Reproducibility and prognostic ability of chronicity parameters in kidney biopsy - Comprehensive evaluation comparing microscopy and artificial intelligence in digital pathology.

INTRODUCTION: Semi-quantitative scoring of various parameters in renal biopsy is accepted as an important tool to assess disease activity and prognostication. There are concerns on the impact of interobserver variability in its prognostic utility, generating a need for computerized quantification. METHODS: We studied 94 patients with renal biopsies, 45 with native diseases and 49 transplant patients with index biopsies for Polyomavirus nephropathy. Chronicity scores were evaluated using two methods. A standard definition diagram was agreed after international consultation and four renal pathologists scored each parameter in a double-blinded manner. Interstitial fibrosis (IF) score was assessed with five different computerized and AI-based algorithms on trichrome and PAS stains. RESULTS: There was strong prognostic correlation with renal function and graft outcome at a median follow-up ranging from 24 to 42 months respectively, independent of moderate concordance for pathologists scores. IF scores with two of the computerized algorithms showed significant correlation with estimated glomerular filtration rate (eGFR) at biopsy but not at the end of follow-up. There was poor concordance for AI based platforms. CONCLUSION: Chronicity scores are robust prognostic tools despite interobserver reproducibility. AI-algorithms have absolute precision but are limited by significant variation when different hardware and software algorithms are used for quantification.

Vancomycin nephrotoxicity: A comprehensive clinico-pathological study.

INTRODUCTION: Vancomycin, a commonly prescribed antibiotic particularly in the setting of multi-drug resistant infections, is limited by its nephrotoxicity. Despite its common occurrence, much remains unknown on the clinicopathologic profile as well as the pathogenesis of vancomycin nephrotoxicity. Clinical studies included patients often with severe comorbidities and concomitant polypharmacy confounding the causal pathogenesis. Animal models cannot recapitulate this complex clinical situation. Kidney biopsy was not commonly performed. METHODS: To address this limitation, we studied 36 patients who had renal biopsies for acute kidney injury (AKI) for suspicion of vancomycin nephrotoxicity. Detailed renal biopsy evaluation, meticulous evaluation of clinical profiles, and up-to-date follow-up allowed for a diagnostic categorization of vancomycin nephrotoxicity (VNT) in 25 patients and absence of vancomycin nephrotoxicity (NO-VNT) in 11 patients. For careful comparison of these two groups, we proceeded to compile a clinicopathologic and morphologic profiles characteristic for each group. RESULTS: Patients with VNT had a characteristic clinical profile including a common clinical background, a high serum trough level of vancomycin, a rapidly developed and severe acute kidney injury, and a recovery of renal function often shortly after discontinuation of vancomycin. This clinical course was correlated with characteristic renal biopsy findings including acute tubulointerstitial nephritis of allergic type, frequent granulomatous inflammation, concomitant and pronounced acute tubular necrosis of nephrotoxic type, and vancomycin casts, in the absence of significant tubular atrophy and interstitial fibrosis. This clinico-pathologic profile was different from that of patients with NO-VNT, highlighting its role in the diagnosis, management and pathogenetic exploration of vancomycin nephrotoxicity. CONCLUSION: Vancomycin nephrotoxicity has a distinctive morphologic and clinical profile, which should facilitate diagnosis, guide treatment and prognostication, and confer pathogenetic insights.

Myoglobin Cast Nephropathy Diagnosed on Renal Biopsy in a Patient Treated for Malarial Infection.

Myoglobin cast nephropathy occurs in cases of acute renal injury in which large amounts of myoglobin accumulate in the renal tubules, presenting as muscle pain, reddish-brown urine, and elevated creatine kinase levels. Our case describes a 60-year-old male who came to the emergency department with fevers, mild abdominal pain, and constitutional symptoms one day after returning to the United States from a trip to Nigeria. Initial workup demonstrated an acute kidney injury and elevated aminotransferase levels and the patient was started onatovaquone-proguanil for possible malaria given a recent diagnosis in Nigeria. Two days later, the patient was found to have rhabdomyolysis, resulting in a renal biopsy that showed myoglobin cast nephropathy. Previous literature has suggested mechanisms for the development of rhabdomyolysis in malarial infection, including inflammatory processes, direct effect of parasite accumulation, and drug-induced toxicity. Our case further implicates antimalarial therapy as a cause of rhabdomyolysis and increases awareness of myoglobin cast nephropathy as a potential complication of malaria.

