Lynch Syndrome Research Articles

MSH2-Mutated Lynch Syndrome With 9 Synchronous Colon and Rectum Adenocarcinomas: An Extremely Rare Case Report

Synchronous colorectal carcinoma is having more than 1 primary carcinoma detected in a single patient at the same time or within 6 months of tumor diagnosis. Metachronous colorectal carcinoma is the presence of more than 1 primary carcinoma detected consecutively in a single person after a set time interval. Patients with Lynch syndrome and Muir-Torre syndrome (a subset of Lynch syndrome) inherit a germline mutation in 1 of the mismatch repair (MMR) genes. Patients with synchronous colorectal carcinoma have a higher proportion of MMR-mutated cancers than patients with solitary colorectal carcinoma. Most studies in the literature indicate that patients with synchronous colorectal cancers typically have only 2 carcinomas. However, there have been reports of a single patient having up to 6 synchronous carcinomas in the large intestine. This report discusses a patient with 9 simultaneous colorectal cancers at the initial diagnosis, along with a history of bladder cancer, sebaceous adenoma, and duodenal adenoma, associated with a germline mutS homolog 2 ( MSH2) mutation. Additionally, the report explores various aspects of having synchronous colorectal cancers. More studies are needed to clarify the clinicopathologic and molecular landscape of these rare tumors and identify the best management and treatment strategies for these patients.

Diverting ileostomy for treatment of ileoanal pouch dysfunction: a technical note.

The ileal pouch-anal anastomosis (IPAA) is a restorative procedure performed after proctocolectomy to improve quality of life in patients with colorectal conditions like ulcerative colitis, familial adenomatous polyposis, and selected cases of Crohn's disease and Lynch syndrome. However, severe pouch dysfunction can occur, often necessitating further surgical intervention. This technical note aims to describe the operative approach and perioperative management for diverting ileostomy as a treatment for dysfunctional ileoanal pouches. Indications for the procedure include complications such as pelvic sepsis, pouchitis, fistulas, and Crohn's disease of the pouch. Preoperative planning involves a multidisciplinary team, stoma site marking, and imaging to assess bowel integrity. The surgical technique utilizes laparoscopic access with careful adhesiolysis to minimize bowel injury, with intraoperative pouchoscopy to identify anatomical landmarks. An ileostomy is created by selecting a tension-free small bowel segment and approximating it to a pre-marked stoma site. Attention is given to preserving bowel length to allow for potential future restorative procedures. Postoperative care focuses on stoma management and addressing ongoing pouch dysfunction symptoms. Diverting ileostomy offers symptom relief for patients with pouch dysfunction while avoiding more complex procedures like pouch excision. It is a valuable option in managing pouch failure.

Mainstreaming cancer genetics: feasibility of an advanced nurse practitioner-led service diagnosing Lynch syndrome from colorectal cancer in Ireland.

Colorectal cancer (CRC) is a common cancer in Ireland. Of all CRCs, 2-4% are attributable to Lynch Syndrome (LS), the most common CRC predisposition syndrome. LS is caused by constitutional pathogenic variants (PVs) affecting mismatch repair (MMR) genes with resultant MMR protein deficiency (dMMR). Screening of all CRCs with MMR immunohistochemistry (IHC) testing is advocated to increase the detection of LS. However, successful implementation requires appropriate downstream management. In Ireland the traditional pathway involves referral to cancer genetics services to assess eligibility for genetic testing. Cancer genetics services in Ireland face many challenges in providing uniform access to timely healthcare with current wait times for assessment in excess of 1 year. An increasingly adopted pathway is that of mainstreaming, whereby genetic testing is managed locally by a multidisciplinary team member. Our institution therefore implemented an Advanced Nurse Practitioner (ANP)-led service with responsibility for the LS Diagnostic Pathway and mainstream genetic testing. Data was extracted from a prospectively maintained database of all newly diagnosed CRC patients discussed at our institutions CRC multidisciplinary meeting (MDM) between January 1st, 2023, and May 31st, 2024. MMR IHC testing was performed in 97.9% of the 385 patients diagnosed with CRC. The median time from histological confirmation of CRC to the availability of the MMR IHC report was 6 days. All 51 patients (100%) who required sequential tumor testing underwent BRAF V600 ± MLH1 promoter methylation testing. Additionally, 100% of the 14 patients eligible for mainstream genetic testing were referred to the ANP-led genetics service. The median time from the initial MDM discussion to the initiation of genetic testing was 69 days, while the median time from testing to the availability of results was 19 days. Patients received their results within a median of 21 days. MMR IHC testing increases the detection of LS through identification of dMMR tumours. Successful downstream delivery of clinical services, however, requires appropriate subsequent management, in a resource-limited environment. Our institutional experience demonstrates the feasibility, efficiency, and effectiveness of an ANP-led mainstreaming model of care for hereditary colorectal cancer.

