The pathology and clinical features of early recurrent membranous glomerulonephritis.

We assessed the earliest manifestations of recurrent membranous glomerulonephritis (MGN) in renal allografts. Clinical, laboratory and pathologic data were reviewed in 21 patients at the initial biopsy within 4 months post-transplant with evidence of MGN and on follow-up biopsies, compared to a biopsy control group of eight transplants without recurrent MGN. The mean time of first biopsy with pathologic changes was 2.7 months. In each earliest biopsy, immunofluorescence (IF) showed granular glomerular basement membrane (GBM) staining for C4d, IgG, kappa and lambda. IF for C3 was negative or showed trace staining in 16/21. On each MGN biopsy positive by IF, 14/19 showed absence of deposits or rare tiny subepithelial deposits by electron microscopy (EM). At the earliest biopsy, the mean proteinuria was 1.1 g/day; 16 patients had <1 g/day proteinuria. Follow-up was available in all patients (mean 35 months posttransplant). A total of 13 patients developed >1 g/day proteinuria; 12 were treated with: rituximab (n = 8), ACEI and increased prednisone dose (n = 2), ACEI or ARB only (n = 2). All patients showed reduction in proteinuria after treatment. A total of 11/16 patients showed progression of disease by EM on follow-up biopsy. Recognition of early allograft biopsy features aids in diagnosis of recurrent MGN before patients develop significant proteinuria.

De novo AL amyloidosis in the kidney allograft.

We report four cases of de novo amyloidosis occurring after 16, 18, 28 and 31 years following kidney transplantation. These patients presented with proteinuria and progressive allograft dysfunction. Kidney biopsy showed AL amyloidosis in all compartments of the allograft kidney. Serum immunofixation studies revealed monoclonal lambda light chains in all four cases. Bone marrow examination showed 10% plasma cells in one case, 5-10% in two cases and less than 5% in one case. Two patients died unexpectedly within 3 months and 1 year of the diagnosis of allograft AL amyloidosis. Of the remaining two, one underwent autologous stem cell transplant that resulted in complete hematologic remission. However, the patient relapsed within 2 years and also developed progressive kidney allograft failure. The patient received a second autologous stem cell transplant with complete hematologic response, followed by a second kidney transplant, which showed no evidence of amyloid at 1-year posttransplant. The remaining case was treated with prednisone and bortezomib, which has stabilized kidney function in the short term. In conclusion, this study shows that AL amyloidosis is an uncommon but important cause of late onset proteinuria in the kidney allograft that results in kidney allograft failure.

Placental transmogrification of the lung, a histologic variant of giant bullous emphysema. Clinicopathological study of three further cases.

Placental transmogrification of the lung was described by Chesney in 1978 as an unusual cystic lesion involving a single pulmonary lobe (3). We studied three additional cases with identical clinical and pathologic features. The patients were a 33-year-old woman and men aged 24 and 27 years. Each patient was first seen with respiratory distress; one had repeated pneumothoraces. Radiographically, an enlarging cystic lesion was present in a lower (two) or middle (one) lobe. The lesion had been present for 10 years in one patient. In two patients, mediastinal shift was noted. Lobectomy was curative in all instances. Grossly there was a uni- or paucilocular cyst lined by papillary structures. Microscopically, the papillae contained proliferating blood vessels, lymphoid nodules, smooth muscle, and fat. Sclerotic foci obliterated the vessels in some areas. The growth pattern and topography resembled those of placental villi. Systematic review of the histologic features in other lungs with marked emphysema revealed a spectrum of similar changes and suggested that the lesion in our patients may be a complication of bulla formation and is most likely the clinico-pathologic analog of the "vanishing lung" syndrome (idiopathic giant bullous emphysema).

Adamantinoma-like Ewing's sarcoma: genomic confirmation, phenotypic drift.

Ewing's sarcoma, a highly malignant neoplasm, is characterized by an 11;22 translocation [t(11;22) (q24;q12)], resulting in the fusion of genes FLII and EWS. Adamantinoma of extragnathic bones, a low-grade malignant neoplasm with epithelial features, is not typically considered in the differential diagnosis of Ewing's sarcoma. In this study, three osseous Ewing's sarcomas with histological, immunohistochemical, or ultrastructural epithelial features were subjected to reverse transcription-polymerase chain reaction and sequencing studies for the Ewing's sarcoma molecular rearrangement. (Two of the three cases were originally described as adamantinomas or nontypical Ewing's sarcoma before the availability of genetic characterization.) In addition, traditional cytogenetic analysis and a unique combined interphase molecular cytogenetic/ immunocytochemical approach with bicolor 11;22 translocation breakpoint flanking probes (cosmids) and pancytokeratin antibodies were performed on one neoplasm. At(11;22) (q24;q12) was found in one neoplasm and a type II EWS/FLI-1 fusion transcript was detected in all three neoplasms. The combined genetic/immunocytochemical approach revealed the presence of the 11 ;22 translocation in the nuclei of cytokeratin immunoreactive cells. These genotypic and phenotypic findings delineate a novel Ewing's sarcoma histologic variant, "adamantinoma-like Ewing's sarcoma."

Clopidogrel-associated thrombotic thrombocytopenic purpura/hemolytic uremic syndrome in a kidney/pancreas transplant recipient.

