Multicenter Clinicopathologic Correlation of Kidney Biopsies Performed in COVID-19 Patients Presenting With Acute Kidney Injury or Proteinuria.

RATIONALE & OBJECTIVE: Kidney biopsy data inform us about pathologic processes associated with infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We conducted a multicenter evaluation of kidney biopsy findings in living patients to identify various kidney disease pathology findings in patients with coronavirus disease 2019 (COVID-19) and their association with SARS-CoV-2 infection. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: We identified 14 native and 3 transplant kidney biopsies performed for cause in patients with documented recent or concurrent SARS-CoV-2 infection treated at 7 large hospital systems in the United States. OBSERVATIONS: Men and women were equally represented in this case series, with a higher proportion of Black (n=8) and Hispanic (n=5) patients. All 17 patients had SARS-CoV-2 infection confirmed by reverse transcriptase-polymerase chain reaction, but only 3 presented with severe COVID-19 symptoms. Acute kidney injury (n=15) and proteinuria (n=11) were the most common indications for biopsy and these symptoms developed concurrently or within 1 week of COVID-19 symptoms in all patients. Acute tubular injury (n=14), collapsing glomerulopathy (n=7), and endothelial injury/thrombotic microangiopathy (n=6) were the most common histologic findings. 2 of the 3 transplant recipients developed active antibody-mediated rejection weeks after COVID-19. 8 patients required dialysis, but others improved with conservative management. LIMITATIONS: Small study size and short clinical follow-up. CONCLUSIONS: Cases of even symptomatically mild COVID-19 were accompanied by acute kidney injury and/or heavy proteinuria that prompted a diagnostic kidney biopsy. Although acute tubular injury was seen among most of them, uncommon pathology such as collapsing glomerulopathy and acute endothelial injury were detected, and most of these patients progressed to irreversible kidney injury and dialysis.

Exceptional response to cyclophosphamide and dexamethasone in a patient with metastatic castrate-resistant prostate cancer and RB1 mutation.

Rates of prostate cancer relapsing from anti-androgen therapies are increasing in the United States and worldwide. It has been suggested that this is caused by variant and altered lineage marker expression within the tumor, allowing for lineage plasticity that then facilitates therapeutic resistance. The genomic landscape of castrate-resistant prostate cancer has been well-defined with the advent of next-generation sequencing, but the clinical applications of these findings as measured by patient outcomes remains poorly understood. Here, we report on a patient with recurrent, metastatic castrate-resistant prostate cancer and identified RB1 mutation with progressive symptomatology, who was treated with cyclophosphamide and dexamethasone after other standard treatment regimens failed. After completing 2 years of treatment, he experienced complete resolution of his symptoms. Disease remission was confirmed on multiple imaging modalities and through serial measurements of prostate-specific antigen levels that showed a reduction of 99%. Our patient's case supports ongoing research that genetic profiling can help elucidate key biological and molecular tumor components, which can then inform targeted, individualized treatment approaches in the management of recurrent, castrate-resistant prostate cancer.

Correlation between body mass index and prostate volume in benign prostatic hyperplasia patients undergoing holmium enucleation of the prostate surgery.

