Publications by authors named "Anil Parwani"

280 Publications

Quantitative Image Analysis for Tissue Biomarker Use: A White Paper From the Digital Pathology Association.

Appl Immunohistochem Mol Morphol 2021 Mar 17. Epub 2021 Mar 17.

GlaxoSmithKline-R&D, Cellular Biomarkers, Collegeville, PA The Ohio State University, Columbus, OH Visiopharm, Hoersholm, Denmark Translational Safety and Bioanalytical Sciences, Amgen Research, Amgen Inc. Moffitt Cancer Center, Tampa, FL Roche Tissue Diagnostics, Tucson, AZ Genentech, South San Francisco, CA PathAI, Boston, MA Johns Hopkins School of Medicine, Baltimore, MD Indica Labs, Albuquerque, NM Yale University School of Medicine, New Haven, CT Department of Pathology, University of Michigan, Ann Arbor, MI.

Tissue biomarkers have been of increasing utility for scientific research, diagnosing disease, and treatment response prediction. There has been a steady shift away from qualitative assessment toward providing more quantitative scores for these biomarkers. The application of quantitative image analysis has thus become an indispensable tool for in-depth tissue biomarker interrogation in these contexts. This white paper reviews current technologies being employed for quantitative image analysis, their application and pitfalls, regulatory framework demands, and guidelines established for promoting their safe adoption in clinical practice.
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http://dx.doi.org/10.1097/PAI.0000000000000930DOI Listing
March 2021

From Glass-Time to Screen-Time.

Arch Pathol Lab Med 2021 Feb 12. Epub 2021 Feb 12.

From the Department of Pathology, Wexner Medical Center, The Ohio State University, Columbus, Ohio.

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http://dx.doi.org/10.5858/arpa.2020-0511-EDDOI Listing
February 2021

The histopathological diagnosis of atypical meningioma: glass slide versus whole slide imaging for grading assessment.

Virchows Arch 2021 Apr 10;478(4):747-756. Epub 2020 Dec 10.

Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy.

Limited studies on whole slide imaging (WSI) in surgical neuropathology reported a perceived limitation in the recognition of mitoses. This study analyzed and compared the inter- and intra-observer concordance for atypical meningioma, using glass slides and WSI. Two neuropathologists and two residents assessed the histopathological features of 35 meningiomas-originally diagnosed as atypical-in a representative glass slide and corresponding WSI. For each histological parameter and final diagnosis, we calculated the inter- and intra-observer concordance in the two viewing modes and the predictive accuracy on recurrence. The concordance rates for atypical meningioma on glass slides and on WSI were 54% and 60% among four observers and 63% and 74% between two neuropathologists. The inter-observer agreement was higher using WSI than with glass slides for all parameters, with the exception of high mitotic index. For all histological features, we found median intra-observer concordance of ≥ 79% and similar predictive accuracy for recurrence between the two viewing modes. The higher concordance for atypical meningioma using WSI than with glass slides and the similar predictive accuracy for recurrence in the two modalities suggest that atypical meningioma may be safely diagnosed using WSI.
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http://dx.doi.org/10.1007/s00428-020-02988-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990834PMC
April 2021

ESR1 genetic alterations and their association with clinicopathologic characteristics in advanced breast cancer: a single academic institution experience.

Hum Pathol 2021 Jan 4;107:80-86. Epub 2020 Nov 4.

Department of Pathology, The Ohio State University, Wexner Medical Center, Columbus, OH, USA. Electronic address:

Estrogen receptor (ER) alpha, a ligand-dependent nuclear transcription factor encoded by the ESR1 gene, is expressed in 70% of breast carcinomas (BCs) and is used as a target for endocrine-based therapies. However, some patients develop resistance to endocrine-based therapies due to ESR1 mutation, which leads to constitutive activation in the absence of ligand. We retrospectively analyzed 223 clinically advanced BCs using the FoundationOne CDX assay and found 13.9% (31/223) of cases had ESR1 genetic alterations (26 mutations and 5 amplifications). All ESR1 mutations occurred within the ligand binding domain, with the most prevalent being Y537S (42.3%) and D538G (38.5%), and all ESR1-mutated cases had a history of aromatase inhibitor use. No significant difference in clinicopathologic features was identified between ESR1-mutated and ESR1-amplified cases except higher frequency of HER2 positivity and TP53 mutations in ESR1-amplified cases. The prevalence of ESR1 mutations in ER-positive BCs was 19.1% (26/136). In comparison to ESR1-nonmutated ER-positive cases, ESR1-mutated cases demonstrated significantly higher percentage of tumor cells with ER and progesterone receptor expression, an increased tendency for overall distant metastasis and liver metastasis, higher frequency of FGF3/4/19 mutations, lower frequency of TP53 mutation, but no difference in overall survival and metastatic/recurrent intervals. In conclusion, our findings suggest that development of ESR1 mutations are selected for under the influence of estrogen deprivation, and a positive correlation between ESR1 mutations and ER protein expression may exist.
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http://dx.doi.org/10.1016/j.humpath.2020.10.007DOI Listing
January 2021

Unusual cerebrospinal fluid finding of intracytoplasmic granules in metaplastic carcinoma of the breast with acinar differentiation.

Diagn Cytopathol 2021 Apr 28;49(4):E152-E155. Epub 2020 Oct 28.

Department of Pathology, The Ohio State University Medical Center and Comprehensive Cancer Center, Columbus, Ohio, USA.

