Machine learning integration of scleroderma histology and gene expression identifies fibroblast polarisation as a hallmark of clinical severity and improvement.

OBJECTIVE: We sought to determine histologic and gene expression features of clinical improvement in early diffuse cutaneous systemic sclerosis (dcSSc; scleroderma). METHODS: Fifty-eight forearm biopsies were evaluated from 26 individuals with dcSSc in two clinical trials. Histologic/immunophenotypic assessments of global severity, alpha-smooth muscle actin (aSMA), CD34, collagen, inflammatory infiltrate, follicles and thickness were compared with gene expression and clinical data. Support vector machine learning was performed using scleroderma gene expression subset (normal-like, fibroproliferative, inflammatory) as classifiers and histology scores as inputs. Comparison of w-vector mean absolute weights was used to identify histologic features most predictive of gene expression subset. We then tested for differential gene expression according to histologic severity and compared those with clinical improvement (according to the Combined Response Index in Systemic Sclerosis). RESULTS: aSMA was highest and CD34 lowest in samples with highest local Modified Rodnan Skin Score. CD34 and aSMA changed significantly from baseline to 52 weeks in clinical improvers. CD34 and aSMA were the strongest predictors of gene expression subset, with highest CD34 staining in the normal-like subset (p<0.001) and highest aSMA staining in the inflammatory subset (p=0.016). Analysis of gene expression according to CD34 and aSMA binarised scores identified a 47-gene fibroblast polarisation signature that decreases over time only in improvers (vs non-improvers). Pathway analysis of these genes identified gene expression signatures of inflammatory fibroblasts. CONCLUSION: CD34 and aSMA stains describe distinct fibroblast polarisation states, are associated with gene expression subsets and clinical assessments, and may be useful biomarkers of clinical severity and improvement in dcSSc.

Case 272: Decubital Ischemic Fasciitis.

HistoryA 92-year-old bedridden woman presented to the emergency department from an assisted living facility with fever, cough, and swelling over the right lateral hip. She had baseline dementia and frailty and had been bedridden for 4 years. She did not have any recent falls or history of trauma at the site of swelling. She had a history of diffuse large B-cell lymphoma that had been diagnosed and treated 7 years ago, and thoracoabdominal CT at last follow-up 3 years ago did not show any recurrence. Physical examination findings were unremarkable except for a painful hard and fixed mass measuring approximately 5 × 5 × 10 cm (in the transverse, anteroposterior, and craniocaudal directions, respectively) located at the right lateral superior thigh. The overlying skin was intact, without any color changes. Pertinent blood test results showed an increased white blood cell count of 13,000/µL (13 × 109/L) (normal range, 3700-11,000/µL [3.7-11 × 109/L]). The remaining hematologic and biochemical test results were normal. Abdominal and pelvic CT performed at presentation did not show any abnormal lymph nodes. Because chest radiography showed consolidation in addition to typical clinical picture, the patient was diagnosed with pneumonia and underwent antibiotic treatment for 3 weeks. US and Doppler US of the mass were performed. MRI was not performed because the patient had a pacemaker; instead, CT of the lower extremity was performed.

Case 272.