BACKGROUND: Benign prostatic obstruction (BPO) due to benign prostatic hyperplasia (BPH) is a leading cause of morbidity in men over the age of 40. This study examined whether there was an association between body mass index (BMI) and pre-operative prostate volume and whether expression of two genes, alpha-2-macroglobulin (A2M) and transforming growth factor beta 3 (TGFB3), was correlated with BMI, pre-operative prostate volume, and age at surgery. METHODS: Medical records of patients who underwent holmium enucleation of the prostate surgery for treatment of BPO were retrospectively reviewed. Surgical specimens were obtained from formalin-fixed paraffin-embedded blocks, and expression of the targeted genes was quantified using a real time PCR approach. Linear regression analysis was performed to assess association between BMI and prostate volume adjusting for demographic characteristics and co-morbidity. Spearman's correlation was used to examine whether gene expression was correlated with BMI, prostate volume, and age at surgery. RESULTS: A total of 278 patients were identified, including 62.9% European Americans (n = 175) and 27.7% Hispanic Americans (n = 77). BMI was significantly correlated with prostate volume (Spearman's rho = 0.123, P = 0.045). In linear regression analysis, BMI was positively associated with prostate volume (ß = 0.01, P = 0.004), while hyperlipidemia was negatively associated with prostate volume (ß = -0.08, P = 0.02). A trend for a positive association was also observed for diabetes (ß = 0.07, P = 0.099). In the race/ethnicity stratified analysis, age at surgery showed a trend for significantly positive association with prostate volume in European Americans (ß = 0.005, P = 0.08), but not in Hispanic Americans. Expression of the A2M gene in the stroma was negatively correlated with age at surgery (P = 0.006). A2M expression in the gland was positively correlated with prostate volume among older men (Age ≥ 70, P = 0.01) and overweight men (BMI 25-30, P = 0.04). TGFB3 expression in the gland was positively correlated with BMI (P = 0.007) among older men. CONCLUSIONS: This study demonstrated the positive correlation between BMI and prostate volume. Expression of TGFB3 and A2M was correlated with BMI, prostate volume, and age at surgery.

The Banff Working Group Classification of Definitive Polyomavirus Nephropathy: Morphologic Definitions and Clinical Correlations.

Polyomavirus nephropathy (PVN) is a common viral infection of renal allografts, with biopsy-proven incidence of approximately 5%. A generally accepted morphologic classification of definitive PVN that groups histologic changes, reflects clinical presentation, and facilitates comparative outcome analyses is lacking. Here, we report a morphologic classification scheme for definitive PVN from the Banff Working Group on Polyomavirus Nephropathy, comprising nine transplant centers in the United States and Europe. This study represents the largest systematic analysis of definitive PVN undertaken thus far. In a retrospective fashion, clinical data were collected from 192 patients and correlated with morphologic findings from index biopsies at the time of initial PVN diagnosis. Histologic features were centrally scored according to Banff guidelines, including additional semiquantitative histologic assessment of intrarenal polyomavirus replication/load levels. In-depth statistical analyses, including mixed effects repeated measures models and logistic regression, revealed two independent histologic variables to be most significantly associated with clinical presentation: intrarenal polyomavirus load levels and Banff interstitial fibrosis ci scores. These two statistically determined histologic variables formed the basis for the definition of three PVN classes that correlated strongest with three clinical parameters: presentation at time of index biopsy, serum creatinine levels/renal function over 24 months of follow-up, and graft failure. The PVN classes 1-3 as described here can easily be recognized in routine renal biopsy specimens. We recommend using this morphologic PVN classification scheme for diagnostic communication, especially at the time of index diagnosis, and in scientific studies to improve comparative data analysis.

Idiopathic Nonviral Cryoglobulinemia Treated Successfully With Rituximab.

Cryoglobulinemia is a systemic inflammatory syndrome that generally involves small-to-medium vessel vasculitis due to cryoglobulin-containing immune complexes. The therapeutic management of idiopathic cryoglobulinemic vasculitis has yet to be defined because no study has evaluated the best strategies. However, treatment of severe vasculitis is traditionally based on a combination of corticosteroids and immunosuppressants or plasmapheresis, and more recently rituximab. We report a case of 77-year-old female patient diagnosed with idiopathic cryoglobulinemia, treated successfully with 6 months prednisone tapering and 2 doses of rituximab (1 g each dose). After receiving the above-mentioned treatment, her creatinine went back to normal with resolution of proteinuria and hematuria, normalization of serum complements, and significant improvement in her clinical picture. We conclude that rituximab could be an effective treatment for idiopathic cryoglobulnemia.

Ipilimumab granulomatous interstitial nephritis.

