Histomorpholgy is one of the mainstays of acute Graft-versus-host disease (GvHD) diagnosis. However, concerns about reproducibility and the most appropriate grading system question its usefulness. Our aim was to assess histomorphological parameters and previously reported grading systems for GvHD regarding reproducibility and validity. Moreover, we propose that sum scores, derived by combining separately scored morphological parameters into a total score, might provide a simplified but equally effective means to grade GvHD. A total of 123 colon biopsies were assessed across four pathologists for intestinal GvHD using a Round-Robin test and results were correlated with clinical findings. Interobserver reproducibility was high for histological parameters that were evaluated as indicators of acute GvHD. Published grading systems were moderately reproducible (ICC 0.679-0.769) while simplified sum scores, in comparison, showed better interrater reliability (ICC 0.818-0.896). All grading systems and sum scores were associated with clinical signs of GvHD and in part with therapy response and survival. However, they were not able to stratify patients according to the clinical severity of GvHD. In a hot-spot analysis 1 crypt apoptotic body (CAB) in 10 crypts was a reasonable cut-off value for minimal diagnostic criteria of GvHD. In conclusion, histology can contribute to the diagnosis of GvHD and is reproducible. Published grading systems are able to reflect clinical findings as are simplified sum scores, which showed improved reproducibility and might be easier to handle as they are based on adding up histological parameters rather than transferring histological findings into a separate grading system. Sum scores will have to be further tested in a prospective setting.

Monoclonal gammopathy (MG) causes various nephropathies, which may suffice for cytoreductive therapy even in the absence of diagnostic criteria for multiple myeloma or B-cell non-Hodgkin lymphoma. The aim of this study was to better understand the significance of light chain (LC) restriction or crystals (LC-R/C) in proximal tubules in the spectrum of LC-induced nephropathies. A consecutive cohort of 320 renal specimens with a history of B-cell dyscrasia was characterized. Special attention was paid to immunohistochemical LC restriction in proximal tubules, tubular crystals or constipation, and ultrastructural findings. Complementary cell culture experiments were performed to assess the role of LC concentrations in generating LC restriction. Light chain restriction or crystals in proximal tubules was found in a quarter of analyzed cases (81/316) and was associated with another LC-induced disease in 70.4% (57/81), especially LC cast-nephropathy (cast-NP) and interstitial myeloma infiltration. LC restriction without significant signs of acute tubular injury was observed in 11.1% (9/81). LC-R/C was not associated with inferior renal function compared to the remainder of cases, when cases with accompanying cast-NP were excluded. Besides crystals, cloudy lysosomes were significantly associated with LC-R/C on an ultrastructural level. In summary, LC-R/C is frequent and strongly associated with cast-NP, possibly indicating that a high load of clonal LC is responsible for this phenomenon, supported by the observation that LC restriction can artificially be generated in cell culture. This and the lack of significant tubular injury in a subgroup imply that in part LC-R/C is a tubular trafficking phenomenon rather than an independent disease process.

Aims Agents targeting vascular endothelial growth factor (VEGF) have increasingly been used for the treatment of advanced malignancies, and have been found to induce renal thrombotic microangiopathy (TMA) and proteinuria. However, histomorphological changes in human biopsies in this setting and the underlying mechanism are not yet fully understood. Therefore, we collected renal biopsy cases with a history of aVEGF therapy to review and compare morphological kidney changes in this context. Methods and results Renal biopsies of 15 patients who had received anti-VEGF (aVEGF) therapy evaluated between 2013 and 2017 at a single centre were morphologically characterised with light microscopy, electron microscopy, and immunohistochemistry (IgA, IgG, IgM, C1q, and C3), and compared with cases with acute TMA caused by atypical haemolytic-uraemic syndrome or hypertension. Morphological overlap with immune complex and cryoglobulinaemic membranoproliferative glomerulonephritis, diabetic glomerulopathy and pre-eclampsia-induced glomerulopathy are discussed. Segmental glomerular capillary microaneurysms and segmental hyalinosis were typical morphological features of aVEGF therapy-induced glomerular microangiopathy, whereas fibrin or platelet thrombi or fragmented erythrocytes were rarely found or were absent. aVEGF therapy-associated microangiopathy was diffusely distributed in the glomeruli, spared preglomerular vessels, and showed morphological characteristics of chronic TMA. In individual cases, aVEGF therapy-induced glomerular microangiopathy was accompanied by immune-complex glomerulonephritis. Conclusion aVEGF therapy-induced glomerular microangiopathy has a characteristic morphology and clinical presentation that helps to differentiate it from other causes of TMA. Awareness of these light microscopic findings allows identification of aVEGF therapy as a trigger of renal disease in critically ill cancer patients, and might therefore help in deciding on further therapy.