Cerebrospinal fluid (CSF) evaluation for total and differential cell count is a common practice in pathology for evaluation of various disease conditions. Although rare, these CSF samples yield interesting and unusual morphological findings, which are not only of academic interest, but also may play key roles in diagnosis. For diagnosing metastatic carcinoma in brain and meninges, CSF examination is one of the important tools along with imaging studies. Metaplastic breast carcinoma (MBC) encompasses a rare (<1% of all breast cancers), aggressive and highly heterogeneous group of tumors. MBC is almost always estrogen receptor, progesterone receptor and Her2 negative (triple negative) and shows frequent early distant metastases as well as sub-optimal response to systemic therapies. The involvement of leptomeninges is most commonly associated with these triple- negative subtypes. In this report, we present an unusual case of malignant cells with prominent intracytoplasmic granules in CSF smears of a 46-year-old female with metastatic MBC with acinar differentiation. An extensive review of literature in English language did not return any other reports of a similar finding.
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http://dx.doi.org/10.1002/dc.24648DOI Listing
April 2021

Practice patterns related to prostate cancer grading: results of a 2019 Genitourinary Pathology Society clinician survey.

Urol Oncol 2020 Sep 15. Epub 2020 Sep 15.

Departments of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD; Departments of Urology and Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD.

Purpose: To survey urologic clinicians regarding interpretation of and practice patterns in relation to emerging aspects of prostate cancer grading, including quantification of high-grade disease, cribriform/intraductal carcinoma, and impact of magnetic resonance imaging-targeted needle biopsy.

Materials And Methods: The Genitourinary Pathology Society distributed a survey to urology and urologic oncology-focused societies and hospital departments. Eight hundred and thirty four responses were collected and analyzed using descriptive statistics.

Results: Eighty percent of survey participants use quantity of Gleason pattern 4 on needle biopsy for clinical decisions, less frequently with higher Grade Groups. Fifty percent interpret "tertiary" grade as a minor/<5% component. Seventy percent of respondents would prefer per core grading as well as a global/overall score per set of biopsies, but 70% would consider highest Gleason score in any single core as the grade for management. Seventy five percent utilize Grade Group terminology in patient discussions. For 45%, cribriform pattern would affect management, while for 70% the presence of intraductal carcinoma would preclude active surveillance.

Conclusion: This survey of practice patterns in relationship to prostate cancer grading highlights similarities and differences between contemporary pathology reporting and its clinical application. As utilization of Gleason pattern 4 quantification, minor tertiary pattern, cribriform/intraductal carcinoma, and the incorporation of magnetic resonance imaging-based strategies evolve, these findings may serve as a basis for more nuanced communication and guide research efforts involving pathologists and clinicians.
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http://dx.doi.org/10.1016/j.urolonc.2020.08.027DOI Listing
September 2020

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and coronavirus disease 19 (COVID-19) - anatomic pathology perspective on current knowledge.

Diagn Pathol 2020 Aug 14;15(1):103. Epub 2020 Aug 14.

Department of Pathology, The Ohio State University, E409 Doan Hall, 410 West 10th Ave, Columbus, OH, 43210, USA.

Background: The world is currently witnessing a major devastating pandemic of Coronavirus disease-2019 (COVID-19). This disease is caused by a novel coronavirus named Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). It primarily affects the respiratory tract and particularly the lungs. The virus enters the cell by attaching its spike-like surface projections to the angiotensin-converting enzyme-2 (ACE-2) expressed in various tissues. Though the majority of symptomatic patients have mild flu-like symptoms, a significant minority develop severe lung injury with acute respiratory distress syndrome (ARDS), leading to considerable morbidity and mortality. Elderly patients with previous cardiovascular comorbidities are particularly susceptible to severe clinical manifestations. BODY: Currently, our limited knowledge of the pathologic findings is based on post-mortem biopsies, a few limited autopsies, and very few complete autopsies. From these reports, we know that the virus can be found in various organs but the most striking tissue damage involves the lungs resulting almost always in diffuse alveolar damage with interstitial edema, capillary congestion, and occasional interstitial lymphocytosis, causing hypoxia, multiorgan failure, and death. A few pathology studies have also reported intravascular microthrombi and pulmonary thrombembolism. Although the clinical presentation of this disease is fairly well characterized, knowledge of the pathologic aspects remains comparatively limited.

Conclusion: In this review, we discuss clinical, pathologic, and genomic features of COVID-19, review current hypotheses regarding the pathogenesis, and briefly discuss the clinical characteristics. We also compare the salient features of COVID-19 with other coronavirus-related illnesses that have posed significant public health issues in the past, including SARS and the Middle East Respiratory Syndrome (MERS).
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http://dx.doi.org/10.1186/s13000-020-01017-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427697PMC
August 2020

Semantic segmentation to identify bladder layers from H&E Images.

Diagn Pathol 2020 Jul 16;15(1):87. Epub 2020 Jul 16.

Center for Biomedical Informatics, Wake Forest School of Medicine, Winston-Salem, NC, USA.

Background: Identification of bladder layers is a necessary prerequisite to bladder cancer diagnosis and prognosis. We present a method of multi-class image segmentation, which recognizes urothelium, lamina propria, muscularis propria, and muscularis mucosa layers as well as regions of red blood cells, cauterized tissue, and inflamed tissue from images of hematoxylin and eosin stained slides of bladder biopsies.

