[A Case of Transverse Colon Cancer Associated with Lynch Syndrome with Excellent Response to Pembrolizumab].

A 47-year-old woman diagnosed with transverse colon cancer with liver, peritoneal, and lymph node metastases was admitted. Modified FOLFOX6(mFOLFOX6)regimen was given as a first line chemotherapy and was followed by pembrolizumab after 1 cycle of the mFOLFOX6, because microsatellite instability(MSI)test of the tumor showed high-frequency MSI. Because of the transverse colon obstruction after 2 cycles of pembrolizumab, she underwent right hemicolectomy. Histological examination of the resected specimen revealed no residual tumor cells in the primary tumor and reginal lymph nodes. Immunohistochemistry for mismatch repair proteins(IHC-MMR)showed loss of MSH2 and MSH6 expression. Genetic test identified a MSH2 pathogenic variant leading to the diagnosis of Lynch syndrome. The present case shows the importance of MSI test or IHC-MMR before the treatment of metastatic colorectal cancer.

Risk of metachronous colorectal cancer after colectomy for first colon cancer in Lynch syndrome: multicenter retrospective study in Japan.

BACKGROUND: We evaluated the risk of metachronous colorectal cancer (mCRC) and explored the optimal extent of colectomy in patients with Lynch syndrome (LS) and first colon cancer (fCC) in Japan, where the extent of colectomy for colon cancer (CC) is shorter than that in Western countries. METHODS: The clinicopathologic and survival data of patients with LS who developed CC were collected from a nationwide database and analyzed retrospectively. The cumulative incidence of mCRC after actual segmental colectomy was compared with that of mCRC when more extensive colectomy was assumed. RESULTS: There were 142 eligible patients (65 female). The median age at fCC surgery was 46.5 (range: 14-80) years. The cumulative incidence of 5-, 10-, and 20-year mCRC rate was 13.4%, 20.8%, and 53.6%, respectively. The incidence was higher in the left-sided group (splenic flexure to rectosigmoid colon, n = 54) than in the right-sided group (cecum to transvers colon, n = 88) (66.3% vs. 45.3% in 20 years, P < 0.01). Assuming that all patients would have undergone hemicolectomy or total colectomy, the estimated mCRC risk was 41.5% and 9.4% (P < 0.01, vs. actual procedures), respectively. The 20-year overall survival rate of all the patients was 83.3% without difference by fCC sidedness (P = 0.38). CONCLUSIONS: To reduce the incidence of mCRC, patients with genetically diagnosed LS and fCC, preferentially located in the left-sided colon, may need to undergo more extended colectomy than that usually performed in Japan. However, such extended colectomy should be counterbalanced with favorable overall survival and actual risk of mCRC development.

Contemporary surgical management of colorectal cancer in Lynch syndrome.

Lynch syndrome is the most common hereditary colorectal cancer syndrome. Although the current literature has been supportive of extended resections in certain Lynch syndrome patients with colon cancer. This article reviews the recent data on the topic and raises questions about the importance of homogenous high-quality prospective data to establish the accurate risk of cancer and future risk of metachronous cancer in the setting of all these risk reduction interventions.

Patterns of care and outcomes of risk reducing surgery in women with pathogenic variants in non-BRCA and Lynch syndrome ovarian cancer susceptibility genes.