History A 92-year-old bedridden woman presented to the emergency department from an assisted living facility with fever, cough, and swelling over the right lateral hip. She had baseline dementia and frailty and had been bedridden for 4 years. She did not have any recent falls or history of trauma at the site of swelling. She had a history of diffuse large B-cell lymphoma that had been diagnosed and treated 7 years ago, and thoracoabdominal CT at last follow-up 3 years ago did not show any recurrence. Physical examination findings were unremarkable except for a painful hard and fixed mass measuring approximately 5 × 5 × 10 cm (in the transverse, anteroposterior, and craniocaudal directions, respectively) located at the right lateral superior thigh. The overlying skin was intact, without any color changes. Pertinent blood test results showed an increased white blood cell count of 13 000/µL (13 ×109/L) (normal range, 3700-11 000/µL [3.7-11 ×109/L]). The remaining hematologic and biochemical test results were normal. Abdominal and pelvic CT performed at presentation did not show any abnormal lymph nodes. Because chest radiography showed consolidation in addition to typical clinical picture, the patient was diagnosed with pneumonia and underwent antibiotic treatment for 3 weeks. US ( Fig 1 ) and Doppler US ( Fig 2 ) of the mass were performed. MRI was not performed because the patient had a pacemaker; instead, CT of the lower extremity was performed ( Fig 3a , 3b ). Figure 1: US image of the mass at the level of the greater trochanter. Figure 2: Doppler US image of the caudal portion of the mass. Figure 3a: (a) Axial unenhanced CT image of the lesion at the level of the greater trochanter. (b) Coronal unenhanced CT image of the mass at the level of the greater trochanter. Figure 3b: (a) Axial unenhanced CT image of the lesion at the level of the greater trochanter. (b) Coronal unenhanced CT image of the mass at the level of the greater trochanter.

Increased detection of Barrett's esophagus-associated neoplasia using wide-area trans-epithelial sampling: a multicenter, prospective, randomized trial.

BACKGROUND AND AIMS: Wide-area transepithelial sampling (WATS) with computer-assisted 3-dimensional analysis is a sampling technique that combines abrasive brushing of the Barrett's esophagus (BE) mucosa followed by neural network analysis to highlight abnormal-appearing cells. METHODS: We performed a randomized trial of referred BE patients undergoing surveillance at 16 medical centers. Subjects received either biopsy sampling followed by WATS or WATS followed by biopsy sampling. The primary outcome was rate of detection of high-grade dysplasia/esophageal adenocarcinoma (HGD/EAC) using WATS in conjunction with biopsy sampling compared with biopsy sampling alone using standard histopathologic criteria. Secondary aims included evaluating neoplasia detection rates based on the procedure order (WATS vs biopsy sampling first), of each procedure separately, and the additional time required for WATS. RESULTS: One hundred sixty patients (mean age, 63.4 years; 76% men; 95% white) completed the trial. The median circumferential and maximal BE extents were 1.0 cm (interquartile range: .0-5.0) and 4.0 cm (interquartile range, 2.0-8.0), respectively. The diagnostic yield for biopsy sampling alone was as follows: HGD/EAC, 7 (4.4%); low-grade dysplasia (LGD), 28 (17.5%); nondysplastic BE (NDBE), 106 (66.25%); and no BE, 19 (11.9%). The addition of WATS to biopsy sampling yielded an additional 23 cases of HGD/EAC (absolute increase, 14.4%; 95% confidence interval, 7.5%-21.2%). Among these 23 patients, 11 were classified by biopsy sampling as NDBE and 12 as LGD/indefinite for dysplasia (IND); 14 received biopsy sampling first and 9 WATS first (not significant) and most (n = 21; 91.7%) had a prior dysplasia history. WATS added an average of 4.5 minutes to the procedure. CONCLUSION: Results of this multicenter, prospective, randomized trial demonstrate that the use of WATS in a referral BE population increases the detection of HGD/EAC. (Clinical trial registration number: NCT03008980.).

Diagnostic Utility of Histological Analysis for Detecting Ongoing Infection During Two-Stage Revision Arthroplasty in Patients With Inflammatory Arthritis.