Methods: Segmentation is carried out using a U-Net architecture. The number of layers was either, eight, ten, or twelve and combined with a weight initializers of He uniform, He normal, Glorot uniform, and Glorot normal. The most optimal of these parameters was found by through a seven-fold training, validation, and testing of a dataset of 39 whole slide images of T1 bladder biopsies.

Results: The most optimal model was a twelve layer U-net using He normal initializer. Initial visual evaluation by an experienced pathologist on an independent set of 15 slides segmented by our method yielded an average score of 8.93 ± 0.6 out of 10 for segmentation accuracy. It took only 23 min for the pathologist to review 15 slides (1.53 min/slide) with the computer annotations. To assess the generalizability of the proposed model, we acquired an additional independent set of 53 whole slide images and segmented them using our method. Visual examination by a different experienced pathologist yielded an average score of 8.87 ± 0.63 out of 10 for segmentation accuracy.

Conclusions: Our preliminary findings suggest that predictions of our model can minimize the time needed by pathologists to annotate slides. Moreover, the method has the potential to identify the bladder layers accurately. Further development can assist the pathologist with the diagnosis of T1 bladder cancer.
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http://dx.doi.org/10.1186/s13000-020-01002-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364471PMC
July 2020

The spectrum of pathological findings in coronavirus disease (COVID-19) and the pathogenesis of SARS-CoV-2.

Diagn Pathol 2020 Jul 14;15(1):85. Epub 2020 Jul 14.

Department of Pathology, The Ohio State University, Columbus, OH, 43210, USA.

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http://dx.doi.org/10.1186/s13000-020-00999-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359764PMC
July 2020

Features, Outcomes, and Management Strategies of Male Breast Cancer: A Single Institution Comparison to Well-Matched Female Controls.

Eur J Breast Health 2020 Jul 20;16(3):201-207. Epub 2020 May 20.

Stefanie Spielman Comprehensive Breast Cancer, The Ohio State University, Columbus, OH, USA.

Objective: The primary objective of this study was to delineate differences in management, overall and distant disease-free survival in males diagnosed with breast cancer and treated at The Ohio State University Comprehensive Cancer Center as compared to comprehensively matched female subjects. Secondary objectives included assessment of clinical and histopathologic features and recurrence score, as measured by Oncotype DX and the modified Magee equation #2.

Materials And Methods: This single institution retrospective study compared male and comprehensively matched female patients (1:2) with stage I-III breast cancer between 1994 and 2014. Recurrence risk was estimated using a modified Magee equation. Overall survival and distant disease-free survival were estimated and compared using Kaplan-Meier and Log-rank methods.

Results: Forty-five male breast cancer patients were included (stage I: 26.7%; stage II: 53.3%; stage III: 20.0%; hormone receptor positive: 97.8%; human epidermal growth factor receptor 2 negative: 84.4%) with a median age of 63.8 (43.0-79.4) years at diagnosis. Intermediate and low recurrence scores were most common in male and female patients respectively; mean score was similar between groups (20.3 vs. 19.8). The proportion of male breast cancer patients treated with adjuvant chemotherapy and post-mastectomy radiation was lower compared to female patients (42.2% vs. 65.3%, p=0.013; 22.7% vs. 44.4%, p=0.030, respectively). Overall survival and distant disease-free survival between male and female patients were similar.

Conclusion: Male breast cancer patient outcomes were similar compared to well-matched female patients suggesting that breast cancer specific factors are more prognostic than gender.
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http://dx.doi.org/10.5152/ejbh.2020.5536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337913PMC
July 2020

The 2019 Genitourinary Pathology Society (GUPS) White Paper on Contemporary Grading of Prostate Cancer.

Arch Pathol Lab Med 2021 Apr;145(4):461-493

and Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada (Trpkov).

Context.—: Controversies and uncertainty persist in prostate cancer grading.

Objective.—: To update grading recommendations.

Data Sources.—: Critical review of the literature along with pathology and clinician surveys.

Conclusions.—: Percent Gleason pattern 4 (%GP4) is as follows: (1) report %GP4 in needle biopsy with Grade Groups (GrGp) 2 and 3, and in needle biopsy on other parts (jars) of lower grade in cases with at least 1 part showing Gleason score (GS) 4 + 4 = 8; and (2) report %GP4: less than 5% or less than 10% and 10% increments thereafter. Tertiary grade patterns are as follows: (1) replace "tertiary grade pattern" in radical prostatectomy (RP) with "minor tertiary pattern 5 (TP5)," and only use in RP with GrGp 2 or 3 with less than 5% Gleason pattern 5; and (2) minor TP5 is noted along with the GS, with the GrGp based on the GS. Global score and magnetic resonance imaging (MRI)-targeted biopsies are as follows: (1) when multiple undesignated cores are taken from a single MRI-targeted lesion, an overall grade for that lesion is given as if all the involved cores were one long core; and (2) if providing a global score, when different scores are found in the standard and the MRI-targeted biopsy, give a single global score (factoring both the systematic standard and the MRI-targeted positive cores). Grade Groups are as follows: (1) Grade Groups (GrGp) is the terminology adopted by major world organizations; and (2) retain GS 3 + 5 = 8 in GrGp 4. Cribriform carcinoma is as follows: (1) report the presence or absence of cribriform glands in biopsy and RP with Gleason pattern 4 carcinoma. Intraductal carcinoma (IDC-P) is as follows: (1) report IDC-P in biopsy and RP; (2) use criteria based on dense cribriform glands (>50% of the gland is composed of epithelium relative to luminal spaces) and/or solid nests and/or marked pleomorphism/necrosis; (3) it is not necessary to perform basal cell immunostains on biopsy and RP to identify IDC-P if the results would not change the overall (highest) GS/GrGp part per case; (4) do not include IDC-P in determining the final GS/GrGp on biopsy and/or RP; and (5) "atypical intraductal proliferation (AIP)" is preferred for an intraductal proliferation of prostatic secretory cells which shows a greater degree of architectural complexity and/or cytological atypia than typical high-grade prostatic intraepithelial neoplasia, yet falling short of the strict diagnostic threshold for IDC-P. Molecular testing is as follows: (1) Ki67 is not ready for routine clinical use; (2) additional studies of active surveillance cohorts are needed to establish the utility of PTEN in this setting; and (3) dedicated studies of RNA-based assays in active surveillance populations are needed to substantiate the utility of these expensive tests in this setting. Artificial intelligence and novel grading schema are as follows: (1) incorporating reactive stromal grade, percent GP4, minor tertiary GP5, and cribriform/intraductal carcinoma are not ready for adoption in current practice.
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http://dx.doi.org/10.5858/arpa.2020-0015-RADOI Listing
April 2021

