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Five hundred eighty renal biopsies from a pool of 27850 archived cases were identified in which a myoglobin stain was performed because of atypical casts. Two hundred and thirty-eight (41%) of these biopsies were found to be positive for myoglobin casts. The morphology of the myoglobin casts ranged from light, almost translucent and refractile, to pink, to dark red and slightly brown granular casts by hematoxylin and eosin, to beaded globular casts that stained brightly fuchsinophilic with Masson trichrome and partially argyrophilic with silver methenamine. All biopsies displayed acute tubular injury associated with intratubular debris and thinning and vacuolization of tubular epithelium. Approximately 20% of myoglobin-positive biopsies showed calcium oxalate or phosphate deposition. Positive myoglobin staining was present in casts, proximal tubular epithelial cells without casts, and also dehisced epithelial cells. Collecting ducts and occasionally the distal tubular epithelium also stained positive. One case showed concurrent myeloma cast nephropathy with "fractured" casts and translucent myoglobin-positive casts. Herein, we describe the morphologic spectrum of myoglobin-positive casts. We conclude that utilization of myoglobin immunohistochemistry is advantageous and, when not available, knowledge of the morphologic spectrum is important., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Cellular crescents are typically inflammatory and associated with rapidly progressive glomerulonephritis. Their pathogenesis involves glomerular basement membrane rupture due to circulating or intrinsic factors. Crescents associated with diabetic glomerulosclerosis are rarely reported. Furthermore, the nature of cells forming crescents in diabetes is unknown. To investigate the nature of crescents in diabetes, we examined renal biopsies from diabetic patients with nodular glomerulosclerosis and crescents (n = 2), diabetes without crescents (n = 5), nondiabetic renal biopsies (n = 3), and crescentic glomerulonephritis with inflammatory crescents (n = 5). Electron microscopy and confocal immunofluorescence analysis with antibodies against nephrin (a podocyte marker) and claudin 1 (parietal epithelial cell marker) were performed. Diabetic glomeruli with crescents contained a mixture of crescentic cells expressing either claudin 1 (11 ± 1.4 cells/glomerulus) or nephrin (5.5 ± 3.0 cells/glomerulus). Rare crescentic cells coexpressed nephrin and claudin 1 (2.5 ± 1.6 cells/glomerulus). In contrast, inflammatory crescents were almost exclusively composed of claudin 1-positive cells (25 ± 5.3 cells/glomerulus). Cells coexpressing claudin 1 and nephrin were absent in inflammatory crescents and all cases without crescents. Electron microscopy showed podocyte bridge formation between the glomerular basement membrane and parietal basement membrane but no glomerular basement membrane rupture as in inflammatory crescents. Crescents in diabetes may occur in diabetes in the absence of a secondary etiology and are composed of a mixture of parietal epithelial cells and visceral podocytes. Cells coexpressing parietal epithelial and podocyte markers suggest that parietal epithelial cells may transdifferentiate into podocytes in response to severe glomerular injury., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Recent genetic studies indicate that Alport syndrome and thin glomerular basement membrane disease (TMD) may both be due to COL4A3, COL4A4, and COL4A5 mutations, but there is continuing uncertainty concerning the diagnosis and management of patients without classic family history and symptoms. We examined kidney pathology and collagen alpha 3 to alpha 5(IV) expression in a series of 16 patients who presented with overlapping signs between TMD and Alport nephritis. All patients presented with hematuria, and 11 also had proteinuria, of whom 5 had nephrotic range proteinuria. Only 9 had family history of hematuria. In 9 of 16 (60%) we found premature glomerulosclerosis in the renal biopsies. Three of 16 had predominantly wide, lamellated glomerullar basement membranes (GBM), and in these, alpha 3 to alpha 5(IV) was absent in glomeruli or skin, diagnostic of Alport nephritis. One patient (12) had a very wide GBM with intramembranous lucencies but no lamellation. Skin biopsy was collagen alpha 5(IV) positive. Nine of 16 patients had predominantly thin GBM by electron microscopy, and 3 had thin and slightly lamellated GBM. Collagen alpha 3 to alpha 5(IV) expression in the kidney or skin biopsy was present in all of the latter 12 patients. Three patients had end-stage renal disease, 7 patients had hypertension, and 1 patient had chronic renal failure. We found that of the 16 patients with presumed TMD, 3 had X-linked Alport nephritis, 2 appeared to have autosomal recessive Alport nephritis, and the remaining patients had either an Alport or a TMD variant. The latter had histologic and/or clinical evidence of progressive renal disease, including premature glomerulosclerosis, hypertension, sustained proteinuria, and either thin or slight GBM lamellation focally, and preserved alpha 3 to alpha 5(IV) expression. These patients have a TMD variant, but an Alport variant with a potentially transmissible severe defect different from benign hematuria cannot be excluded., (Copyright 2002, Elsevier Science (USA). All rights reserved.)