OBJECTIVES: Guidelines recommend risk-reducing bilateral salpingo-oophorectomy (RRSO) for women with pathogenic variants of non-BRCA and Lynch syndrome-associated ovarian cancer susceptibility genes. Optimal timing and findings at the time of RRSO for these women remains unclear. We sought to characterize practice patterns and frequency of occult gynecologic cancers for these women at our two institutions. METHODS: Women with germline ovarian cancer susceptibility gene pathogenic variants who underwent RRSO between 1/2000-9/2019 were reviewed in an IRB-approved study. All patients were asymptomatic with no suspicion for malignancy at time of RRSO. Clinico-pathologic characteristics were extracted from the medical records. RESULTS: 26 Non-BRCA (9 BRIP1, 9 RAD51C, and 8 RAD51D) and 75 Lynch (36 MLH1, 18 MSH2, 21 MSH6) pathogenic variants carriers were identified. Median age at time of RRSO was 47. There were no occurrences of occult ovarian or fallopian tube cancer in either group. Two patients (3%) in the Lynch group had occult endometrial cancer. Median follow up was 18 and 35 months for non-BRCA and Lynch patients, respectively. No patient developed primary peritoneal cancer upon follow up. Post-surgical complications occurred in 9/101 (9%) of patients. Hormone replacement therapy (HRT) was rarely used despite reported post-menopausal symptoms in 6/25 (23%) and 7/75 (37%) patients, respectively. CONCLUSIONS: No occult ovarian or tubal cancers were observed in either group. No recurrent or primary gynecologic-related cancers occurred upon follow-up. Despite frequent menopausal symptoms, HRT use was rare. Both groups experienced surgical complications when hysterectomy and/or concurrent colon surgery was performed suggesting concurrent surgeries should only be performed when indicated.

[Surgical strategies for hereditary colorectal cancer]. / Operative Strategien bei hereditären kolorektalen Karzinomen.

Hereditary colorectal cancer (hCRC) represents a major diagnostic and therapeutic challenge. In addition to the usual diagnostic methods, the family history, histological confirmation and mutation analysis play an important role in identifying the type of hereditary CRC. The diagnosis and classification of hCRC are carried out based on the anamnesis, clinical presentation and histology and the further treatment is determined depending on the underlying type of hCRC. For familial adenomatous polyposis (FAP) coloproctomucosectomy after the end of puberty is always recommended, whereas the treatment recommendations for other forms, such as attenuated FAP (aFAP), MUTYH-associated polyposis (MAP) and hereditary nonpolyposis colon cancer (HNPCC, Lynch syndrome), range from close surveillance and endoscopic control, through segmental resection up to colectomy. Irrespective of the type of hCRC, the treatment regimens necessitate an individualized approach and require close interdisciplinary cooperation. When colorectal resection is performed, minimally invasive procedures should principally be prioritized and some studies could demonstrate a potential benefit of robotic surgery compared to laparoscopy.

Universal screening for Lynch syndrome in operated colorectal cancer by immunohistochemistry: a cohort of patients in Liaoning province, China.

OBJECTIVE: Lynch syndrome (LS) is the most common hereditary colorectal cancer syndrome worldwide. Due to the decreasing family size in Liaoning province. The Bethesda and Amsterdam II criteria have lower sensitivity and specificity and are not suitable for the local population. Immunohistochemistry screening for mutations in DNA mismatch repair (MMR) in newly diagnosed colorectal cancer can improve the detection rate of LS. METHODS: All newly diagnosed colorectal cancer patients who underwent surgery between January 2018 and June 2020 at Cancer Hospital of China Medical University and Shengjing Hospital of China Medical University from Liaoning China were included retrospectively, and the ratio of universal LS screening by immunohistochemistry, MMR protein deficiency (dMMR) ratio, MLH1 loss, MSH2 loss, MSH6 loss, and PMS2 loss was analyzed. The clinicopathological characteristics of patients with pMMR and dMMR were analyzed. RESULTS: A total of 7019 colorectal cancer patients underwent surgery and 4802 (68.41%) patients were screened by immunohistochemistry for MMR, 258 (5.37%) cases were reported to have a loss of MMR expression. In the dMMR group, a higher number of patients were under 50 years old, more tumors were located at the right colon, less patients have lymph node metastasis, more tumors were stage II, and histological types of mucinous carcinoma or signet ring carcinoma were more common, compared with the pMMR group. Only 2.71% dMMR patients meet Amsterdam criteria II, 2.71% of patients meet Revised Bethesda guidelines, and 17.83% meet Chinese LS criteria. Twenty-five dMMR patients were confirmed by next-generation sequencing and five families were confirmed as Lynch family. CONCLUSION: These data imply that universal screening for LS by immunohistochemistry may be effective in Liaoning province.

