patients with AIS tested for hrHPV, 92% had positive results and 8% had negative results. CONCLUSIONS: The cytologic sensitivity for the detection of AIS remains low. It is directly related to the coexistence of squamous lesions. Cytology and hrHPV as stand-alone screening tests fail in the early detection of a small proportion of glandular lesions, although combined testing will improve their detection rates.

Mismatch Repair Protein Expression in Endometrioid Intraepithelial Neoplasia/Atypical Hyperplasia: Should We Screen for Lynch Syndrome in Precancerous Lesions?

Screening for Lynch syndrome (LS) is routinely performed in patients with endometrial carcinoma. Currently, no screening recommendations exist for LS in precancerous lesions. The study goal was to determine the incidence of abnormal protein expression in endometrioid intraepithelial neoplasia/atypical hyperplasia (EIN/AH). We analyzed mismatch repair (MMR) protein expression by immunohistochemistry in EIN/AH concurrent with MMR-deficient endometrial carcinomas, and in endometrial biopsy/curettage specimens with EIN/AH from an unselected group of patients. Of 63 patients with MMR-deficient endometrial carcinoma, 34 demonstrated loss of MLH1/PMS2 expression; 1 showed loss of PMS2 alone; 12 showed loss of MSH2/MSH6, and 15 had loss of MSH6 alone. Genetic testing identified deleterious mutations in 14 cases (LS). 15 tumors demonstrated MLH1 promoter hypermethylation. Abnormal MMR expression in EIN/AH and adjacent carcinoma was concordant in 100% of LS cases and 71% of MLH1 promoter hypermethylation cases. Of 118 patients from the unselected group with EIN/AH, 4 (3%) cases demonstrated absent expression of one or more MMR proteins. Of these, 2 patients were later confirmed to have deleterious mutations in subsequent specimens with endometrial carcinoma. The prevalence of abnormal MMR expression in EIN/AH adjacent to carcinoma and in the unselected group of patients with EIN/AH is similar to the reported prevalence of LS in endometrial carcinoma. Identifying patients at high risk for LS through abnormal MMR expression in EIN/AH provides the benefit of early surveillance, treatment and timely diagnosis for the patient and affected family members.