BACKGROUND: Surgeons often rely on intra-operative histology (frozen sections [FS]) to determine the next step in surgical management during the second stage (re-implantation surgery) of 2-stage revision arthroplasty. The purpose of the study is to assess the accuracy of permanent sections (PS) and FS in the diagnosis of persistent infection during re-implantation in patients with an inflammatory arthritis. METHODS: From 2001 to 2016, 47 planned second-stage revision total hip arthroplasty and total knee arthroplasty in patients with inflammatory arthritis were identified. Revisions were classified as having persistent infection if they were Musculoskeletal Infection Society positive at the time of second stage. PS or FS was considered to be positive for infection when at least one of the specimens demonstrated an acute inflammation. Receiver operating characteristic analysis was performed to obtain the diagnostic parameters. RESULTS: There were 9 (19%) persistent infections. Both PS and FS had very high specificity (PS = FS = 94.7%). Sensitivity of PS was higher than FS, although not statistically significant (PS = 88.9%, FS = 55.6%, P = .083). Overall, PS had a better diagnostic utility than FS (area under the curve: PS vs FS = 0.92 vs 0.75, P = .045). Four specimens had discrepancies between PS and FS histology. In all 4 instances, the specimens were read as positive (infected) by PS, but negative by FS. CONCLUSION: Histological analysis is recommended at the time of re-implantation surgery even in patients with inflammatory arthritis. PS had a better diagnostic utility than FS suggesting that areas of acute inflammation may be scattered and may not always be captured in the specimens taken for FS.

Radiation-induced focal cortical necrosis of the femur presenting as a lytic lesion.

Management of soft tissue sarcomas is often complicated, requiring radiation before and in some cases after limb-sparing surgery. Radiation necrosis is a severe complication after radiation treatment and is typically dose related and involves medullary bone. We report on two cases of hitherto unreported focal circumscribed intra-cortical lytic lesions within the radiation portal, which appeared 19 months and 31 months, respectively, after the conclusion of radiation treatment. Both patients had a history of soft tissue sarcoma treated with radiation (66 Gy) and surgical resection. Biopsy of these lesions showed necrotic bone attributed to radiation.

Intraoperative Frozen Section Histology: Matched for Musculoskeletal Infection Society Criteria.

BACKGROUND: The current gold standard to diagnose periprosthetic joint infection (PJI)-the Musculoskeletal Infection Society (MSIS) criteria, requires a battery of tests, the results of which may not be available at the time of decision-making. Thus, surgeons often rely on intraoperative frozen section histology. However, the accuracy of frozen sections has not been determined when matched for the MSIS criteria. We aimed to (1) assess the value of intraoperative histology in the diagnosis of PJI and (2) evaluate discrepancy rate between frozen and permanent section analysis. METHODS: A retrospective review of patients who underwent revision total hip or total knee arthroplasty for either PJI or mechanical failure in 2013 was conducted. Two hundred procedures where tissue samples for frozen sections had been collected were identified and included into the study. Results of frozen sections were compared to the modified MSIS criteria. Discrepancy rate between frozen and permanent sections was also calculated. RESULTS: Frozen sections had sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 73.7% (95% confidence interval [CI], 59.7%-87.7%), 98.8% (95% CI, 97.1%-100.0%), 94.1% (95% CI, 90.6%-97.6%), 93.3.4% (95% CI, 84.4%-100.0%), 94.0% (95% CI, 90.7%-97.3%), respectively. There were 10 discrepancies between the results of frozen and permanent sections (N = 421 samples), thereby yielding 97.6% concordance. CONCLUSION: When matched to the MSIS criteria, intraoperative frozen section histology yields a high specificity, positive predictive value, negative predictive value, accuracy, and moderate sensitivity. The discrepancy rate between frozen and permanent sections is low and both demonstrate good approximation of MSIS criteria.

Colorectal Tumors From Different Racial and Ethnic Minorities Have Similar Rates of Mismatch Repair Deficiency.

