PURPOSE:Germline CHEK2 c.1100delC-associated breast cancer (BC) patients have been reported with worse prognosis than patients without the variant. However, results are based on older cohorts and treatment regimens. As part of the Hebon-CHEK2 study, we aim to study prognosis in a Dutch cohort of genetically tested ER-positive BC patients diagnosed from 2006 onwards. METHODS:All patients underwent genetic testing based on personal and family history risk, and data on BC outcomes were collected. Hazard ratios (HRs) and 95 % confidence intervals (CI) for the association of CHEK2-status with prognosis were estimated via delayed entry Cox regression models, adjusted for age and year of diagnosis, tumor size, nodal status, and primary treatment regimens. Furthermore, we meta-analyzed our results with previous studies. RESULTS:We included 480 CHEK2 BC patients and 944 BC patients without the variant. Median follow-up was 6.0 years. Heterozygotes were more often diagnosed with small tumors, and lymph node positive disease. No significant difference was found for recurrent disease and distant disease-free survival, neither before 5 years (HR = 0.73; 95 %CI = 0.35-1.53 and HR = 0.99; 95 %CI = 0.44-2.21, respectively), nor after 5 years follow-up (HR = 0.29; 95 %CI = 0.06-1.28 and HR = 0.39; 95 %CI = 0.10-1.39, respectively). Also no significant difference in BC-specific survival (HR = 0.77; 95 %CI = 0.42-1.39) or overall survival (HR = 0.69; 95 %CI = 0.43-1.08) was found. Meta-analysis of our results with previous studies showed a worse BC-specific survival for heterozygotes. CONCLUSION:In our study, with more recent years of diagnosis and treatment, we found no difference in prognosis, as opposed to previous studies. Further research is needed to validate our findings.

Genetic diagnosis of rare diseases requires accurate identification and interpretation of genomic variants. Clinical and molecular scientists from 37 expert centers across Europe created the Solve-Rare Diseases Consortium (Solve-RD) resource, encompassing clinical, pedigree and genomic rare-disease data (94.5% exomes, 5.5% genomes), and performed systematic reanalysis for 6,447 individuals (3,592 male, 2,855 female) with previously undiagnosed rare diseases from 6,004 families. We established a collaborative, two-level expert review infrastructure that allowed a genetic diagnosis in 506 (8.4%) families. Of 552 disease-causing variants identified, 464 (84.1%) were single-nucleotide variants or short insertions/deletions. These variants were either located in recently published novel disease genes (n = 67), recently reclassified in ClinVar (n = 187) or reclassified by consensus expert decision within Solve-RD (n = 210). Bespoke bioinformatics analyses identified the remaining 15.9% of causative variants (n = 88). Ad hoc expert review, parallel to the systematic reanalysis, diagnosed 249 (4.1%) additional families for an overall diagnostic yield of 12.6%. The infrastructure and collaborative networks set up by Solve-RD can serve as a blueprint for future further scalable international efforts. The resource is open to the global rare-disease community, allowing phenotype, variant and gene queries, as well as genome-wide discoveries.

PTEN Hamartoma Tumor Syndrome (PHTS) is a rare hereditary syndrome. PHTS has a variable phenotype characterized by benign lesions and increased cancer risks. Clarifying the extent of the benign phenotype could facilitate early recognition of PHTS patients before cancer development. Therefore, we assessed the spectrum, frequency, and age of excerpt of pathology-confirmed benign lesions in PHTS patients. Pathology reports were collected for 379 patients with a pathogenic PTEN variant from the Dutch nationwide pathology databank (Palga). Benign lesions were classified as PHTS-related based on current clinical diagnostic guidelines and non-PHTS-related lesions by ICD-10 codes. Age of last follow-up was year of pathology request minus birth year. Analyses were stratified by sex and index status. Patients presented mainly with gastrointestinal (54%), skin (47%), thyroid (31%) and vascular lesions (26%). Males developed lipomas at an early age (9 years (5-34)). Females developed endometrial hyperplasia (16%) at an earlier age (41 years (35-49)) and uterine polyps (13%) more often than the general population. No significant differences were observed between sexes or index and non-index patients. The results are reflective of current diagnostic guidelines. Early-onset lipomas may be useful for early detection of PHTS patients. Additionally, uterine polyps should be considered for inclusion as a PHTS-related lesion.