Contralateral lymph node metastasis in recurrent ipsilateral breast cancer with Lynch syndrome: a locoregional event.

INTRODUCTION: Contralateral axillary lymph node metastasis (CALNM) in breast cancer (BC) is considered a distant metastasis, marking stage 4cancer. Therefore, it is generally treated as an incurable disease. However, in clinical practice, staging and treatment remain controversial due to a paucity of data, and the St. Gallen 2021 consensus panel recommended a curative approach in patients with oligometastatic disease. Aberrant lymph node (LN) drainage following previous surgery or radiotherapy is common. Therefore, CALNM may be considered a regional event rather than systemic disease, and a re-sentinel procedure aided by lymphoscintigraphy permits adequate regional staging. CASE REPORT: Here, we report a 37-year-old patient with Lynch syndrome who presented with CALNM in an ipsilateral relapse of a moderately differentiated invasive ductal BC (ER 90%, PR 30%, HER2 negative, Ki-67 25%, microsatellite stable), 3 years after the initial diagnosis. Lymphoscintigraphy detected a positive sentinel LN in the contralateral axilla despite no sign of LN involvement or distant metastases on FDG PET/CT or MRI. The patient underwent bilateral mastectomy with sentinel node dissection, surgical reconstruction with histological confirmation of the CALNM, left axillary dissection, adjuvant chemotherapy, and anti-hormone therapy. In addition to her regular BC follow-up visits, the patient will undergo annual colonoscopy, gastroscopy, abdominal, and vaginal ultrasound screening. In January 2023, the patient was free of progression for 23 months after initiation of treatment for recurrent BC and CALNM. CONCLUSION: This case highlights the value of delayed lymphoscintigraphy and the contribution of sentinel procedure for local control in the setting of recurrent BC. Aberrant lymph node drainage following previous surgery may be the underlying cause of CALNM. We propose that CALNM without evidence of systemic metastasis should be considered a regional event in recurrent BC, and thus, a curative approach can be pursued. The next AJCC BC staging should clarify the role of CALNM in recurrent BC to allow for the development of specific treatment guidelines.

Universal tumor screening for lynch syndrome on colorectal cancer biopsies impacts surgical treatment decisions.

Universal tumor screening (UTS) for Lynch syndrome (LS) on colorectal cancer (CRC) can be performed on biopsies or resection specimens. The advantage of biopsies is the chance to provide preoperative genetic counseling/testing (GC/T) so patients diagnosed with LS can make informed decisions regarding resection extent. We evaluated utilization of UTS on biopsies, percentage of patients with deficient mismatch repair (dMMR) who underwent GC/T preoperatively, and whether surgical/treatment decisions were impacted. We performed a retrospective review of medical records to assess CRC cases with dMMR immunohistochemical staining from 1/1/2017 to 2/26/2021. 1144 CRC patients had UTS using MMR immunohistochemistry; 559 biopsies (48.9%) and 585 resections (51.1%). The main reason UTS was not performed on biopsy was it occurred outside our health system. 58 (5%) of CRCs were dMMR and did not have MLH1 promoter hypermethylation (if MLH1 and PMS2 absent). 28/58 (48.3%) of dMMR cases were diagnosed on biopsy. Of those 28, 14 (50%) eventually underwent GC/T, and 7 (25%) had GT results prior to surgery. One of the 7 had incomplete documentation of results affecting their treatment plan. Of the remaining 6 with complete documentation, 5 underwent surgery and one was treated with immunotherapy only. Three patients elected a more extensive surgery. 6/28 (21.4%) dMMR patients identified on biopsy made an informed surgical/treatment decision based on their dMMR status/LS diagnosis. When applied, UTS on biopsy followed by genetic counseling and testing informs surgical decision-making. Process and implementation strategies are in place to overcome challenges to more broadly optimize this approach.

Patterns of DNA mismatch repair protein expression for primary and recurrent colorectal cancer at an advanced surgical unit: A retrospective audit.

