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.
Pancreatic ductal adenocarcinoma (PDAC) is aggressive, with an overall five-year survival rate of 9%, and few patients are candidates for pancreatectomy at presentation. The role of neoadjuvant ...therapy (NAT) is evolving, especially for high-risk potentially resectable tumors. Owing to the increasing number of NAT resection specimens, we aim to characterize the histologic changes associated with NAT and to compare two tumor regression grading schemes. One hundred eighteen resections for PDAC were selected from the cases between 2011 and 2018, 59 not treated and 59 treated with NAT. All H&E stained tumor slides were reviewed for histologic changes and graded using the four-tier modified Ryan score (recommended by College of American Pathologists) and the three-tier MD Anderson (MDA) score. The histologic changes evaluated included blue/grey fibrosis, islet cell hyperplasia, dystrophic calcification, amyloid deposition, cholesterol clefts, nerve hypertrophy, elastotic stromal/vascular change, abscess formation, and eosinophilic tumor cell changes. There were statistically significant differences for dystrophic calcification, eosinophilic tumor cell changes, elastotic stromal/vascular change, islet cell hyperplasia, and nerve hypertrophy between the two groups, with these features seen more frequently in NAT cases. Blue/grey stromal fibrosis was present in all cases regardless of NAT, except few complete regression cases and one treated case with intraneural invasion only. Blue/grey fibrosis is a useful histologic visual clue to suggest the possibility of adjacent tumor in the majority of PDAC cases regardless of NAT. By Kaplan-Meier analysis, neither grading scheme correlated with overall survival in our cohort. However, the MDA score was significantly correlated with both time to primary tumor recurrence (p = 0.002) and time to distant recurrence (p = 0.04), whereas the modified Ryan score was not.
•We identified morphologic changes associated with neoadjuvant-treated pancreatic ductal adenocarcinoma.•We provided histomorphologic clues to help identify residual tumor in challenging post-treatment pancreatectomy specimens.•This study supports that the three-tier MDA score may better risk stratify patients with treated pancreatic cancer.
Universal screening for mismatch repair deficiency (dMMR) in cancer is increasingly being implemented to detect Lynch syndrome and aid in treatment decisions. The mismatch repair (MMR) ...immunohistochemistry (IHC) concordance rate between primary colorectal cancer (CRC) and metastasis is unknown. At times, only metastatic tumor is available for screening (lymph node, liver, lung etc.) rather than the primary tumor. Therefore, it is important to confirm that tissue from metastases can be used for screening for dMMR. We tested dMMR primary and metastatic tumor to assess concordance between the two. We identified dMMR CRC resected at Ohio State University from 1999 to 2013 and stained a corresponding metastasis for all four MMR proteins (MLH1, MSH2, MSH6, PMS2) with IHC. A total of 50 primary CRC with dMMR and available regional lymph nodes (LN; 26 cases) or other metastatic tissue (24 cases) were identified. Thirteen cases were explained by
MLH1
hypermethylation and 10 cases had Lynch syndrome. Two cases had somatic MMR mutations and the etiology for dMMR was unknown in 25 cases. All cases showed concordance in IHC staining between the primary tumor and corresponding metastatic tissue. In 36 cases, metastatic LN/other site was resected at the same time as the primary tumor. In 14 cases, time lapsed median 16.5 months; quartile (Q)1 8.0; Q3 25; range 3–69 from the primary resection until metastatic resection. Metastatic tissue can be used to screen for Lynch syndrome and dMMR.
Abstract
Objectives
Small sample size limits the number of immunostains that may be attempted in colorectal carcinoma (CRC) biopsy specimens. We investigated the utility of dual stain with special ...AT-rich sequence binding protein 2 (SATB2) or caudal-type homeobox 2 (CDX2) and cytokeratin 20 (CK20) or villin in identifying CRC.
Methods
Tissue microarrays with 222 CRCs and 375 other carcinomas were built. Dual stain was performed pairing nuclear stains CDX2 or SATB2 with CK20 or villin.
Results
All four single stains showed excellent sensitivity (93%-99%) but variable specificity (56%-88%) for CRC. All four dual stains also showed excellent sensitivity (90%-96%) while much improved specificity (88%-98%) compared with single stains. SATB2 dual stain (with CK20 or villin) showed a higher specificity than CDX2 dual stain (with CK20 or villin) with a comparable sensitivity.