BACKGROUND & AIMS: Microsatellite instability (MSI) in colorectal cancer cells results from deficient mismatch repair (MMR) protein function, either acquired or from germline alterations such as in patients with Lynch syndrome. Universal screening initiatives for Lynch syndrome have been encouraged. However, little is known about the true prevalence of MMR deficiency and MSI in colorectal tumors among individuals from different racial and ethnic subgroups or their clinical effects in these populations. METHODS: We performed a retrospective analysis of 253 surgically resected, primary colorectal adenocarcinoma specimens identified from the University of Miami tumor registry from 2005 through 2010. We collected clinical data, including overall survival (OS), the proportion of patients alive at specific intervals, from non-Hispanic white, Hispanic, and black patients matched by stage. We performed immunohistochemical staining to detect MMR proteins in all specimens and polymerase chain reaction analysis of 51 tumors to detect MSI. RESULTS: We detected MMR deficiency in 28 of 253 cases (11.1%), evenly distributed among blacks (9.6%), non-Hispanic whites (10.4%), and Hispanics (12.6%) (P = .79). Combined deficiencies in MLH1 and PMS2 were found in 23 of 28 MMR-deficient samples (82.1%); MSH2 and MSH6 were most frequently absent in tumor samples from Hispanics (P = .03). Eleven of 51 tumor samples (21.6%) had high levels of MSI, and we observed a high level of concordance between MMR and MSI (κ = .81). OS was significantly better in patients whose tumors had deficient MMR (hazard ratio for patients with MMR-deficient tumors vs MMR proteins intact = 0.37; 95% confidence interval, 0.15-0.91; P = .03). Race and ethnicity were not significant predictors of OS. CONCLUSIONS: MMR deficiency in colorectal tumors occurs with similar rates among patients of different racial and ethnic groups, which is based on immunohistochemical analysis of 253 primary tumor specimens. This finding indicates the potential value of universal testing of colorectal cancer by immunohistochemistry in minority populations and confirms the benefit of MMR deficiency to OS.

Coexisting sarcoidal granulomatous inflammation and diffuse tenosynovial giant cell tumor of the knee after a total knee replacement: a case report.

Sarcoidosis is a systemic inflammatory disorder characterized by non-caseating granulomas, predominantly involving lung, mediastinal lymph nodes and other organs. Synovium involvement is infrequent, and as far as we know, involvement of a periprosthetic membrane has not been reported in the English literature. Intra-articular diffuse tenosynovial giant cell tumor ("conventional diffuse pigmented villonodular synovitis") is an uncommon, locally aggressive neoplasm with few previous case reports in which it arose in periprosthetic tissues after knee arthroplasty. We describe a unique case of an intraarticular mass next to a total knee prosthesis implanted 6 years ago in a patient with a history of pulmonary sarcoidosis. Clinically, this 67-year-old gentleman presented with progressive left knee pain, effusion and marked instability. MRI showed a large complex effusion with synovial thickening in the supra patella recess and the medial and lateral gutters. In addition, a large multilobulated mass with mixed low and high signal intensity was present in the posterior joint space, extending into the popliteal area. A two-stage operation was performed. Histologically, the mass from the posterior joint space showed characteristic features of diffuse tenosynovial giant cell tumor, while the synovium from the anterior compartment demonstrated sarcoidal granulomatous inflammation. Orthopaedic wear debris was found within the giant cells of these sarcoidal granulomata. The histologic features are different from those "usual" macrophage reactions to the particles of debris. In this article, we also included two optional links (highlighted in blue in the figures) to digital whole slide image (WSI), which allow the readers to navigate the entire microscope slides.

Solitary C1 spinal osteochondroma causing vertebral artery compression and acute cerebellar infarct.

Osteochondroma is a common benign bone lesion, usually involving the long bones. Spinal involvement is rare. The clinical presentation of spinal osteochondroma varies according to the site of the lesion. The most common reported clinical presentation is secondary to encroachment of the lesion on the spinal canal or nerve roots. Less common presentations such as a palpable neck mass, dysphagia, sleep apnea, paralysis of left vocal cord or acute respiratory distress have been reported when the lesions compress the anatomic structures anteriorly. We describe a rare case of a young patient who presented with an emergent critical condition of acute cerebellar infarct as a result of vertebral artery compression caused by a solitary C1 spinal osteochondroma.

Update on the role of pathology and laboratory medicine in diagnosing periprosthetic infection.

