The Clinicopathologic Spectrum of Membranous Nephropathy with Lupus-Like Features.

INTRODUCTION: The pathologic features of membranous lupus nephritis (MLN) are occasionally encountered in secondary membranous nephropathy (sMN) without overt clinical evidence of systemic lupus erythematosus. Moreover, some sMN with lupus-like features (lupus-like membranous nephropathy [LL-MN]) have a clinical presentation more typical of primary membranous nephropathy (pMN). Based on the confounding clinical and pathologic presentation, it is unclear how to categorize and treat these patients. METHODS: We performed immunohistochemical staining for recently discovered target antigens associated with MN -NELL-1, THSD7A, and EXT1/2 and compared the clinicopathologic presentation of patients with LL-MN to those with pMN and MLN. RESULTS: From 2015 to 2020, there were 21 patients with MLN and 99 with MN, of which 59% were diagnosed pMN and 41% sMN. 44% of sMN patients showed lupus-like features (LL-fx). All LL-MN patients were negative for PLA2R and NELL1, but 12% were positive for EXT1/2. 50% of LL-MN patients had an identifiable systemic disease, of which 56% were autoimmune disease (AD) and 44% infection. Compared to pMN, LL-MN had a higher incidence of underlying AD (p = 0.02). Within pMN, 24% also had LL-fx (LL-pMN), and all but 1 were PLA2R- (78%) or NELL1-positive (15%). Only 5% of pMN patients had an AD, 66% of which showed LL-fx. Most idiopathic LL-MN were treated and behaved clinically similarly to pMN. There were no differences in outcome in terms of progression toward end-stage renal disease or mortality between LL-MN versus pMN and MLN. CONCLUSION: LL-MN appears to have a significant association with underlying AD and has a subset showing EXT1/2 positivity, whereas most LL-pMN and idiopathic LL-MN likely represent an atypical pathologic presentation of pMN.

Subepithelial deposits with microspherular structures in membranous glomerulonephritis.

Rare cases of membranous glomerulopathy (MGN) with subepithelial deposits consisting of microspherular structures identified by electron microscopy have been described in the literature as either MGN with spherules or podocyte infolding glomerulopathy (PIG). The paucity of available studies shows a strong association with underlying autoimmune disease. To further understand the significance of subepithelial microspherular deposits, we retrospectively identified native kidney biopsies from 10 patients diagnosed as MGN with subepithelial microspherular structures identified by ultrastructural examination at the University of Rochester Medical Center (URMC) during an 11-year period. The majority were Caucasian (80%) with a mean age of 51.3 (±12.9) years. 50% had an autoimmune disorder, of which 80% were SLE. Two SLE cases had concomitant rheumatoid arthritis and Sjogren's syndrome. One additional case had antiphospholipid syndrome and showed lupus-like features on biopsy. 40% were idiopathic and negative for PLA2R, NELL1, and THSD7A. MGN with subepithelial microspherular structures is frequently associated with an underlying autoimmune disease. The majority are negative for markers of primary MGN (PLA2R, THSD7A, and NELL1) and show features suggestive of secondary MGN.

The spectrum of renal diseases with lupus-like features: a single-center study.

BACKGROUND: A subset of patients without overt systemic lupus erythematosus (SLE) present with biopsy findings typically seen in lupus nephritis (LN). Although a minority eventually develops SLE, many do not. It remains unclear how to classify or treat these patients. Our study attempted to further understand the clinical and pathological characteristics of cases with lupus-like nephritis (LLN). METHODS: Among 2700 native kidney biopsies interpreted at University of Rochester Medical Center (URMC) from 2010 to 2019, we identified 27 patients with biopsies showing lupus-like features (LL-fx) and 96 with LN. Of those with LL-fx, 17 were idiopathic LLN and 10 were associated with a secondary etiology (e.g., infection/drugs). RESULTS: At the time of biopsy, the LLN-group tended to be slightly older (44 vs. 35), male (58.8 vs. 17.7%, p = .041), and Caucasian (47.0 vs. 28.1%, p = .005). Chronic kidney disease was the most common biopsy indication in LLN (21.4 vs. 2.8%, p = .001). Both LN and LLN presented with nephrotic-range proteinuria (mean 5.73 vs. 4.40 g/d), and elevated serum creatinine (mean 1.66 vs. 1.47 mg/dL). Tubuloreticular inclusions (TRIs; p < .001) and fibrous crescents (p = .04) were more often seen in LN, while more tubulointerstitial scarring was seen in LLN (p = .011). At mean follow-up of 1684 d (range: 31-4323), none of the LLN patients developed ESRD. A subset of both LN and cases with LL-fx overlapped with other autoimmune diseases. CONCLUSIONS: Lupus-like pathologic features are seen in a wide array of disease processes. The findings suggest that LLN may be a manifestation of an autoimmune process that overlaps with SLE.