Convergence of Digital Pathology and Artificial Intelligence Tools in Anatomic Pathology Practice: Current Landscape and Future Directions.

Adv Anat Pathol 2020 07;27(4):221-226

Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN.

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http://dx.doi.org/10.1097/PAP.0000000000000271DOI Listing
July 2020

Whole Slide Imaging: Technology and Applications.

Adv Anat Pathol 2020 Jul;27(4):251-259

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

Pathology has benefited from advanced innovation with novel technology to implement a digital solution. Whole slide imaging is a disruptive technology where glass slides are scanned to produce digital images. There have been significant advances in whole slide scanning hardware and software that have allowed for ready access of whole slide images. The digital images, or whole slide images, can be viewed comparable to glass slides in a microscope, as digital files. Whole slide imaging has increased in adoption among pathologists, pathology departments, and scientists for clinical, educational, and research initiatives. Worldwide usage of whole slide imaging has grown significantly. Pathology regulatory organizations (ie, College of American Pathologists) have put forth guidelines for clinical validation, and the US Food and Drug Administration have also approved whole slide imaging for primary diagnosis. This article will review the digital pathology ecosystem and discuss clinical and nonclinical applications of its use.
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http://dx.doi.org/10.1097/PAP.0000000000000273DOI Listing
July 2020

Genetic alterations and their association with clinicopathologic characteristics in advanced breast carcinomas: focusing on clinically actionable genetic alterations.

Hum Pathol 2020 08 21;102:94-103. Epub 2020 May 21.

Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, 43210, USA. Electronic address:

Breast carcinomas (BCs) are genetically heterogeneous and associated with numerous mutations which can be used to predict outcomes and initiate targeted therapies. We investigated clinicopathologic characteristics associated with gene mutations detected using the FoundationOne CDx assay in a cohort of 223 clinically advanced BCs (66 locally recurrent and 157 metastatic) from our institution. One hundred fifty unique mutations were identified (total 1008) in the cohort, with the most prevalent (>10%) including TP53 (53.8%), PIK3CA (35%), MYC (22%), CCND1 (19.7%), FGF19 (19.7%), FGF4 (16.6%), FGF3 (16.1%), ZNF703 (14.8%), ESR1 (13.9%), FGFR1 (13.5%), PTEN (12.1%), and CDH1 (10.8%). ERBB2 genetic alteration was most common in human epidermal growth factor receptor 2 (HER2)-positive BCs, and GATA3 and ESR1 mutations were only identified in hormone receptor-positive BC. Mutations enriched in triple-negative BCs (TNBCs) included TP53, PTEN, RB1, and CDKN2A/B. CDH1 mutation was predominantly found in lobular carcinomas, and PIK3CA mutation was also enriched. Mutations enriched in metaplastic carcinomas with heterologous mesenchymal differentiation included TP53, PTEN, MCL1, CDKN2A/B, and NOTCH2. An increase in mutations of CCND1, FGF19, FGF4, FGF3, ESR1, and EMSY was identified in metastatic BCs compared with locally recurrent BCs. Overall, PIK3CA was the most frequent clinically actionable genetic alteration (35%), followed by MYC (22%), CCND1 (19.7%), and FGF3/FGF4/FGFR1 (16%). In conclusion, our study provides genetic insight into the biology of advanced BCs and summarizes their most frequent clinically actionable genetic alterations, generating useful genomic information for potential improvement of patient management.
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http://dx.doi.org/10.1016/j.humpath.2020.05.005DOI Listing
August 2020

High tumor mutation burden is associated with DNA damage repair gene mutation in breast carcinomas.

Diagn Pathol 2020 May 11;15(1):50. Epub 2020 May 11.

Department of Pathology, The Ohio State University Wexner Medical Center, 410 W. 10th Ave, Columbus, 43210, OH, USA.

Background: Immunotherapy has demonstrated encouraging clinical benefits in patients with advanced breast carcinomas and Programmed death ligand 1 (PD-L1) expression has been proposed as an immunotherapy biomarker. Challenges with current PD-L1 testing exist and tumor mutation burden (TMB) is emerging as a biomarker to predict clinical response to immunotherapy in melanoma and non-small cell lung cancer patients. However, TMB has not been well characterized in breast carcinomas.