The genetic landscape of Lynch syndrome in the Israeli population.

Deciphering the spectrum and founder disease-causing variants (DCVs) in specific populations can shape and facilitate the diagnostic process of Lynch Syndrome (LS). The aim of this report was to comprehensively update on the genetic landscape of LS in the ethnically diverse Israeli-Jewish population. The cohort included 1080 carriers from 588 families; some from underrepresented, understudied Israeli ethnic groups recruited from 8 genetic institutes and high-risk clinics throughout the country. Variant classification was performed according to the American College of Medical Genetics criteria. A total of 157 DCVs were identified, 12 are reported here for the first time, and 9 reclassified. MSH2 DCVs were identified in 286 families (49%). Most DCVs (125/157, 80%) were noted in one or two families only. Sixteen DCVs, each detected in ≥ 5 families, and accounted for LS in 378/588 (64%) families. Constitutional mismatch repair deficiency (CMMRD) was diagnosed in 7 families. Twenty-five carriers (2.3%) had an additional DCV or risk alleles in another cancer susceptibility gene. In conclusion, MMR gene variant distribution in Israel is diverse. MSH2 is most commonly mutated due to founder DCVs. Though the 16 prevalent LS-associated DCVs were frequently detected in our cohort, none of them is frequently reported in the general population. These data should facilitate variant interpretation, spouse and cascade testing.

Prospective Screening of Cancer Syndromes in Patients with Mesenchymal Tumors

Background: The etiology of most mesenchymal tumors is unknown, and knowledge about syndromes with an increased risk of tumors in bone or soft tissue is sparse. Methods: We present a prospective germline analysis of 312 patients with tumors suspected of being sarcomas at a tertiary sarcoma center. Germline and tumor whole genome sequencing, tumor transcriptome, and methylome analyses were performed. Results: Germline pathogenic or likely pathogenic variants associated with an increased risk of tumors were detected in 24 patients (8%), of which 11 (4%) harbored a detectable second hit in the tumor. Second hits were confirmed in genes with (NF1, RB1, TP53, EXT2, and SDHC) and without (ATM, CDC73, MLH1, MSH6, POLG, and KCNQ1) known association with mesenchymal tumor predisposition. Sarcomas from two Lynch syndrome patients showed mismatch repair deficiency, predicting a treatment response to immune checkpoint inhibitors (Level 1 biomarker according to the FDA (Federal Drug Administration) and ESMO (European Society for Medical Oncology)). None of the three CHEK2 carriers had a second hit in the tumor, suggesting a weak link to sarcoma. Conclusions: We conclude that second-hit analyses can be used in standard of care to identify syndrome-related tumors. This approach can help distinguish true manifestations of tumor syndromes from unrelated germline findings and enhance the understanding of germline predisposition in soft tissue tumors. Prospective screening using germline whole genome sequencing should be considered when comprehensive somatic sequencing is introduced into clinical practice.

Compliance of a Tertiary Centre With Molecular Testing Strategies for Lynch Syndrome in Colorectal Cancer.

Introduction Lynch syndrome is one of the most common hereditary cancers associated with germline alterations of DNA mismatch repair genes. Recent advances have shed light on its molecular pathogenesis, leading to the development of various testing strategies. The aim of this study is to evaluate whether all colorectal adenocarcinomas undergo immunohistochemistry (IHC) and microsatellite instability (MSI) testing to identify potential Lynch syndrome patients. Methods This study evaluated the compliance of MSI and IHC testing for Lynch syndrome in a tertiary cancer research centre. All patients undergoing colorectal cancer resectionbetween April 2022 and December 2022were identified from a prospectively maintained register. The histology, MSI, and IHC testing reports for these patients were recorded to check if they were done and reported. Only patients with colorectal adenocarcinoma were included in this study. Results A total of 314 patients had colorectal cancer resections. A total of 301 were included in the study, with a median age of 65 years (IQR = 35-95). Thirteen (4.14%) patients did not have MSI and IHC testing reported on the system. Of these, eight (61.53%) did not have an MSI/IHC testing request, four (30.76%) did not have sufficient specimens to be sent for further testing, one (7.69%) had MSI and IHC testing but the final report was yet to be authorized. Out of the eight who did not have the testing done, three had early polyp cancer and one had a goblet cell adenocarcinoma. Conclusion According to the data, our hospital has a 97.45% compliance with current guidelines, not considering the insufficient sample for testing and the authorization of the final report. A more comprehensive proforma may be needed to provide a feedback loop for further MSI and IHC testing when entering data into the system. Further auditing is required to check the effectiveness of the proforma in achieving complete compliance.

