The Lynch syndrome is hereditary nonpolyposis in patients with colorectal cancer. This diagnosis has implications for treatment and for the risk of cancer among family members. In this study of 1066 ...patients with newly diagnosed colorectal cancer, 23 patients and 52 family members were positive for Lynch syndrome mutations. Had the criteria of age and the presence or absence of a family history been used to select patients for genetic screening, many mutations would have remained undetected.
In 1066 patients with newly diagnosed colorectal cancer, 23 patients (and 52 family members) were positive for Lynch syndrome mutations. Routine screening for hereditary nonpolyposis may be beneficial to patients and their family members.
Large-scale screening for germ-line mutations that lead to the onset of disease in adulthood is becoming increasingly possible owing to technical advances. Even when screening is technically feasible, however, it does not necessarily follow that it is desirable.
1
Issues that affect screening include the accuracy, sensitivity, and specificity of the test, the benefit to the patient, the possibly negative ramifications of the results, and the cost.
2
One disease discussed as a plausible candidate for screening is the Lynch syndrome (hereditary nonpolyposis colorectal cancer).
1
The Lynch syndrome is caused mainly by mutations in the DNA mismatch-repair genes
MLH1, MSH2, MSH6,
and . . .
The definition of tumor deposits (TDs) in colonic adenocarcinoma has been modified in different editions of the AJCC/TNM staging system. Studies have shown that the presence of TD is associated with ...advanced tumor growth and poor prognosis. Most of these data were obtained in patients with simultaneous lymph node (LN) metastases. Reports focusing on the impact of TD in patients without LN metastasis are limited. We retrospectively restaged all right-sided colonic adenocarcinomas over a 10-year period using criteria from the fifth, sixth, and seventh AJCC edition. We compared the number of tumor nodule interpreted as LN and TD in each edition and evaluated the stage migration caused by TD definition change. We then assessed clinical significance of TD in the AJCC seventh edition by comparing 5-year overall survival of N1c patients versus other N category (N0, N1, N2) patients with similar T and M status. We showed that the average number of tumor nodules interpreted as LNs per case and the number of cases with positive LNs were significantly decreased with the seventh edition compared with fifth/sixth; however, numbers of cases with TDs and <12 LNs were significantly increased with the seventh edition compared with fifth/sixth. These changes, however, resulted in minimal effects on the final stage grouping. Our survival analysis showed that N1c patients had significantly worse survival compared with N0 patients. Although not statistically significant, the hazard ratios indicated that the N1c group might have worse survival than the N1 group and better survival than the N2 group. Therefore, we conclude that TDs predict patient outcome at least similarly to positive LNs.
Mismatch repair protein (MMR) immunohistochemistry is an important tool in screening for Lynch syndrome in colorectal cancer patients. Unusual staining patterns such as heterogeneous MSH6 staining ...have been reported in colorectal and endometrial cancers. We aim to better understand MSH6 staining heterogeneity in colorectal cancer by comparative sequencing of different tumor areas for MMR and DNA polymerase mutations. Whole-section slides of 1754 colorectal cancers were reviewed for heterogeneous MSH6 staining, defined as discrete tumor areas with abrupt loss of staining juxtaposed to tumor areas with retained staining. Nine cases (0.05%) demonstrated heterogeneous MSH6 staining; none received neoadjuvant therapy prior to the specimen collection. The area of tumor with loss of MSH6 expression ranged from 5% to 60% (average 22%). Four cases had enough tissue remaining in both retained and lost MSH6 areas to perform tumor sequencing on both areas. All 9 cases were negative for MSH6 germline mutation; MSH6 heterogeneous staining was seen in tumors with MLH1 or PMS2 abnormalities (6 cases of MLH1 methylation, 2 PMS2 germline mutation, 1 MLH1 germline mutation). In addition, case 1 also had a somatic POLD1 exonuclease domain mutation (p.Y405C) in the MSH6 loss area but not in the intact area. We recommend reporting MSH6 heterogeneous pattern as MSH6 staining is present with a comment stating that the heterogeneous pattern typically does not indicate germline mutation in MSH6 but is commonly associated with abnormality in another MMR gene such as MLH1 or PMS2, or even other DNA repair genes such as DNA polymerase.