Drug-induced interstitial nephritis is a recognized cause of acute and chronic renal failure. Some of them lead to the formation of granulomata. T-cell-mediated immune response is implicated in the pathogenesis. Here, we describe the case of a 74-year-old male patient with metastatic melanoma who was referred to our clinic with a history of rash and worsening renal function. Because of subacute onset, progressively worsening renal function in the presence of skin rash, elevated liver enzymes, and in the background of exposure, medication-induced interstitial nephritis was suspected. He received 3 doses of ipilimumab, a novel drug used in the treatment of metastatic melanoma within 3 months before the onset of renal failure. A renal biopsy was done, which showed granulomatous interstitial nephritis. Renal biopsy findings, temporal relation between renal failure and exposure to medication, and review of the literature supported a diagnosis of ipilimumab-induced renal failure. He was started on steroids, and renal function recovered in the next 1 month. Immune-related adverse reaction is one of the common side effects of ipilimumab. Ipilimumab-induced hepatitis and colitis has been previously reported in the literature. This is the first ever case report of ipilimumab-induced granulomatous interstitial nephritis.

Successful conversion to belatacept after thrombotic microangiopathy in kidney transplant patients.

Thrombotic microangiopathy (TMA) is a severe complication of kidney transplantation. TMA may occur de novo or as recurrent disease post-transplant. De novo disease is usually associated with immunosuppressive drugs or can be seen as a part of endothelial damage that accompanies antibody-mediated rejection. Treatment for de novo TMA is limited to plasma exchange and change in immunosuppression. We report two cases of de novo TMA post-transplant that were successfully treated by converting to belatacept for maintenance immunosuppression.

A unique case of Schistosoma-related ureteral stricture: Diagnosis and surgical reconstruction.

Background: Chronic infection with Schistosoma haematobium can lead to pathology of the upper and lower urinary tracts. While well known as a cause of squamous cell carcinoma of the bladder, relatively little research exists on ureteral involvement. Here, we present a unique case of bilateral ureteral obstruction from schistosomiasis with concomitant ureteral stone disease. Case presentation: A 43-year-old male Somalian immigrant was diagnosed with a right proximal ureteral stone and bilateral multifocal ureteral narrowing causing obstruction with preserved renal function. He underwent a staged repair with right robotic pyelolithotomy and non-transecting ureteroureterostomy, followed by left robotic ureteroureterostomy with stricture excision. Pathology revealed Schistosoma ova. Conclusion: Ureteral stricture from schistosomiasis represents a rare diagnosis for urologists in non-endemic countries. Bilateral ureteral narrowing and concomitant ureteral stone burden presented both diagnostic and reconstructive challenges, requiring a staged repair. Minimally invasive reconstruction was achieved using robotic assistance with good functional outcome.

Clear cell renal cell carcinoma molecular variations in non-Hispanic White and Hispanic patients.

BACKGROUND: The United States is becoming increasingly diverse, but few molecular studies have assessed the progression of clear cell renal cell carcinoma (ccRCC) in diverse patient populations. This study examined ccRCC molecular variations in non-Hispanic White (NHW) and Hispanic patients and their effect on the association of gene expression with high-grade (Grade 3 or 4) ccRCC and overall mortality. METHODS: A total of 156 patients were included in VHL sequencing and/or TempO-Seq analysis. DESeq2 was used to identify the genes associated with high-grade ccRCC. Logistic regression analysis was performed to assess whether race and ethnicity was associated with high/moderate impact VHL somatic mutations and the ccA/ccB subtype. Cox regression analysis was performed to assess association of molecular subtype and gene expression with overall mortality. RESULTS: NHWs had moderate or high impact mutations in the VHL gene at a higher frequency than Hispanics (40.2% vs. 27.4%), while Hispanics had a higher frequency of the ccA subtype than NHWs (61.9% vs. 45.8%). ccA was more common in patients with BMI≥35 (65.2%) than in those with BMI < 25 (45.0%). There were 11 differentially expressed genes between high- and low-grade tumors. The Haptoglobin (HP) gene was most significantly overexpressed in high- compared to low-grade ccRCC in all samples (p-adj = 1.7 × 10-12 ). When stratified by subtype, the 11 genes were significantly differentially expressed in the ccB subtype, but none of them were significant after adjusting for multiple testing in ccA. Finally, patients with the ccB subtype had a significantly increased risk of overall mortality (HR 4.87; p = 0.01) compared to patients with ccA, and patients with high HP expression and ccB, had a significantly increased risk of mortality compared to those with low HP expression and ccA (HR 6.45, p = 0.04). CONCLUSION: This study reports ccRCC molecular variations in Hispanic patients who were previously underrepresented.