DNAR-13. LONG TERM FOLLOW-UP OF A LYNCH SYNDROME-ASSOCIATED GLIOBLASTOMA RESISTANT TO STANDARD-OF-CARE CHEMORADIATION

Abstract BACKGROUND Lynch syndrome is caused by pathogenic germline variants in the DNA mismatch repair (MMR) genes, predisposing individuals to malignancies, including glioblastoma (GBM). MMR-deficient tumors are resistant to monofunctional alkylators such as temozolomide but not to bifunctional alkylators such as the nitrosourea lomustine. Anti-programmed cell death protein 1 (PD1) immune checkpoint inhibitor (ICI) pembrolizumab represents another treatment option, which is approved by the United States Food and Drug Administration (FDA) for the treatment of mismatch repair deficient cancers. METHODS We present a patient with multifocal GBM and Lynch syndrome who experienced rapid progression following standard-of-care chemoradiation, followed by durable responses to lomustine and then to pembrolizumab. RESULTS A 58-year-old man with Lynch syndrome (MSH2 mutation) and prior history of colon cancer presented with seizures. Magnetic resonance imaging (MRI) brain identified right frontal and left parietal masses. Right frontal tumor was resected; pathology was consistent with GBM, IDH wildtype, MGMT-unmethylated. Both lesions were treated with radiation therapy (60 Gy, 30 fractions) with concurrent and adjuvant temozolomide. After two cycles of adjuvant temozolomide, his left parietal tumor progressed and was subtotally resected, followed by four cycles of lomustine (stopped due to myelotoxicity). He remained progression-free for 15 months. Surveillance MRI identified new enhancement involving the left frontal lobe, left periventricular white matter, and right internal auditory canal, concerning for leptomeningeal dissemination. MRI spine identified no additional lesions. Cerebrospinal fluid cytology was negative for tumor cells on two occasions. Patient was treated with pembrolizumab. He remains on treatment with stable disease four months after ICI initiation and 31 months after GBM diagnosis. CONCLUSIONS Patients with MMR-deficient GBM resist standard chemoradiation. Alternatives such as nitrosourea or ICI therapy may achieve durable responses. While data is insufficient to administer these agents as upfront therapy in this specific setting, both should be considered as options for recurrent disease.

PATH-18. CURRENT STATUS OF CANCER GENOMIC PROFILING (CGP) TESTS IN BRAIN TUMOR TREATMENT - COMPLEMENTING BRAIN TUMOR PATHOLOGICAL DIAGNOSIS WITH CGP-

Abstract INTRODUCTION Cancer genomic profiling (CGP) tests are currently used in the search for therapeutic targets and have become an auxiliary tool in diagnosis according to the new WHO classification (WHO 2021), which requires the integration of pathomorphological and molecular diagnostics. Here, we report on brain tumor cases at our institution that underwent CGP testing. METHODS From May 2020 to the present, 27 brain tumor cases that underwent CGP testing at our institution were included in this study. There were 14 males and 13 females, ranging from 18 to 70 years (average 48.4 years). The tests conducted included Foundation One CDx, GeneMineTop, and NCC OncoPanel. RESULTS The cases that underwent CGP testing included 13 cases of glioblastoma IDH-wildtype, 3 cases of astrocytoma, IDH-mutant, grade 4, 4 cases of astrocytoma IDH-mutant, grade 3, 3 cases of oligodendroglioma, 1p/19q codeleted, grade 3, 1 case of astrocytoma, IDH-mutant, grade 2, 1 case of ependymoma, 1 case of pilocytic astrocytoma and 1 case of PitNEC. CGP testing enabled molecular diagnostics such as IDH mutation and TERTp mutation. Based on the results, therapeutic suggestions were possible for 5 out of 25 cases (20%) (BRAF V600E mutation 1 case, IDH1 R132H mutation 1 case, TMB high 3 cases). Checkpoint inhibitors were used in a case with high TMB. Genetic risk assessment by a genetic counselor was conducted for all cases, and one high TMB case was diagnosed as hereditary cancer. A germline pathogenic variant in MSH6 was detected, leading to a diagnosis of Lynch syndrome. CONCLUSION Molecular diagnostics through CGP testing served as an aid in diagnosis according to WHO2021. Cases where drug suggestions were feasible underwent treatment with targeted molecular therapies and checkpoint inhibitor. We experienced cases where hereditary cancer syndromes such as Lynch syndrome were diagnosed through the detection of germline pathogenic variants.

