A Primary Telangiectatic Mandibular Osteosarcoma With Germ-Line Malignancy-Associated DNA Damage Repair Gene Polymorphisms: A Case Report.

Primary mandibular telangiectatic osteosarcomas are very rare lesions, with only nine cases reported. Histologically, these lesions show multiple cystic blood-filled cavities traversed by neoplastic bone in septa lined by high-grade malignant cells. Here, we report an 81-year-old woman who presented with a mandibular mass, which was surgically resected and analyzed by histologic examination and whole exome DNA sequencing. A diagnosis of telangiectatic osteosarcoma was given. Comparative sequencing data analysis of paired benign and tumor DNA revealed 1577 variants unique to the tumor DNA, which clustered into several gene families, including those regulating DNA repair and apoptosis. Comparison of benign and tumor DNA revealed many shared gene polymorphisms associated with an increased cancer risk. These included polymorphisms in the ATM, p53, BRCA1, and BRCA2 and many other genes. Interestingly, the patient's family history showed an unusually high cancer incidence, likely related to these cancer risk-associated polymorphisms. To our knowledge, this is the first-time sequencing applied to a mandibular telangiectatic osteosarcoma. Our findings may shed light on the molecular origins of these rare tumors and how they may relate to other tumors in related kindreds.

Unveiling renal pathology's potential: exploring a rare subtype of amyloid - apolipoprotein CII amyloidosis in the youngest patient: a case report and literature review.

In this clinical case report, we present a rare subtype of amyloidosis, apolipoprotein CII (apo CII), which was diagnosed through a renal biopsy and subsequently confirmed by identifying the p.K41T mutation via germline DNA sequencing. Upon reviewing the literature, five patients exhibiting identical mutation were identified via renal biopsy, while an additional patient was diagnosed through biopsies of the fat pad and bone marrow. Notably, our patient is the youngest recorded case. We pioneered the application of immunofluorescence and immunogold electron microscopy techniques for apo CII evaluation. Our report provides a detailed description of this case, supplemented by an extensive review encompassing apo CII, documented instances of apo CII amyloidosis with renal or systemic involvement, and potential underlying mechanisms.

Metastatic Ovarian Serous Adenocarcinoma Clinically Presenting as Inflammatory Breast Cancer.

Metastatic disease to the breast is a rare event, accounting for 0.5-2% of all breast cancers. Outside of metastases from the contralateral breast, malignant ovarian epithelial tumors are the most common origin of these metastases. Here, we present a very rare case of a high-grade ovarian serous adenocarcinoma presenting clinically as inflammatory breast cancer in a 70-year-old woman.

Punctate IgG staining particles localize in the budding ballooning clusters of reactive foot processes in minimal change disease.

The etiology of minimal change disease (MCD) remains a mystery as the only characteristic findings are the diffuse effacement of foot processes seen on electron microscopy (EM). Punctate IgG staining found floating outside glomerular capillary loops in MCD cases was recently identified as autoimmune antibodies against nephrin of podocytes. We hypothesized that the punctate IgG staining is located on budding ballooning clusters (BBC) of reactive foot processes in Bowman's space found on EM. We identified seven patients with MCD cases showing IgG staining that were subsequently evaluated for BBC on EM. We concurrently examined 12 negative controls, either unremarkable cases or tubulointerstitial diseases, by EM. Immunogold labeling was performed to confirm the presence of IgG and determine localization. In seven MCD cases, there were positive punctate IgG staining particles outside of the glomerular basement membranes (GBM) along with concurrent punctate staining for C3, kappa, and lambda. By EM, all seven (100%) MCD cases revealed BBC that was characterized by ballooning foot processes ranging from 1 to 6 µm and was either budding or detached from the GBM in 3-7 clusters; no electron-dense materials were seen in BBC. BBC was also seen in only 1 of 12 (8%) negative controls. Immunogold labeling identified IgG particles within BBC of MCD by EM, but not in the negative control. Our data suggest that BBC are EM structures of reactive foot processes that are most likely correlated with punctate IgG staining seen in cases of MCD, supported by immunogold labeling for IgG.

