Publications by authors named "David S Klimstra"

333 Publications

Artificial Intelligence and Early Detection of Pancreatic Cancer: 2020 Summative Review.

Pancreas 2021 Mar;50(3):251-279

Sander Lab, Harvard Medical School, Boston, MA.

Abstract: Despite considerable research efforts, pancreatic cancer is associated with a dire prognosis and a 5-year survival rate of only 10%. Early symptoms of the disease are mostly nonspecific. The premise of improved survival through early detection is that more individuals will benefit from potentially curative treatment. Artificial intelligence (AI) methodology has emerged as a successful tool for risk stratification and identification in general health care. In response to the maturity of AI, Kenner Family Research Fund conducted the 2020 AI and Early Detection of Pancreatic Cancer Virtual Summit (www.pdac-virtualsummit.org) in conjunction with the American Pancreatic Association, with a focus on the potential of AI to advance early detection efforts in this disease. This comprehensive presummit article was prepared based on information provided by each of the interdisciplinary participants on one of the 5 following topics: Progress, Problems, and Prospects for Early Detection; AI and Machine Learning; AI and Pancreatic Cancer-Current Efforts; Collaborative Opportunities; and Moving Forward-Reflections from Government, Industry, and Advocacy. The outcome from the robust Summit conversations, to be presented in a future white paper, indicate that significant progress must be the result of strategic collaboration among investigators and institutions from multidisciplinary backgrounds, supported by committed funders.
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http://dx.doi.org/10.1097/MPA.0000000000001762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041569PMC
March 2021

Genomic characterization of small cell carcinomas of the uterine cervix.

Mol Oncol 2021 Apr 8. Epub 2021 Apr 8.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Small cell carcinoma (SCC) of the uterine cervix is a rare and aggressive form of neuroendocrine carcinoma, which resembles small cell lung cancer (SCLC) in its histology and poor survival rate. Here we sought to define the genetic underpinning of SCCs of the uterine cervix and compare their mutational profiles with those of human papillomavirus (HPV)-positive head and neck squamous cell carcinomas, HPV-positive cervical carcinomas and SCLCs using publicly available data. Using a combination of whole-exome and targeted massively parallel sequencing, we found that the nine uterine cervix SCCs, which were HPV18-positive (n=8) or HPV16-positive (n=1), harbored a low mutation burden, few copy number alterations and other than TP53 in two cases no recurrently mutated genes. The majority of mutations were likely passenger missense mutations, and only few affected previously described cancer-related genes. Using RNA-Sequencing, we identified putative viral integration sites on 18q12.3 and on 8p22 in two SCCs of the uterine cervix. The overall non-silent mutation rate of uterine cervix SCCs was significantly lower than those described for SCLCs, HPV-driven cervical adeno- and squamous cell carcinomas or HPV-positive head and neck squamous cell carcinomas. Unlike SCLCs, which are reported to harbor almost universal inactivating TP53 and RB1 mutations and a dominant tobacco smoke-related signature 4, uterine cervix SCCs rarely harbored mutations affecting these genes (2/9, 22% TP53; 0% RB1) and displayed a dominant aging (67%) or APOBEC mutational signature (17%), akin to HPV-driven cancers, including cervical adeno- and squamous cell carcinomas and head and neck squamous cell carcinomas. Taken together, in contrast to SCLCs, which are characterized by highly recurrent TP53 and RB1 alterations, uterine cervix SCCs were positive for HPV leading to inactivation of the suppressors p53 and RB, suggesting that these SCCs are convergent phenotypes.
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http://dx.doi.org/10.1002/1878-0261.12962DOI Listing
April 2021

Platinum-Based Treatment for Well- and Poorly Differentiated Pancreatic Neuroendocrine Neoplasms.

Pancreas 2021 Feb;50(2):138-146

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.

Objectives: Pancreatic neuroendocrine neoplasms include well-differentiated tumors (PanNETs) and poorly differentiated carcinomas (PanNECs). Previous reports suggested a role for platinum-based therapy largely in PanNEC. We sought to investigate the role of platinum-based therapy in pancreatic neuroendocrine neoplasms regardless of tumor grade and differentiation.

Methods: Patients with pancreatic neuroendocrine neoplasms treated with platinum-based therapy at Memorial Sloan Kettering (1994-2016) and Verona University Hospital (2008-2016) were retrospectively identified. Response to treatment by RECIST v1.1, overall survival, and progression-free survival were defined. Among patients with available tissue, DAXX, ATRX, Rb, and p53 expression was evaluated to support the histologic grade of differentiation.

Results: Fifty PanNETs, 29 PanNECs, and 22 high-grade tumors with undeterminable differentiation were included. No patients achieved complete response. Overall rate of partial response was 31%, 41% for PanNEC, and 20% for PanNETs. Among PanNETs, partial response was achieved in 33% of G1 (2/6), 10% of G2 (2/19), and 24% of G3 (6/25) tumors. Median overall survival was 29.3 months for PanNETs and 10.9 months for PanNEC (P < 0.001). There was no significant difference in median progression-free survival (P = 0.2).

Conclusions: Platinum-based therapies demonstrated increased activity in PanNEC; however, promising efficacy was also observed in PanNETs, irrespective of grade.
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http://dx.doi.org/10.1097/MPA.0000000000001740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880539PMC
February 2021

(Re) Defining the High-Power Field for Digital Pathology.

J Pathol Inform 2020 9;11:33. Epub 2020 Oct 9.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: The microscope high-power field (HPF) is the cornerstone for histopathology diagnostic evaluation such as the quantification of mitotic figures, lymphocytes, and tumor grading. With traditional light microscopy, HPFs are typically evaluated by quantifying histologic events in 10 fields of view at × 400 magnification. In the era of digital pathology, new variables are introduced that may affect HPF evaluation. The aim of this study was to determine the parameters that influence HPF in whole slide images (WSIs).

Materials And Methods: Glass slides scanned on various devices (Leica's Aperio GT450, AT2, and ScanScope XT; Philips UltraFast Scanner; Hamamatsu's Nanozoomer 2.0HT; and 3DHistech's P1000) were compared to acquired digital slides reviewed on each vendor's respective WSI viewer software (e.g., Aperio ImageScope, ImageScope DX, Philips IMS, 3DHistech CaseViewer, and Hamamatsu NDP.view) and an in-house developed vendor-agnostic viewer. WSIs were reviewed at "×40" equivalent HPF on different sized monitors with varying display resolutions (1900 × 1080-4500 × 3000) and aspect ratios (e.g., Food and Drug Administration [FDA]-cleared 27" Philips PS27QHDCR, FDA-cleared 24" Dell MR2416, 24" Hewlett Packard Z24n G2, and 28" Microsoft Surface Studio). Digital and microscopic HPF areas were calculated and compared.