•MSH6 heterogeneous staining was seen in 9 cases of colorectal cancers with MLH1 or PMS2 abnormalities; not MSH6 germline mutation•One case had a somatic POLD1 exonuclease domain mutation (p.Y405C) in the MSH6 loss of expression area but not in the intact area•MSH6 heterogeneous staining pattern is usually due to a secondary MSH6 somatic alteration, most commonly at the genomic locus c.3261•MSH6 heterogeneous staining is associated with an abnormality in another MMR gene or other DNA repair gene, but not MSH6 germline mutation
Hydrophilic polymer coating of medical devices serves to lubricate the device and prevent device-related complications. The coating can be mechanically disrupted and result in downstream injury via ...presumed thromboembolism. This process has been reported in the brain, heart, lung, and skin, and has been replicated through animal studies and in vitro histologic processing of the polymer coating. We report the first description of hydrophilic polymer–associated ischemic enterocolitis in a series of 7 specimens (small bowel=2, colon=4, aortic thrombus=1) from 3 patients. We report a 4% incidence among all patients with an ischemic bowel resection between April 29, 2014 and August 8, 2016. All patients developed bowel ischemia within 1 day of aortic repair, and all bowel resection specimens showed polymers, mainly in the submucosal vessels in areas of extensive ischemia. The polymers appeared as basophilic, intravascular, serpiginous structures. In a patient who developed acute paralysis after the aortic repair, identical polymers were identified in the aortic thrombus and the ischemic bowel segment. We demonstrate that the polymers display an altered morphology over time and with various graft types, and that the degrading polymers are associated with a foreign body giant cell reaction. Special stains can aid in diagnosis, with the polymers turquoise on a colloidal iron stain, pink on von Kossa and mucicarmine stains, and pale blue on trichrome. Clinical follow-up was available up to 115 weeks1 patient died, and 2 are alive and well. In summary, we report a new diagnostic entity to be considered in the differential diagnosis of iatrogenic ischemic injuries in the gastrointestinal tract. Awareness of this entity is important to elucidate the cause of ischemia and to prevent misdiagnosis of the polymers and their associated giant cell reaction as a parasitic infection, granulomatous vasculitis, sarcoidosis, and idiopathic inflammatory bowel disease.
Pancreatic adenocarcinoma is the third leading cause of cancer death in the United States. Surgery remains the mainstay of treatment, and frozen section analysis is used to confirm diagnosis and ...determine resectability and margin status.
To evaluate use and accuracy of frozen section and how diagnosis impacts surgical procedure.
We reviewed patients with planned pancreatic resections between January 2014 and March 2019 with at least 1 frozen section. Pathology reports including frozen sections, preoperative cytology, and operative notes were reviewed. Frozen sections were categorized by margin, primary pancreatic diagnosis, metastasis, or vascular resectability. The deferral and error rates and surgeons' response were noted.
We identified 898 planned pancreatic resections and 221 frozen sections that were performed on 152 cases for 102 margins, 94 metastatic lesions, 20 primary diagnoses, and 5 to confirm vascular resectability. The diagnosis was deferred to permanent sections in 13 of 152 cases (8.6%) on 16 of 221 frozen sections (7.2%): 6 for metastasis, 8 for margins, and 2 for primary diagnosis. Discrepancies/errors were identified in 4 of 152 cases (2.6%) and 4 of 221 frozen sections (1.8%). Surgeons' responses were different than expected in 8 of 221 frozen sections (3.6%), but their actions were explained by other intraoperative findings in 6 of 8.
Frozen section remains an important diagnostic tool used primarily for evaluation of margins and metastasis during pancreatectomy. In most cases, a definitive diagnosis is rendered, with occasional deferrals and few errors. Intraoperative findings explain most cases where surgeons act differently than expected based on frozen section diagnosis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
AIM:To investigate our clinical experience with the colonic manifestations of phosphatase and tensin homolog on chromosome ten(PTEN)hamartoma tumor syndrome(PHTS)and to perform a systematic ...literature review regarding the same.METHODS:This study was approved by the appropriate institutional review board prior to initiation.A clinical genetics database was searched for patients with PHTS or a component syndrome that received gastrointestinal endoscopy or pathology interpretation at our center.These patient’s records were retrospectively reviewed for clinical characteristics(including family history and genetic testing),endoscopy results and pathology findings.We also performed a systematic review of the literature for case series of PHTS or component syndromes that reported gastrointestinal manifestations and investigations published after consensus diagnostic criteria were established in 1996.These results were compiled and reported.RESULTS:Eight patients from our institution met initial inclusion criteria.Of these,5 patients underwent4.2 colonoscopies at mean age 45.8±10.8 years.All were found to have colon polyps during their clinical course and polyp histology included adenoma,hyperplastic,ganglioneuroma and juvenile.No malignant lesions were identified.Two had multiple histologic types.One patient underwent colectomy due to innumerable polyps and concern for future malignant potential.Systematic literature review of PHTS patients undergoing endoscopy revealed 107 patients receiving colonoscopy at mean age 37.4 years.Colon polyps were noted in92.5%and multiple colon polyp histologies were reported in 53.6%.Common polyp histologies included hyperplastic(43.6%),adenoma(40.4%),hamartoma(38.3%),ganglioneuroma(33%)and inflammatory(24.5%)polyps.Twelve(11.2%)patients had colorectal cancer at mean age 46.7 years(range 35-62).Clinical outcomes secondary to colon polyposis and malignancy were not commonly reported.CONCLUSION:PHTS has a high prevalence of colon polyposis with multiple histologic types.It should be considered a mixed polyposis syndrome.Systematic review found an increased prevalence of colorectal cancer and we recommend initiating colonoscopy for colorectal cancer surveillance at age 35 years.