A Rare Case of Solitary Fibrous Tumor of the Kidney.

Solitary fibrous tumor (SFT), originally described in the pleura, is a rare mesenchymal neoplasm characterized by a wide spectrum of clinical presentations and histopathological features. Over the years, SFTs have been reported in various anatomical locations, including soft tissues, visceral organs, and, uncommonly, the kidney. While SFTs primarily arise from the pleura, their occurrence in the kidney is an infrequent phenomenon, accounting for a minute fraction of all renal tumors. This case report presents a unique instance of a solitary fibrous tumor originating in the kidney, highlighting its clinical, radiological, and histopathological characteristics, as well as the challenges associated with accurate diagnosis and appropriate management. The rarity of such cases underscores the importance of comprehensive evaluation and awareness among clinicians and pathologists to ensure timely diagnosis and effective treatment strategies. Here, we report a case of SF of the kidney (SFT-K) located in the renal pelvis in a 39-year-old Caucasian female.

Role of the mechanisms for antibody repertoire diversification in monoclonal light chain deposition disorders: when a friend becomes foe.

The adaptive immune system of jawed vertebrates generates a highly diverse repertoire of antibodies to meet the antigenic challenges of a constantly evolving biological ecosystem. Most of the diversity is generated by two mechanisms: V(D)J gene recombination and somatic hypermutation (SHM). SHM introduces changes in the variable domain of antibodies, mostly in the regions that form the paratope, yielding antibodies with higher antigen binding affinity. However, antigen recognition is only possible if the antibody folds into a stable functional conformation. Therefore, a key force determining the survival of B cell clones undergoing somatic hypermutation is the ability of the mutated heavy and light chains to efficiently fold and assemble into a functional antibody. The antibody is the structural context where the selection of the somatic mutations occurs, and where both the heavy and light chains benefit from protective mechanisms that counteract the potentially deleterious impact of the changes. However, in patients with monoclonal gammopathies, the proliferating plasma cell clone may overproduce the light chain, which is then secreted into the bloodstream. This places the light chain out of the protective context provided by the quaternary structure of the antibody, increasing the risk of misfolding and aggregation due to destabilizing somatic mutations. Light chain-derived (AL) amyloidosis, light chain deposition disease (LCDD), Fanconi syndrome, and myeloma (cast) nephropathy are a diverse group of diseases derived from the pathologic aggregation of light chains, in which somatic mutations are recognized to play a role. In this review, we address the mechanisms by which somatic mutations promote the misfolding and pathological aggregation of the light chains, with an emphasis on AL amyloidosis. We also analyze the contribution of the variable domain (VL) gene segments and somatic mutations on light chain cytotoxicity, organ tropism, and structure of the AL fibrils. Finally, we analyze the most recent advances in the development of computational algorithms to predict the role of somatic mutations in the cardiotoxicity of amyloidogenic light chains and discuss the challenges and perspectives that this approach faces.

AL(light chain)-amyloidogenesis by mesangial cells involves active participation of lysosomes: An ultrastructural study.

Amyloid formation by cells is a stepwise process that occurs in macrophages and cells capable of transforming into a macrophage phenotype. One such cell is the mesangial cell in the kidney. It has been shown that mesangial cells are engaged in AL (light chain associated)- amyloidogenesis after transforming phenotypically from a smooth muscle to a macrophage phenotype. The actual process of amyloid fibril formation has not been dissected. This ultrastructural study which includes the examination of lysosomal gradient specimens addresses this issue by analyzing the sequence of events that takes place as fibrils are formed in endosomes and lysosomes. The findings indicate that fibrillogenesis begins in endosomes but is completed and most pronounced in the lysosomal compartment. As early as 10 min after incubation of human mesangial cells with AL-LCs, amyloid fibrils are formed in endosomes but mostly occurs in the mature lysosomal compartment. This is the first time that fibril formation is demonstrated experimentally occurring inside human mesangial cells and the entire sequence of events taking place is elucidated.