Biopsy-proven acute tubular necrosis associated with vancomycin in an adult patient.

Vancomycin causing acute kidney injury has traditionally been associated with acute interstitial nephritis. There have been a few case reports of biopsy-proven acute tubular necrosis (ATN) from vancomycin in the pediatric literature and only one previous report in the adult population. Here, we report a second case of biopsy-proven ATN resulting from vancomycin toxicity.

Native BK virus nephropathy in lung transplant: a case report and literature review.

Classically described in renal allografts, BK virus nephropathy is increasingly recognized in native kidneys of other non-renal solid organ transplants. We discuss a 68-year-old woman with a history of bilateral lung transplant referred for worsening renal function, confirmed to have BK virus nephropathy by biopsy with a serum BK virus polymerase chain reaction of over 59 million copies/mL. She was managed with a reduction in immunosuppression and intravenous cidofovir with no improvement in her clinical parameters. The seven prior reported cases of polyoma virus nephropathy in lung transplant recipients are reviewed, and the challenges of screening and management are discussed.

Feasibility of optical coherence tomography imaging to characterize renal neoplasms: limitations in resolution and depth of penetration.

UNLABELLED: What's known on the subject? and What does the study add? Optical coherence tomography has been used for the diagnosis of retinal disease and has been used experimentally for imaging of vascular plaques, gastrointestinal pathology, bladder cancer, prostate cancer, and recently to examine benign kidney microanatomy. It has not been previously used to image kidney cancer. This study presents the first data on the utility of OCT in the imaging for renal neoplasms. It found that OCT was most successful in distinguishing AML and TCC from normal parenchyma. OCT had more limited success at differentiating oncocytoma. Clear cell tumors and other renal cancer subtypes had a more heterogenous appearance, precluding reliable identification using OCT. The study shows that higher resolution versions of OCT, such as OCM, will be needed to allow optical coherence imaging to reach clinical utility in the assessment of renal neoplasms. OBJECTIVES: • To determine the appearance of normal and neoplastic renal tissue when imaged with optical coherence tomography (OCT). • To preliminarily assess the feasibility of using OCT to differentiate normal and neoplastic renal tissue. PATIENTS AND METHODS: • After radical or partial nephrectomy in 20 subjects, normal renal parenchyma and neoplastic tissue samples were obtained. • The tissue was evaluated with light microscopy and using a bench-top laboratory OCT system with a lateral resolution of 10 µm. • OCT images were compared with histological slides to evaluate the ability of OCT to differentiate renal neoplasms. RESULTS: • Pathological subtypes included eight clear-cell, three papillary and two chromophobe renal carcinomas; two oncocytomas; one angiomyolipoma (AML); two transitional cell carcinomas (TCCs); and one haematoma. • Using OCT, benign renal parenchyma showed recognizable glomeruli and tubules. • TCC had a distinctive appearance on OCT whereas AML showed a unique identifiable signature because of its fat content. Oncocytomas had a lobulated appearance, which appeared subtly different from renal carcinoma. • Renal carcinoma lacked recognizable anatomical elements and had a heterogeneous appearance making differentiation from normal parenchyma at times difficult. • Subtypes of renal cancer appeared to vary on OCT imaging although discrimination was unreliable. CONCLUSIONS: • OCT imaging for renal neoplasms was most successful in distinguishing AML and TCC from normal parenchyma and malignant tumours. Oncocytoma differed subtly from renal carcinoma, making distinction more challenging. • Clear-cell tumours and other renal carcinoma subtypes had a heterogeneous appearance on OCT, which precluded reliable differentiation from normal parenchyma and between renal carcinoma subtypes. • Higher resolution versions of optical coherence imaging, such as optical coherence microscopy, will be necessary to achieve clinical utility.