Results: A significant variation of HPF area occurred between differing monitor size and display resolutions with minor differences between WSI viewers. No differences were identified by scanner or WSIs scanned at different resolutions (e.g., 0.5, 0.25, 0.24, and 0.12 μm/pixel).

Conclusion: Glass slide HPF at × 400 magnification with conventional light microscopy was not equivalent to "×40" digital HPF areas. Digital HPF quantification may vary due to differences in the tissue area displayed by monitor sizes, display resolutions, and WSI viewers but not by scanner or scanning resolution. These findings will need to be further clinically validated with potentially new digital metrics for evaluation.
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http://dx.doi.org/10.4103/jpi.jpi_48_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737490PMC
October 2020

DEAD-box RNA helicase protein DDX21 as a prognosis marker for early stage colorectal cancer with microsatellite instability.

Sci Rep 2020 12 16;10(1):22085. Epub 2020 Dec 16.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

DEAD-box RNA helicase DDX21 (also named nucleolar RNA helicase 2) is a nuclear autoantigen with undefined roles in cancer. To explore possible roles of autoimmune recognition in cancer immunity, we examined DDX21 protein expression in colorectal cancer tissue and its association with patient clinical outcomes. Unbiased deep proteomic profiling of two independent colorectal cancer cohorts using mass spectrometry showed that DDX21 protein was significantly upregulated in cancer relative to benign mucosa. We then examined DDX21 protein expression in a validation group of 710 patients, 619 of whom with early stage and 91 with late stage colorectal cancers. DDX21 was detected mostly in the tumor cell nuclei, with high expression in some mitotic cells. High levels of DDX21 protein were found in 28% of stage I, 21% of stage II, 30% of stage III, and 32% of stage IV colorectal cancer cases. DDX21 expression levels correlated with non-mucinous histology in early stage cancers but not with other clinicopathological features such as patient gender, age, tumor location, tumor grade, or mismatch repair status in any cancer stage. Kaplan-Meier analyses revealed that high DDX21 protein levels was associated with longer survival in patients with early stage colorectal cancer, especially longer disease-free survival in patients with microsatellite instability (MSI) cancers, but no such correlations were found for the microsatellite stable subtype or late stage colorectal cancer. Univariate and multivariate analyses also identified high DDX21 protein expression as an independent favorable prognostic marker for early stage MSI colorectal cancer.
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http://dx.doi.org/10.1038/s41598-020-79049-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745018PMC
December 2020

Pancreatobiliary Maljunction-Associated Gallbladder Cancer is as Common in the West, Shows Distinct Clinicopathologic Characteristics and Offers an Invaluable Model for Anatomy-Induced Reflux-Associated Physio-Chemical Carcinogenesis.

Ann Surg 2020 Nov 12. Epub 2020 Nov 12.

Department of Pathology and Research Center for Translational Medicine (KUTTAM), Koç University, Istanbul, Turkey.

Objective: To determine the associations of pancreatobiliary maljunction (PBM) in the West.

Background: PBM (anomalous union of common bile duct and pancreatic duct) is mostly regarded as an Asian-only disorder, with 200X risk of gallbladder cancer (GBC), attributed to reflux of pancreatic enzymes.

Methods: Radiologic images of 840 patients in the U.S. who underwent pancreatobiliary resections were reviewed for PBM and contrasted with 171 GBC cases from Japan.

Results: Eight % of the US GBCs (24/300) had PBM (similar to Japan; 15/171, 8.8%), in addition to 1/42 bile duct carcinomas and 5/33 choledochal cysts. None of the 30 PBM cases from the US had been diagnosed as PBM in the original work-up. PBM was not found in other pancreatobiliary disorders. Clinicopathologic features of the 39 PBM-associated GBCs (US:24, Japan:15) were similar; however, comparison with non-PBM GBCs revealed that they occurred predominantly in females (F/M = 3); at younger (<50-year-old) age (21% vs. 6.5% in non-PBM GBCs; p = 0.01); were uncommonly associated with gallstones (14% vs. 58%; p < 0.001); had higher rate of tumor-infiltrating lymphocytes (69% vs. 44%; p = 0.04); arose more often through adenoma-carcinoma sequence (31% vs. 12%; p = 0.02); and had a higher proportion of non-conventional carcinomas (21% vs. 7%; p = 0.03).

Conclusions: PBM accounts for 8% of GBCs also in the West but is typically undiagnosed. PBM-GBCs tend to manifest in younger age and often through adenoma-carcinoma sequence, leading to unusual carcinoma types. If PBM is encountered, cholecystectomy and surveillance of bile ducts is warranted. PBM-associated GBCs offer an invaluable model for variant anatomy-induced chemical (reflux-related) carcinogenesis.
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http://dx.doi.org/10.1097/SLA.0000000000004482DOI Listing
November 2020

Alterations in Ki67 Labeling Following Treatment of Poorly Differentiated Neuroendocrine Carcinomas: A Potential Diagnostic Pitfall.

Am J Surg Pathol 2021 01;45(1):25-34

Memorial Sloan Kettering Cancer Center, New York, NY.

Assessment of the Ki67 index is critical for grading well-differentiated neuroendocrine tumors (WD-NETs), which can show a broad range of labeling that defines the WHO grade (G1-G3). Poorly differentiated neuroendocrine carcinomas (PD-NECs) have a relatively high Ki67 index, >20% in all cases and commonly exceeding 50%. After anecdotally observing PD-NECs with an unexpectedly low and heterogeneous Ki67 index following chemotherapy in 5 cases, we identified 15 additional cases of treated high-grade neuroendocrine neoplasms (HG-NENs). The study cohort comprised 20 cases; 11 PD-NECs, 8 mixed adenoneuroendocrine carcinomas, and 1 WD-NET, G3 from various anatomic sites (gastrointestinal tract, pancreas, larynx, lung, and breast). The Ki67 index was evaluated on pretreatment (when available) and posttreatment samples. Topographic heterogeneity in the Ki67 index was expressed using a semi-quantitative score of 0 (no heterogeneity) to 5 (>80% difference between maximal Ki67 and minimal Ki67 indices). Relative to the pretreatment group (n=9, mean Ki67 of 86.3%, range 80% to 100%), the neoplasms in the posttreatment group (n=20, mean Ki67 of 47.7%, range 1% to 90%) showed a significantly lower Ki67 index (18/20 cases). Of the 18 cases with a relatively low Ki67 index, 15 showed heterogeneous labeling (mean heterogeneity score of 2.3, range 1 to 5) and in 3 cases it was a homogeneously low. This phenomenon was observed in all subtypes of HG-NENs. In 6 cases, the alterations in Ki67 index following treatment were sufficient to place these HG-NENs in the WHO G1 or G2 grade, erroneously suggesting a diagnosis of WD-NET, and in 9 cases there was sufficient heterogeneity in the Ki67 index to suggest that a limited biopsy may sample an area of low Ki67, even though hotspot regions with a Ki67 index of >20% persisted. In 7 cases, the alterations in the Ki67 index were accompanied by morphologic features resembling a WD-NET. These observations suggest that there is a potential for misinterpretation of previously treated PD-NECs as WD-NETs, or for assigning a lower grade in G3 WD-NETs. While the prognostic significance of treatment-associated alterations in Ki67 index is unknown, awareness of this phenomenon is important to avoid this diagnostic pitfall when evaluating treated NENs.
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http://dx.doi.org/10.1097/PAS.0000000000001602DOI Listing
January 2021

Discordant DNA mismatch repair protein status between synchronous or metachronous gastrointestinal carcinomas: frequency, patterns, and molecular etiologies.