Methods: The study cohort included 62 advanced breast cancer patients (13 primary and 49 metastatic). Genetic alterations and TMB were determined by FoundationOne CDx next generation sequencing (NGS) and the association with clinicopathologic features was analyzed.

Results: High TMB was observed in a relatively low frequency (3/62, 4.8%). TMB levels were positively associated tumor infiltrating lymphocytes and significantly higher TMB was observed in breast carcinomas with DNA damage repair gene mutation(s). There was no significant association between TMB levels and other analyzed clinicopathologic characteristics.

Conclusions: Our data indicate the importance of DNA damage repair proteins in maintaining DNA integrity and immune reaction and breast carcinoma patients with DDR mutation may benefit from immunotherapy.
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http://dx.doi.org/10.1186/s13000-020-00971-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212599PMC
May 2020

HER2 intratumoral heterogeneity is independently associated with distal metastasis and overall survival in HER2-positive breast carcinomas.

Breast Cancer Res Treat 2020 Jun 25;181(3):519-527. Epub 2020 Apr 25.

Department of Pathology, Wexner Medical Center at The Ohio State University, 410 W. 10th Ave, Columbus, OH, 43210, USA.

Purpose: Human epidermal growth factor receptor 2 (HER2) intratumoral heterogeneity (ITH) occurs in a subset of breast cancers. Our recent study revealed it as an independent predictive factor for the response to anti-HER2 neoadjuvant therapy. In this study, we aimed to investigate its association with distal metastasis.

Methods: HER2 ITH was assessed using HER2 gene protein assay (GPA) on whole tissue sections of pretreatment biopsies from a cohort of 158 HER2-positive invasive breast carcinomas and correlated with patients' clinical follow-up outcomes along with other clinicopathologic characteristics.

Results: Fifty-seven cases (36%) showed HER2 ITH including 19 with genetic, 8 with both genetic and non-genetic, and 30 with non-genetic ITH. Multivariate analysis demonstrated larger tumor size, positive resected lymph node(s), negative PR, and the presence of HER2 ITH were independently associated with distal metastasis. Additionally, multivariate analysis demonstrated larger tumor size and the presence of HER2 ITH were the only independent factors associated with decreased overall survival (death).

Conclusion: The presence of HER2 ITH is an independent factor associated with poor overall survival and increased distal metastasis in HER2-positive breast cancer patients.
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http://dx.doi.org/10.1007/s10549-020-05650-1DOI Listing
June 2020

A Validation Study of Human Epidermal Growth Factor Receptor 2 Immunohistochemistry Digital Imaging Analysis and its Correlation with Human Epidermal Growth Factor Receptor 2 Fluorescence Hybridization Results in Breast Carcinoma.

J Pathol Inform 2020 4;11. Epub 2020 Feb 4.

Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.

Background: The Visiopharm human epidermal growth factor receptor 2 (HER2) digital imaging analysis (DIA) algorithm assesses digitized HER2 immunohistochemistry (IHC) by measuring cell membrane connectivity. We aimed to validate this algorithm for clinical use by comparing with pathologists' scoring and correlating with HER2 fluorescence hybridization (FISH) results.

Materials And Methods: The study cohort consisted of 612 consecutive invasive breast carcinoma specimens including 395 biopsies and 217 resections. HER2 IHC slides were scanned using Philips IntelliSite Scanners, and the digital images were analyzed using Visiopharm HER2-CONNECT App to obtain the connectivity values (0-1) and scores (0, 1+, 2+, and 3+). HER2 DIA scores were compared with Pathologists' manual scores, and HER2 connectivity values were correlated with FISH results.

Results: The concordance between HER2 DIA scores and pathologists' scores was 87.3% (534/612). All discordant cases ( = 78) were only one-step discordant (negative to equivocal, equivocal to positive, or vice versa). Five cases (0.8%) showed discordant HER2 IHC DIA and FISH results, but all these cases had relatively low copy numbers (between 4 and 6). HER2 IHC connectivity showed significantly better correlation with copy number than ratio.

Conclusions: HER2 IHC DIA demonstrates excellent concordance with pathologists' scores and accurately discriminates between FISH positive and negative cases. HER2 IHC connectivity has better correlation with copy number than ratio, suggesting copy number may be more important in predicting HER2 protein expression, and response to anti-HER2-targeted therapy.
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http://dx.doi.org/10.4103/jpi.jpi_52_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7032021PMC
February 2020

Commentary: Automated Diagnosis and Gleason Grading of Prostate Cancer - Are Artificial Intelligence Systems Ready for Prime Time?

Authors:
Anil V Parwani

J Pathol Inform 2019 23;10:41. Epub 2019 Dec 23.

Department of Pathology, The Ohio State University Wexner Medical Centre, Columbus, OH, USA.

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http://dx.doi.org/10.4103/jpi.jpi_56_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011461PMC
December 2019

Cytopathology of Xp11 translocation renal cell carcinoma: a report of 5 cases.

J Am Soc Cytopathol 2020 Mar - Apr;9(2):95-102. Epub 2020 Jan 28.

Department of Pathology, The Ohio State University College of Medicine, Wexner Medical Center, Columbus, Ohio. Electronic address:

Introduction: Xp11.2 translocation-associated RCC (Xp11RCC) defined by molecular alterations involving TFE3 genetic rearrangements constitutes a large percentage of primary renal neoplasms in children, but less than 4% of adult cases. Fewer than 10 single case reports constitute the English cytopathology literature regarding this neoplasm. Our objective is to describe and illustrate the cytopathology of this uncommon renal neoplasm from a series of 5 cases using cytologic imprints, effusion specimens, and fine-needle aspiration (FNA) cytology.

