Patients diagnosed with an endometrial cancer precursor lesion on biopsy may be found to have endometrial cancer at the time of subsequent surgery. The current study seeks to identify patients with endometrial intraepithelial neoplasia (EIN) on biopsy that may be harboring an occult carcinoma. Immunohistochemical stains for gene loss of expression (LOE) for 6 genes, PTEN, ARID1A, MSH6, MSH2, MLH1, and PMS2, were performed on 113 biopsy specimens with EIN. For the 95 patients with follow-up histology, 40 patients had cancer, 41 had EIN, and 14 had normal endometrium. PTEN LOE was found frequently in both EIN and endometrial cancer, and therefore had low positive predictive value. All specimens with ARID1A, MSH6, MSH2, MLH1, or PMS2 LOE on biopsy were subsequently found to have cancer. LOE of any gene was associated with modest sensitivity (0.78) in identifying patients with endometrial cancer who had EIN on biopsy. Further investigation is warranted to determine if gene LOE is a useful clinical tool when evaluating patients with EIN on biopsy.

Objective The benefit of evaluating the precursor of endometrial carcinoma, endometrial hyperplasia (intraepithelial neoplasia [EIN]), for loss of mismatch repair (MMR) protein expression and Lynch syndrome has yet to be determined. The present study aims to establish the incidence and type of loss of MMR protein expression in unselected premalignant lesions of endometrial adenocarcinoma, as well as the agreement of immunohistochemical staining in pretreatment endometrial biopsy (EMB) specimens with subsequent uterine resections. Methods A retrospective review identified 112 endometrial biopsies meeting criteria for endometrial EIN. Slides made from tissue microarray blocks were evaluated using antibodies against MLH1, PMS2, MSH2, and MSH6. Cases with a deficit in MLH1 were evaluated for gene promoter hypermethylation by polymerase chain reaction analysis. Fifty-four subsequent hysterectomy specimens were retrieved and assessed for MMR protein expression. Results Of the 112 endometrial biopsies with EIN, 4.5% (5/112) exhibited loss of MMR protein expression. The majority (4/5) demonstrated a deficit of MLH1, of which all exhibited inactivation via promoter hypermethylation. A single case displayed an absence of MSH6. Age was not significantly associated with MMR deficiency. There was no significant association between MMR status in the EMB and a subsequent diagnosis of cancer. Immunohistochemical staining in all successive hysterectomy cases was concordant with the pattern observed in the EMB specimen. Conclusions Sporadic hypermethylation of MLH1 seems to be the primary mechanism underlying defective MMR protein expression in EIN. Among our cohort, only 1 patient (<1%) had a mutation suggestive of a hereditary inheritance. Hence, the utility of evaluating EIN for MMR protein expression as a screen for Lynch syndrome is limited, regardless of age.

Li-Fraumeni Syndrome (LFS) is a hereditary cancer predisposition syndrome with up to 90% lifetime cancer risk. Cancer screening, including annual whole-body MRI (WBMRI), is recommended due to known survival advantage, with cancer detection rate of 7% on initial screening. Intervention and cancer detection rates on subsequent screenings are unknown. Clinical data for pediatric and adult LFS patients (n=182) were reviewed, including instances of WBMRI screening and interventions based on screening results. For each WBMRI screening, interventions including biopsy and secondary imaging, as well as rate of cancer diagnosis, were analyzed comparing initial versus subsequent WBMRI. Of the total cohort (n=182), we identified 68 adult patients and 50 pediatric patients who had undergone at least two WBMRI screenings, with a mean of 3.8+1.9 (adults) and 4.0+2.1 (pediatric) screenings. Findings on initial screening led to an imaging or invasive intervention in 38% of adults and 20% of children. On follow up, overall intervention rates were lower for adults (19%, p=0.0026) and stable for children (19%, p=NS). Thirteen cancers were detected overall (7% of adult and 14% of pediatric scans), on both initial (pediatric: 4%, adult: 3%) and subsequent (pediatric: 10%, adult: 6%) screenings. Rates of intervention after WBMRI screening decreased significantly in adults between first and subsequent exams and remained stable in pediatric patients. Cancer detection rates were similar on screening (3-4% initial, 6-10% subsequent) for both children and adults. These findings provide important data for counseling LFS patients about screening outcomes.

Cancer predisposition syndromes (CPS), or genetic syndromes leading to increased cancer risk, are responsible for at least 10% of all childhood cancers. With advances in both tumor and germline sequencing, these syndromes have been uncovered both in patients with and without syndromic features and family history of cancer. Recognition of CPS in children and use of associated screening guidelines can improve morbidity and mortality from childhood cancer. Given the multidisciplinary approach needed for management of CPS, knowledge of clinical features and surveillance guidelines are essential for the general pediatrician. Pediatricians also play a vital role in anticipatory guidance regarding cancer prevention strategies and management of psychosocial stressors associated with ongoing screening. This article discusses 10 of the more common pediatric CPS, reasons to refer patients for CPS genetic testing and evaluation, and general cancer prevention strategies. [ Pediatr Ann . 2022;51(1):e15–e21.]

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