mu heavy chain deposition disease is very rare. We report the first case of glomerulonephritis in a woman without evidence of hematopoietic malignancy. Nodular glomerulosclerosis and monotypic mu heavy chain mesangial deposits were identified by immunofluorescence without kappa or lambda deposits. Electron microscopy showed fibrillar mesangial deposits of 16-18 nm in diameter. Serum immunoglobulins, cryoglobulins, serum immunoelectrophoresis, and immunofixation, bone marrow biopsy, and Bence Jones proteins in urine were negative. The patient has stable renal disease and is free of malignancy 6 years after the initial occurrence of proteinuria.

Triton tumors are rare variants of malignant peripheral nerve sheath tumor (MPNST) with muscle differentiation, often seen in patients with neurofibromatosis 1 (NF1). Individuals affected with NF1 harbor mutations in the NF1 tumor suppressor gene and develop neurofibromas and MPNSTs. The NF1 gene is expressed in Schwann cells and its expression is lost in schwannian neoplasms, suggesting a role in malignant development. Separately, there is evidence that p53 suppressor gene mutations are involved in MPNSTs. To determine the role of the NF1 and p53 genes in the development of the malignant Triton tumor we examined 2 such tumors, 1 from a 3-year-old boy without clinical manifestations of NF1 and another from a 24-year-old man with NF1. Histological analysis of these tumors showed both neural and muscle differentiation with S-100 and desmin immunoreactivity, respectively. Reverse transcribed RNA polymerase chain reaction (RT-PCR) of NF1 mRNA showed NF1 expression in the sporadic tumor. Strong nuclear immunoreactivity for p53 was observed throughout the malignant population in both tumors. This was confirmed by loss of heterozygosity for p53 in the non-NF1 patient, suggesting that p53 is involved in both hereditary and sporadic Triton tumors. The finding of preserved NF1 gene expression in the non-NF1-related Triton tumor suggests that different genetic events predispose to the development of this rare neoplasm in sporadic cases.

Although matrix metalloproteinases (MMPs) are implicated in breast cancer progression, the contribution of MMP-1 and MMP-3 to this process, has not been thoroughly investigated. Matrix metalloproteinases (MMPs) are important at several points during multistage neoplastic progression. Immunohistochemistry (Strept-ABC-HRP method) and in situ hybridization were performed to detect MMP-1, MMM-3 proteins, and MMP-3 mRNA, respectively, in 77 infiltrative breast carcinomas. MMP-1, MMP-3 protein, and MMP-3 mRNA detection were analyzed in parallel with clinicopathologic features (menopausal status, histological type, nuclear and histological grade, stage) and the immunohistochemical reactivity of estrogen (ER), progesterone (PR) receptors, and c-erbB-2 oncoprotein in breast carcinomas. Statistical analysis was performed using the multiple linear regression test. Immunoreactivity for MMP-1 and MMP-3 was observed in 59 of 77 (77%) and 22 of 77 (28.5%) breast carcinomas and was evaluated separately in cancer cells and in stromal fibroblasts. MMP-3 mRNA was detected in 72 of 77 (93.5%) carcinomas exclusively in stromal cells within the tumors or in the marginal portion of tumors. MMP-1 protein immunoreactivity in stromal fibroblasts but not in cancer cells showed a statistically significant correlation with tumor stage (P=.04). MMP-1 reactivity either in stromal or in cancer cells showed a statistically significant inverse correlation with PR expression (P=.04 and P=.04, respectively). MMP-3 protein immunoreactivity in cancer or stromal cells and MMP-3 mRNA expression was not associated with the clinicopathologic features studied. MMP-3 mRNA was detected more often in ductal carcinomas. These results indicate that MMP-1 may contribute to breast cancer invasiveness. Furthermore, they suggest differential functions for MMP-1 and MMP-3 in breast cancer progression.