Congenital granular cell epulis: 24 new cases with more differences than similarities to granular cell tumor.

Congenital granular cell epulis (CGCE) is a rare tumor of gingiva that is exclusive to newborns, has marked female predominance, and is rarely associated with other abnormalities. Although benign in behavior, CGCE can be lethal by obstruction of respiration and/or deglutition and can require a multidisciplinary team of specialist at birth for survival of an otherwise normal infant. Histologically, CGCE resembles granular cell tumor (GCT), but unlike GCT, which is Schwannian-derived, derivation of CGCE remains an enigma, largely because of its low prevalence. This study presents 24 new cases of CGCE, the largest series since the original description 150 years ago and permits detailed study of homogeneity of cases diagnosed as CGCE as well as detailed comparisons of CGCE with GCT by clinical, morphological, immunohistochemical, and ultrastructural studies. The data show homogeneity within the CGCE cases, more differences than similarities between CGCE and GCT, and no immunohistochemical staining for common placental proteins/hormones in CGCE. The findings support a primitive mesenchymal cell origin, and a progressive degenerative process in CGCE, rather than neoplasia. Prenatal detection of this lesion is important to facilitate adequate preparations for support of these infants during labor and delivery.

Shining light on the transcriptome: Molecular regulatory networks leading to a fast-growth phenotype by continuous light in an environmentally sensitive teleost (Atherinopsidae).

Photoperiod can profoundly affect the physiology of teleost fish, including accelerated growth here defined as "fast growth phenotypes". However, molecular regulatory networks (MRNs) and biological processes being affected by continuous illumination and which allow some teleost species evident plasticity to thrive under this condition are not yet clear. Therefore, to provide a broad perspective of such mechanisms, Chirostoma estor fish were raised and sampled for growth under a simulated control (LD) 12 h Light: 12 h Dark or a continuous illumination (LL) 24 h Light: 0 h Dark since fertilization. The experiment lasted 12 weeks after hatching (wah), the time at which fish were sampled for growth, length, and whole-body cortisol levels. Additionally, 3 heads of fish from each treatment were used to perform a de novo transcriptome analysis using Next-Generation Sequencing. Fish in LL developed the fast growth phenotype with significant differences visible at 4 wah and gained 66% more mass by 12 wah than LD fish. Cortisol levels under LL were below basal levels at all times compared to fish in LD, suggesting circadian dysregulation effects. A strong effect of LL was observed in samples with a generalized down-regulation of genes except for Reactive Oxygen Species responses, genome stability, and growth biological processes. To our knowledge, this work is the first study using a transcriptomic approach to understand environmentally sensitive MRNs that mediate phenotypic plasticity in fish submitted to continuous illumination. This study gives new insights into the plasticity mechanisms of teleost fish under constant illumination.

Multiple myeloma presenting as acute tubulointerstitial nephritis.

BACKGROUND: Acute tubulointerstitial nephritis (ATIN) is a very rare paraneoplastic manifestation in patients with multiple myeloma (MM). It is an uncommon pattern of renal disease in such patients. CASE PRESENTATION: We report a case of an 82-year-old male who was admitted with acute kidney injury. Renal biopsy showed typical findings of light chain-associated ATIN with scattered inflammatory cells in the interstitium and associated active tubulitis. No other common manifestations of MM were present at the time of presentation, including hypercalcemia, hyperuricemia, proteinuria, bone pain or lytic bone lesions. Subsequent immunoassays revealed significant serum lambda light chain burden and Bence Jones protein in urine. Immunofluorescence demonstrated linear tubular basement membranes with positive staining for lambda light chain (3+). Electron microscopy (EM) further showed interstitial edema and inflammation. All the aforementioned findings are consistent with ATIN and supported the diagnosis of MM. CONCLUSIONS: In conclusion, light chain-associated ATIN should be considered in the differential diagnosis of acute interstitial nephritis. Henceforth, serum free light chains as well as serum and urine protein electrophoresis should be included in the workup of such patients.