Fam Cancer 2020 Oct 9. Epub 2020 Oct 9.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

The widespread use of tumor DNA mismatch repair (MMR) protein immunohistochemistry in gastrointestinal tract (GIT) carcinomas has unveiled cases where the MMR protein status differs between synchronous/metachronous tumors from the same patients. This study aims at examining the frequency, patterns and molecular etiologies of such inter-tumoral MMR discordances. We analyzed a cohort of 2159 colorectal cancer (CRC) patients collected over a 5-year period and found that 1.3% of the patients (27/2159) had ≥ 2 primary CRCs, and 25.9% of the patients with ≥ 2 primary CRCs (7/27) exhibited inter-tumoral MMR discordance. We then combined the seven MMR-discordant CRC patients with three additional MMR-discordant GIT carcinoma patients and evaluated their discordant patterns and associated molecular abnormalities. The 10 patients consisted of 3 patients with Lynch syndrome (LS), 1 with polymerase proofreading-associated polyposis (PAPP), 1 with familial adenomatous polyposis (FAP), and 5 deemed to have no cancer disposing hereditary syndromes. Their MMR discordances were associated with the following etiologies: (1) PMS2-LS manifesting PMS2-deficient cancer at an old age when a co-incidental sporadic MMR-proficient cancer also occurred; (2) microsatellite instability-driven secondary somatic MSH6-inactivation occurring in only one-and not all-PMS2-LS associated MMR-deficient carcinomas; (3) "compound LS" with germline mutations in two MMR genes manifesting different tumors with deficiencies in different MMR proteins; (4) PAPP or FAP syndrome-associated MMR-proficient cancer co-occurring metachronously with a somatic MMR-deficient cancer; and (5) non-syndromic patients with sporadic MMR-proficient cancers co-occurring synchronously/metachronously with sporadic MMR-deficient cancers. Our study thus suggests that inter-tumoral MMR discordance is not uncommon among patients with multiple primary GIT carcinomas (25.9% in patients with ≥ 2 CRCs), and may be associated with widely varied molecular etiologies. Awareness of these patterns is essential in ensuring the most effective strategies in both LS detection and treatment decision-making. When selecting patients for immunotherapy, MMR testing should be performed on the tumor or tumors that are being treated.
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http://dx.doi.org/10.1007/s10689-020-00210-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032798PMC
October 2020

A consensus developed morphological re-evaluation of 196 high-grade gastroenteropancreatic neuroendocrine neoplasms and its clinical correlations.

Neuroendocrinology 2020 Oct 1. Epub 2020 Oct 1.

High-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) are classified according to morphology as well differentiated neuroendocrine tumours (NET) G3 or poorly differentiated neuroendocrine carcinomas (NEC). Little data exist concerning which morphological criteria this subdivision should be based on. Uncertainty exists if the NEC group should be further subdivided according to proliferation rate. Clinical data on NET G3 and NEC with a lower Ki-67 range are limited. 213 patients with high-grade GEP-NEN (Ki-67>20%) were included from the Nordic NEC Registries. Four experienced NET pathologists re-evaluated the cases to develop the best morphological criteria to separate NET G3 from NEC, assuming longer survival in NET G3. Organoid growth pattern, capillary network in direct contact to tumour cells and absence of desmoplastic stroma were found to best separate NET G3 from NEC. Of 196 patients with metastatic disease, NET G3 was found in 12.3%, NEC with a Ki-67<55% (NEC <55) in 29.6%, and NEC with a Ki-67≥55% (NEC ≥55) in 56.6%. Only in 1.5% the morphology was ambiguous. Of 164 patients receiving 1-line chemotherapy, 88% received platinum/etoposide treatment. Response-rate was higher for NEC ≥55 (44%) compared to NEC <55 (25%) and NET G3 (24%) (P=0.025 and P=0.026). Median progression free survival was 5 months for all groups. Median overall survival was 33 months for NET G3 compared to 11 months for both NEC <55 and NEC ≥55 (P=0.004 and 0.003).
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http://dx.doi.org/10.1159/000511905DOI Listing
October 2020

Diagnosis of digestive system tumours.

Int J Cancer 2021 Mar 19;148(5):1040-1050. Epub 2020 Nov 19.

WHO Classification of Tumours Group, International Agency for Research on Cancer (IARC), World Health Organization, Lyon, France.

The WHO Classification of Tumours provides the international standards for the classification and diagnosis of tumours. It enables direct comparisons to be made between different countries. In the new fifth edition, the series has gone digital with the launch of a website as well as a series of books, known widely as the WHO Blue Books. The first volume to be produced is on the classification of Digestive System tumours, replacing the successful 2010 version. It has been rewritten and updated accordingly. This article summarises the major diagnostic innovations that have occurred over the last decade and that have now been incorporated in the classification. As an example, it incorporates the recently proposed classification of neuroendocrine tumours, based on the recognition that neuroendocrine tumours and carcinomas differ substantially in the genetic abnormalities that drive their growth, findings relevant to treatment selection and outcome prediction. Several themes have emerged during the production process. One is the importance of the progression from hyperplasia to dysplasia to carcinoma in the evolution of the malignant process. Advances in imaging techniques and endoscopy have resulted in enhanced access to precancerous lesions in the gastrointestinal and biliary tract, necessitating both changes in classification schema and clinical practice. Diagnosis of tumours is no longer the sole purview of pathologists, and some patients now receive treatment before tissue is obtained, based on clinical, radiological and liquid biopsy results. This makes the classification relevant to many disciplines involved in the care of patients with tumours of the digestive system.
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http://dx.doi.org/10.1002/ijc.33210DOI Listing
March 2021

Molecular profiling and analysis of genetic aberrations aimed at identifying potential therapeutic targets in fibrolamellar carcinoma of the liver.

Cancer 2020 Sep 14;126(18):4126-4135. Epub 2020 Jul 14.

Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Background: Fibrolamellar carcinoma (FLC) is a rare primary liver cancer of young adults. A functional chimeric transcript resulting from the in-frame fusion of the DNAJ homolog, subfamily B, member 1 (DNAJB1), and the catalytic subunit of protein kinase A (PRKACA) genes on chromosome 19 is believed to be unique in FLC, with a possible role in pathogenesis, yet with no established therapeutic value. The objective of the current study was to understand the molecular landscape of FLC and to identify potential novel therapeutic targets.