EPCO-56. INHERITED PREDISPOSITION TO ADULT GLIOMAS: OVERVIEW OF THE CURRENT CLINICAL PRACTICE AND FUTURE RECOMMENDATIONS

Abstract Gliomas are the most common adult primary malignant brain tumor and occur in ages 45-65 years old. While most gliomas are sporadic in nature, a small portion is related to cancer predisposition syndromes (CPS), such as Li Fraumeni or Lynch syndromes. Given that 5–10% of patients will have a family history of glioma, there is currently an effort in identifying germline variants associated with gliomas. Additionally, with the advent of somatic tumor testing, it is possible to pick up suspected germline mutations in genes that cause CPS. Our experience includes a 32-year-old patient diagnosed with astrocytoma IDH mutant, Grade 2 who was found to have a BRAC1 mutation on somatic brain tumor testing. 10 years later, the patient was found with metastatic ovarian cancer and a germline BRAC1 mutation. Early identification of CPS can lead to early detection or prevention of malignancies in affected patients and relatives. However, gliomas are rarely the primary or presenting tumor of CPS, and guidance of CPS screening for these individuals is still lacking. Due to the increasing interest and importance of CPS testing in patients with glioma we have developed a collaborative protocol between our neuro-oncologists and genetic counselors aso that patients have access to germline testing. We propose that all patients with glioma at age of 50 or under, patients with strong family history of cancer including gliomas, and patients with suspected germline mutations based on tumoral somatic mutational profile should be referred to the genetic counselors. Our preliminary findings include 8 patients who completed germline genetic testing. Of these, one patient tested positive for a BRCA1 pathogenic variant. We are planning to continue to collect this data to better inform clinical practice.

More subtle microsatellite instability better predicts fluorouracil insensitivity in colorectal cancer patients

Microsatellite instability (MSI) is now widely used as an indispensable biomarker. However, the relationship between MSI-H (high) and defective DNA mismatch repair (MMR) is not as straightforward as has been expected. Genome-edited cells carrying Lynch syndrome mutations do not exhibit drastic MSI typical in MSI-H (i.e. Type B) but more subtle MSI (i.e. Type A). In this study, we explored a connection between Type A MSI and 5-fluorouracil (5-FU) resistance in colorectal cancer patients. Using our precision and high-resolution MSI assay technique, tumour microsatellites were analysed in 30 colorectal cancer patients treated with FOLFOX or CAPOX. Among 30 tumours, eleven (37%) were judged as Type A MSI-positive. In Type A MSI+ tumours, the patient response to fluoropyrimidine and oxaliplatin was significantly poor (Fisher’s exact test, p = 0.021). Accordingly, median PFS and OS were significantly poor in Type A+ patients (log-rank test, p < 0.001/p = 0.009). Type A MSI was an independent predictor of patient prognosis in this pilot cohort (Cox regression analysis, p = 0.003). Thus, more subtle Type A MSI better predicts fluoropyrimidine insensitivity in colorectal cancer patients, which may shed light on a hitherto overlooked connection between the MSI phenotypes and drug resistance in human cancer.

Lynch syndrome – a case report and literature review

Lynch syndrome – a case report and literature review

Addressing sexual health in the care of patients with hereditary breast and ovarian cancer and Lynch syndrome: Patient perspectives

Addressing sexual health in the care of patients with hereditary breast and ovarian cancer and Lynch syndrome: Patient perspectives

Imaging of Upper Tract Urothelial Carcinoma.