Increased hereditary cancer risk is one of the hallmarks of PTEN Hamartoma Tumor Syndrome (PHTS) which is caused by a pathogenic germline variant in PTEN. Case reports and some cohort studies have described ovarian cancer (OC) in PHTS patients. Previously, we observed an enrichment of non-serous OC in PHTS compared to sporadic cases (3% vs 1%). However, ovarian cancer is currently not considered a PHTS-related cancer. The aim of this study was to describe five PHTS patients with a pathogenic germline variant in PTEN with non-serous OC. Three of the non-serous OCs were mucinous carcinomas (49, 51 and 52 years) and two were malignant germ cell tumors (8 and 15 years) and all were diagnosed before genetic testing and PHTS diagnosis. In addition to OC, the described patients developed other PHTS-related benign and malignant lesions. We provide further evidence that non-serous ovarian cancer, especially mucinous, endometrioid and malignant germ cell tumors should be further investigated as potential PHTS-related cancers.

PURPOSE:Patients with PTEN Hamartoma Tumor Syndrome (PHTS) have high hereditary cancer risks for breast, endometrial, and thyroid cancer. Patients develop multiple primary cancers, but these risks remain uncertain. We aimed to provide the second primary cancer risk. METHODS:This European cohort study assessed second primary cancer risks with Kaplan-Meier analyses using data from medical files, registries and/or patient questionnaires. RESULTS:Overall, 279 adult PHTS patients with (a history of) cancer were included (80% female). Among females, 106 (54%) developed a PHTS-related second primary cancer after a PHTS-related first primary cancer, whereas 10 (29%) males developed a PHTS-related second primary cancer after a PHTS-related first primary cancer. The 5- and 10-year PHTS-related second primary cancer risks were 24.5% (95% CI = 18.1-32.5) and 45.7% (95% CI = 36.9-55.4) in females and 14.5% (95% CI = 5.7-34.1) and 19.8% (95% CI = 8.6-41.9) in males, respectively. Furthermore, 5- and 10-year risks for a second primary breast cancer after a first primary breast cancer were 23.3% (95% CI = 14.9-35.2) and 45.6% (95% CI = 33.0-60.2) in females, respectively. CONCLUSION:This study demonstrated that PHTS patients have high second primary cancer risks, which is driven by breast cancer in females. Hence, identifying patients with PHTS before or at first primary cancer diagnosis is essential to enable potential early detection or prevention of a second primary cancer through surveillance or risk-reducing surgery.

PTEN hamartoma tumour syndrome (PHTS) patients have a high hereditary risk of cancer, especially breast (BC), endometrial (EC), and thyroid cancer (TC). However, the prognosis of PHTS-related cancers is unknown. This European cohort study included adult PHTS patients with data from medical files, registries, and/or questionnaires. Overall survival (OS) was assessed using Kaplan-Meier analyses and were compared with sporadic cancer and the general population using standardized mortality (SMR) and relative survival rates (RSR). Survival bias was addressed using left-truncation. Overall, 147 BC patients were included. The 10y-OS was 77% (95%CI = 66–90), decreasing with increasing stage from 90% (95%CI = 73–100) for stage 0 to 0% (95%CI = 0–0) for stage IV. BC relative survival was comparable to sporadic BC in the first two years (2y-RSR = 1.1; 95%CI = 1.1–1.1) and increasing thereafter (5y-RSR = 1.7; 95%CI = 1.6–1.7). For TC (N = 56) and EC (N = 35), 10y-OS was 87% (95%CI = 74–100) and 64% (95%CI = 38–100), respectively. Overall and cancer-specific mortality in female PHTS patients exceeded general population rates (SMR = 3.7; 95%CI = 2.6–5.0 and SMR = 2.7; 95%CI = 1.6–4.4). The prognosis of PHTS-related cancers was comparable to the general population. The higher overall mortality in PHTS patients is presumably related to their higher cancer incidence. These findings, and the high survival observed in early-stage cancer, emphasise the importance of recognising PHTS early to facilitate cancer surveillance.