Methods: Archival fresh, formalin-fixed, paraffin-embedded samples from patients with FLC who prospectively consented to an institutional review board-approved protocol were analyzed using Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT), a next-generation sequencing assay encompassing up to 468 key cancer genes. Custom targeted RNA-Seq was performed in selected patients. Demographics, treatment, and outcome data were collected prospectively. Survival outcomes were estimated and correlated with mutation and/or copy number alterations.

Results: A total of 33 tumor samples from 31 patients with FLC were analyzed. The median age of the patients at the time of diagnosis was 18 years and approximately 53% were women. The DNAJB1-PRKACA fusion transcript was detected in 100% of patients. In 10 of 31 patients in which MSK-IMPACT did not detect the fusion, its presence was confirmed by targeted RNA-Seq. TERT promoter mutation was the second most common, and was detected in 7 patients. The median follow up was 30 months (range, 6-153 months). The 3-year overall survival rate was 84% (95% CI, 61%-93%).

Conclusions: The DNAJB1-PRKACA fusion transcript is nonspecific and nonsensitive to FLC. Its potential therapeutic value currently is under evaluation. Opportunities currently are under development for therapy that may be driven or related to the DNAJB1-PRKACA fusion transcript or any therapeutic target identified from next-generation sequencing in patients with FLC.
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http://dx.doi.org/10.1002/cncr.32960DOI Listing
September 2020

Maspin as a Prognostic Marker for Early Stage Colorectal Cancer With Microsatellite Instability.

Front Oncol 2020 10;10:945. Epub 2020 Jun 10.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, United States.

Colorectal cancers are among the most common cancers and a leading cause of cancer death. In our pursuit to discover molecular markers for better characterization and precision theranostics of these cancers, we first conducted global deep proteome analyses and identified maspin (serpin B5, peptidase inhibitor 5) as an upregulated protein in tumor tissue. We then validated its expression in a large cohort of 743 patients with colorectal cancers of all stages and found that both cytoplasmic and nuclear expression varied widely between different patients. Comparison with clinicopathological features revealed that maspin expression levels correlate significantly only with mismatch repair (MMR) status but not with other features. To elucidate the prognostic significance of maspin, we analyzed two outcome-annotated cohorts, one of 572 early stage cancer patients and another of 93 late stage cancer patients. Kaplan-Meier survival, univariate, and multivariate analyses revealed that maspin overexpression predicts longer overall and disease-free survival for early stage microsatellite instability (MSI) subtype colorectal cancer, but there is no correlation with survival for patients with early stage cancer of the microsatellite stability (MSS) subtype or late stage cancer. Our study identifies maspin expression as an independent prognostic marker for risk stratification of early stage MSI subtype colorectal cancer and may provide guidance for improved therapeutic management.
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http://dx.doi.org/10.3389/fonc.2020.00945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297950PMC
June 2020

Validation of a digital pathology system including remote review during the COVID-19 pandemic.

Mod Pathol 2020 11 22;33(11):2115-2127. Epub 2020 Jun 22.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.

Remote digital pathology allows healthcare systems to maintain pathology operations during public health emergencies. Existing Clinical Laboratory Improvement Amendments regulations require pathologists to electronically verify patient reports from a certified facility. During the 2019 pandemic of COVID-19 disease, caused by the SAR-CoV-2 virus, this requirement potentially exposes pathologists, their colleagues, and household members to the risk of becoming infected. Relaxation of government enforcement of this regulation allows pathologists to review and report pathology specimens from a remote, non-CLIA certified facility. The availability of digital pathology systems can facilitate remote microscopic diagnosis, although formal comprehensive (case-based) validation of remote digital diagnosis has not been reported. All glass slides representing routine clinical signout workload in surgical pathology subspecialties at Memorial Sloan Kettering Cancer Center were scanned on an Aperio GT450 at ×40 equivalent resolution (0.26 µm/pixel). Twelve pathologists from nine surgical pathology subspecialties remotely reviewed and reported complete pathology cases using a digital pathology system from a non-CLIA certified facility through a secure connection. Whole slide images were integrated to and launched within the laboratory information system to a custom vendor-agnostic, whole slide image viewer. Remote signouts utilized consumer-grade computers and monitors (monitor size, 13.3-42 in.; resolution, 1280 × 800-3840 × 2160 pixels) connecting to an institution clinical workstation via secure virtual private network. Pathologists subsequently reviewed all corresponding glass slides using a light microscope within the CLIA-certified department. Intraobserver concordance metrics included reporting elements of top-line diagnosis, margin status, lymphovascular and/or perineural invasion, pathology stage, and ancillary testing. The median whole slide image file size was 1.3 GB; scan time/slide averaged 90 s; and scanned tissue area averaged 612 mm. Signout sessions included a total of 108 cases, comprised of 254 individual parts and 1196 slides. Major diagnostic equivalency was 100% between digital and glass slide diagnoses; and overall concordance was 98.8% (251/254). This study reports validation of primary diagnostic review and reporting of complete pathology cases from a remote site during a public health emergency. Our experience shows high (100%) intraobserver digital to glass slide major diagnostic concordance when reporting from a remote site. This randomized, prospective study successfully validated remote use of a digital pathology system including operational feasibility supporting remote review and reporting of pathology specimens, and evaluation of remote access performance and usability for remote signout.
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http://dx.doi.org/10.1038/s41379-020-0601-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306935PMC
November 2020

Targeting therapeutic vulnerabilities with PARP inhibition and radiation in IDH-mutant gliomas and cholangiocarcinomas.

Sci Adv 2020 Apr 22;6(17):eaaz3221. Epub 2020 Apr 22.

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Mutations in isocitrate dehydrogenase (IDH) genes occur in multiple cancer types, lead to global changes in the epigenome, and drive tumorigenesis. Yet, effective strategies targeting solid tumors harboring IDH mutations remain elusive. Here, we demonstrate that IDH-mutant gliomas and cholangiocarcinomas display elevated DNA damage. Using multiple in vitro and preclinical animal models of glioma and cholangiocarcinoma, we developed treatment strategies that use a synthetic lethality approach targeting the reduced DNA damage repair conferred by mutant IDH using poly(adenosine 5'-diphosphate) ribose polymerase inhibitors (PARPis). The therapeutic effects are markedly enhanced by cotreatment with concurrent, localized radiation therapy. PARPi-buttressed multimodality therapies may represent a readily applicable approach that is selective for IDH-mutant tumor cells and has potential to improve outcomes in multiple cancers.
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http://dx.doi.org/10.1126/sciadv.aaz3221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176409PMC
April 2020

Guidelines on the histopathology of chronic pancreatitis. Recommendations from the working group for the international consensus guidelines for chronic pancreatitis in collaboration with the International Association of Pancreatology, the American Pancreatic Association, the Japan Pancreas Society, and the European Pancreatic Club.