Clinical outcomes and patterns of population-based management of urachal carcinoma of the bladder: An analysis of the National Cancer Database.

BACKGROUND: Given the low incidence of urachal carcinoma of the bladder (UCB), there is limited published data from contemporary population-based cohorts. This study aimed to describe demographic, clinicopathological features, and survival outcomes of patients diagnosed with UCB. METHODS: The National Cancer Database (2004-2016) was queried for UCB patients. Descriptive analyses characterized demographics and clinicopathologic features. We assessed 5-year overall survival (OS) rates of the entire cohort and subgroups of localized/locally advanced and metastatic disease. We utilized Cox proportional hazards models to assess the association between covariates of interest and all-cause mortality and to examine the impact of surgical technique and chemotherapy. RESULTS: We identified 841 patients with UCB. The most common histologic subtype was non-mucinous adenocarcinoma (39.6%). Approximately 50% had ≥cT2 disease, and 14.3% were metastatic at diagnosis. Altogether, partial cystectomy (60%) was most performed, and lymph node dissection was performed in 377 patients (44.8%), with specific temporal increase in utilization over the study period (p < 0.001). Overall, median OS was 59 months, and 5-year OS was 49%. In patients with localized/locally advanced disease, we found no association between partial and radical cystectomy (Hazards ratio [HR] 1.75; 95% CI 0.72-4.3) as well as receipt of perioperative chemotherapy (HR 1.97, 95% CI 0.79-4.90) and outcomes. Lastly, receipt of systemic therapy was not associated with survival benefit (HR 0.785, 95% CI 0.37-1.65) in metastatic disease cohort. CONCLUSION: This large population-based cohort provides insight into the surgical management and systemic therapy, without clear evidence on the association of chemotherapy and survival in the perioperative and metastatic setting.

Renal Cell Carcinoma in End-Stage Renal Disease: A Review and Update.

Renal cell carcinoma (RCC) occurring in the setting of end-stage renal disease (ESRD) shows unique clinicopathological characteristics. The two most frequent types of ESRD-associated RCC are acquired cystic kidney disease-associated renal cell carcinoma (ACKD-RCC) and clear-cell papillary renal cell carcinoma (ccpRCC). Other types of RCC also occur in ESRD, albeit with different frequencies from the non-ESRD general population. The histological features of RCC do not vary in the setting of ESRD vs. non-ESRD, yet other findings, such as multifocality and multiple tumor types, are more frequent in ESRD. Studies have generated novel and important knowledge of the etiology, epidemiology, diagnosis, treatment, immunophenotype, and molecular characteristics of ESRD-associated RCC. Knowledge of these data is important for both pathologists and other physicians who may encounter ESRD patients with RCC. This review presents a comprehensive summary and update of the literature on RCC in ESRD, with a focus on the two most frequent types, ACKD-RCC and ccpRCC.

Mediastinal Germ Cell Tumors: A Review and Update on Pathologic, Clinical, and Molecular Features.

Mediastinal germ cell tumors (MGCTs) are the most common extragonadal germ cell tumors (GCTs) and most often arise in the anterior mediastinum with a male predilection. MGCTs also have a predilection for patients with Klinefelter syndrome and possibly other genetic conditions. MGCTs, as GCTs at other extragonadal sites, are thought to arise from germ cells improperly retained during migration along the midline during embryogenesis. Similar to their counterparts in the testes, MGCTs are classified into seminomatous and nonseminomatous GCTs. Seminomatous MGCT represents pure seminoma, whereas nonseminomatous MGCTs encompass pure yolk sac tumors, embryonal carcinoma, choriocarcinoma, mature or immature teratoma, and mixed GCTs with any combination of GCT types, including seminoma. Somatic-type or hematologic malignancies can also occur in association with a primary MGCT. MGCTs share molecular findings with GCTs at other sites, most commonly the presence of chromosome 12p gains and isochromosome i(12p). Treatment includes neoadjuvant chemotherapy followed by surgical resection of residual tumor, with the exception of benign teratomas, which require only surgical resection without chemotherapy. In this review, we highlight and provide an update on pathologic, clinical, and molecular features of MGCTs. Immunohistochemical profiles of each tumor type, as well as differential diagnostic considerations, are discussed.