Conclusions
SATB2 dual stain shows the greatest potential clinical utility in identifying CRC and is superior to CDX2 dual stain. More important, SATB2 dual stain could be helpful for specimens with limited tissues or those having a nonclassic staining pattern.
Lynch syndrome (LS) is the most common form of hereditary colon cancer. Germline mutations in the mismatch-repair (MMR) genes MLH1, MSH2 (EPCAM), MSH6, and PMS2, followed by a second hit to the ...remaining allele, lead to cancer development. Universal tumor screening for LS is routinely performed on colon cancer, and screening has identified patients with unexplained MMR deficiency that lack MLH1 methylation and a germline mutation. Tumor sequencing has since identified double somatic (DS) mutations in the MMR gene corresponding with the absent protein in 69% of these patients. We assessed whether histomorphology could distinguish patients with DS mutations from those with LS. Colorectal cancer patients with DS mutations were identified from population-based cohorts from Iceland (2000-2009); Columbus, Ohio (1999-2005); and the state of Ohio (2013-2016). Next-generation sequencing was performed on tumors with unexplained MMR deficiency. Patients with LS from Ohio cohorts were the comparison group. The histologic features associated with MMR deficiency (tumor-infiltrating lymphocytes, Crohn-like reaction, histologic subtype, necrosis) were evaluated. We identified 43 tumors with DS mutations and 48 from patients with LS. There was no significant difference in histologic features between tumors in LS patients and tumors with DS mutations. Because histology of tumors with DS mutations is indistinguishable from those caused by LS, tumor sequencing for evaluation of DS mutations should be considered to help clarify sporadic versus hereditary causes of unexplained MMR deficiency.
•Double somatic mutations in mismatch-repair (MMR) genes can cause MMR deficiency.•Lynch syndrome and double somatic colorectal carcinomas have similar histology.•Tumor sequencing can help in cases of unexplained MMR deficiency.
We conducted an institutional study to compare the clinical and pathological efficacy between the neoadjuvant therapy (NAT)‐modified FOLFIRINOX (mFOLF) vs nanoparticle albumin–bound paclitaxel plus ...gemcitabine (nab‐P/G) for borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC) patients who completed resection. The study retrospectively enrolled patients with pathologically confirmed BRPC or LAPC from 2010 to 2018 at our institution. The survival rates were determined by the Kaplan‐Meier method and log‐rank test was used to test differences. Cox's proportional hazard model was used to assess survival with respect to covariates. Seventy‐two patients who completed at least two cycles of neoadjuvant chemotherapy and surgical resection were included, with 52 (72.2%) patients receiving mFOLF and 20 (27.8%) receiving nab‐P/G. Patients treated with mFOLF had statistically higher rates of RECIST 1.1 partial or complete response (16/52 vs 1/20, P = .028). Additionally, mFOLF patients had greater pathological tumor size reduction, fewer positive lymph nodes, and higher treatment response grade compared to the nab‐P/G patients (all P < .05). The median overall survival was 33.3 months vs 27.1 months (P = .105), and distant metastasis‒free survival (DMFS) was 21.3 months vs 14.6 months (P = .042) in the mFOLF vs nab‐P/G groups, respectively. On multivariate analysis, mFOLF (hazard ratio, 0.428; 95% confidence interval CI, 0.186‐0.987) and abnormal postoperative CA 19‐9 (hazard ratio, 2.47; 95% CI, 1.06‐5.76) were associated with DMFS. Among patients with BRPC and LAPC who complete surgical resection, neoadjuvant mFOLF was associated with improved pathological and clinical outcomes compared with nab‐P/G.
Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with poor survival rates. For borderline resectable or unresectable disease, intensive multi‐drug chemotherapy regimens with either modified FOLFIRINOX (mFOLF) or nab‐paclitaxel plus gemcitabine are preferred. We retrospectively compared these two chemotherapy regimens in patients who completed resection and found the mFOLF group had better overall clinical and pathological response rates. Randomized clinical trials are needed, and this study provides valuable information in the interim.