AimsPatients with PTEN hamartoma tumour syndrome (PHTS) have an increased risk of developing cancer due to a pathogenic germline variant in the PTEN tumour suppressor gene. Early recognition of PHTS facilitates initiation of cancer surveillance which is highly effective in preventing the development of advanced malignancies. PHTS is rare and due to its varied phenotype, even within families, oral abnormalities may be a valuable tool in the identification of these patients at an early stage before cancer development.Materials and methodsBetween 1997 and 2020, phenotypic characteristics were evaluated in 81 paediatric (median age: 9 years) and 86 adult (median age: 40 years) PHTS patients by one of 2 medical experts during yearly surveillance visits at a Dutch PHTS expertise centre. Oral features evaluated included gingival hypertrophy, oral papillomas, and high palate (in adults).ResultsWithin adults, gingival hypertrophy was present in 94%, oral papillomas in 88%, and a high palate in 89%. All adult patients had at least one of these oral features, and 99% showed at least 2 oral features. Oral features were less common in paediatric patients, especially under 11 years of age. Gingival hypertrophy was observed in 44% and oral papillomas in 54% of paediatric patients.ConclusionsThe presence of 2 or 3 oral features may indicate PHTS in adults or adolescents, especially if macrocephaly is present. Dental professionals are well-positioned to recognise these oral manifestations could be related to PHTS. They can initiate an overall clinical assessment of the patient by alerting the patient's medical practitioner of the findings and the possible need for genetic testing. This could significantly improve outcomes, including life expectancy, for patients and possibly for their relatives.Clinical relevanceDental professionals are ideally placed to recognise oral features and initiate early assessment of PHTS which could significantly improve patient outcomes.

BACKGROUND:Individuals with germline pathogenic variants in BRCA1 or BRCA2 are at a high risk of breast and ovarian carcinomas with BRCA1/2 deficiency and homologous recombination deficiency that can be detected by analysis of genome-wide genomic instability features such as large-scale state transitions, telomeric allelic imbalances, and genomic loss of heterozygosity. Malignancies with homologous recombination deficiency are more sensitive to platinum-based therapies and poly(ADP-ribose) polymerase inhibitors. We investigated the fraction of non-breast or ovarian malignancies that have BRCA1/2 deficiency and genomic instability features. METHODS:The full tumor history of a large, historical, clinic-based, consecutive cohort of 2965 individuals with germline pathogenic variants in BRCA1/2 was retrieved from the Dutch nationwide pathology databank (Palga). In total, 169 non-breast or ovarian malignancies were collected and analyzed using targeted next-generation sequencing and shallow whole-genome sequencing to determine somatic second-hit alterations and genomic instabilities indicative of homologous recombination deficiency, respectively. RESULTS:BRCA1/2 deficiency was detected in 27% (21/79) and 23% (21/90) of 20 different types of non-breast or ovarian malignancies in individuals with germline pathogenic variants in BRCA1 and BRCA2, respectively. These malignancies had a higher genomic instability score than BRCA1- or BRCA2-proficient malignancies (P < .001 and P < .001, respectively). CONCLUSIONS:BRCA1/2 deficiency and genomic instability features were found in 27% and 23% of a broad spectrum of non-breast or ovarian malignancies in individuals with germline pathogenic variants in BRCA1 and BRCA2, respectively. Evaluation of the effectiveness of poly(ADP-ribose) polymerase inhibitors in these individuals should be focused on tumors with a confirmed absence of a wild-type allele.

PurposeFemales with biallelic CHEK2 germline pathogenic variants (gPVs) more often develop multiple breast cancers than individuals with monoallelic CHEK2 gPVs. This study is aimed at expanding the knowledge on the occurrence of other malignancies.MethodsExome sequencing of individuals who developed multiple primary malignancies identified three individuals with the CHEK2 (NM_007194.4) c.1100del p.(Thr367MetfsTer15) loss-of-function gPV in a biallelic state. We collected the phenotypes of an additional cohort of individuals with CHEK2 biallelic gPVs (n=291).ResultsIn total, 157 individuals (53.4%; 157/294 individuals) developed ≥1 (pre)malignancy. The most common (pre)malignancies next to breast cancer were colorectal- (n=19), thyroid- (n=19) and prostate (pre)malignancies (n=12). Females with biallelic CHEK2 loss-of-function gPVs more frequently developed ≥2 (pre)malignancies and at an earlier age compared to females biallelic for the CHEK2 c.470T>C p.(Ile157Thr) missense variant. Furthermore, 26 males (31%; 26/84 males) with CHEK2 biallelic gPVs developed ≥1 (pre)malignancies of 15 origins.ConclusionOur study suggests that CHEK2 biallelic gPVs likely increase the susceptibility to develop multiple malignancies in various tissues, both in females and males. However, it is possible that a substantial proportion of individuals with CHEK2 biallelic gPVs is missed as diagnostic testing for CHEK2 often is limited to individuals who developed breast cancer.