Pleomorphic giant cell carcinoma of prostate: Rare tumor with unique clinicopathological, immunohistochemical, and molecular features.

Pleomorphic giant cell carcinoma (PGCC) of the prostate is a rare entity categorized as a variant of prostatic acinar adenocarcinoma in the 2016 World Health Organization (WHO) classification system. PGCC differs from conventional prostatic adenocarcinoma by having bizarre, markedly enlarged, and pleomorphic cells. It differs from high grade urothelial carcinoma by negativity for urothelial differentiation markers, and can be distinguished from sarcomatoid carcinoma by lack of spindle cells. Including two new cases described herein, there have been 51 cases of prostate PGCC reported in the English literature. Clinical features shared by cases of prostate PGCC include poor prognosis, occurrence in older patients, and frequent association with prior therapy. Pathologic features common to cases of prostate PGCC include admixture with a high-grade conventional prostate carcinoma component and absent or reduced expression of prostate differentiation markers. More recent studies have begun to elucidate the molecular characteristics of PGCC, detecting specific mutations and chromosomal translocations, and showing evidence of a high degree of molecular instability in these tumors. We report novel findings in two cases of PGCC including a PIK3CA p.His1047Arg mutation not previously described. One of our cases is the first to clearly demonstrate chronological loss of prostate markers during dedifferentiation from prior conventional prostate carcinoma to PGCC. Herein, we present our two new cases and comprehensively review the literature on all reported cases of PGCC with critical commentary on findings in cases of this rare tumor.

Pathology Trainee Redeployment and Education During the COVID-19 Pandemic: An Institutional Experience.

Pathology training programs throughout the United States have endured unprecedented challenges dealing with the ongoing coronavirus disease 2019 pandemic. At Houston Methodist Hospital, the Department of Pathology and Genomic Medicine planned and executed a trainee-oriented, stepwise emergency response. The focus was on optimizing workflows among areas of both clinical and anatomic pathology, maintaining an excellent educational experience, and minimizing trainee exposure to coronavirus disease 2019. During the first phase of the response, trainees were divided into 2 groups: one working on-site and the other working remotely. With the progression of the pandemic, all trainees were called back on-site and further redeployed within our department to meet the significantly increased workload demands of our clinical laboratory services. Adjustments to trainee educational activities included, among others, the organization of a daily coronavirus disease 2019 virtual seminar series. This series served to facilitate communication between faculty, laboratory managers, and trainees. Moreover, it became a forum for trainees to provide updates on individual service workflows and volumes, ongoing projects and research, as well as literature reviews on coronavirus disease 2019-related topics. From our program's experience, redeploying pathology trainees within our department during the coronavirus disease 2019 pandemic resulted in optimization of patient care while ensuring trainee safety, and importantly, helped to maintain continuous high-quality education through active involvement in unique learning opportunities.

Seminal vesicle invasion combined with extraprostatic extension is associated with higher frequency of biochemical recurrence and lymph node metastasis than seminal vesicle invasion alone: Proposal for further pT3 prostate cancer subclassification.

