Renal Manifestations of IgG4-Related Disease: A Concise Review.

IgG4-related disease (IgG4-RD) is an immune-mediated disorder marked by fibro-inflammatory masses that can infiltrate multiple organ systems. Due to its relatively recent discovery and limited understanding of its pathophysiology, IgG4-related disease may be difficult to recognize and is consequently potentially underdiagnosed. Renal involvement is becoming regarded as one of the key features of this disease. To date, the most well-recognized renal complication of IgG4-related disease is tubulointerstitial nephritis, but membranous glomerulonephritis, renal masses, and retroperitoneal fibrosis have also been reported. This concise review has two objectives. First, it will briefly encapsulate the history, epidemiology, and presentation of IgG4-related disease. Second, it will examine the reported renal manifestations of IgG4-related disease, exploring the relevant histology, imaging, clinical features, and treatment considerations. This synthesis will be highly relevant for nephrologists, rheumatologists, general internists, and renal pathologists to raise awareness and help improve early recognition of IgG4-related kidney disease (IgG4-RKD).

Characterization of Membranous Nephropathy with Microspherular Deposits.

Introduction: Membranous nephropathy (MN) is a common cause of adult nephrotic syndrome in the USA. The typical ultrastructural finding is of global uniformly dense subepithelial electron-dense immune complex deposits along glomerular basement membranes. However, early reports described deposits with a unique microspherular substructure. There was variability in what was identified as microspherular, sometimes overlapping with other entities such as podocyte infolding glomerulopathy. Currently, the nature, composition, and clinical significance of these microspherular deposits (MSDs) remain unknown. Method: We report the clinicopathologic features of a series of MN cases with MSD, with detailed ultrastructural characterization as well as PLA2R and THSD7A immunohistochemical and IgG subclass-staining characteristics. The proportion of MSD to overall deposits is segregated into two groups: global MSD with >50% MSD (n = 14) and segmental MSD with <50% (n = 5). Results: The size and appearance of the microspherules were nearly identical in global and segmental MSD groups (mean diameter of 77.9 nm and 77.2 nm, respectively), with subepithelial (n = 19) or intramembranous (n = 12) distributions in all cases. Mesangial MSDs (n = 5) were only found in the global MSD group. The majority of biopsies (86% of global MSD and 100% of segmental MSD) were Ehrenreich-Churg stage 2 or above; early stage 1 was only observed in the global MSD group. All but 3 cases were PLA2R/THSD7A double negative; 1 THSD7A positive in global MSD and 2 PLA2R positive in segmental MSD. IgG1 was the dominant subclass in the global MSD group, and IgG4 was dominant in the segmental MSD group, including the 2 PLA2R-positive cases. Conclusion: The findings suggest that MSDs are more commonly associated with secondary MN. This case series is the largest to date, and the findings may yield etiologic and prognostic information on this rare but unique subset of MN and provide a well-characterized cohort of cases for future studies.

Metabolically Active Zones Involving Fatty Acid Elongation Delineated by DESI-MSI Correlate with Pathological and Prognostic Features of Colorectal Cancer.

Colorectal cancer (CRC) is the second leading cause of cancer deaths. Despite recent advances, five-year survival rates remain largely unchanged. Desorption electrospray ionization mass spectrometry imaging (DESI) is an emerging nondestructive metabolomics-based method that retains the spatial orientation of small-molecule profiles on tissue sections, which may be validated by 'gold standard' histopathology. In this study, CRC samples were analyzed by DESI from 10 patients undergoing surgery at Kingston Health Sciences Center. The spatial correlation of the mass spectral profiles was compared with histopathological annotations and prognostic biomarkers. Fresh frozen sections of representative colorectal cross sections and simulated endoscopic biopsy samples containing tumour and non-neoplastic mucosa for each patient were generated and analyzed by DESI in a blinded fashion. Sections were then hematoxylin and eosin (H and E) stained, annotated by two independent pathologists, and analyzed. Using PCA/LDA-based models, DESI profiles of the cross sections and biopsies achieved 97% and 75% accuracies in identifying the presence of adenocarcinoma, using leave-one-patient-out cross validation. Among the m/z ratios exhibiting the greatest differential abundance in adenocarcinoma were a series of eight long-chain or very-long-chain fatty acids, consistent with molecular and targeted metabolomics indicators of de novo lipogenesis in CRC tissue. Sample stratification based on the presence of lympovascular invasion (LVI), a poor CRC prognostic indicator, revealed the abundance of oxidized phospholipids, suggestive of pro-apoptotic mechanisms, was increased in LVI-negative compared to LVI-positive patients. This study provides evidence of the potential clinical utility of spatially-resolved DESI profiles to enhance the information available to clinicians for CRC diagnosis and prognosis.

C3 Glomerulopathy: A Review with Emphasis on Ultrastructural Features.

C3 glomerulopathy (C3G) is a rare disease resulting from dysregulation of the alternative complement pathway, resulting in the deposition of complement component 3 (C3) in the kidney. It encompasses two major subgroups: dense deposit disease and C3 glomerulonephritis (C3GN). Although the alternative complement pathway is typically a very tightly controlled system, dysregulation can be a result of genetic mutations in the fluid phase or membrane-bound inhibitors or accelerators. In addition, de novo/acquired autoantibodies against any of the regulatory proteins can alter complement activation either by negating an inhibitor or activating an accelerator. Triggering events can be complex; however, the final pathway is characterized by the uncontrolled deposition of C3 in glomeruli and the formation of the membrane attack complex. Light microscopic findings can be quite heterogeneous with a membranoproliferative pattern most commonly encountered. Diagnostic confirmation of C3G is based on a characteristic pattern of glomerular immunofluorescence staining, with C3-dominant deposits that are at least 2 orders of intensity greater than staining for any immunoglobulin (Ig) or C1q. Electron microscopy is necessary for diagnosing DDD in particular, but can also help to distinguish C3GN from other glomerular disease mimickers.