Upper tract urothelial carcinoma (UTUC) originates in the renal pelvis or ureters and typically affects elderly patients, with its incidence increasing over the past few decades. UTUC is a distinct clinical entity with more aggressive clinical behavior than that of lower tract urothelial carcinoma. Due to the significant challenge of acquiring an adequate tissue sample for biopsy, comprehensive risk stratification is required for treatment planning, including radical nephroureterectomy and kidney-sparing management. Imaging plays an important integrated role in risk assessment along with endoscopy and pathologic examination. Lifelong surveillance is required after treatment due to the high incidence of recurrent and metachronous tumors. Lynch syndrome is a frequently unrecognized genetic disorder associated with UTUC that warrants specific attention in patient management. UTUC may manifest with diverse imaging findings, including filling defects, wall thickening, and mass-forming lesions. CT urography is the preferred modality for diagnosis and staging or restaging of UTUC, with numerous technical variations. Efforts have been made to optimize image quality and radiation exposure. Due to its poor sensitivity for small lesions, use of MR urography is limited to special clinical scenarios (eg, when patients have contraindications to iodinated contrast agents). Fluorine 18 fluorodeoxyglucose PET helps to detect metastatic lesions. Image-guided biopsy may be considered for uncertain lesions. Radiologists need to be familiar with the imaging findings and their differential diagnoses. ©RSNA, 2024 Supplemental material is available for this article.

One-stop Colon and Endometrial screening (OnCE): A prospective study of combined cancer screening for Lynch syndrome

One-stop Colon and Endometrial screening (OnCE): A prospective study of combined cancer screening for Lynch syndrome

Upfront tumor next-generation sequencing for diagnosis of Lynch syndrome in endometrial cancer

Upfront tumor next-generation sequencing for diagnosis of Lynch syndrome in endometrial cancer

Characteristics of Cancer in Subjects Carrying Lynch Syndrome-Associated Gene Variants in Taiwanese Population: A Hospital-Based Study in Taiwan.

Lynch syndrome (LS) is an autosomal dominant disorder characterized by increased risks of colorectal and endometrial cancers. LS is defined by pathogenic variants in mismatch repair (MMR) genes, including MLH1, MSH2, and MSH6. Data on the prevalence and associated cancer risks of LS in the Han Chinese population remain limited. In this study, using a broad biobank approach through the Taiwan Precision Medicine Initiative (TPMI), we identified LS-associated MMR gene variants within a cohort of 42,828 participants from a Taiwanese medical center. A total of 89 individuals were found to carry pathogenic MMR variants: MLH1 (n = 22, 25%), MSH2 (n = 47, 53%), and MSH6 (n = 20, 22%). The overall prevalence of MMR variants was calculated, and cancer incidence rates among carriers were determined. The prevalence of MMR variants in the study population was 1 in 481. The distribution of MLH1, MSH2, and MSH6 variants were 24.7%, 52.8%, and 22.5%, respectively. Cumulative cancer incidence rates of carriers were 40.9% for MLH1 carriers, 29.8% for MSH2, and 40% for MSH6. Among the 19 individuals who underwent colonoscopy screening, the prevalence of polyps was similar to that of the control group (adenoma detection rate: 32% vs 26%, p = 0.585). A meticulous analysis of the detected polyps in seven participants, considering factors such as location, size, morphology, and pathological features, showed no significant differences from controls. A significant cancer risk is associated with LS-related MMR variants in the Taiwanese population. The apparent under diagnosis of LS highlights the urgent need for enhanced surveillance and genetic counseling in this demographic. Our findings suggest that adjustments in the current screening protocols may be warranted to better identify and manage at-risk individuals.

Elucidating the roles of SOD3 correlated genes and reactive oxygen species in rare human diseases using a bioinformatic-ontology approach.

Superoxide Dismutase 3 (SOD3) scavenges extracellular superoxide giving a hydrogen peroxide metabolite. Both Reactive Oxygen Species diffuse through aquaporins causing oxidative stress and biomolecular damage. SOD3 is differentially expressed in cancer and this research utilises Gene Expression Omnibus data series GSE2109 with 2,158 cancer samples. Genome-wide expression correlation analysis was conducted with SOD3 as the seed gene. Categorical SOD3 Pearson Correlation gene lists incrementing in correlation strength by 0.01 from ρ≥|0.34| to ρ≥|0.41| were extracted from the data. Positively and negatively SOD3 correlated genes were separated for each list and checked for significance against disease overlapping genes in the ClinVar and Orphanet databases via Enrichr. Disease causal genes were added to the relevant gene list and checked against Gene Ontology, Phenotype Ontology, and Elsevier Pathways via Enrichr before the significant ontologies containing causal and non-overlapping genes were reviewed with a literature search for possible disease and oxidative stress associations. 12 significant individually discriminated disorders were identified: Autosomal Dominant Cutis Laxa (p = 6.05x10-7), Renal Tubular Dysgenesis of Genetic Origin (p = 6.05x10-7), Lethal Arteriopathy Syndrome due to Fibulin-4 Deficiency (p = 6.54x10-9), EMILIN-1-related Connective Tissue Disease (p = 6.54x10-9), Holt-Oram Syndrome (p = 7.72x10-10), Multisystemic Smooth Muscle Dysfunction Syndrome (p = 9.95x10-15), Distal Hereditary Motor Neuropathy type 2 (p = 4.48x10-7), Congenital Glaucoma (p = 5.24x210-9), Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome (p = 3.77x10-16), Classical-like Ehlers-Danlos Syndrome type 1 (p = 3.77x10-16), Retinoblastoma (p = 1.9x10-8), and Lynch Syndrome (p = 5.04x10-9). 35 novel (21 unique) genes across 12 disorders were identified: ADNP, AOC3, CDC42EP2, CHTOP, CNN1, DES, FOXF1, FXR1, HLTF, KCNMB1, MTF2, MYH11, PLN, PNPLA2, REST, SGCA, SORBS1, SYNPO2, TAGLN, WAPL, and ZMYM4. These genes are proffered as potential biomarkers or therapeutic targets for the corresponding rare diseases discussed.