PTEN hamartoma tumor syndrome (PHTS) has a broad clinical spectrum including various benign and malignant tumors at varying age of diagnosis. Many patients remain unrecognized, unaware of their increased cancer risk. We aimed to describe the cancer spectrum, age of onset and histopathological cancer characteristics to assess whether specific cancer characteristics could improve PHTS recognition. Genetic testing results and pathology reports were collected for patients tested for germline PTEN variants between 1997 and 2020 from the diagnostic laboratory and the Dutch nationwide pathology databank (Palga). The cancer spectrum and age of onset were assessed in patients with (PTENpos) and without (PTENneg) a germline PTEN variant. Histopathological cancer characteristics were assessed in a nested cohort. 341 PTENpos patients (56% females) and 2882 PTENneg patients (66% females) were included. PTENpos patients presented mostly with female breast (BC, 30%), endometrial (EC, 6%), thyroid (TC, 4%) or colorectal cancer (4%). PTENpos were significantly younger at cancer onset (43 vs. 47 years) and had more often (46% vs. 18%) a second BC than PTENneg. PTEN detection rates were highest for BC <40 years (9%), TC <20 years (15%) and EC <50 years (28%), and dropped to 6%, 4%, and 15% by age 60. Histopathological characteristics were similar between groups. No histopathological cancer characteristics were distinctive for PHTS. However, PTENpos were significantly younger at cancer onset. Therefore early-onset BC, EC, or TC warrants consideration of PHTS diagnostics either through a pre-screen for other PHTS features or direct germline testing.

AIMS:Systemic sclerosis (SSc) is characterized by vasculopathy, inflammation, and fibrosis, and carries one of the worst prognoses if patients also develop pulmonary arterial hypertension (PAH). Although PAH is a known prognosticator, patients with SSc-PAH demonstrate disproportionately high mortality, presumably due to cardiac involvement. In this cross-sectional study, the relationship between cardiac involvement revealed by cardiovascular magnetic resonance (CMR) and systemic microvascular disease severity measured with nailfold capillaromicroscopy (NCM) in patients with SSc-PAH is evaluated and compared with patients with idiopathic PAH (IPAH). METHODS AND RESULTS:Patients with SSc-PAH and IPAH underwent CMR, echocardiography, and NCM with post-occlusive reactivity hyperaemia (PORH) testing on the same day. CMR imaging included T2 (oedema), native, and post-contrast T1 mapping to measure the extracellular volume fraction (ECV, fibrosis) and adenosine-stress-perfusion imaging measuring the relative myocardial upslope (microvascular coronary perfusion). Measures of peripheral microvascular function were related to CMR indices of oedema, fibrosis, and myocardial perfusion. SSc-PAH patients (n = 20) had higher T2 values and a trend towards a higher ECV, compared with IPAH patients (n = 5), and a lower nailfold capillary density (NCD) and reduced capillary recruitment after PORH. NCD correlated with ECV and T2 (r = -0.443 and -0.464, respectively, P < 0.05 for both) and with markers of diastolic dysfunction on echocardiography. PORH testing, but not NCD, correlated with the relative myocardial upslope (r = 0.421, P < 0.05). CONCLUSION:SSc-PAH patients showed higher markers of cardiac fibrosis and inflammation, compared with IPAH patients. These markers correlated well with peripheral microvascular dysfunction, suggesting that SSc-driven inflammation and vasculopathy concurrently affect peripheral microcirculation and the heart. This may contribute to the disproportionate high mortality in SSc-PAH.