Renal amyloidosis: Pathogenesis.

For many years amyloidosis was considered an extremely rare, somewhat mysterious disease. However, in the last 2-3 decades its pathogenesis, particularly that of renal amyloidosis has been carefully dissected in the research laboratory using in-vitro and, to a lesser extent, in-vivo models. These have provided a molecular understanding of sequential events that take place in the renal mesangium leading to the formation of amyloid fibrils and eventual extrusion into the mesangial matrix, which itself becomes seriously damaged and, in due time, replaced by the fibrillary material. Amyloid, once considered to be an "inert" substance, has been proven to be involved in crucial biological processes that result in the destruction and eventual replacement of normal renal constituents. This review centers on mechanisms involved in the renal glomerular amyloidosis to understand its pathogenesis.

Glomerulopathic Light Chain-Mesangial Cell Interactions: Sortilin-Related Receptor (SORL1) and Signaling.

INTRODUCTION: Deciphering the intricacies of the interactions of glomerulopathic Ig light chains with mesangial cells is key to delineate signaling events responsible for the mesangial pathologic alterations that ensue. METHODS: Human mesangial cells, caveolin 1 (CAV1), wild type (WT) ,and knockout (KO), were incubated with glomerulopathic light chains purified from the urine of patients with light chain-associated (AL) amyloidosis or light chain deposition disease. Associated signaling events induced by surface interactions of glomerulopathic light chains with caveolins and other membrane proteins, as well as the effect of epigallocatechin-3-gallate (EGCG) on the capacity of mesangial cells to intracellularly process AL light chains were investigated using a variety of techniques, including chemical crosslinking with mass spectroscopy, immunofluorescence, and ultrastructural immunolabeling. RESULTS: Crosslinking experiments provide evidence suggesting that sortilin-related receptor (SORL1), a transmembrane sorting receptor that regulates cellular trafficking of proteins, is a component of the receptor on mesangial cells for glomerulopathic light chains. Colocalization of glomerulopathic light chains with SORL1 in caveolae and also in lysosomes when light chain internalization occurred, was documented using double immunofluorescence and immunogold labeling ultrastructural techniques. It was found that EGCG directly blocks c-Fos cytoplasmic to nuclei signal translocation after interactions of AL light chains with mesangial cells, resulting in a decrease in amyloid formation. CONCLUSION: Our findings document for the first time a role for SORL1 linked to glomerular pathology and signaling events that take place when certain monoclonal light chains interact with mesangial cells. This finding may lead to novel therapies for treating renal injury caused by glomerulopathic light chains.

Electron microscopy in renal pathology: overall applications and guidelines for tissue, collection, preparation, and stains.

Electron microscopy is a mainstay in the analysis of renal biopsies, where it is typically employed in a correlative fashion along with light and immunofluorescence microscopy. Despite the development of a growing armamentarium of molecular and biochemical analytic methods as well as new immunostains with a widening panel of immunoreactants, electron microscopy remains crucial to the diagnosis of a number of disorders involving the renal glomerulus, vasculature, and tubulointerstitial compartment. The number of renal biopsies continues to grow and the indications for these biopsies continue expanding together with our understanding of disease processes. Proper collection of biopsies and careful analysis of data emanating from diagnostic modalities, clinical information, imaging, gross and microscopic tissue analysis, including a wide range of ancillary studies, represent the essential paradigm for generating detailed diagnoses with clinical significance. This communication offers a guide to the pre-analytic and analytic process for renal biopsy examination, discusses diagnostic keys and pitfalls for an important category of renal diseases (immune complex disorders), and provides an introduction to a useful adjunct diagnostic method (ultrastructural immunolabeling). Renal pathologists should render expert diagnoses that guide patient management, provide prognostic information and lead to targeted new therapeutic interventions that are currently available.