Expression of osteopontin (OPN) by ovarian tumors is not known. Neoplasms arising from the ovarian epithelium are distinguished in adenocarcinomas and borderline tumors (LMPs), which overall have a favorable prognosis even with omental implants. Tissues from primary ovarian tumors and their metastases from 30 patients (16 LMPs and 14 adenocarcinomas) were evaluated for OPN expression by immunohistochemistry, Western blotting, and in situ hybridization. OPN was weak or absent in 93% of ovarian adenocarcinomas or their metastases. In contrast, 81.5% of the LMPs and 50% of omental and lymph node implants were OPN positive (P < .028). Histological type, grade, or clinical stage did not correlate with OPN expression. Expression of OPN primarily by ovarian neoplasms with favorable prognosis is an intriguing new finding of potential importance in the pathogenesis of ovarian LMPs.

Ovarian tumors of low malignant potential (LMPs) histologically lack invasion and have excellent prognosis in contrast to invasive carcinomas. Integrins are heterodimeric adhesion molecules thought to play a role in cell migration and tumor progression. The alpha(v)beta3 integrin in particular mediates melanoma invasion in vitro and promotes neoplastic angiogenesis, facilitating breast cancer metastasis. In addition, alpha(v)beta3 expression has been detected in ovarian cancer cell lines and in a limited number of human ovarian cancer samples. The distribution pattern of this integrin in LMPs is not known. We examined tissue sections from 19 LMPs and 31 ovarian carcinomas for alpha(v)beta3, in addition to alpha5beta1 and alpha2beta1 integrins, which have been shown to be expressed in ovarian cancer cell lines. Variable immunoreactivities of alpha5beta1 and alpha2beta1 were detected in both LMPs and ovarian carcinomas. Most (74.2%) ovarian carcinomas were alpha(v)beta3 positive, whereas only 36.8% of LMPs were positive, which is statistically significant (P = .009). These results establish the distribution pattern of alpha2beta1, alpha5beta1, and alpha(v)beta3 integrins in LMPs. The biological significance of the less frequent expression of alpha(v)beta3 in LMPs compared with carcinomas of the ovary needs further elucidation.

Parathyroid-like protein (PLP), or parathyroid hormone-related peptide, is a well-recognized mediator of paraneoplastic hypercalcemia (humoral hypercalcemia of malignancy syndrome). In this study we examined the expression of PLP by 40 invasive squamous cell carcinomas (SCCs) of the cervix and selected carcinomas of nonsquamous histology. Using a polyclonal antibody to human PLP, 93% of SCCs, including two tumors from patients with humoral hypercalcemia of malignancy syndrome, showed moderate to strong cytoplasmic immunoperoxidase staining for PLP. The strongest staining often was observed in areas of invasion associated with stromal desmoplasia. The small number of weak or negatively stained SCCs were all poorly differentiated tumors. Although native uninvolved squamous epithelium showed weak to moderate staining of the superficial layers, there was variable or full-thickness immunostaining in areas of dysplasia. Normal endocervical glands and stroma as well as cervical adenocarcinomas and neuroendocrine carcinomas were negative. In situ hybridization studies showed abundant PLP mRNA within SCC in patients with hypercalcemia. However, PLP mRNA was of relatively low abundance in tumors of normocalcemic patients. Ultrastructural studies showed cytoplasmic, membrane-bound, granular inclusions in tumor cells from the hypercalcemic patients. Our data suggest that increased PLP gene transcription contributes to the increased production of PLP and the pathogenesis of humoral hypercalcemia of malignancy syndrome.