Pancreatology 2020 Jun 29;20(4):586-593. Epub 2020 Apr 29.

Department of Pathology, Royal Liverpool University Hospital, Liverpool, UK. Electronic address:

Background: Chronic pancreatitis is a complex multifactorial fibro-inflammatory disease. Consensus guidelines are needed for the histopathological evaluation of non-autoimmune chronic pancreatitis (CP).

Methods: An international working group with experts on the histopathology of CP evaluated 15 statements generated from evidence on seven key clinically relevant questions. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to evaluate the level of evidence available for each statement. To determine the level of agreement, the working group voted on the statements for strength of agreement, using a nine-point Likert scale, and Cronbach's alpha reliability coefficients were calculated.

Results: Strong consensus was obtained for 12 statements relating to all seven key questions including that: the cardinal features of CP are the triad of fibrosis, loss of acinar tissue and duct changes; there are no unique histopathological features that distinguish the different aetiologies of CP; clinical history and laboratory investigations, including genetic testing, are important in establishing the aetiology of CP; there is no reproducible and universally accepted histological grading system for assessing severity of CP, although classification as "mild", "moderate" and "severe" is usually applied; scoring systems for fibrosis are not validated for clinical use; asymptomatic fibrosis is a common finding associated with ageing, and not necessarily evidence of CP; there are no obvious diagnostic macroscopic features of early CP; histopathology is not the gold standard for the diagnosis of CP; and cytology alone is not a reliable method for the diagnosis of CP.

Conclusions: Cardinal histopathological features of CP are well-defined and internationally accepted and pathological assessment is relevant for the purpose of differential diagnosis with other pancreatic diseases, especially cancer. However, a reliable diagnosis of CP requires integration of clinical, laboratory and imaging features and cannot be made by histology alone.
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http://dx.doi.org/10.1016/j.pan.2020.04.009DOI Listing
June 2020

Novel artificial intelligence system increases the detection of prostate cancer in whole slide images of core needle biopsies.

Mod Pathol 2020 10 11;33(10):2058-2066. Epub 2020 May 11.

Paige.AI, 11 East Loop Road, FL5, New York, NY, 10044, USA.

Prostate cancer (PrCa) is the second most common cancer among men in the United States. The gold standard for detecting PrCa is the examination of prostate needle core biopsies. Diagnosis can be challenging, especially for small, well-differentiated cancers. Recently, machine learning algorithms have been developed for detecting PrCa in whole slide images (WSIs) with high test accuracy. However, the impact of these artificial intelligence systems on pathologic diagnosis is not known. To address this, we investigated how pathologists interact with Paige Prostate Alpha, a state-of-the-art PrCa detection system, in WSIs of prostate needle core biopsies stained with hematoxylin and eosin. Three AP-board certified pathologists assessed 304 anonymized prostate needle core biopsy WSIs in 8 hours. The pathologists classified each WSI as benign or cancerous. After ~4 weeks, pathologists were tasked with re-reviewing each WSI with the aid of Paige Prostate Alpha. For each WSI, Paige Prostate Alpha was used to perform cancer detection and, for WSIs where cancer was detected, the system marked the area where cancer was detected with the highest probability. The original diagnosis for each slide was rendered by genitourinary pathologists and incorporated any ancillary studies requested during the original diagnostic assessment. Against this ground truth, the pathologists and Paige Prostate Alpha were measured. Without Paige Prostate Alpha, pathologists had an average sensitivity of 74% and an average specificity of 97%. With Paige Prostate Alpha, the average sensitivity for pathologists significantly increased to 90% with no statistically significant change in specificity. With Paige Prostate Alpha, pathologists more often correctly classified smaller, lower grade tumors, and spent less time analyzing each WSI. Future studies will investigate if similar benefit is yielded when such a system is used to detect other forms of cancer in a setting that more closely emulates real practice.
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http://dx.doi.org/10.1038/s41379-020-0551-yDOI Listing
October 2020

Simple mucinous cysts of the pancreas have heterogeneous somatic mutations.

Hum Pathol 2020 07 5;101:1-9. Epub 2020 May 5.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, 10065 NY, USA. Electronic address:

Simple mucinous cysts of the pancreas have an epithelial lining resembling pancreatic intraepithelial neoplasia but may have a clinical presentation similar to premalignant mucinous neoplasms such as intraductal papillary mucinous neoplasms. Whether the epithelial lining shares genomic alterations with other pancreatic preinvasive neoplasms such as PanIN and intraductal papillary mucinous neoplasm has not been determined. We performed targeted sequencing analysis using a custom-designed MiSeq panel including the full coding regions of 18 pancreatic cancer genes on 13 clinically and pathologically well-characterized simple mucinous cysts. We detected 59 mutations in 15 genes in the cohort, with a median of 4 mutations per cyst (range = 0-16 mutations per cyst). The mutated genes and rate of detected mutations were as follows: KMT2C (MLL3) (62%), KRAS (15%), BRAF (8%), RNF43 (8%), CDKN2a (8%), TP53 (15%), and SMAD4 (8%). No GNAS mutations were detected. Four cases (31%) had no mutations detected. These findings place the majority of simple mucinous cysts of the pancreas in the spectrum of early, low-grade mucinous neoplasia, albeit with a different spectrum of genomic alterations compared with PanIN and intraductal papillary mucinous neoplasm.
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http://dx.doi.org/10.1016/j.humpath.2020.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7321854PMC
July 2020

Genetic and clinical correlates of entosis in pancreatic ductal adenocarcinoma.

Mod Pathol 2020 09 29;33(9):1822-1831. Epub 2020 Apr 29.

The David M. Rubenstein Center for Pancreatic Cancer Research, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Entosis is a type of regulated cell death that promotes cancer cell competition. Though several studies have revealed the molecular mechanisms that govern entosis, the clinical and genetic correlates of entosis in human tumors is less well understood. Here we reviewed entotic cell-in-cell (CIC) patterns in a large single institution sequencing cohort (MSK IMPACT clinical sequencing cohort) of more than 1600 human pancreatic ductal adenocarcinoma (PDAC) samples to identify the genetic and clinical correlates of this cellular feature. After case selection, 516 conventional PDACs and 21 ASCs entered this study and ~45,000 HPFs (median 80 HPFs per sample) were reviewed; 549 entotic-CICs were detected through our cohort. We observed that entotic-CIC occurred more frequently in liver metastasis compared with primary in PDAC. Moreover, poorly differentiated adenocarcinoma or adenosquamous carcinoma had more entotic-CIC than well or moderately differentiated adenocarcinoma. With respect to genetic features TP53 mutations, KRAS amplification, and MYC amplification were significantly associated with entosis in PDAC tissues. From a clinical standpoint entotic CICs were independently associated with a poor prognosis by multivariate Cox regression analysis when considering all cases or primary PDACs specifically. These results provide a contextual basis for understanding entosis in PDAC, a highly aggressive cancer for which molecular insights are needed to improve survival.
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http://dx.doi.org/10.1038/s41379-020-0549-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452867PMC
September 2020

Gastrointestinal tissue-based molecular biomarkers: a practical categorisation based on the 2019 World Health Organization classification of epithelial digestive tumours.