AIM: Lynch syndrome is an inherited cancer syndrome associated with an increased lifetime risk of colorectal cancer (CRC) and characterized by germline mutations to one of four DNA mismatch repair (MMR) genes. Immunohistochemical (IHC) testing is used to screen for Lynch syndrome; however, despite routine completion following resection of primary CRC, it is only variably completed following resection of recurrent disease. This may be significant, as MMR protein expression can change from primary to recurrent CRC. The primary aim of this study is to investigate how MMR profiles change from primary to recurrent CRC; the secondary aim is to assess rates of MMR testing of primary and recurrent disease. METHOD: We conducted a retrospective analysis of patients undergoing surgery for recurrent CRC from 2018-19 at a high-volume institution. MMR profiles were obtained following both primary and recurrent resection of CRC, and MMR protein expression was evaluated from both time points. RESULTS: A total of 107 patients met the inclusion criteria and IHC results were obtained for both primary and recurrent resections in 85 cases. MMR profiles changed in nine patients (10.6%), with a loss of staining from primary to recurrent disease in six (7.1%) and a gain of staining in three (3.5%). IHC testing was completed following 88.7% of primary and 39.3% of recurrent resections. CONCLUSION: MMR profiles can change from primary to recurrent CRC and repeat MMR testing for recurrent CRC is completed in only a minority of cases.

[Two Cases Suspected of Lynch Syndrome Caused by Juvenile Rectal Cancer].

Case 1: A 28-year-old man was admitted to our hospital because of bloody stools that persisted for several months. Colonoscopy showed a 1/2 circumferential type 2 tumor in the rectum. Laparoscopic high anterior resection(D3)was performed for rectal cancer cT3N0M0, cStage Ⅱa. The final diagnosis was pStage Ⅱa, and MSI-high. XELOX therapy was performed for 3 months to prevent recurrence, and the patient is alive without recurrence. Case 2: A 51-year-old man, father of case 1 patient, was admitted to our hospital because of anemia and dyspnea. Colonoscopy showed a circumferential type 2 tumor in the ascending colon. Laparoscopic right hemicolectomy(D3)was performed for ascending colon cancer cT4b N2aM0, cStage Ⅲc. The final diagnosis was pT3N0M0, pStage Ⅱa, and MSI-high. The patient is alive no recurrence without adjuvant chemotherapy. Both patients had a family history of colorectal cancer, were MSI-high, met the Amsterdam criteria Ⅱ and the revised Bethesda guidelines, and were suspected of having Lynch syndrome. A detailed family history and appropriate information provision were considered useful.

Surgical management of a congenital genital tract abnormality in a patient with Lynch syndrome.

Lynch syndrome (LS), also known as hereditary non-polyposis colorectal cancer, is an inherited cancer syndrome which increases the risk of developing colorectal cancer and endometrial cancer. Individuals with LS have an increased risk of cancers of the ovary, urinary tract, stomach, small intestine, pancreas, biliary tract, brain and skin. Cancer risk reduction is recommended through chemoprevention (aspirin), surveillance (colonoscopy, assessment of the endometrium and ovaries via USS, aspiration biopsy and tumour marker monitoring; CA125) or risk reduction surgery, that is, total hysterectomy and bilateral salpingo-oophorectomy.This is a case of a nulliparous woman in her early 30s with LS and a congenital genital tract malformation. She had a unicornuate (left) uterus and a vestigial (right) uterine horn. There was an inability to obtain a conclusive set of endometrial biopsies in this patient due to the nature of the patient's congenital uterine abnormality. In this case, surgery was recommended to excise the vestigial horn and fallopian tube in order to optimise surveillance and fertility.

Survival outcomes associated with Lynch syndrome colorectal cancer and metachronous rate after subtotal/total versus segmental colectomy: Meta-analysis.