There are indications for immune dysregulation in PTEN Hamartoma Tumour Syndrome (PHTS), however information on the clinical immune phenotype is lacking. We aimed to assess the frequency of infections and autoimmune disease in PHTS patients. A retrospective cohort study including 81 paediatric and 109 adult PHTS patients and 73 female adult controls and self-reported data from yearly surveillance visits. Differences between adult patients and controls were assessed with odds ratios (OR). Of paediatric patients, 1% reported fungal infections, 23% tonsillectomy/adenoidectomy, 36% bacterial infections requiring antibiotics, and 2% autoimmune disease. Of adult patients, up to 67% repeatedly reported fungal infections, and 73% was ever affected which was similar to controls. Compared to controls, adult patients more often reported (signs of) viral infections: tonsillectomy/adenoidectomy (78%; OR = 7.4 (95%CI: 3.7-15.8)), frequent infections during childhood (43%; OR = 2.5 (95%CI: 1.3-5.2)), and flu or cold infections more often than others (49%; OR = 3.9 (95%CI: 2.0-8.0)). Autoimmune disease was also more frequent (24%, OR = 2.7 (95%CI: 1.1-7.3)) in adult patients, and antibiotics use (38%, OR = 4.7 (95%CI: 1.3-23.0)) in female adult patients. PHTS patients experience a broad clinical phenotype of immune dysregulation. At adult age, this consists of more often viral and bacterial infections and autoimmune disease, and repetitive fungal infections.

Females with PTEN Hamartoma Tumor Syndrome (PHTS) have breast cancer risks up to 76%. This study assessed associations between breast cancer and lifestyle in European female adult PHTS patients. Data were collected via patient questionnaires (July 2020–March 2023) and genetic diagnoses from medical files. Associations between lifestyle and breast cancer were calculated using logistic regression corrected for age. Index patients with breast cancer before PHTS diagnosis (breast cancer index) were excluded for ascertainment bias correction. In total, 125 patients were included who completed the questionnaire at a mean age of 44 years (SD = 13). This included 21 breast cancer indexes (17%) and 39 females who developed breast cancer at 43 years (SD = 9). Breast cancer patients performed about 1.1 times less often 0–1 times/week physical activity than ≥2 times (ORtotal-adj = 0.9 (95%CI 0.3–2.6); consumed daily about 1.2–1.8 times more often ≥1 than 0–1 glasses of alcohol (ORtotal-adj = 1.2 (95%CI 0.4–4.0); ORnon-breastcancer-index-adj = 1.8 (95%CI 0.4–6.9); were about 1.04–1.3 times more often smokers than non-smokers (ORtotal-adj = 1.04 (95%CI 0.4–2.8); ORnon-breastcancer-index-adj = 1.3 (95%CI 0.4–4.2)); and overweight or obesity (72%) was about 1.02–1.3 times less common (ORtotal-adj = 0.98 (95%CI 0.4–2.6); ORnon-breastcancer-index-adj = 0.8 (95%CI 0.3–2.7)). Similar associations between lifestyle and breast cancer are suggested for PHTS and the general population. Despite not being statistically significant, results are clinically relevant and suggest that awareness of the effects of lifestyle on patients’ breast cancer risk is important.

Supplementary Table 1. Clinical characteristics of BRCA1/2 carriers including index cases in the Northern Netherlands (study population) and in the rest of the Netherlands (reference population). Supplementary Table 2. Overview of number of carriers (excluding index cases) at risk at each age-decade and number of breast cancer event for each age-decade. Supplementary Table 3. Cumulative incidence of breast cancer in BRCA1/2 carriers, excluding index cases, in the study population (Northern Netherlands) and reference population (rest of the Netherlands). Estimation of risks weighted to an equal contribution from the different birth cohorts in each population. Supplementary Table 4. Relative risks (hazard ratios (95% confidence interval)) of breast cancer for mutation spectrum, excluding index cases. Supplementary Table 5. Regional differences in the breast cancer risk of BRCA1/2 carriers including index cases (adjusted for birth year) in the Netherlands: the study population (Northern Netherlands) compared to the reference population (the rest of the Netherlands.)