Technological and implant design advances have helped reduce the frequency of aseptic total joint arthroplasty failure, but periprosthetic joint infections (PJI) remain a clinical important problem with high patient morbidity. Misinterpreting PJI as aseptic mechanical loosening commonly leads to unsatisfactory revision arthroplasty, persistent infection, and poor long-term results. While there is no single "gold standard" diagnostic test for PJI, recent collaborative efforts by Orthopaedic and Infectious Disease Societies have developed algorithms for diagnosing PJI. However, the efficacy of individual tests as well as diagnostic thresholds are controversial. We review the recommended thresholds for commonly used screening tests as well as tissue histopathology and confirmatory tests to diagnose periprosthetic infection. We also update lesser-known laboratory tests, and we briefly summarize rapidly evolving molecular tests to diagnose periprosthetic infection. Pathologists hold a critical role in assisting with PJI diagnosis, maintaining laboratory test quality and interpreting test results. Collaboration between clinicians and pathologists is essential to provide optimal patient care and reduce the burden of PJI.

An immunohistochemical panel to distinguish ovarian from uterine serous papillary carcinomas.

Serous papillary carcinomas (SPCs) share a similar morphology regardless of whether they originate from the ovary or the uterus. Identification of the site of origin of the tumor can be a challenging and a diagnostic dilemma, particularly, in the setting of a pelvic mass or peritoneal carcinomatosis. Recognition of the site of origin influences the staging, management, and prognosis of these malignancies. The purpose of this study is to identify a panel of markers to distinguish the ovarian serous papillary carcinomas (OSPC) from the uterine serous papillary carcinomas (USPC). Formalin-fixed, paraffin-embedded archival tissue from 46 cases of SPCs (33 uterine and 13 ovarian) were stained using antibodies for estrogen receptor (ER), WT1, insulin-like growth factor-II mRNA-binding protein 3 (IMP3), p53, and p16. The OSPC expressed ER (92%), WT1 (100%), IMP3 (92%), p53 (92%), and p16 (92%). The USPCs expressed ER (30%), WT1 (64%), IMP3 (85%), p53 (64%), and p16 (76%). Only ER expression was significantly higher in OSPC compared with USPCs (P<0.001). The combined ER(+)WT1(+) phenotype was present in 92% of the OSPC, whereas only 18% of the USPCs had the same phenotype (P<0.001). Furthermore, 71% of the OSPCs expressed ER(+), p53(+), WT1(+), IMP3(+), and p16(+) immunophenotype, whereas in USPCs, the tumor cells showed immunophenotypic diversity, with only 6% of the USPCs expressing reactivity to all the 5 markers (P<0.001). This study suggests that ER alone or in combination with a limited panel of markers may be used to identify the site of origin of SPCs.

Endocrine tumors as part of inherited tumor syndromes.

The endocrine system is an embryological diverse system consisted of a variety of glands, such as pituitary, parathyroid, thyroid, adrenal, endocrine pancreas, and the diffuse neuroendocrine system. Endocrine tumor can be presented as a sporadic event, or as part of an inherited tumor syndrome. During the past century, inherited tumor syndromes have emerged as an important group of diseases. With the growing knowledge of each inherited tumor syndrome in the molecular genetic level, many changes in clinical management have occurred. This review focuses on the endocrine tumors involving the pituitary, parathyroid, thyroid, adrenal, and endocrine pancreas, in the setting of inherited tumor syndromes. We discuss the specific clinical, molecular genetic, and pathologic features of endocrine tumor in each gland and their associated inherited tumor syndromes. By understanding the pathogenesis of inherited endocrine tumor syndromes and recognizing the unique features of pathologic findings, pathologists bear the responsibility to provide the clinicians the guidelines in terms of screening and treatment of inherited tumor syndromes.

Reproducibility of pathologic scoring systems for periprosthetic adverse local tissue reactions: A cross-sectional study.