BACKGROUND: Lynch syndrome is associated with the most common form of heritable bowel cancer. There remains limited level 1 evidence on survival outcomes and rate of metachronous tumor associated with Lynch syndrome colorectal cancer. METHODS: A systematic literature search of original studies was performed on Ovid searching MEDLINE, Embase, Cochrane Database of Systematic Reviews, American College of Physicians ACP Journal Club, Database of Abstracts of Reviews of Effects DARE, and Clinical Trials databases from inception of database to February 2021. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guideline was followed. The data were pooled using a random-effects model. All of the P values were 2-tailed, and statistical analysis was performed using RevMan v. 5.3 Cochrane Collaboration. RESULTS: From 1,942 studies, 15 studies met the inclusion criteria and were included for qualitative and quantitative synthesis. The five-year overall survival was 89.5% (82.0-94.1%), P < .01; I2 = 89%. The ten-year overall survival was 80.5% (68.7-88.6%), P < .01; I2 = 81%. The fifteen-year overall survival was 70% (33.7%-91.5%), P < .01; I2 = 93%. Univariate meta-regression analysis showed no statistically significant difference in 5-year overall survival by sex, age, MLH1, MSH2, MSH6, nor tumor location (right versus left colon). The metachronous tumor rate was 12% to 33% with a follow-up period of up to 15 years, significantly lower in patients who underwent subtotal/total colectomy (0-6%). CONCLUSION: The overall survival of patients with colorectal cancer with Lynch syndrome was approximately 90% at 5 years, 80% at 10 years, and 70% at 15 years. The metachronous tumor rate was approximately 10% to 30% at up to 15 years, significantly improved by subtotal/total colectomy.

Trousseau Syndrome in a 25-Year-Old Woman with Occult Colon Malignancy, Lynch Syndrome, and Chronic Thromboembolic Pulmonary Hypertension.

We present a rare case of thrombosis associated with an occult colon malignancy (Trousseau syndrome) in a 25-year-old woman who also presented with previously unidentified Lynch syndrome and acute-on-chronic thromboembolic pulmonary hypertension. Staged treatment included bilateral pulmonary endarterectomy under deep hypothermic circulatory arrest, followed 11 days later by laparoscopic subtotal colectomy and creation of a primary anastomosis. The patient tolerated both procedures well and recovered normal functional status. Final pathologic analysis of the resected colon mass revealed a pT3N0, stage IIA adenocarcinoma; no adjuvant therapy was administered. At her one-year follow-up visit, the patient was cancer-free, remained on lifelong apixaban anticoagulation, and was undergoing routine monitoring and genetic counseling. This case highlights the need for multidisciplinary management of a patient with severe chronic thromboembolic pulmonary hypertension and a concomitant malignancy.

The importance of genetics for timing and extent of surgery in inherited colorectal cancer syndromes.

Approximately 5% of colorectal cancers arise within an inherited colorectal cancer syndrome, with known underlying genetic etiologies. These syndromes increase the risk of colorectal and extracolonic cancers. Identification of a specific genetic pathogenic variant defines the syndrome, and quantifies the elevated risks compared to the general population. Thus, knowing and understanding the risks associated with each pathogenic variant allows for risk-stratification and a more individualized management strategy. These factors influence both the timing of surgery and the extent of colorectal surgery for patients with these syndromes. Familial Adenomatous Polyposis (FAP) is a dominantly inherited polyposis syndrome caused by pathogenic variant in the APC gene and results in a near 100% chance of developing colorectal cancer if not treated. There is a genotype-phenotype correlation in which the affected gene locus is associated with severity of polyposis and the risk of desmoid disease. Prophylactic surgery ranging from total abdominal colectomy or total proctocolectomy is recommended before cancer develops. Lynch syndrome is a non-polyposis inherited syndrome caused by a pathogenic variant in MLH1, MSH2, MSH6, or PMS2. Although prophylactic colectomy in Lynch syndrome is uncommon, total abdominal colectomy as prophylaxis in the setting of colon cancer is recommended due to the likelihood of metachronous colorectal cancer. This article reviews the role of genetics surgical decision making with respect to the timing and extent of surgery within the hereditary colorectal cancer syndromes.