Histopathology 2020 Sep 4;77(3):340-350. Epub 2020 Jul 4.

Precision Medicine Centre of Excellence, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.

Molecular biomarkers have come to constitute one of the cornerstones of oncological pathology. The method of classification not only directly affects the manner in which patients are diagnosed and treated, but also guides the development of drugs and of artificial intelligence tools. The aim of this article is to organise and update gastrointestinal molecular biomarkers in order to produce an easy-to-use guide for routine diagnostics. For this purpose, we have extracted and reorganised the molecular information on epithelial neoplasms included in the 2019 World Health Organization classification of tumours. Digestive system tumours, 5th edn.
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http://dx.doi.org/10.1111/his.14120DOI Listing
September 2020

STAT1 as a potential prognosis marker for poor outcomes of early stage colorectal cancer with microsatellite instability.

PLoS One 2020 10;15(4):e0229252. Epub 2020 Apr 10.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America.

Proteomic analyses indicate that STAT1 protein (signal transducer and activator of transcription 1 or transcription factor ISGF-3 components p91/p84) is upregulated in some colorectal cancers. This study examined 736 colorectal cancer patients for the expression of STAT1 protein in tissue specimens, including 614 early stage patients and 122 advanced stage patients. Tissue microarrays were constructed, and STAT1 expression was examined by immunohistochemistry and scored semi-quantitatively. Among all cases, 9% of cases displayed high levels of cytoplasmic expression of STAT1 and 15% of cases had positive nuclear expression. Based on statistical analyses of a cohort of 559 early stage patients with survival data and no neoadjuvant therapy, we found that high levels of cytoplasmic expression of STAT1 correlated with shorter survival time in early stage colorectal cancer, particularly of the microsatellite instability (MSI) subtype. Additional analysis of a 244-case cohort of colorectal cancers from the Cancer Genome Atlas found that STAT1 gene expression correlated positively with PD-L1 (CD274) and PD-1 (PDCD1) but had no correlation with KRAS or BRAF mutation status. STAT1 expression showed no clear correlation with any of the 4 clinical diagnostic markers of mismatch repair, MLH1, MSH2, MSH6, and PMS2, suggesting its potential as an independent outcome marker for MSI cancers. Our findings suggest that STAT1 may be used as a potential prognostic protein marker for stratifying the outcome risk of early stage MSI colorectal cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229252PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147729PMC
July 2020

Prolyl 4-hydroxylase alpha 1 protein expression risk-stratifies early stage colorectal cancer.

Oncotarget 2020 Feb 25;11(8):813-824. Epub 2020 Feb 25.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Colorectal cancer (CRC) is one of the most prevalent and lethal malignancies. Especially for early stage CRC, prognostic molecular markers are needed to guide therapy. In this study, we first extracted total proteomes from matched pairs of fresh cancer and benign mucosal tissues from 22 CRC patients. Global proteomic profiling with Fourier transform liquid chromatography-mass spectrometry sequencing and label free quantitation uncovered that P4HA1 (prolyl 4-hydroxylase alpha 1) was overexpressed in CRC relative to benign colonic mucosa. We then investigated expression by immunohistochemical staining with P4HA1-specific antibodies using CRC tissue microarrays. Independent validation cohorts of 599 cases of early stage CRC and 91 cases of late stage CRC were examined. Multivariate and univariate survival analyses revealed that high expression of P4HA1 protein was an independent poor prognostic marker for patients with early stage CRC, especially of the microsatellite stable subtype. Our study provides strong support for P4HA1 as a predictive protein marker for precision diagnostics, therapeutic decision-making, and drug development for early stage colorectal cancer and demonstrates the utility of proteomic profiling to identify novel protein biomarkers.
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http://dx.doi.org/10.18632/oncotarget.27491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055541PMC
February 2020

Smooth muscle tumors of the gastrointestinal tract: an analysis of prognostic features in 407 cases.

Mod Pathol 2020 07 12;33(7):1410-1419. Epub 2020 Feb 12.

Washington University School of Medicine, St. Louis, MO, USA.

Smooth muscle tumors represent the second most common mural mesenchymal neoplasm in the gastrointestinal tract, but established criteria for prognostic assessment of these tumors are lacking. A large cohort of surgically resected intramural gastrointestinal smooth muscle tumors from 31 institutions was analyzed to identify potential prognostic features. Pathologic features were assessed by expert gastrointestinal and/or soft tissue pathologists at each center. Immunohistochemical confirmation was required. A total of 407 cases from the esophagus (n = 97, 24%), stomach (n = 180, 44%), small bowel (n = 74, 18%), and colorectum (n = 56, 14%) were identified. Patients ranged in age from 19 to 92 years (mean 55 years), with a slight female predominance (57%). Mean tumor size was 5.4 cm, with the largest tumor measuring 29 cm. Disease progression following surgery, defined as local recurrence, metastasis, or disease-related death, occurred in 56 patients (14%). Colorectal tumors were most likely to progress, followed by small bowel and gastric tumors. None of the esophageal tumors in this series progressed. Receiver operator characteristic analysis identified optimal cutoffs of 9.8 cm and 3 mitoses/5 mm for discriminating between progressive and non-progressive tumors. Histologic features strongly associated with progression by univariate analysis included moderate-to-severe atypia, high cellularity, abnormal differentiation (defined as differentiation not closely resembling that of normal smooth muscle), tumor necrosis, mucosal ulceration, lamina propria involvement, and serosal involvement (P < 0.0001 for all features). Age, sex, and margin status were not significantly associated with progression (P = 0.23, 0.82, and 0.07, respectively). A risk assessment table was created based on tumor site, size, and mitotic count, and Kaplan-Meier plots of progression-free survival for each subgroup revealed progression-based tiers. Based on our findings, it appears that nonesophageal gastrointestinal smooth muscle tumors measuring >10 cm and/or showing ≥3 mitoses/5 mm may behave aggressively, and therefore close clinical follow-up is recommended in these cases.
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http://dx.doi.org/10.1038/s41379-020-0492-5DOI Listing
July 2020

Development of Genome-Derived Tumor Type Prediction to Inform Clinical Cancer Care.

JAMA Oncol 2020 Jan;6(1):84-91

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.

Importance: Diagnosing the site of origin for cancer is a pillar of disease classification that has directed clinical care for more than a century. Even in an era of precision oncologic practice, in which treatment is increasingly informed by the presence or absence of mutant genes responsible for cancer growth and progression, tumor origin remains a critical factor in tumor biologic characteristics and therapeutic sensitivity.