BACKGROUND: Several previous studies have described broad histologic classifications of peri-prosthetic reactions that likely reflect the underlying mechanism of arthroplasty failure; however, a consensus has not yet been reached about the relative importance of individual observations. QUESTION/PURPOSE: The purpose of this study was to evaluate the inter-examiner repeatability of commonly used histopathologic grading methods, and to determine the utility of assigning a more simple, global categorization in patients undergoing revision THA surgery of implants with a variety of bearing combinations. METHODS: Between March 2013 and February 2020, a total of 2131 patients underwent revision hip arthroplasty surgery at a one center, of which 12% (248 of 2131) of patients were enrolled. Two pathologists independently reviewed microscope slides of periprosthetic tissue from these patients, of which 425 slides (229 hips, 222 subjects) were reviewed by both pathologists. Separate slides were used for a priori training of the pathologists. Slides were evaluated with the Campbell Aseptic Lymphocyte-dominant Vasculitis-Associated Lesion (ALVAL) score, the Oxford ALVAL score as modified by Grammatopolous, the Fujishiro and Natu scores, and a proposed simplified pattern classification, similar to that of Krenn et al., that incorporates individual factors of these existing scoring methods and was previously shown to correspond to Magnetic Resonance Imaging findings. Inter-rater agreement was assessed using Gwet's AC1 and AC2 coefficients and correspondence analysis was used to examine associations between individual factors of prior scoring methods with the proposed major pattern. RESULTS: Almost perfect inter-rater repeatability (Gwet's AC2 > 0.8) was found for 71% (15/21) of the individual factors, and substantial interrater agreement was found for the proposed major overall pattern (Gwet's AC1: 0.80, 95%CI: 0.72-0.85). Correspondence analysis was able to explain 89-91% of data variability and was able to identify individual features not commonly associated with a major pattern, but discriminatory of the major pattern, such as "Lymph Cuff Thickness 0.25-0.5″ with ALVAL. CONCLUSION: In contrast to prior examinations, excellent interrater agreement was found that may be attributable to a priori training of raters with a test set of slides or difficulty of interpreting grading criteria. The proposed simplified major pattern classification may facilitate evaluation of histopathologic tissue samples.

A Brief Overview and Update on Major Molecular Genomic Alterations in Solid, Bone and Soft Tissue Tumors, and Hematopoietic As Well As Lymphoid Malignancies.

CONTEXT.­: Recent advances in comprehensive genomic profiling by next-generation sequencing have uncovered the genomic alterations at the molecular level for many types of tumors; as such, numerous small specific molecules that target these alterations have been developed and widely used in the management of these cancers. OBJECTIVE.­: To provide a concise molecular genomic update in solid, bone and soft tissue tumors, hematopoietic as well as lymphoid malignancies; discuss its clinical applications; and familiarize practicing pathologists with the emerging cancer biomarkers and their diagnostic utilities. DATA SOURCES.­: This review is based on the National Comprehensive Cancer Network guidelines and peer-reviewed English literature. CONCLUSIONS.­: Tumor-specific biomarkers and molecular/genomic alterations, including pan-cancer markers, have been significantly expanded in the past decade thanks to large-scale high-throughput technologies and will continue to emerge in the future. These biomarkers can be of great value in diagnosis, prognosis, and/or targeted therapy/treatment. Familiarization with these emerging and ever-changing tumor biomarkers will undoubtedly aid pathologists in making accurate and state-of-the-art diagnoses and enable them to be more actively involved in the care of cancer patients.

Perianal mammary-type myofibroblastoma.

We report a unique case of an extramammary mammary-type myofibroblastoma of the perianal region. The patient was a 40-year old female with no significant past history, who presented with a right side painless perianal mass. Gross examination of the excised mass showed a well-circumscribed, apparently encapsulated, nodular mass weighing 30 g and measuring 5 cm. in the greatest dimension. The cut surface showed solid, yellow homogenous tissue. Microscopically, the neoplasm was composed of bland spindled cells generally arranged into short fascicles with abundant myxoid stroma. The cells stained strongly for desmin and CD34. To our knowledge, a review of the literature discloses only ten cases of extramammary, mammary-type myofibroblastoma.