The 8th edition of the American Joint Committee on Cancer (AJCC) TNM staging system subdivides prostatic pT3 tumors into pT3a, which includes cases with extraprostatic extension (EPE) and pT3b, which is defined by the presence of seminal vesicle invasion (SVI) with or without EPE. Yet, it is not established whether combined SVI and EPE impart a worse prognosis compared to SVI alone. We studied a cohort of 69 prostatectomy patients with SVI with or without EPE. Patient age at the time of radical prostatectomy was documented and Gleason score and presence or absence of EPE and/or SVI were determined. Biochemical recurrence (BCR) was defined as a PSA rise >0.2 ng/mL. The frequency of BCR was 33.9% in cases with combined EPE and SVI versus 12.5% in cases with SVI alone (relative risk = 2.71). An additional cohort of 88 patients also showed a higher frequency of lymph node metastasis of 29% in patients with combined SVI and EPE at the time of radical prostatectomy versus a 10% frequency of lymph node metastasis in patients with SVI alone (relative risk = 2.9). Based on our data, we propose further subdividing pT3 prostate cancers into three groups: EPE alone (pT3a), SVI alone (pT3b), and combined EPE and SVI (pT3c). This classification system would more accurately identify patients with pT3 prostate cancer who are more likely to experience worse outcomes and provide clinicians with additional information to aid in follow-up and postoperative treatment decisions.

Lesions of anogenital mammary-like glands: Four cases including novel pathologic and immunohistochemical observations.

Anogenital mammary-like glands, formerly described as ectopic breast tissue, are currently considered to be normal histologic components of the anogenital region. Anogenital mammary-like glands can give rise to many lesions identical to counterparts in the native female breast. We describe four cases of such lesions, including fibroadenoma, gynecomastia-like hyperplasia, and ectopic mammary-type tissue with a spectrum of usual ductal hyperplasia, apocrine metaplasia, adenosis, and pseudolactational change. All four cases occurred in young women (ages 29-38) who presented with vulvar or perianal masses. Similar to previously reported cases, these lesions shared histologic and immunohistochemical characteristics identical to native female breast lesions. Novel findings in our cases included (1) the first case of gynecomastia-like change to be reported in the perianal area of a female, (2) Immunohistochemical staining identifying a 3-layered epithelium characterized by a population of CK14 and CK5/6 positive and hormone receptor negative superficial luminal cells, and (3) diffuse, strong positivity for GATA3 in all cases. Our study adds to the literature on these rare lesions and highlights findings which may be useful in understanding the pathogenesis and improving the diagnosis of anogenital mammary-like gland lesions.

Hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cell carcinoma: Morphological appraisal with a comprehensive review of differential diagnoses.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant syndrome wherein affected individuals are at risk for the development of cutaneous leiomyomas, early-onset multiple uterine leiomyomas, and an aggressive subtype of renal cell cancer. HLRCC is caused by germline mutations in the fumarate hydratase (FH) gene, which inactivates the enzyme and alters the function of the tricarboxylic acid/Krebs cycle. This article reviews the hitherto described morphologic features of HLRCC-associated renal cell carcinoma (RCC) and outlines the differential diagnosis and ancillary use of immunohistochemistry and molecular diagnostics for these tumors. The morphologic spectrum of HLRCC-associated RCC is wide and histologic features, including tumor cells with prominent nucleoli, perinucleolar halos, and multiple architectural patterns within the same tumor, which are suggestive of this diagnosis. FH immunohistochemistry in conjunction with genetic counseling and germline FH testing are the important parameters for detection of this entity. These kidney tumors warrant prompt treatment as even smaller sized lesions can demonstrate aggressive behavior and systemic oncologic treatment in metastatic disease should, if possible, be part of a clinical trial. Screening procedures in HLRCC families should preferably be evaluated in large cohorts.

Lack of expression of ALK and CD30 in breast carcinoma by immunohistochemistry irrespective of tumor characteristics.