Multiple myeloma presenting as acute tubulointerstitial nephritis

Background Acute tubulointerstitial nephritis (ATIN) is a very rare paraneoplastic manifestation in patients with multiple myeloma (MM). It is an uncommon pattern of renal disease in such patients. Case presentation We report a case of an 82-year-old male who was admitted with acute kidney injury. Renal biopsy showed typical findings of light chain-associated ATIN with scattered inflammatory cells in the interstitium and associated active tubulitis. No other common manifestations of MM were present at the time of presentation, including hypercalcemia, hyperuricemia, proteinuria, bone pain or lytic bone lesions. Subsequent immunoassays revealed significant serum lambda light chain burden and Bence Jones protein in urine. Immunofluorescence demonstrated linear tubular basement membranes with positive staining for lambda light chain (3+). Electron microscopy (EM) further showed interstitial edema and inflammation. All the aforementioned findings are consistent with ATIN and supported the diagnosis of MM. Conclusions In conclusion, light chain-associated ATIN should be considered in the differential diagnosis of acute interstitial nephritis. Henceforth, serum free light chains as well as serum and urine protein electrophoresis should be included in the workup of such patients.

Monoclonal glomerulopathy with features of cryoglobulinemic glomerulopathy in murine multiple myeloma model.

In vivo and animal models of monoclonal light chain-associated renal diseases are limited. The Vk*MYC transgenic model with multiple myeloma in 50-70 weeks old mice with renal involvement has been reported before, but detailed renal pathologic changes have not been well documented. This study fully investigated pathologic changes in the kidneys of Vk*MYC transgenic model using light microscopy, immunofluorescence stains for kappa and lambda light chains, and electron microscopy. Compared to the kidneys of wild-type mice, the kidneys of transgenic mice showed either mesangial segmental expansion, some with associated hypercellularity, and/or thrombotic obstruction of glomerular capillaries. The glomeruli revealed stronger lambda staining than kappa light chain staining. Six out of 12 kidneys from transgenic mice showed abundant electron-dense deposits when examined ultrastructurally. The deposits were located in glomerular capillary lumina in three cases. Large luminal and subendothelial deposits were characterized by randomly disposed microtubular structures measuring up to 16 nm in diameter, with overall features most consistent with cryoglobulins. In summary, about 50% of kidneys from the Vk*MYC mice with myeloma had features most consistent with monoclonal cryoglobulinemic glomerulopathy.

Understanding Mesangial Pathobiology in AL-Amyloidosis and Monoclonal Ig Light Chain Deposition Disease.

Patients with plasma cell dyscrasias produce free abnormal monoclonal Ig light chains that circulate in the blood stream. Some of them, termed glomerulopathic light chains, interact with the mesangial cells and trigger, in a manner dependent of their structural and physicochemical properties, a sequence of pathological events that results in either light chain-derived (AL) amyloidosis (AL-Am) or light chain deposition disease (LCDD). The mesangial cells play a key role in the pathogenesis of both diseases. The interaction with the pathogenic light chain elicits specific cellular processes, which include apoptosis, phenotype transformation, and secretion of extracellular matrix components and metalloproteinases. Monoclonal light chains associated with AL-Am but not those producing LCDD are avidly endocytosed by mesangial cells and delivered to the mature lysosomal compartment where amyloid fibrils are formed. Light chains from patients with LCDD exert their pathogenic signaling effect at the cell surface of mesangial cells. These events are generic mesangial responses to a variety of adverse stimuli, and they are similar to those characterizing other more frequent glomerulopathies responsible for many cases of end-stage renal disease. The pathophysiologic events that have been elucidated allow to propose future therapeutic approaches aimed at preventing, stopping, ameliorating, or reversing the adverse effects resulting from the interactions between glomerulopathic light chains and mesangium.

Renal amyloidosis with emphasis on the diagnostic role of electron microscopy.