Lymphoid Enhancer Binding Factor 1 (LEF1) and Paired Box Gene 8 (PAX8): A Limited Immunohistochemistry Panel to Distinguish Solid Pseudopapillary Neoplasms and Pancreatic Neuroendocrine Tumors.

Solid pseudopapillary neoplasms (SPNs) and pancreatic neuroendocrine tumors (PanNETs) are distinctive entities. However, due to overlapping morphologies, distinguishing them remains a diagnostic challenge. Our study investigates the utility of immunohistochemistry for nuclear lymphoid enhancer binding factor 1 (LEF1) and paired box gene 8 (PAX8) in differentiating these 2 entities. LEF1 and PAX8 immunohistochemistry were performed on fine-needle aspiration cell blocks and surgical resection specimens diagnosed as SPN or PanNET at our institution from January 2007 to August 2016. Eight SPN and 25 PanNET cell blocks and 17 SPN and 34 PanNET surgical resection specimens were examined. On cell blocks, positive staining for LEF1 had high frequency, sensitivity, and specificity for SPN (88%, 88%, and 88%) as did positive staining for PAX8 for PanNET (76%, 76%, and 75%). The findings on surgical resection specimens were consistent with those from cell blocks (LEF1+ in SPN: 100%, 100%, and 97%; PAX8+ in PanNET: 59%, 59%, and 100%). A combined LEF1+/PAX8- phenotype showed high sensitivity and specificity for SPN (cell block: 63% and 100%; surgical specimen: 100% and 98%) as did a LEF1-/PAX8+ phenotype for PanNET (cell block: 64% and 100%; surgical specimen: 59% and 100%). SPN and PanNET exhibit opposite immunophenotypic profiles with LEF1+/PAX8- in SPN and LEF1-/PAX8+ in PanNET. The combination of these 2 stains provides an effective means of distinguishing these 2 entities.

Polyomavirus (BK) cytopathic effect in urine cytology is not associated with high risk of developing high-grade urothelial carcinoma.

INTRODUCTION: Polyomavirus cytopathic effect (BK-CPE) is classified as "negative for high-grade urothelial carcinoma" (NHGUC) in the Paris System for Reporting Urinary Cytology. However, polyomaviruses have been historically associated with tumor development and have been recently reported as an independent risk factor for renourinary carcinoma in transplant patients. The aim of the present study was to investigate the relationship between polyomavirus infection in the urinary tract and the subsequent risk of developing high-grade urothelial carcinoma (HGUC) in the general population. MATERIALS AND METHODS: A retrospective case-control study was conducted to assess BK-CPE in all urinary cytology examinations performed from 2009 to 2011 for cases with an interpretation of NHGUC, NHGUC with BK, atypical urothelial cells (AUCs), or AUCs with BK. The endpoint of the present study was a diagnosis of HGUC on either bladder biopsy or urine cytology for those patients with subsequent follow-up data. RESULTS: A total of 252 cases with a urinary cytology interpretation of NHGUC, 234 with NHGUC + BK, 255 with AUCs, and 64 with AUCs + BK were identified. The surgical and cytological follow-up data showed that the overall risk of the development of HGUC for those with NHGUC, NHGUC + BK, AUCs, and AUCs + BK was 6.0%, 6.8%, 23.5%, and 12.5%, respectively. No statistically significant differences were found between the patients with NHGUC and those with NHGUC + BK. A statistically significant difference was found for patients with AUCs compared with patients with NHGUC + BK and those with AUCs + BK (P < 0.001). CONCLUSIONS: The presence of BK-CPE in urine cytology samples does not increase the overall risk of the development of HGUC. Our results support the recommendation from the Paris System for Reporting Urinary Cytology to place urine samples with BK-CPE in the NHGUC category.