Navigated tissue characterization during skin cancer surgery.

PURPOSE: Basal cell carcinoma (BCC) is the most commonly diagnosed skin cancer and is treated by surgical resection. Incomplete tumor removal requires surgical revision, leading to significant healthcare costs and impaired cosmesis. We investigated the clinical feasibility of a surgical navigation system for BCC surgery, based on molecular tissue characterization using rapid evaporative ionization mass spectrometry (REIMS). METHODS: REIMS enables direct tissue characterization by analysis of cell-specific molecules present within surgical smoke, produced during electrocautery tissue resection. A tissue characterization model was built by acquiring REIMS spectra of BCC, healthy skin and fat from ex vivo skin cancer specimens. This model was used for tissue characterization during navigated skin cancer surgery. Navigation was enabled by optical tracking and real-time visualization of the cautery relative to a contoured resection volume. The surgical smoke was aspirated into a mass spectrometer and directly analyzed with REIMS. Classified BCC was annotated at the real-time position of the cautery. Feasibility of the navigation system, and tissue classification accuracy for ex vivo and intraoperative surgery were evaluated. RESULTS: Fifty-four fresh excision specimens were used to build the ex vivo model of BCC, normal skin and fat, with 92% accuracy. While 3 surgeries were successfully navigated without breach of sterility, the intraoperative performance of the ex vivo model was low (< 50%). Hypotheses are: (1) the model was trained on heterogeneous mass spectra that did not originate from a single tissue type, (2) during surgery mixed tissue types were resected and thus presented to the model, and (3) the mass spectra were not validated by pathology. CONCLUSION: REIMS-navigated skin cancer surgery has the potential to detect and localize remaining tumor intraoperatively. Future work will be focused on improving our model by using a precise pencil cautery tip for burning localized tissue types, and having pathology-validated mass spectra.

Reliable identification of prostate cancer using mass spectrometry metabolomic imaging in needle core biopsies.

Metabolomic profiling can aid in understanding crucial biological processes in cancer development and progression and can also yield diagnostic biomarkers. Desorption electrospray ionization coupled to mass spectrometry imaging (DESI-MSI) has been proposed as a potential adjunct to diagnostic surgical pathology, particularly for prostate cancer. However, due to low resolution sampling, small numbers of mass spectra, and little validation, published studies have yet to test whether this method is sufficiently robust to merit clinical translation. We used over 900 spatially resolved DESI-MSI spectra to establish an accurate, high-resolution metabolic profile of prostate cancer. We identified 25 differentially abundant metabolites, with cancer tissue showing increased fatty acids (FAs) and phospholipids, along with utilization of the Krebs cycle, and benign tissue showing increased levels of lyso-phosphatidylethanolamine (PE). Additionally, we identified, for the first time, two lyso-PEs with abundance that decreased with cancer grade and two phosphatidylcholines (PChs) with increased abundance with increasing cancer grade. Importantly, we developed and internally validated a multivariate metabolomic classifier for prostate cancer using 534 spatial regions of interest (ROIs) in the training cohort and 430 ROIs in the test cohort. With excellent statistical power, the training cohort achieved a balanced accuracy of 97% and validation on testing data set demonstrated 85% balanced accuracy. Given the validated accuracy of this classifier and the correlation of differentially abundant metabolites with established patterns of prostate cancer cell metabolism, we conclude that DESI-MSI is an effective tool for characterizing prostate cancer metabolism with the potential for clinical translation.

Erratum: Tertiary Lymphoid Structures Associate with Tumour Stage in Urothelial Bladder Cancer.

[This corrects the article DOI: 10.3233/BLC-170120.].

Tertiary Lymphoid Structures Associate with Tumour Stage in Urothelial Bladder Cancer.

BACKGROUND: Urothelial bladder cancer (UBC) is a highly prevalent disease in North America, however its optimal management remains elusive. The contribution of B cell associated responses is poorly understood in bladder cancer. Lymphoid neogenesis is a hallmark of an active immune response at tumor sites that sometimes leads to formation of tertiary lymphoid structures (TLS) that resemble germinal centers formed in secondary lymphoid organs. OBJECTIVE: This study was conducted with an aim to investigate the presence and characteristics of TLS in UBC with a focus to compare and contrast the TLS formation in treatment naive low grade non-muscle invasive (NMIBC) and muscle invasive bladder cancers (MIBC). METHODS: The study cohort consisted of transurethral bladder resection tumour (TURBT) specimens from 28 patients. Sections showing lymphoid aggregates in hematoxylin and eosin (H&E) stained TURBT specimens were further subjected to multi-color immunohistochemistry using immune cell markers specific to CD20+ B cells, CD3+ and CD8+ T cells, PNAd+ high endothelial venules, CD208+ mature dendritic cells, CD21+ follicular dendritic cells to confirm the hallmarks of classical germinal centers. RESULTS: Our pilot study investigating the presence of TLS in bladder cancer patients is the first to demonstrate that well-formed TLS are more common in aggressive high grade MIBC tumors compared to low grade NIMBC. CONCLUSIONS: These novel findings suggest B cell mediated anti-tumour humoral immune responses in bladder cancer progression.