Myeloid bodies is not an uncommon ultrastructural finding.

The presence of myeloid bodies (MBs) is classically associated with Fabry disease (FD). However, MBs are also identified in patients without clinical evidence of FD. We attempt to further understand the clinicopathologic significance of incidental MBs in those without FD. Among the 4400 renal biopsies accessioned at the University of Rochester Medical Center from 2010 to 2021, we identified 32 cases showing MBs, 6 of which had FD. Medications were compared between a non-FG and a control-group of randomly selected cases without MBs (non-MBs). Both Fabry-group (FG) and non-Fabry-group (non-FG) were predominantly middle-aged (mean 48 years vs 56, respectively). Non-FG had slight female predominance (1:4), while all in FG were female. The majority of both non-FG and non-MBs cohort were on the same medications reported to cause phospholipidosis except sertraline and hydralazine (p = .04), which were more frequent in non-FG. Ultrastructurally, non-FG tended to show focal MBs in predominantly podocytes, while FG showed more extensive MBs in not only podocytes but also parietal, tubular, endothelial, and myocyte cells (p = .03). In addition, half of FG had another superimposed renal disease including kappa-light chain deposition disease, thin-basement membrane nephropathy, and lithium-related changes. MBs are encountered not only in FD but in other settings including CADs, toxins, and other inheritable diseases. Although secondary causes of MBs typically show less extensive involvement compared to FD, these features overlap. Given the challenges in diagnosing female carriers, the finding of MBs, though not specific to FD, may be the only clue that leads to further work-up and timely diagnosis, underscoring the importance of considering FD among other etiologies in differential diagnosis.

Sonographic Evaluation of Genitourinary Inflammatory Pseudotumors and Its Mimics.

ABSTRACT: Inflammatory pseudotumor is a relatively rare, nonneoplastic lesion composed of inflammatory cells and myofibroblastic spindle cells that can be identified on sonographic evaluation of the genitourinary system. These lesions are thought to be an inflammatory response to insults such as surgery, trauma, infection, or malignancy. Such lesions need to be distinguished from true neoplasms and other benign lesions, including inflammatory responses and infectious processes. Identification of inflammatory pseudotumors and its mimics is important for radiologists to guide patient treatment and follow-up. This pictorial essay presents sonographic features of inflammatory pseudotumors of the genitourinary tract and its mimics with cross-sectional imaging and histopathology, where available.

Validation of GEMCaP as a DNA Based Biomarker to Predict Prostate Cancer Recurrence after Radical Prostatectomy.

PURPOSE: We aimed to validate GEMCaP (Genomic Evaluators of Metastatic Cancer of the Prostate) as a novel copy number signature predictive of prostate cancer recurrence. MATERIALS AND METHODS: We randomly selected patients who underwent radical prostatectomy at Cleveland Clinic or University of Rochester from 2000 to 2005. DNA isolated from the cancer region was extracted and subjected to high resolution array comparative genomic hybridization. A high GEMCaP score was defined as 20% or greater of genomic loci showing copy number gain or loss in a given tumor. Cox regression was used to evaluate associations between the GEMCaP score and the risk of biochemical recurrence. RESULTS: We report results in 140 patients. Overall 38% of patients experienced recurrence with a median time to recurrence of 45 months. Based on the CAPRA-S (Cancer of the Prostate Risk Assessment Post-Surgical) score 39% of the patients were at low risk, 42% were at intermediate risk and 19% were at high risk. The GEMCaP score was high (20% or greater) in 31% of the cohort. A high GEMCaP score was associated with a higher risk of biochemical recurrence (HR 2.69, 95% CI 1.51-4.77) and it remained associated after adjusting for CAPRA-S score and age (HR 1.94, 95% CI 1.06-3.56). The C-index of GEMCaP alone was 0.64, which improved when combined with the CAPRA-S score and patient age (C-index = 0.75). CONCLUSIONS: A high GEMCaP score was associated with biochemical recurrence in 2 external cohorts. This remained true after adjusting for clinical and pathological factors. The GEMCaP biomarker could be an efficient and effective clinical risk assessment tool to identify patients with prostate cancer for early adjuvant therapy.

Cautery artifact understages urothelial cancer at initial transurethral resection of large bladder tumours.