Lynch syndrome: Diagnosis based on immunomicroscopy and family history of a young patient with colorectal carcinoma

Lynch syndrome is a genetic condition that alters the production of DNA compatibility genes, which are responsible for monitoring the process of new cell formation in the body. Once compromised, this watchdog system fails and allows abnormal cells to develop, which sometimes initiates a process of malignization, resulting in the appearance of malignant tumours, especially in the colon and endometrial tissue. This text reports the clinical case of a young patient who was diagnosed with colorectal carcinoma and, after extensive outpatient and anatomopathological research, associated with a positive family history, was diagnosed with Lynch syndrome.

Diagnostic Performance of Faecal Immunochemical Testing (FIT) in Patients with Lynch Syndrome Scheduled for Colonoscopic Surveillance.

Lynch syndrome (LS) carries a substantial lifetime risk of colorectal cancer which is currently mitigated by biennial colonoscopy surveillance. Paramount to the surveillance programme is the removal of adenomas before malignant transformation but there is an associated service burden and morbidity of repeated endoscopy. We investigated if faecal immunochemical testing (FIT) for faecal haemoglobin has the diagnostic performance to replace colonoscopy. In this retrospective cohort study, patients due to undergo planned surveillance for LS between November 2020 and April 2022 were sent two FIT kits prior to colonoscopy. Test diagnostic performance of colorectal cancer (CRC), advanced and non-advanced adenoma detection was calculated for single and double FIT strategies. A faecal-Hb of 10 µg Hb/g was considered positive. In total, 78 patients, with 45 (57.7%) female, median age 52 years (IQR 41-63), completed at least one FIT and colonoscopy. The median time from FIT to colonoscopy was 47 days. A single FIT was positive in 7/30 cases of adenoma (2/3 advanced, 5/27 non-advanced). A total of 64 (82.1% of FIT1T returners) completed a second FIT. Using the greatest of the two FITs (FIT2TMAX) 8/26 (2/3 advanced, 4/23 non-advanced), patients with adenomas were identified. There were no cases of CRC. The sensitivity for adenoma detection was 23.3% and 23.1%, respectively. In patients with LS awaiting colonoscopy, FIT has a low sensitivity for detecting adenomas and advanced adenomas. This is not improved by the addition of a second FIT test.

Upper tract urothelial carcinoma: epidemiology, presentation, and high-risk endemic populations.

Upper tract urothelial carcinoma (UTUC) only accounts for 5-10% of all urothelial cancers but these patients present with high stage disease and 2 out of 3 patients have evidence of muscle-invasion at time of diagnosis. Furthermore, 10% of UTUC patients have associated Lynch syndrome and therefore diagnosis of UTUC should prompt timely evaluation and familial counseling. The purpose of this review is to outline the current evidence on the epidemiology, presentation, and high-risk endemic populations of UTUC through review of contemporary publications occurring over the preceding 18 months. Both the American Urological Association (AUA) and European Association of Urology (EAU) have published updated guidelines within the last 18 months for the management of UTUC. Of note, the updated guidelines give special consideration to identifying patients with risk factors for Lynch syndrome and recommend universal histologic testing for those with high probability of having Lynch syndrome cancers as well as referral for genetic counseling and germline testing. UTUC is an overall rare malignancy but tends to present with advanced stage and muscle-invasion. A proper understanding of the epidemiology, presentation, and high-risk endemic populations is necessary to develop preventive and interventional strategies.