Objective: To evaluate whether data derived from routine clinical DNA sequencing of tumors could complement conventional approaches to enable improved diagnostic accuracy.

Design, Setting, And Participants: A machine learning approach was developed to predict tumor type from targeted panel DNA sequence data obtained at the point of care, incorporating both discrete molecular alterations and inferred features such as mutational signatures. This algorithm was trained on 7791 tumors representing 22 cancer types selected from a prospectively sequenced cohort of patients with advanced cancer.

Results: The correct tumor type was predicted for 5748 of the 7791 patients (73.8%) in the training set as well as 8623 of 11 644 patients (74.1%) in an independent cohort. Predictions were assigned probabilities that reflected empirical accuracy, with 3388 cases (43.5%) representing high-confidence predictions (>95% probability). Informative molecular features and feature categories varied widely by tumor type. Genomic analysis of plasma cell-free DNA yielded accurate predictions in 45 of 60 cases (75.0%), suggesting that this approach may be applied in diverse clinical settings including as an adjunct to cancer screening. Likely tissues of origin were predicted from targeted tumor sequencing in 95 of 141 patients (67.4%) with cancers of unknown primary site. Applying this method prospectively to patients under active care enabled genome-directed reassessment of diagnosis in 2 patients initially presumed to have metastatic breast cancer, leading to the selection of more appropriate treatments, which elicited clinical responses.

Conclusions And Relevance: These results suggest that the application of artificial intelligence to predict tissue of origin in oncologic practice can act as a useful complement to conventional histologic review to provide integrated pathologic diagnoses, often with important therapeutic implications.
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http://dx.doi.org/10.1001/jamaoncol.2019.3985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865333PMC
January 2020

DNAJB1-PRKACA fusions occur in oncocytic pancreatic and biliary neoplasms and are not specific for fibrolamellar hepatocellular carcinoma.

Mod Pathol 2020 04 1;33(4):648-656. Epub 2019 Nov 1.

Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Recently discovered DNAJB1-PRKACA oncogenic fusions have been considered diagnostic for fibrolamellar hepatocellular carcinoma. In this study, we describe six pancreatobiliary neoplasms with PRKACA fusions, five of which harbor the DNAJB1-PRKACA fusion. All neoplasms were subjected to a hybridization capture-based next-generation sequencing assay (MSK-IMPACT), which enables the identification of sequence mutations, copy number alterations, and selected structural rearrangements involving ≥410 genes (n = 6) and/or to a custom targeted, RNA-based panel (MSK-Fusion) that utilizes Archer Anchored Multiplex PCR technology and next-generation sequencing to detect gene fusions in 62 genes (n = 2). Selected neoplasms also underwent FISH analysis, albumin mRNA in-situ hybridization, and arginase-1 immunohistochemical labeling (n = 3). Five neoplasms were pancreatic, and one arose in the intrahepatic bile ducts. All revealed at least focal oncocytic morphology: three cases were diagnosed as intraductal oncocytic papillary neoplasms, and three as intraductal papillary mucinous neoplasms with mixed oncocytic and pancreatobiliary or gastric features. Four cases had an invasive carcinoma component composed of oncocytic cells. Five cases revealed DNAJB1-PRKACA fusions and one revealed an ATP1B1-PRKACA fusion. None of the cases tested were positive for albumin or arginase-1. Our data prove that DNAJB1-PRKACA fusion is neither exclusive nor diagnostic for fibrolamellar hepatocellular carcinoma, and caution should be exercised in diagnosing liver tumors with DNAJB1-PRKACA fusions as fibrolamellar hepatocellular carcinoma, particularly if a pancreatic lesion is present. Moreover, considering DNAJB1-PRKACA fusions lead to upregulated protein kinase activity and that this upregulated protein kinase activity has a significant role in tumorigenesis of fibrolamellar hepatocellular carcinoma, protein kinase inhibition could have therapeutic potential in the treatment of these pancreatobiliary neoplasms as well, once a suitable drug is developed.
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http://dx.doi.org/10.1038/s41379-019-0398-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125037PMC
April 2020

A semicentennial of pancreatic pathology: the genetic revolution is here, but don't throw the baby out with the bath water!

Hum Pathol 2020 01 12;95:99-112. Epub 2019 Sep 12.

Technical University of Munich, Munich, Germany.

The last 50 years have witnessed an explosion in our understanding of the pathology of pancreatic diseases. Entities known to exist 50 years ago have been defined more precisely and are now better classified. New entities, previously not recognized, have been discovered and can now be treated. Importantly, new tools have been developed that have unraveled the fundamental biological drivers of a number of pancreatic diseases. Many of these same tools have also been applied clinically, supplementing the tried and true hematoxylin and eosin stained slide with a plethora of new, highly sensitive and specific tests that improve diagnostic accuracy and delineate best treatments. As exciting as these many advances are, our knowledge of pancreatic pathology remains incomplete, and there is much to be learned.
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http://dx.doi.org/10.1016/j.humpath.2019.08.024DOI Listing
January 2020

Sclerosing epithelioid mesenchymal neoplasm of the pancreas - a proposed new entity.

Mod Pathol 2020 03 5;33(3):456-467. Epub 2019 Aug 5.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

We have encountered pancreatic tumors with unique histologic features, which do not conform to any of the known tumors of the pancreas or other anatomical sites. We aimed to define their clinicopathologic features and whether they are characterized by recurrent molecular signatures. Eight cases were identified; studied histologically and by immunohistochemistry. Selected cases were also subjected to whole-exome sequencing (WES; n = 4), RNA-sequencing (n = 6), Archer FusionPlex assay (n = 5), methylation profiling using the Illumina MethylationEPIC (850k) array platform (n = 6), and TERT promoter sequencing (n = 5). Six neoplasms occurred in females. The mean age was 43 years (range: 26-75). Five occurred in the head/neck of the pancreas. All patients were treated surgically; none received neoadjuvant/adjuvant therapy. All patients are free of disease after 53 months of median follow-up (range: 8-94). The tumors were well-circumscribed, and the median size was 1.8 cm (range: 1.3-5.8). Microscopically, the unencapsulated tumors had a geographic pattern of epithelioid cell nests alternating with spindle cell fascicles. Some areas showed dense fibrosis, in which enmeshed tumor cells imparted a slit-like pattern. The predominant epithelioid cells had scant cytoplasm and round-oval nuclei with open chromatin. The spindle cells displayed irregular, hyperchromatic nuclei. Mitoses were rare. No lymph node metastases were identified. All tumors were positive for vimentin, CD99 and cytokeratin (patchy), while negative for markers of solid pseudopapillary neoplasm, neuroendocrine, acinar, myogenic/rhabdoid, vascular, melanocytic, or lymphoid differentiation, gastrointestinal stromal tumor as well as MUC4. Whole-exome sequencing revealed no recurrent somatic mutations or amplifications/homozygous deletions in any known oncogenes or tumor suppressor genes. RNA-sequencing and the Archer FusionPlex assay did not detect any recurrent likely pathogenic gene fusions. Single sample gene set enrichment analysis revealed that these tumors display a likely mesenchymal transcriptomic program. Unsupervised analysis (t-SNE) of their methylation profiles against a set of different mesenchymal neoplasms demonstrated a distinct methylation pattern. Here, we describe pancreatic neoplasms with unique morphologic/immunophenotypic features and a distinct methylation pattern, along with a lack of abnormalities in any of key genetic drivers, supporting that these neoplasms represent a novel entity with an indolent clinical course. Given their mesenchymal transcriptomic features, we propose the designation of "sclerosing epithelioid mesenchymal neoplasm" of the pancreas.
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http://dx.doi.org/10.1038/s41379-019-0334-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000300PMC
March 2020

A multimodality test to guide the management of patients with a pancreatic cyst.