INTRODUCTION: We sought to determine how frequently cautery (thermal) artifact precludes an accurate determination of stage at initial transurethral resection of bladder tumour (TURBT) of large bladder tumours. METHODS: We queried our institution's billing data to identify patients who underwent TURBT for large bladder tumours >5cm (CPT 52240) by two urologists at an academic centre from January 2009 through April 2013. Only patients who underwent initial-staging TURBT for urothelial cancer were included. Pathological reports were reviewed for stage, number of separate pathological specimens per TURBT, and presence of cautery artifact. Operative reports were reviewed for whether additional cold cup biopsies were taken of other suspicious areas of the bladder, resident involvement, and type of electrocautery. RESULTS: We identified 119 patients who underwent initial staging TURBT for large tumours. Cautery artifact interfered with accurate staging in 7/119 (6%) of cases. Of these, six patients underwent restaging TURBT, with 50% percent experiencing upstaging to T2 disease. Tumour size, tumour grade, whether additional cold cup biopsies were taken, number of separate pathological specimens sent, and resident involvement were not associated with cautery artifact (all p>0.05). Bipolar resection had a higher rate of cautery artifact 5/42 (12%), compared to monopolar resection 2/77 (2.6%) approaching significance (p=0.095). CONCLUSIONS: Cautery artifact may delay accurate staging at initial TURBT for large tumours by understaging up to 6% of patients.

Testicular Microlithiasis in the Setting of Primary Extragonadal Germ Cell Tumor: A Case Series.

The clinical significance of testicular microlithiasis (TM) in patients with primary extragonadal germ cell tumor (EGCT) is not well understood. When EGCT is suspected, sonographic and physical examination of the testicles should be performed to evaluate for testicular lesion or atrophy; negative testicular ultrasound with current technology virtually excludes the possibility of occult primary lesion. Although EGCTs are known to be associated with elevated level of serum tumor markers, the utility of tumor markers in the presence of TM is not well understood. Current guidelines for TM follow-up and management do not include any potential correlation between TM and primary EGCT, an association that should be addressed on future updates.

A case series of transformation of teratoma to primitive neuroectodermal tumor: evolving management of a rare malignancy.

Primitive neuroectodermal tumor (PNET) is a pathologic diagnosis that encompasses several different tumor types, including central nervous system tumors and Ewing's sarcomas. Teratoma, a common element of germ cell tumor (GCT), has the ability to transform to malignant PNET in a small number of patients. Making a definitive diagnosis of PNET is difficult given its deviation from elements of GCT and its non-specific pathologic findings. Establishing the diagnosis is crucial as PNETs respond poorly to standard platinum-based chemotherapy used for treatment of GCT. Primary treatment for PNET is surgical, though this is often not feasible in many patients due to extensive disease at diagnosis. As an alternative, chemotherapy regimens traditionally used for Ewing's sarcoma, such as vincristine, doxorubicin and cyclophosphamide alternating with ifosfamide and etoposide, have shown limited efficacy in the neoadjuvant, adjuvant, and palliative settings. Future research should delineate the genetic underpinnings of PNET and develop therapeutic options accordingly.

Clinical and pathologic features and clinical impact of false negative thyroid fine-needle aspirations.

BACKGROUND: Although thyroid fine-needle aspiration (TFNA) is an excellent test in evaluating thyroid nodules, there are occasionally false negatives (FN). The clinical impact and pathologic features of FN TFNA is understudied in the peer-reviewed literature. METHODS: A cohort of patients with thyroid cancer was separated into those with referring FN TFNA and those with referring true positive (TP) TFNA. Preoperative characteristics, pathologic finding, and clinical outcomes were compared within the 2 groups. RESULTS: A total of 192 patients with TP TFNA (n = 162) and FN TFNA (n = 30) were included in the study. There were no significant differences in the demographics or length of follow-up of the 2 groups. The FN TFNA group was more likely to have a larger clinical nodule size and experienced a significant delay from initial TFNA to surgery. The FN TFNA group was more likely to be diagnosed with the follicular variant of papillary thyroid cancer (73.3% vs 25.9%, P < .001), less likely to have positive lymph nodes at surgery (6.7% vs 35.8%, P = .001), and more likely to undergo 2-step surgery (30% vs 9.9%, P = .007). Despite the delay in diagnosis, persistent/recurrent or metastatic disease, incidence of aggressive histologic variants, and pT4 disease was not different in the 2 groups. CONCLUSIONS: The clinical impact of FN TFNA at our high-volume center is minimal. Cancers in this setting are low grade, and outcomes are not adversely affected despite the delay in diagnosis.

Copy number and gene expression differences between African American and Caucasian American prostate cancer.