Materials And Methods: Review was made of our cytopathology and surgical pathology databases. FNA biopsy smears and imprint smears were performed using a standard technique. Effusion samples were processed using liquid-based slides.

Results: Five cytologic specimens from 4 patients with histopathologically confirmed Xp11RCC were identified (mean age: 36 years) over a period of 7 years. All cases contained large cells with voluminous amounts of vacuolated cytoplasm arranged in non-descript clusters and as single forms. A "tigroid" pattern consisting of linear strips of detached cytoplasm was seen in both imprint smear cases and the single FNA case. Psammomatous calcifications, true papillary structures, and hyaline globules were absent in all cases. Four examples were diagnosed as Xp11RCC, but 3 represented metastatic disease, and 1 was diagnosed using both cytology and core needle tissue histopathology. The remaining case was diagnosed nonspecifically as a clear cell malignant neoplasm.

Conclusions: The cytopathologic features of Xp1RCC are relatively nonspecific, and overlap with other renal cell carcinoma subtypes. A definitive diagnosis is only possible with ancillary immunohistochemistry with or without additional TFE3 fluorescence in situ hybridization.
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http://dx.doi.org/10.1016/j.jasc.2019.10.005DOI Listing
January 2020

Quantitative digital imaging analysis of HER2 immunohistochemistry predicts the response to anti-HER2 neoadjuvant chemotherapy in HER2-positive breast carcinoma.

Breast Cancer Res Treat 2020 Apr 30;180(2):321-329. Epub 2020 Jan 30.

Department of Pathology, The Ohio State University, Columbus, OH, USA.

Purpose: Patients with HER2-positive breast cancer commonly receive anti-HER2 neoadjuvant chemotherapy and pathologic complete response (pCR) can be achieved in up to half of the patients. HER2 protein expression detected by immunohistochemistry (IHC) can be quantified using digital imaging analysis (DIA) as a value of membranous connectivity. We aimed to investigate the association HER2 IHC DIA quantitative results with response to anti-HER2 neoadjuvant chemotherapy.

Methods: Digitized HER2 IHC whole slide images were analyzed using Visiopharm HER2-CONNECT to obtain quantitative HER2 membranous connectivity from a cohort of 153 HER2+ invasive breast carcinoma cases treated with anti-HER2 neoadjuvant chemotherapy (NAC). HER2 connectivity and other factors including age, histologic grade, ER, PR, and HER2 fluorescence in situ hybridization (FISH) were analyzed for association with the response to anti-HER2 NAC.

Results: Eighty-three cases (54.2%) had pCR, while 70 (45.8%) showed residual tumor. Younger age, negative ER/PR, higher HER2 DIA connectivity, higher HER2 FISH ratio and copy number were significantly associated with pCR in univariate analysis. Multivariate analysis demonstrated only age, HER2 DIA connectivity, PR negativity, and HER2 copy number was significantly associated with pCR, whereas HER2 DIA connectivity had the strongest association.

Conclusions: HER2 IHC DIA connectivity is the most important factor predicting pCR to anti-HER2 neoadjuvant chemotherapy in patients with HER2-positive breast cancer.
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http://dx.doi.org/10.1007/s10549-020-05546-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006811PMC
April 2020

Next generation diagnostic pathology: use of digital pathology and artificial intelligence tools to augment a pathological diagnosis.

Authors:
Anil V Parwani

Diagn Pathol 2019 12 27;14(1):138. Epub 2019 Dec 27.

Division of Digital and Computational Pathology, Department of Pathology, The Ohio State University, Columbus, USA.

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http://dx.doi.org/10.1186/s13000-019-0921-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933733PMC
December 2019

Multifocal Extraprostatic Extension of Prostate Cancer.

Am J Clin Pathol 2020 03;153(4):548-553

Departments of Pathology Pittsburgh, PA.

Objectives: To investigate the prognostic utility of multifocal extraprostatic extension (EPE) on biochemical recurrence after radical prostatectomy.

Methods: We conducted retrospective analysis of biochemical recurrence and prognostic pathologic variables in 673 men with stage pT3a/pT3b prostate cancer from 2000 to 2012. Extent of EPE on radical prostatectomy was divided into three groups: focal EPE (tumor dimension <0.8 mm), established (≥ 0.8 mm), and multifocal (more than one focus of EPE <0.8 mm).

Results: Type of EPE had significant effect on recurrence with progressively lower progression-free probability and higher recurrence probability from focal to established to multifocal. Multifocal and established tumors exhibited worse prognostic features and higher hazard ratio than focal. In multivariate analysis, established and multifocal were independent prognostic factors with the greatest adverse prognostic significance associated with multifocal.

Conclusions: Identification of multifocal EPE provides important prognostic information associated with increased likelihood of recurrence compared to focal and established tumors.
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http://dx.doi.org/10.1093/ajcp/aqz193DOI Listing
March 2020

Diagnostic concordance between whole slide imaging and conventional light microscopy in cytopathology: A systematic review.

Cancer Cytopathol 2020 01 10;128(1):17-28. Epub 2019 Oct 10.

Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, Italy.