Sci Transl Med 2019 07;11(501)

Department of Surgery, St. Vincent's University Hospital, Dublin D04 T6F4, Ireland.

Pancreatic cysts are common and often pose a management dilemma, because some cysts are precancerous, whereas others have little risk of developing into invasive cancers. We used supervised machine learning techniques to develop a comprehensive test, CompCyst, to guide the management of patients with pancreatic cysts. The test is based on selected clinical features, imaging characteristics, and cyst fluid genetic and biochemical markers. Using data from 436 patients with pancreatic cysts, we trained CompCyst to classify patients as those who required surgery, those who should be routinely monitored, and those who did not require further surveillance. We then tested CompCyst in an independent cohort of 426 patients, with histopathology used as the gold standard. We found that clinical management informed by the CompCyst test was more accurate than the management dictated by conventional clinical and imaging criteria alone. Application of the CompCyst test would have spared surgery in more than half of the patients who underwent unnecessary resection of their cysts. CompCyst therefore has the potential to reduce the patient morbidity and economic costs associated with current standard-of-care pancreatic cyst management practices.
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http://dx.doi.org/10.1126/scitranslmed.aav4772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859881PMC
July 2019

Clinical-grade computational pathology using weakly supervised deep learning on whole slide images.

Nat Med 2019 08 15;25(8):1301-1309. Epub 2019 Jul 15.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

The development of decision support systems for pathology and their deployment in clinical practice have been hindered by the need for large manually annotated datasets. To overcome this problem, we present a multiple instance learning-based deep learning system that uses only the reported diagnoses as labels for training, thereby avoiding expensive and time-consuming pixel-wise manual annotations. We evaluated this framework at scale on a dataset of 44,732 whole slide images from 15,187 patients without any form of data curation. Tests on prostate cancer, basal cell carcinoma and breast cancer metastases to axillary lymph nodes resulted in areas under the curve above 0.98 for all cancer types. Its clinical application would allow pathologists to exclude 65-75% of slides while retaining 100% sensitivity. Our results show that this system has the ability to train accurate classification models at unprecedented scale, laying the foundation for the deployment of computational decision support systems in clinical practice.
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http://dx.doi.org/10.1038/s41591-019-0508-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418463PMC
August 2019

Histomorphology of pancreatic cancer in patients with inherited ATM serine/threonine kinase pathogenic variants.

Mod Pathol 2019 12 8;32(12):1806-1813. Epub 2019 Jul 8.

Department of Pathology, the Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Germline pathogenic variants in the ATM serine/threonine kinase (ATM) gene are associated with an increased risk of pancreatic ductal adenocarcinoma. It is important to identify germline ATM pathogenic variants in pancreatic cancer patients because these alterations are potentially targetable with chemotherapeutic drugs and/or radiation and have implications for other family members. As germline pathogenic variants in other genes have been associated with distinct histologic subtypes of pancreatic cancer, we studied the histomorphology of pancreatic cancer in 23 patients with germline ATM pathogenic variants. The histologic subtype was ductal adenocarcinoma in 19/23 (83%) of the patients, adenosquamous carcinoma in 1/23 (4%), and colloid (mucinous non-cystic) carcinoma in 3/23 (13%). The percentage of colloid (mucinous non-cystic) carcinomas is higher than we have previously observed in patients with familial and sporadic pancreatic cancer (1 and 2% in prior reports, p < 0.01 and p < 0.01, respectively). Three carcinomas (2 colloid carcinomas, 1 ductal adenocarcinoma) arose in association with intraductal papillary mucinous neoplasms. Among the resected pancreata, non-invasive precursor lesions, including pancreatic intraepithelial neoplasia and incipient intraductal papillary mucinous neoplasms, were identified in 83%. We conclude that pancreatic cancers in patients with germline ATM pathogenic variants are more frequently of colloid (mucinous non-cystic) morphology but are overall morphologically diverse supporting the utility of universal germline genetic testing for patients with pancreatic cancer.
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http://dx.doi.org/10.1038/s41379-019-0317-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403604PMC
December 2019

Validation of mitotic cell quantification via microscopy and multiple whole-slide scanners.

Diagn Pathol 2019 Jun 26;14(1):65. Epub 2019 Jun 26.

Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.

Background: The establishment of whole-slide imaging (WSI) as a medical diagnostic device allows that pathologists may evaluate mitotic activity with this new technology. Furthermore, the image digitalization provides an opportunity to develop algorithms for automatic quantifications, ideally leading to improved reproducibility as compared to the naked eye examination by pathologists. In order to implement them effectively, accuracy of mitotic figure detection using WSI should be investigated. In this study, we aimed to measure pathologist performance in detecting mitotic figures (MFs) using multiple platforms (multiple scanners) and compare the results with those obtained using a brightfield microscope.

Methods: Four slides of canine oral melanoma were prepared and digitized using 4 WSI scanners. In these slides, 40 regions of interest (ROIs) were demarcated, and five observers identified the MFs using different viewing modes: microscopy and WSI. We evaluated the inter- and intra-observer agreements between modes with Cohen's Kappa and determined "true" MFs with a consensus panel. We then assessed the accuracy (agreement with truth) using the average of sensitivity and specificity.

Results: In the 40 ROIs, 155 candidate MFs were detected by five pathologists; 74 of them were determined to be true MFs. Inter- and intra-observer agreement was mostly "substantial" or greater (Kappa = 0.594-0.939). Accuracy was between 0.632 and 0.843 across all readers and modes. After averaging over readers for each modality, we found that mitosis detection accuracy for 3 of the 4 WSI scanners was significantly less than that of the microscope (p = 0.002, 0.012, and 0.001).

Conclusions: This study is the first to compare WSIs and microscopy in detecting MFs at the level of individual cells. Our results suggest that WSI can be used for mitotic cell detection and offers similar reproducibility to the microscope, with slightly less accuracy.
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http://dx.doi.org/10.1186/s13000-019-0839-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593538PMC
June 2019