With advancements in the field of digital pathology, there has been a growing need to compare the diagnostic abilities of pathologists using digitized whole slide images (WSI) against using ...traditional hematoxylin and eosin (H&E)-stained glass slides for primary diagnosis. One of the most common specimens received in pathology practices is an endoscopic gastric biopsy with a request to rule out Helicobacter pylori (H. pylori) infection. The current standard of care is the identification of the organisms on H&E-stained slides. Immunohistochemical or histochemical stains are used selectively. However, due to their small size (2-4 μm in length by 0.5-1 μm in width), visualization of the organisms can present a diagnostic challenge. The goal of the study is to compare the ability of pathologists to identify H. pylori on H&E slides using a digital platform against the gold standard of H&E glass slides using routine light microscopy. Diagnostic accuracy rates using glass slide vs. digital slide were 81% vs. 72% (p=0.0142) based on H&E slides alone. When H. pylori IHC slides were provided, the diagnostic accuracy was significantly improved to comparable rates (96% glass vs. 99% digital, p=0.2199). Furthermore, differences in practice settings (academic/subspecialized vs. community/general) and the duration of sign-out experience did not significantly impact the accuracy of detecting H. pylori on digital slides. We concluded that digital WSI, although amenable in different practice settings and teaching environments, it does present some shortcomings in accuracy and precision, especially in certain circumstances and thus is not yet fully capable of completely replacing glass slide review for identification of H. pylori. We specifically recommend reviewing glass slides and/or performing ancillary stains, especially when there is a discrepancy between the degree of inflammation and the presence of microorganisms on digital image.
Lynch syndrome (LS) is an autosomal dominant cancer predisposition syndrome attributable to deleterious germline mutations in mismatch repair (MMR) genes. The syndrome is typified by early-onset, ...frequently right-sided colorectal cancers (CRCs) with characteristic histologic features and tendency for multiplicity and an increased risk for extracolonic tumors at particular sites; it accounts for 1% to 5% of CRC. Deficient mismatch repair (dMMR) function manifests as immunohistochemically detectable absence of one or more MMR proteins and microsatellite instability (MSI). Approximately 15% of sporadic, noninherited CRC are characterized by high-level MSI, nearly always owing to transcriptional silencing of MLH1; these sporadic and LS cases exhibit considerable phenotypic overlap. Identification of CRC with dMMR is desirable to identify LS and because MSI status is prognostic and potentially predictive. This review will discuss the history of LS, the principles of MMR and MSI, the clinicopathologic features of LS-associated and sporadic high-level MSI CRC, the fundamentals of clinical testing for dMMR CRC, and the results of the Columbus-area Lynch syndrome study. We conclude with our approach to population-based LS screening based on institutional experience with nearly 2000 cases.
The American Joint Committee on Cancer's Cancer Staging Manual 7th edition defines pericolonic tumor deposits (TDs) as discrete tumor foci in pericolic fat showing no evidence of residual lymph node ...(LN). This definition relies on subjective features rather than size (5th edition) or shape (6th edition) and introduced the category N1c. Although typically straightforward, metastases are encountered for which the distinction between LNs and TDs is unclear. For data to be meaningful, agreement on distinguishing features between positive LNs and TDs is needed.
To assess agreement among gastrointestinal pathologists evaluating difficult metastases and to report the distinguishing features they found helpful.
Twenty-five tumor metastases from right-sided colonic adenocarcinomas were selected in which the distinction between positive LNs and TDs was challenging. Virtual slides were reviewed by 7 gastrointestinal pathologists. A list of features potentially helpful in differentiating positive LNs and TDs was ranked for usefulness by each pathologist. Every metastasis was diagnosed as positive LN or TD. For each case diagnosed as positive LN, reviewers were asked to list every feature used in diagnosis.
Complete agreement was found for 11 of 25 metastases, 5 positive LNs and 6 TDs (κ statistic, 0.48; 95% confidence interval, 0.28-0.67). Top-ranked features included round shape, peripheral lymphocyte rim, peripheral lymphoid follicles, possible subcapsular sinus, residual LN in surrounding fibroadipose tissue, and thick capsule. The top used features were similar among reviewers.
Significant agreement on positive LNs and TDs in difficult colonic adenocarcinoma metastases was found among evaluators, but inconsistency remains. Round shape, peripheral lymphocyte rim, peripheral lymphoid follicles, possible subcapsular sinus, residual LN in surrounding fibroadipose tissue, and thick capsule were most often used to aid in diagnosis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
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