Many studies have examined the diagnostic concordance of whole slide imaging (WSI) and light microscopy (LM) for surgical pathology. In cytopathology, WSI use has been more limited, mainly because of technical issues. The aim of this study was to review the literature and determine the overall diagnostic concordance of WSI and LM in cytopathology. A systematic search of PubMed, Scopus, and the Cochrane Library was performed, with data extracted from the included articles. A quality assessment of studies was performed with a modified Quality Assessment of Diagnostic Accuracy Studies 2 tool. The primary outcome was concordance for the diagnoses rendered by WSI and LM as shown by the concordance rate with the original diagnosis, intra-observer and interobserver concordance with the κ coefficient, or a percentage. Secondary outcomes included the time taken to reach a diagnosis and the quality and perception of WSI. A descriptive survey was provided. Among 1867 publications, a total of 19 studies (1%) were included. Overall, the concordance between WSI and the original diagnosis was 84.1%, the intra-observer concordance between WSI and LM was 92.5% with a κ coefficient of 0.66, and the interobserver κ coefficient was 0.69. The time to reach a diagnosis was longer with WSI in all studies. The quality of WSI was good, but diagnostic confidence and cytologist preference were higher for LM. In conclusion, the concordance of WSI with LM is acceptable and in line with systematic reviews in surgical pathology. However, the time required for scanning and technical issues represent barriers to complete adoption. It is foreseeable that technical advances and rigorous validation study design will help to improve the diagnostic concordance of WSI with LM in cytopathology.
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http://dx.doi.org/10.1002/cncy.22195DOI Listing
January 2020

The Landscape of Digital Pathology in Transplantation: From the Beginning to the Virtual E-Slide.

J Pathol Inform 2019 1;10:21. Epub 2019 Jul 1.

Department of Diagnostics and Public Health, University and Hospital Trust of Verona, Verona, Italy.

Background: Digital pathology has progressed over the last two decades, with many clinical and nonclinical applications. Transplantation pathology is a highly specialized field in which the majority of practicing pathologists do not have sufficient expertise to handle critical needs. In this context, digital pathology has proven to be useful as it allows for timely access to expert second-opinion teleconsultation. The aim of this study was to review the experience of the application of digital pathology to the field of transplantation.

Methods: Papers on this topic were retrieved using PubMed as a search engine. Inclusion criteria were the presence of transplantation setting and the use of any type of digital image with or without the use of image analysis tools; the search was restricted to English language papers published in the 25 years until December 31, 2018.

Results: Literature regarding digital transplant pathology is mostly about the digital interpretation of posttransplant biopsies (75 vs. 19), with 15/75 (20%) articles focusing on agreement/reproducibility. Several papers concentrated on the correlation between biopsy features assessed by digital image analysis (DIA) and clinical outcome (45/75, 60%). Whole-slide imaging (WSI) only appeared in recent publications, starting from 2011 (13/75, 17.3%). Papers dealing with preimplantation biopsy are less numerous, the majority (13/19, 68.4%) of which focus on diagnostic agreement between digital microscopy and light microscopy (LM), with WSI technology being used in only a small quota of papers (4/19, 21.1%).

Conclusions: Overall, published studies show good concordance between digital microscopy and LM modalities for diagnosis. DIA has the potential to increase diagnostic reproducibility and facilitate the identification and quantification of histological parameters. Thus, with advancing technology such as faster scanning times, better image resolution, and novel image algorithms, it is likely that WSI will eventually replace LM.
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http://dx.doi.org/10.4103/jpi.jpi_27_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639852PMC
July 2019

Computational pathology definitions, best practices, and recommendations for regulatory guidance: a white paper from the Digital Pathology Association.

J Pathol 2019 11 3;249(3):286-294. Epub 2019 Sep 3.

Department of Development Sciences, Genentech Inc., South San Francisco, CA, USA.

In this white paper, experts from the Digital Pathology Association (DPA) define terminology and concepts in the emerging field of computational pathology, with a focus on its application to histology images analyzed together with their associated patient data to extract information. This review offers a historical perspective and describes the potential clinical benefits from research and applications in this field, as well as significant obstacles to adoption. Best practices for implementing computational pathology workflows are presented. These include infrastructure considerations, acquisition of training data, quality assessments, as well as regulatory, ethical, and cyber-security concerns. Recommendations are provided for regulators, vendors, and computational pathology practitioners in order to facilitate progress in the field. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.5331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6852275PMC
November 2019

E-cadherin is downregulated in benign prostatic hyperplasia and required for tight junction formation and permeability barrier in the prostatic epithelial cell monolayer.

Prostate 2019 08 18;79(11):1226-1237. Epub 2019 Jun 18.

Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

Background: We previously reported the presence of prostate-specific antigen (PSA) in the stromal compartment of benign prostatic hyperplasia (BPH). Since PSA is expressed exclusively by prostatic luminal epithelial cells, PSA in the BPH stroma suggests increased tissue permeability and the compromise of epithelial barrier integrity. E-cadherin, an important adherens junction component and tight junction regulator, is known to exhibit downregulation in BPH. These observations suggest that the prostate epithelial barrier is disrupted in BPH and E-cadherin downregulation may increase epithelial barrier permeability.

Methods: The ultra-structure of cellular junctions in BPH specimens was observed using transmission electron microscopy (TEM) and E-cadherin immunostaining analysis was performed on BPH and normal adjacent specimens from BPH patients. In vitro cell line studies using benign prostatic epithelial cell lines were performed to determine the impact of small interfering RNA knockdown of E-cadherin on transepithelial electrical resistance and diffusion of fluorescein isothiocyanate (FITC)-dextran in transwell assays.