Leiomyosarcoma of the scrotum: a case report and literature review.

Leiomyosarcoma (LMS) is one of the most common forms of soft tissue sarcoma with approximately 2,500 cases per year in the United States. The symptoms LMS vary depending upon the location, size, and spread of the tumor. In early stages, it may not be associated with any obvious symptoms so diagnosis and treatment may be delayed. In some cases, it can grow quickly and behave aggressively. Most types of LMS occur in the abdomen or in the uterus; although, scrotal LMS can be a very rare presentation of the disease. Here we present our case of a large, ulcerated scrotal LMS originating from subcutaneous tissue but not invading spermatic cord or tunica. Radical orchiectomy with high ligation of spermatic cord was performed, and patient had an uneventful postoperative course. This disease entity remains rare in the literature, and warrants larger studies in order to better understand treatment and oncologic outcomes. When LMS is identified early and is removed by surgical excision, prognosis can be good and full recovery quite likely. When LMS is already large or has spread to other parts of the body, treatment is relatively more complex and the prognosis poor. Hence, prompt diagnosis and treatment of genitourinary LMS require prompt attention, referral to tertiary, referral center should be strongly considered.

The Current State of Communication of Urgent and Significant, Unexpected Diagnoses in Anatomic Pathology.

CONTEXT.­: The concept of critical diagnoses in anatomic pathology is relatively recent and rigorous study of the issue is quite limited. The College of American Pathologists and Association of Directors of Anatomic and Surgical Pathology issued a consensus statement in 2012. There has been no multi-institutional study of communication policies since then. OBJECTIVE.­: To survey the policies of anatomic pathology laboratories regarding communication of critical values. DESIGN.­: A survey of the Association of Directors of Anatomic and Surgical Pathology membership was performed using a 14-question electronic survey tool. RESULTS.­: Responses were received from 38 institutions. Thirty-five of 38 (92%) had a policy on anatomic pathology critical values. Twenty-five of 38 (66%) respondents had read the College of American Pathologists/Association of Directors of Anatomic and Surgical Pathology consensus statement. Twelve of 38 (32%) institutions divided critical values into 2 categories, of which 9 used the College of American Pathologists/Association of Directors of Anatomic and Surgical Pathology terminology; 24 used only a single term, of which 11 used critical value. There was substantial variation in the diagnoses that were considered critical. A direct phone call to the responsible provider was uniformly considered an acceptable means of communication; all other methods had mixed or low support. The most common time frame was same day; many laboratories did not specify a timeframe. Most laboratories document date, time, and person to whom the result was communicated in the final report or an addendum report. Eighteen of 38 (47%) laboratories report an auditing mechanism for communication. CONCLUSIONS.­: Policies for communication of critical/urgent/significant, unexpected results in anatomic pathology are the norm. However, there remains significant variation between institutions in the details of these policies.

Investigation of confocal microscopy for differentiation of renal cell carcinoma versus benign tissue. Can an optical biopsy be performed?