Our understanding of renal diseases with structured deposits has improved in the last two decades with the development of new diagnostic techniques that also changed the role of ultrastructural pathology in diagnostic decision-making. This review article addresses the current role of electron microscopy in the evaluation of structured deposits and discusses the impact of new developments. The diagnosis in a subset of structured deposits, amyloidosis, relies on morphologic and tinctorial characteristics at the light microscopic level. Congo red staining of tissue with demonstrable birefringence upon polarization has been regarded as the mainstay during tissue evaluation; however, there are pitfalls that must be considered, and electron microscopy remains a crucial adjunct investigative tool. Ultrastructurally the amyloid fibrils are unique with their characteristic appearance. They are randomly arranged, rigid, criss-crossing, non-branching, 7-15 nm (0.07-0.15 um) in diameter and of variable length. The morphology of fibrils is very similar in the different types of amyloidosis. By scanning electron microscopy amyloid fibrils appear artfully displayed. Immunofluorescence and immunohistochemical stains can be used to characterize the type of amyloidosis while mass spectroscopy is extremely useful in cases where typing of the amyloid using the above-mentioned techniques is difficult or equivocal.

Clinicopathologic predictors of renal outcomes in light chain cast nephropathy: a multicenter retrospective study.

Light chain cast nephropathy (LCCN) in multiple myeloma often leads to severe and poorly reversible acute kidney injury. Severe renal impairment influences the allocation of chemotherapy and its tolerability; it also affects patient survival. Whether renal biopsy findings add to the clinical assessment in predicting renal and patient outcomes in LCCN is uncertain. We retrospectively reviewed clinical presentation, chemotherapy regimens, hematologic response, and renal and patient outcomes in 178 patients with biopsy-proven LCCN from 10 centers in Europe and North America. A detailed pathology review, including assessment of the extent of cast formation, was performed to study correlations with initial presentation and outcomes. Patients presented with a mean estimated glomerular filtration rate (eGFR) of 13 ± 11 mL/min/1.73 m2, and 82% had stage 3 acute kidney injury. The mean number of casts was 3.2/mm2 in the cortex. Tubulointerstitial lesions were frequent: acute tubular injury (94%), tubulitis (82%), tubular rupture (62%), giant cell reaction (60%), and cortical and medullary inflammation (95% and 75%, respectively). Medullary inflammation, giant cell reaction, and the extent of cast formation correlated with eGFR value at LCCN diagnosis. During a median follow-up of 22 months, mean eGFR increased to 43 ± 30 mL/min/1.73 m2. Age, ß2-microglobulin, best hematologic response, number of cortical casts per square millimeter, and degree of interstitial fibrosis/tubular atrophy (IFTA) were independently associated with a higher eGFR during follow-up. This eGFR value correlated with overall survival, independently of the hematologic response. This study shows that extent of cast formation and IFTA in LCCN predicts the quality of renal response, which, in turn, is associated with overall survival.

Thyroid-Like Low-Grade Nasopharyngeal Papillary Adenocarcinoma with Biphasic Histology.

Thyroid-like low-grade nasopharyngeal papillary adenocarcinoma (TL-LGNPPA) is a rare primary adenocarcinoma of nasopharynx. The immunohistochemical pattern of this tumor is similar to that of papillary thyroid carcinoma making this neoplasm a challenging diagnosis. A case of TL-LGNPPA with biphasic morphology is presented. The removed tumor from the nasopharynx exhibited a polypoid appearance. Microscopically, it was composed of papillary structures admixed with a few solid areas of spindle cells. The papillae were lined by columnar epithelium. Both the epithelium and the spindle cells were strongly positive for TTF-1 and CK19 and negative for CK5/6, S-100, and thyroglobulin. Cellular atypia, necrosis, and high mitotic rate were absent. Ki67 was less than 2% in the neoplastic cells. No local recurrence or distant metastasis was reported after 12 months of follow-up. Caution should be taken to differentiate TL-LGPPA from other TTF-1-positive neoplasms, especially papillary thyroid carcinoma, as the prognosis for these two tumors is entirely different.