[Current management status of hereditary colorectal cancer].

Hereditary colorectal cancer accounts for approximately 5% of all colorectal cancer cases, mainly including familial adenomatous polyposis and Lynch syndrome. Total proctocolectomy plus ileal pouch-anal anastomosis and total colectomy plus ileorectal anastomosis are two major procedures for familial adenomatous polyposis, however, the exact impact of these two procedures on surgical efficacy, oncologic efficacy as well as functional results still remains uncertain. Segmental colectomy and total colectomy are two major procedures for Lynch syndrome, each of them both has advantages and disadvantages, and there still lacks a consensus about the optimal strategy because of the nature of retrospective study with a relatively insufficient evidence support. As a result, we would make a review about the current surgical treatment status and future perspectives of hereditary colorectal cancer.

[A Case of Lynch Syndrome with Repeated Asynchronous Colorectal Cancer in a Short Period].

This case was a 73-year-old woman who previously underwent a partial colectomy for ascending colon cancer at the age of 70. She had a history of cancer of the uterus, descending colon, bladder, and left ureter. She had a family history of colorectal cancer and met the Amsterdam Ⅱ criteria for Lynch syndrome. She was diagnosed as Lynch syndrome with a MSH2 germline mutation by genetic analysis. One year later, a partial colectomy was performed for sigmoid colon cancer. Six months later, colonofiberscopy revealed early-stage cancer in the rectum, and EMR was performed. Despite adequate surveillance, she had frequent recurrences of advanced colorectal cancer within a short period of time. We report here risk factors of colorectal cancer in Lynch syndrome and indications for prophylactic total colectomy.

Screening and risk reducing surgery for endometrial or ovarian cancers in Lynch syndrome: a systematic review.

OBJECTIVE: Lynch syndrome is a hereditary cancer syndrome caused by mismatch repair gene mutations, and female carriers are at an increased risk of endometrial and ovarian cancer. The best approach to screening is not yet clear and practice varies across countries and centers. We aimed to provide evidence to inform the best approach to screening and risk reduction. METHODS: A systematic search of the literature was conducted (Medline, Embase, PubMed). Studies evaluating the following were included: women with Lynch syndrome (by mismatch repair mutation or Amsterdam II criteria), screening methods for endometrial and/or ovarian cancer, intervention included endometrial biopsy, transvaginal ultrasound, or serum cancer antigen 125 (CA-125), outcomes evaluated were number of cancers and/or endometrial hyperplasia. RESULTS: A total of 18 studies of Lynch syndrome carriers which screened for endometrial cancer using transvaginal ultrasound and/or hysteroscopy/endometrial biopsy revealed an incidence of 3.9% at the time of screening. Most (64.1%) endometrial cancers detected were from screening, with the balance detected in symptomatic women at the first screening visits, regular review, or between screening intervals. In mismatch repair carriers, the overall sensitivity of endometrial screening was 66.7%, and the number needed to screen ranged between 4 and 38 (median 7). The sensitivity of endometrial biopsy was 57.1% and the number needed to screen was 23-380 (median 78). The sensitivity of transvaginal ultrasound was 34.4% and the number needed to screen was 35-973 (median 170). Fourteen studies which screened for ovarian cancer using transvaginal ultrasound and/or CA-125 revealed an incidence of 1.3% at the time of screening and 42.9% of ovarian cancers were detected at asymptomatic screening. The sensitivity of ovarian screening was 54.6%, and the number needed to screen was 9-191 (median 23) in mismatch repair carriers. Thirteen studies reported 5.8% incident endometrial cancers and 0.5% ovarian cancers at time of risk reducing surgery. CONCLUSIONS: There is limited evidence to support screening for endometrial and ovarian cancer in Lynch syndrome and data on mortality reduction are not available. Further prospective, randomized trials comparing targeted screening methods are needed. Risk reducing surgery remains the most reliable way to reduce endometrial and ovarian cancer risk in Lynch syndrome.