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.

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.

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.

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.

Significance of atypical endometrial cells in women younger than 40 years of age.

INTRODUCTION: The presence of atypical endometrial cells in the Papanicolaou (Pap) test has been associated with an increased rate of endometrial malignancy, with reported rates ranging from 14% to 47%. However, most reported studies have focused on patients who were aged >40 years. The purpose of the present study was to investigate the clinical significance of identifying atypical endometrial cells in Pap test samples in women aged <40 years of age. MATERIALS AND METHODS: A search of the cytology Pap test database was performed from 2000 to 2014 using the keywords "atypical endometrial cells" or "atypical glandular cells favor endometrial origin" in women aged <40 years. The available ThinPrep slides were reviewed. The patients' clinical presentation, follow-up endometrial biopsy findings, treatment, and clinical follow-up data were recorded. Endometrial carcinoma tissue sections were screened for Lynch syndrome. RESULTS: The database search yielded 63 study cases. Of these 63 patients, 52 had subsequently undergone endometrial biopsy. Of the 52 patients with follow-up biopsy findings available, 9 (17.3%) had premalignant (5 with atypical hyperplasia) or malignant (4 with endometrioid adenocarcinoma) lesions. In addition, 16 patients (30.8%) had other endometrial pathologic features. The 9 patients with premalignant or malignant endometrial lesions (8 white, 1 black) were overweight or obese; 3 of the patients did not have any clinical symptoms. All 4 patients with endometrioid adenocarcinoma had negative Lynch syndrome screening findings. CONCLUSIONS: Our results suggest that it is important to recognize the presence of atypical endometrial cells in the Pap tests from young patients, given its association with the finding of premalignant and malignant pathologic features in subsequent endometrial biopsies.

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.