CD30 is a member of the tumor necrosis factor family of cell surface receptors normally expressed in lymphocytes, as well as some lymphomas, but has been described in other malignancies. Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor that belongs to the insulin receptor superfamily, and is normally expressed in neural cells, but has been detected in several malignancies. There is conflicting data in the literature that describes the expression of these receptors in breast cancer, and the aim of this study is to test the expression of CD30 and ALK in a cohort of Middle Eastern patients with breast carcinoma.Cases of invasive breast cancer from the archives of AUBMC were reviewed over a period of 9 years, and the blocks that were used for immunohistochemical staining for ER, PR, Her-2/neu were selected. Immunohistochemical staining for CD30 (JCM182) and ALK (5A4 and D5F3) was performed.Two hundred eighty-four cases were identified (2 cases were male), with a mean age of 55 ±â€Š12. CD30 and ALK expression was not seen in any of the cases.Our cohort showed complete negativity to both CD30 and ALK, adding to the conflicting data available in the literature, and more studies are needed to reliably identify a trend of expression of CD30 and ALK in breast carcinoma, especially in the Middle East.

The effects of the Bethesda System 2014 on endometrial cell reporting and follow-up endometrial biopsies in women 45 years of age and over.

INTRODUCTION: The Bethesda System (TBS) guidelines for reporting the presence of endometrial cells on Papanicolaou tests increased the reporting age from 40 (TBS 2001) to 45 (TBS 2014) years. Exfoliated endometrial cells (EMC) are usually a normal finding. Nevertheless, benign-appearing EMC occasionally correspond to endometrial hyperplasia or malignancy, especially in older, postmenopausal women. This study assesses the impact of this age cutoff change. MATERIALS AND METHODS: This retrospective review compares endometrial biopsies following TBS 2001 and TBS 2014. Papanicolaou tests with EMC reported in women older than age 40 or 45 years were correlated with follow-up endometrial biopsies performed between May 25, 2014, to May 26, 2015, and May 27, 2015, to May 26, 2016, respectively. RESULTS: The number of reported EMC declined from 770 to 492 (a 36.1% decrease). The follow-up endometrial biopsy rate for Papanicolaou tests reporting EMC using TBS 2001 was 13.6% (105 of 770) versus TBS 2014 at 13.8% (68 of 492; P = 0.92). For TBS 2001, 15% of women aged 45 and older had follow-up biopsies (65 of 434; P = 0.62). Most follow-up biopsies showed benign endometrium. In the TBS 2001 group, 1 biopsy showed malignancy and another showed complex hyperplasia with atypia. Both patients were older than 45 years. The TBS 2014 group contained 1 biopsy of malignancy and 1 with simple hyperplasia with focal atypia. CONCLUSIONS: The implementation of TBS 2014 reduced the frequency of reporting benign-appearing endometrial cells. The follow-up biopsy rate has remained essentially the same, but the total number of biopsies performed decreased, with a similar low yield of significant abnormalities.

Health effects associated with waterpipe smoking.

OBJECTIVE: It is widely held that waterpipe smoking (WPS) is not associated with health hazards. However, several studies have documented the uptake of several toxicants and carcinogens during WPS that is strongly associated with harmful health effects. This paper reviews the literature on the health effects of WPS. DATA SOURCES: Three databases-PubMed, MEDLINE and EMBASE-were searched until August 2014 for the acute and long-term health effects of WPS using the terms 'waterpipe' and its synonyms (hookah, shisha, goza, narghileh, arghileh and hubble-bubble) in various spellings. STUDY SELECTION: We included original clinical studies, case reports and systematic reviews and focused on clinical human studies. ∼10% of the identified studies met the selection criteria. DATA EXTRACTION: Data were abstracted by all three authors and summarised into tables. Abstracted data included study type, results and methodological limitations and were analysed jointly by all three authors. DATA SYNTHESIS: WPS acutely leads to increased heart rate, blood pressure, impaired pulmonary function and carbon monoxide intoxication. Chronic bronchitis, emphysema and coronary artery disease are serious complications of long-term use. Lung, gastric and oesophageal cancer are associated with WPS as well as periodontal disease, obstetrical complications, osteoporosis and mental health problems. CONCLUSIONS: Contrary to the widely held misconception, WPS is associated with a variety of adverse short-term and long-term health effects that should reinforce the need for stronger regulation. In addition, this review highlights the limitations of the published work, which is mostly cross-sectional or retrospective. Prospective studies should be undertaken to assess the full spectrum of health effects of WPS, particularly in view of its growing popularity and attractiveness to youth.