Results: The number of kiss points in tight junctions was reduced in BPH epithelial cells as compared with the normal adjacent prostate. Immunostaining confirmed E-cadherin downregulation and revealed a discontinuous E-cadherin staining pattern in BPH specimens. E-cadherin knockdown increased monolayer permeability and disrupted tight junction formation without affecting cell density.

Conclusions: Our results indicate that tight junctions are compromised in BPH and loss of E-cadherin is potentially an important underlying mechanism, suggesting targeting E-cadherin loss could be a potential approach to prevent or treat BPH.
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http://dx.doi.org/10.1002/pros.23806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599563PMC
August 2019

Digital pathology and artificial intelligence.

Lancet Oncol 2019 05;20(5):e253-e261

Center for Biomedical Informatics, Wake Forest School of Medicine, Winston-Salem, NC, USA.

In modern clinical practice, digital pathology has a crucial role and is increasingly a technological requirement in the scientific laboratory environment. The advent of whole-slide imaging, availability of faster networks, and cheaper storage solutions has made it easier for pathologists to manage digital slide images and share them for clinical use. In parallel, unprecedented advances in machine learning have enabled the synergy of artificial intelligence and digital pathology, which offers image-based diagnosis possibilities that were once limited only to radiology and cardiology. Integration of digital slides into the pathology workflow, advanced algorithms, and computer-aided diagnostic techniques extend the frontiers of the pathologist's view beyond a microscopic slide and enable true utilisation and integration of knowledge that is beyond human limits and boundaries, and we believe there is clear potential for artificial intelligence breakthroughs in the pathology setting. In this Review, we discuss advancements in digital slide-based image diagnosis for cancer along with some challenges and opportunities for artificial intelligence in digital pathology.
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http://dx.doi.org/10.1016/S1470-2045(19)30154-8DOI Listing
May 2019

Introduction to Digital Image Analysis in Whole-slide Imaging: A White Paper from the Digital Pathology Association.

J Pathol Inform 2019 8;10. Epub 2019 Mar 8.

Indica Labs, Inc., Corrales, NM, USA.

The advent of whole-slide imaging in digital pathology has brought about the advancement of computer-aided examination of tissue via digital image analysis. Digitized slides can now be easily annotated and analyzed via a variety of algorithms. This study reviews the fundamentals of tissue image analysis and aims to provide pathologists with basic information regarding the features, applications, and general workflow of these new tools. The review gives an overview of the basic categories of software solutions available, potential analysis strategies, technical considerations, and general algorithm readouts. Advantages and limitations of tissue image analysis are discussed, and emerging concepts, such as artificial intelligence and machine learning, are introduced. Finally, examples of how digital image analysis tools are currently being used in diagnostic laboratories, translational research, and drug development are discussed.
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http://dx.doi.org/10.4103/jpi.jpi_82_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437786PMC
March 2019

Comprehensive Study of Telecytology Using Robotic Digital Microscope and Single Z-Stack Digital Scan for Fine-Needle Aspiration-Rapid On-Site Evaluation.

J Pathol Inform 2018 24;9:49. Epub 2018 Dec 24.

Department of Pathology, The Ohio State University, Columbus, Ohio, USA.

Background: The current technology for remote assessment of fine-needle aspiration-rapid on-site evaluation (FNA-ROSE) is limited. Recent advances may provide solutions. This study compared the performance of VisionTek digital microscope (VDM) (Sakura, Japan) and Hamamatsu NanoZoomer C9600-12 single Z-stack digital scan (SZDS) to conventional light microscopy (CLM) for FNA-ROSE.

Methods: We assembled sixty FNA cases from the thyroid ( = 16), lymph node ( = 16), pancreas ( = 9), head and neck ( = 9), salivary gland ( = 5), lung ( = 4), and rectum ( = 1) based on a single institution's routine workflow. One Diff-Quik-stained slide was selected for each case. Two board-certified cytopathologists independently evaluated the cases using VDM, SZDS, and CLM. A "washout" period of at least 14 days was placed between the reviews. The results were categorized into satisfactory versus unsatisfactory for adequacy assessment (AA) and unsatisfactory, benign, atypical, suspicious, and malignant for preliminary diagnosis (PD).

Results: For AA, the Cohen's kappa statistics (CKS) scores of intermodality agreement (IMA) were 0.74-0.94 (CLM vs. VDM) and 0.86-1 (CLM vs. SZDS). The discordant rates of IMA were 3.3% (4/120) for VDM versus CLM, and 1.7% (2/120) for SZDS versus CLM. For PD, the CKS scores of IMA ranged 0.7-0.93. The overall discordant rates of IMA were 15% (18/120) for CLM versus VDM and 10.8% (13/120) for CLM versus SZDS. The discordant rates of IMA with 2 or higher degrees were 5.8% (7/120) for CLM versus VDM and 1.7% (2/120) for CLM versus SZDS. The average time spent per slide was 270 s for VDM, significantly longer than that for CLM (113 s) or for SZDS (122 s).

Conclusions: Our data demonstrate that both VDM and SZDS are suitable to provide AA and reasonable PD evaluation. VDM, however, has a significantly longer turnaround time and worse diagnostic performance. The study demonstrates both the potentials and challenges of using VDM and SZDS for FNA-ROSE.
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http://dx.doi.org/10.4103/jpi.jpi_75_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6319035PMC
December 2018