•MLH1 methylated endometrial tumors have poor prognostic features including larger size.•Tumor volume and mismatch repair class are associated with lymph node involvement.•Women with MLH1 methylated ...tumors have reduced recurrence-free survival.•Recurrence rate by MMR class differed dramatically in advanced stage endometrial cancer.•MMR defective tumors with MLH1 methylation may exhibit chemoresistance.
To determine the relationship between mismatch repair (MMR) classification and clinicopathologic features including tumor volume, and explore outcomes by MMR class in a contemporary cohort.
Single institution cohort evaluating MMR classification for endometrial cancers (EC). MMR immunohistochemistry (IHC)±microsatellite instability (MSI) testing and reflex MLH1 methylation testing was performed. Tumors with MMR abnormalities by IHC or MSI and MLH1 methylation were classified as epigenetic MMR deficiency while those without MLH1 methylation were classified as probable MMR mutations. Clinicopathologic characteristics were analyzed.
466 endometrial cancers were classified; 75% as MMR proficient, 20% epigenetic MMR defects, and 5% as probable MMR mutations. Epigenetic MMR defects were associated with advanced stage, higher grade, presence of lymphovascular space invasion, and older age. MMR class was significantly associated with tumor volume, an association not previously reported. The epigenetic MMR defect tumors median volume was 10,220mm3 compared to 3321mm3 and 2,846mm3, for MMR proficient and probable MMR mutations respectively (P<0.0001). Higher tumor volume was associated with lymph node involvement. Endometrioid EC cases with epigenetic MMR defects had significantly reduced recurrence-free survival (RFS). Among advanced stage (III/IV) endometrioid EC the epigenetic MMR defect group was more likely to recur compared to the MMR proficient group (47.7% vs 3.4%) despite receiving similar adjuvant therapy. In contrast, there was no difference in the number of early stage recurrences for the different MMR classes.
MMR testing that includes MLH1 methylation analysis defines a subset of tumors that have worse prognostic features and reduced RFS.
Lynch syndrome is the most common cause of inherited endometrial cancer, attributable to germline pathogenic variants (PV) in mismatch repair (MMR) genes. Tumor microsatellite instability (MSI-high) ...and MMR IHC abnormalities are characteristics of Lynch syndrome. Double somatic MMR gene PV also cause MSI-high endometrial cancers. The aim of this study was to determine the relative frequency of Lynch syndrome and double somatic MMR PV.
341 endometrial cancer patients enrolled in the Ohio Colorectal Cancer Prevention Initiative at The Ohio State University Comprehensive Cancer Center from 1/1/13–12/31/16. All tumors underwent immunohistochemical (IHC) staining for the four MMR proteins, MSI testing, and MLH1 methylation testing if the tumor was MMR-deficient (dMMR). Germline genetic testing for Lynch syndrome was undertaken for all cases with dMMR tumors lacking MLH1 methylation. Tumor sequencing followed if a germline MMR gene PV was not identified.
Twenty-seven percent (91/341) of tumors were either MSI-high or had abnormal IHC indicating dMMR. As expected, most dMMR tumors had MLH1 methylation; (69, 75.8% of the dMMR cases; 20.2% of total). Among the 22 (6.5%) cases with dMMR not explained by methylation, 10 (2.9% of total) were found to have Lynch syndrome (6 MSH6, 3 MSH2, 1 PMS2). Double somatic MMR PV accounted for the remaining 12 dMMR cases (3.5% of total).
Since double somatic MMR gene PV are as common as Lynch syndrome among endometrial cancer patients, paired tumor and germline testing for patients with non-methylated dMMR tumor may be the most efficient approach for LS screening.
•2.9% of endometrial cancers (EC) are due to Lynch syndrome.•Double somatic mismatch repair gene mutations (3.5%) are as common as Lynch syndrome (2.9%) among EC patients.•EC with absence of MSH6, PMS2, or microsatellite instability with normal IHC are more likely due to Lynch syndrome.•EC with absence of MLH1 & PMS2 and no MLH1 methylation are more likely due to double somatic mismatch repair mutations.•Endometrial cancers with absence of MSH2 & MSH6 are more likely due to double somatic mismatch repair gene mutations.
PDF