BACKGROUND: The goal of our study was to investigate the molecular underpinnings associated with the relatively aggressive clinical behavior of prostate cancer (PCa) in African American (AA) compared to Caucasian American (CA) patients using a genome-wide approach. METHODS: AA and CA patients treated with radical prostatectomy (RP) were frequency matched for age at RP, Gleason grade, and tumor stage. Array-CGH (BAC SpectralChip2600) was used to identify genomic regions with significantly different DNA copy number between the groups. Gene expression profiling of the same set of tumors was also evaluated using Affymetrix HG-U133 Plus 2.0 arrays. Concordance between copy number alteration and gene expression was examined. A second aCGH analysis was performed in a larger validation cohort using an oligo-based platform (Agilent 244K). RESULTS: BAC-based array identified 27 chromosomal regions with significantly different copy number changes between the AA and CA tumors in the first cohort (Fisher's exact test, P < 0.05). Copy number alterations in these 27 regions were also significantly associated with gene expression changes. aCGH performed in a larger, independent cohort of AA and CA tumors validated 4 of the 27 (15%) most significantly altered regions from the initial analysis (3q26, 5p15-p14, 14q32, and 16p11). Functional annotation of overlapping genes within the 4 validated regions of AA/CA DNA copy number changes revealed significant enrichment of genes related to immune response. CONCLUSIONS: Our data reveal molecular alterations at the level of gene expression and DNA copy number that are specific to African American and Caucasian prostate cancer and may be related to underlying differences in immune response.

"Sandwich" plating for intra-articular distal radius fractures with volar and dorsal metaphyseal comminution.

INTRODUCTION: Intra-articular distal radius fractures with volar and dorsal comminution present a special challenge to the hand surgeon. METHODS: Ten patients formed the study cohort. All plates were low profile and stainless steel. Radiographic parameters, range of motion, and strength compared to the uninjured side were recorded. Functional outcome was evaluated by Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire and Gartland and Werley scoring system. RESULTS: Median age at surgery was 58 years (range, 24 to 86). Mean follow-up was 17 months (range, 12 to 28). According to the AO classification system, there were three type C2 and seven type C3 fractures. Median preoperative dorsal angulation was 24 deg; median postoperative dorsal angulation was 3 deg. Eighty percent (8) of the fractures also had an intra-articular step-off or gap, all of which were corrected to neutral by the procedure. Compared with the contralateral side, mean extension and flexion were 73 and 75%, respectively, pronation and supination were 95 and 88%, respectively, and grip strength and thumb pinch were 72 and 87%, respectively. Mean postoperative DASH score was 16 points, and 70% (7) of the patients had Gartland and Werley scores of good or excellent. None of the patients needed to have their plates removed, and no extensor tendon rupture was reported. CONCLUSIONS: The "sandwich" plating technique is an effective method of regaining near-anatomic reconstruction of intra-articular, volarly and dorsally comminuted distal radius fractures. Results from this study demonstrate that patients can expect to regain about 80% of their range of motion and strength. Moreover, 70% of the patients will have good to excellent functional outcomes. This is the first study to examine range of motion and functional outcome of low-profile "sandwich" plating without plate removal.

Impact of socioeconomic factors on prostate cancer outcomes in black patients treated with surgery.

OBJECTIVES: The role of socioeconomic factors in the worse outcome of black men with prostate cancer remains unclear. To determine whether socioeconomic factors affect prostate cancer outcomes, we studied a cohort of only black patients to minimize known confounding factors. METHODS: We studied black men treated with radical prostatectomy at New York Veterans Administration Medical Center and Memorial Sloan-Kettering Cancer Center between 1990 and 2005. A centralized pathology review process determined the Gleason score of all cases. Prostate-specific antigen (PSA) recurrence at both sites was defined as PSA of 0.2 or greater with a confirmatory rise. By matching patients' home zip codes to the U.S. Census Bureau database, we obtained corresponding socioeconomic data regarding median household income (income) and percentage of population with a high school (degree). We analyzed income, education, and clinical and pathological parameters for the whole cohort. RESULTS: We studied 430 black patients. They resided in neighborhoods where median household income was $41,498.10 and mean percentage of high school graduates was 73.4%. A total of 88 patients (20.9%) had PSA recurrence. Median follow-up for survivors was 37 months. Neither income nor education evaluated as continuous or categorical variables were predictors of PSA recurrence. When evaluated as composite categorical variable, the combination of greater income and education did not predict disease-free survival. CONCLUSIONS: Data suggest that socioeconomic factors have limited impact on PSA recurrence in black men treated with radical prostatectomy. Thus, biologic factors might have a role in the poor outcomes in this population.