Background: PTEN Hamartoma Tumor Syndrome (PHTS) is a rare syndrome with a broad phenotypic spectrum, including increased risks of breast (BC, 67%-78% at age 60 years), endometrial (EC, 19%-28%), and thyroid cancer (TC, 6%-38%). Current risks are likely overestimated due to ascertainment bias. We aimed to provide more accurate and personalized cancer risks. Methods: This was a European, adult PHTS cohort study with data from medical files, registries, and/or questionnaires. Cancer risks and hazard ratios were assessed with Kaplan-Meier and Cox regression analyses, and standardized incidence ratios were calculated. Bias correction consisted of excluding cancer index cases and incident case analyses. Results: A total of 455 patients were included, including 50.5% index cases, 372 with prospective follow-up (median 6 years, interquartile range = 3-10 years), and 159 of 281 females and 39 of 174 males with cancer. By age 60 years, PHTS-related cancer risk was higher in females (68.4% to 86.3%) than males (16.4% to 20.8%). Female BC risks ranged from 54.3% (95% confidence interval [CI] = 43.0% to 66.4%) to 75.8% (95% CI = 60.7% to 88.4%), with two- to threefold increased risks for PTEN truncating and approximately two-fold for phosphatase domain variants. EC risks ranged from 6.4% (95% CI = 2.1% to 18.6%) to 22.1% (95% CI = 11.6% to 39.6%) and TC risks from 8.9% (95% CI = 5.1% to 15.3%) to 20.5% (95% CI = 11.3% to 35.4%). Colorectal cancer, renal cancer, and melanoma risks were each less than 10.0%. Conclusions: Females have a different BC risk depending on their PTEN germline variant. PHTS patients are predominantly at risk of BC (females), EC, and TC. This should be the main focus of surveillance. These lower, more unbiased and personalized risks provide guidance for optimized cancer risk management.

Personal and family history at initial referral of the family and personal DNA test.

BACKGROUND:Individuals with Lynch syndrome are at increased hereditary risk of colorectal and endometrial carcinomas with microsatellite instability (MSI-H) and mismatch repair-deficiency (dMMR), which make these tumors vulnerable to therapy with immune checkpoint inhibitors. Our aim is to assess how often other tumor types in these individuals share these characteristics. METHODS:We retrieved the full tumor history of a historical clinic-based cohort of 1745 individuals with Lynch syndrome and calculated the standardized incidence ratio for all tumor types. MSI status, somatic second hit alterations, and immunohistochemistry-based MMR status were analyzed in 236 noncolorectal and nonendometrial malignant tumors. RESULTS:In individuals with Lynch syndrome MSI-H/dMMR occurred both in Lynch-spectrum and in non-Lynch-spectrum malignancies (85% vs 37%, P < .01). MSI-H/dMMR malignancies were found in nearly all non-Lynch-spectrum tumor types. Almost all breast carcinomas had medullary features, and most of them were MSI-H/dMMR. Breast carcinoma with medullary features were shown to be associated with Lynch syndrome (standardized incidence ratio = 38.8, 95% confidence interval = 16.7 to 76.5). CONCLUSIONS:In individuals with Lynch syndrome, MSI-H/dMMR occurs in more than one-half of the malignancies other than colorectal and endometrial carcinomas, including tumor types without increased incidence. The Lynch-spectrum tumors should be expanded to breast carcinomas with medullary features. All malignancies in patients with Lynch syndrome, independent of subtype, should be tested for MSI-H/dMMR in case therapy with immune checkpoint inhibitors is considered. Moreover, Lynch syndrome should be considered an underlying cause of all MSI-H/dMMR malignancies other than colorectal and endometrial carcinomas.

OBJECTIVE:Expert-opinion based guidelines state that endometrial cancer surveillance (ECS) might be considered for patients with PTEN Hamartoma Tumor Syndrome (PHTS) based on an elevated lifetime risk of endometrial cancer. We aimed to evaluate the yield of ECS by annual transvaginal ultrasound (TVUS) and endometrial biopsy (EMB) in PHTS patients.METHODS:PHTS patients who visited our PHTS expert center between August 2012 and September 2020 and opted for annual ECS were included. Data on surveillance visits, diagnostics, reports of abnormal uterine bleeding and pathology results were retrospectively gathered and analyzed.RESULTS:Surveillance was initiated in 25 women with a total of 93 gynecological surveillance visits during 76 surveillance years. The median age at first visit was 39 years (range 31-60) with a median follow-up duration of 38 months (range 6-96). Hyperplasia with and without atypia was detected six and three times, respectively, in seven (28%) women. The median age at hyperplasia detection was 40 years (range 31-50). In six asymptomatic women hyperplasia was detected during annual surveillance visits, while in one patient hyperplasia with atypia was detected during an additional visit due to abnormal uterine bleeding. In seven out of nine hyperplasias detected with EMB, TVUS beforehand showed no abnormalities. No (interval) carcinomas occurred.CONCLUSIONS:ECS in women with PHTS enables detection of a substantial number of asymptomatic premalignancies, such as hyperplasia with and without atypia, suggesting that ECS may be beneficial with regard to cancer prevention. The addition of EMB to TVUS likely improves the detection of premalignancies.