Tacrolimus (FK506) is one of the principal immunosuppressive agents used after solid organ transplantations to prevent allograft rejection. Chronic renal injury induced by tacrolimus is characterized by linear fibrosis in the medullary rays; however, the early morphologic findings of acute tacrolimus nephrotoxicity are not well characterized. Kidney injury molecule-1 (KIM-1) is a specific injury biomarker that has been proven to be useful in the diagnosis of mild to severe acute tubular injury on renal biopsies. This study was motivated by a patient with acute kidney injury associated with elevated serum tacrolimus levels in whom KIM-1 staining was present only in proximal tubules located in the medullary rays in the setting of otherwise normal light, immunofluorescent, and electron microscopy. We subsequently evaluated KIM-1 expression in 45 protocol and 39 indicated renal transplant biopsies to determine whether higher serum levels of tacrolimus were associated with acute segment specific injury to the proximal tubule, as reflected by KIM-1 staining in the proximal tubules of the cortical medullary rays. The data suggest that tacrolimus toxicity preferentially affects proximal tubules in medullary rays and that this targeted injury is a precursor lesion for the linear fibrosis seen in chronic tacrolimus toxicity.
Squamous cell carcinoma (SCC) of the head and neck is commonly linked to infection by human papillomavirus (HPV) and immunohistochemically confirmed to be positive for p16 (a surrogate marker for HPV infection), analogous to what is seen in HPV-associated dysplasia and carcinoma of the uterine cervix. Thus, p16-positive metastatic SCC in the thoracic/neck lymph nodes is often considered to be of head and neck primary. However, two recent USCAP abstracts reported that p16 was expressed in a significant percent of primary lung SCC and small cell carcinoma, but HPV analyzed by molecular techniques was negative in all of these p16-positive tumors. The aim of the current study was to determine the incidence of p16-positive primary pulmonary SCC cases at our institution. 49 cases of primary pulmonary SCC were stained for p16 using a standard immunohistochemical staining method of formalin-fixed, paraffin-embedded tissue. Primary pulmonary SCC was defined as patients with SCC diagnosed on resection specimens with no radiographic or clinical evidence of SCC elsewhere. All cases were either of moderate or poor differentiation. The p16 nuclear staining was graded as 0 no staining, 1+ 10% staining, 2+ 50% expression, and 3+ more than 50% of nuclear staining in the SCC. 12 of the 49 cases (24.5%) showed positive nuclear staining for p16. In the positive cases, five cases were 3+, 6 cases were 2+, and one case was 1+. Our study found that approximately 1/4 of primary pulmonary SCC cases can exhibit p16 staining, indicating that p16 is not an entirely specific marker for metastatic SCC of head and neck origin in the thoracic/neck area.
Most melanomas present as thin lesions (1.0 mm) with a good prognosis; however, a small percentage of patients with thin lesions experience recurrence or metastasis. The aim of our study was to identify a distinct pattern of gene expression within thin melanomas known to have eventually metastasized to regional lymph nodes or distant sites compared with those that followed the typical course with good response to wide local excision alone. Patients who were disease-free for a minimum of 10 y served as controls (n D 10) to the experimental group who developed metastasis (n D 9). Laser capture microdissection was used to specifically isolate cancer cells from formalin-fixed paraffin-embedded tissue with subsequent gene expression analysis on Affymetrix Human Transcriptome Array 2.0 Arrays. Although gene expression differences were observed between the patients with thin melanoma with poor clinical outcome and those with good clinical outcome, neither the number of genes nor the magnitude of the fold difference was very substantial or significant. Cluster analysis with this subset of genes could definitively separate a subset of the poor responders from the good responders, but there remained a mixed group of tumors that could not be predicted from gene expression alone. Pathway analysis identified cellular processes that were regulated based on the response, including categories commonly associated with melanoma progression. Ultimately, we concluded that there were very few differences between these groups. Future research will be required and investigation of the mutational landscape may be another strategy to uncover genomic changes that drive recurrence and metastasis in thin melanoma.
A rat model of antineutrophil cytoplasmic antibody (ANCA) associated vasculitides reveals crescentic glomerulonephritis as seen in human renal biopsies and diffuse lung hemorrhage that is not well documented in human lung biopsies. A 64-year-old male, with shortness of breath and mild elevation of serum creatinine, was found to have a positive serum test for ANCA, but negative antiglomerular basement membrane antibody. A renal biopsy showed pauci-immune type of crescentic glomerulonephritis and focal arteritis. The prior lung wedge biopsy was retrospectively reviewed to show diffuse hemorrhage and hemosiderosis with focal giant cells. In addition, small arteries revealed subtle neutrophil aggregation, and margination along vascular endothelium, but no definitive vasculitis. The pathology of ANCA associated vasculitides results from activated neutrophils by ANCA and subsequent activation of the alternative complement cascade with endothelial injury, neutrophil aggregation and margination. Our findings, after the correlation between lung biopsy and renal biopsy, imply that the top differential diagnosis in the lung biopsy should be microscopic polyangiitis when diffuse pulmonary hemorrhage and hemosiderosis are present in this ANCA-positive patient.
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