OBJECTIVE: Novel optical imaging modalities are under development with the goal of obtaining an "optical biopsy" to efficiently provide pathologic details. One such modality is confocal microscopy which allows in situ visualization of cells within a layer of tissue and imaging of cellular-level structures. The goal of this study is to validate the ability of confocal microscopy to quickly and accurately differentiate between normal renal tissue and cancer. METHODS: Specimens were obtained from patients who underwent robotic partial nephrectomy for renal mass. Samples of suspected normal and tumor tissue were extracted from the excised portion of the kidney and stained with acridine orange. The stained samples were imaged on a Nikon E600 C1 Confocal Microscope. The samples were then submitted for hematoxylin and eosin processing and read by an expert pathologist to provide a gold-standard diagnosis that can later be compared to the confocal images. RESULTS: This study included 11 patients, 17 tissue samples, and 118 confocal images. Of the 17 tissue samples, 10 had a gold-standard diagnosis of cancer and seven were benign. Of 118 confocal images, 66 had a gold-standard diagnosis of cancer and 52 were benign. Six confocal images were used as a training set to train eight observers. The observers were asked to rate the test images on a six point scale and the results were analyzed using a web based receiver operating characteristic curve calculator. The average accuracy, sensitivity, specificity, and area under the empirical receiver operating characteristic curve for this study were 91%, 98%, 81%, and 0.94 respectively. CONCLUSION: This preliminary study suggest that confocal microscopy can be used to distinguish cancer from normal tissue with high sensitivity and specificity. The observers in this study were trained quickly and on only six images. We expect even higher performance as observers become more familiar with the confocal images.

Primary Malignant Melanoma of the Bladder Treated by Robotic Partial Cystectomy and Immunotherapy.

Background: Primary malignant melanoma (PMM) of the urinary tract is a rare entity, with only 28 cases reported in the literature. We present an interesting case of a 27-year-old Caucasian woman, with family history of melanoma, who initially presented with gross hematuria, and was subsequently found to have PMM of the bladder. Case Presentation: Initially diagnosis was made through transurethral resection of the bladder tumor with clinical suspicion of residual disease in the patient. Subsequently, she underwent robotic partial cystectomy with pelvic lymph node dissection followed by 1 year of pembrolizumab, a PD-1 checkpoint inhibitor. Subsequent imaging demonstrated no evidence of metastatic disease or local recurrence. Conclusion: This case report presents a unique management of a rare pathological diagnosis with the use of robotic partial cystectomy, and a PD-1 checkpoint inhibitor therapy that ultimately has led to a 2-year recurrence-free survival period for this young patient.

A "Pathology Explanation Clinic (PEC)" for Patient-Centered Laboratory Medicine Test Results.

This concept paper addresses communication issues arising between physicians and their patients. To facilitate the communication of essential diagnostic pathology information to patients, and address their questions and concerns, we propose that "Pathology Explanation Clinics" be created. The Pathology Explanation Clinics would provide a channel for direct communications between pathologists and patients. Pathologists would receive special training as "Certified Pathologist Navigators" in preparation for this role. The goal of Pathology Explanation Clinics would be to help fill gaps in communication of information contained in laboratory reports to patients, further explain its relevance, and improve patient understanding of the meaning of such information and its impact on their health and health-care choices. Effort would be made to ensure that Certified Pathologist Navigators work within the overall coordination of care by the health-care team.

Whole-transcriptome sequencing identified gene expression signatures associated with aggressive clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most prevalent subtype of kidney cancer, yet molecular biomarkers have not been used for the prognosis of ccRCC to aide clinical decision making. This study aimed to identify genes associated with ccRCC aggressiveness and overall survival (OS). Samples of ccRCC tumor tissue were obtained from 33 patients who underwent nephrectomy. Gene expression was determined using whole-transcriptome sequencing. The Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma (TCGA-KIRC) RNA-seq data was used to test association with OS. 290 genes were differentially expressed between tumors with high and low stage, size, grade, and necrosis (SSIGN) score (≥7 vs. ≤3) with P ADJ<0.05. Four genes, G6PD, APLP1, GCNT3, and PLPP2, were also over-expressed in advanced stage (III and IV) and high grade (3 and 4) ccRCC and tumor with necrosis (P ADJ<0.05). Investigation stratifying by stage found that APLP1 and PLPP2 overexpression were significantly associated with poorer OS in the early stage (Quartile 1 vs. Quartile 4, HR = 3.87, 95% CI:1.25-11.97, P = 0.02 and HR = 4.77, 95% CI:1.37-16.57, P = 0.04 respectively). These genes are potential biomarkers of ccRCC aggressiveness and prognosis that direct clinical and surgical management.