BACKGROUND: We present a case report of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS) developing in a kidney/pancreas transplant recipient after the initiation of treatment with clopidogrel for symptomatic coronary artery disease. METHODS: A 35-year-old male kidney/pancreas recipient developed unstable angina 5 years after transplantation. The patient was treated with clopidogrel as adjunct therapy. A TTP/HUS condition developed, was diagnosed early, and successfully reversed with the implementation of plasmapheresis and cessation of clopidogrel and cyclosporine A. RESULTS: The patient continues taking cyclosporine A with good renal function 6 months after the incident, and successfully underwent coronary artery by-pass grafting 3 months after the event. DISCUSSION: This case demonstrates that early identification and treatment can reverse the TTP/HUS process associated with thienopyridine-derived agents. We strongly recommend that drugs of the thienopyridine class be used cautiously in transplant recipients, especially those taking calcineurin-inhibitors.

Cytogenetic findings in a case of epithelioid sarcoma and a review of the literature.

Cytogenetic studies of epithelioid sarcoma, a rare malignant soft tissue neoplasm of adolescents and young adults, are few. A characteristic anomaly has not yet been identified for this sarcoma. In this study, cytogenetic studies of a primary epithelioid sarcoma of a 15-year-old male revealed the following abnormalities: t(6;8)(p25;q11.2) and add(7)(p15).

ras mutations and expression in head and neck squamous cell carcinomas.

Mutational activation and overexpression of the family of ras proto-oncogenes have been associated with many human tumors. The role of mutations of H-ras, K-ras, and N-ras, as well as expression of the respective protein products (p21s) in normal mucosa, dysplastic mucosa, and squamous cell carcinomas (SCCs) of the head and neck has not been fully described. In our study, 51 tumors (40 paraffin embedded and 11 fresh frozen) were examined to determine if mutational activation of ras is an important molecular event in head and neck SCC. Analyses of codons 12, 13, and 61 of H-ras, K-ras, and N-ras revealed no mutations, suggesting that mutational activation of ras is not important in the majority of head and neck SCCs. Immunocytochemistry (ICC) was used to define the expression of H-ras, K-ras, and N-ras in normal mucosa, dysplastic mucosa, and SCC of the head and neck and to determine if expression of ras family members correlated with early or late events in the development of SCC. Expression of p21N-ras in nine samples of histologically normal head and neck mucosa revealed moderate staining in the basal proliferative layers with progressively less staining as cells matured. The most superficial layers of normal mucosa failed to express p21N-ras. A low level of p21H-ras was expressed in all layers of normal mucosa while K-ras was not expressed. ICC of SCC tumor sections revealed cytoplasmic expression of N-ras in nine of nine tumors, H-ras in five of nine tumors, and K-ras in one of nine tumors. Expression of H-ras, K-ras, and N-ras in head and neck SCC was not related to histologic differentiation or TNM staging; however, p21N-ras was overexpressed in seven of nine tumors. Furthermore, the pattern of N-ras expression in dysplastic lesions revealed expression in all layers of the mucosa in contrast to normal mucosa, which expresses p21N-ras primarily in the basal proliferative layer. The change in p21N-ras expression pattern in dysplastic mucosa and its overexpression in the majority of tumors suggest that loss of control of N-ras expression may be an early step in carcinogenesis of head and neck SCC.

Primary pulmonary chondrosarcoma mimicking bronchogenic cyst on CT and MRI.

Pulmonary chondrosarcoma is a rarely encountered primary tumor of the lung. We present a case with computed tomography and magnetic resonance imaging features mimicking a bronchogenic cyst.

Proteinuria after kidney transplantation, relationship to allograft histology and survival.

Proteinuria is associated with reduced kidney allograft survival. Herein we assessed the association between proteinuria, graft histology and survival. The cohort included 613 kidney allograft recipients who had proteinuria (measured) and surveillance biopsies at 1-year posttransplant. Proteinuria >150 mg/day was detected in 276 patients (45%) and in 182 of these, proteinuria was below 500. In >84% of patients even low levels of proteinuria were associated with albuminuria. Proteinuria was associated with the presence of graft glomerular pathology and the use of sirolimus. Eighty percent of patients with proteinuria >1500 mg/day had glomerular pathology on biopsy. However, lower levels of proteinuria were not associated with specific pathologies at 1 year. Compared to no sirolimus, sirolimus use was associated with higher prevalence of proteinuria (40% vs. 76%, p < 0.0001) and higher protein excretion (378 + 997 vs. 955 + 1986 mg/day, p < 0.0001). Proteinuria was associated with reduced graft survival (HR = 1.40, p = 0.001) independent of other risk factors including, glomerular pathology, graft function, recipient age and acute rejection. The predominant pathology in lost allografts (n = 57) was glomerular, particularly in patients with 1-year proteinuria >500. Thus, proteinuria, usually at low levels (<500 mg/day), is present in 45% of recipients at 1 year. However, and even low levels of proteinuria relate to poor graft survival. Proteinuria and glomerular pathology relate independently to survival.

Interpreting post-transplant proteinuria in patients with proteinuria pre-transplant.

Increasing numbers of patients receive kidney transplants before initiation of dialysis or shortly thereafter. Some of these patients have significant proteinuria pre-transplant making the interpretation of post-transplant proteinuria problematic. In this study, we evaluated post-transplant proteinuria in 115 patients who had urine protein measured within 3 months of transplant and assessed the association of proteinuria with allograft pathology. Proteinuria declined rapidly from 3650 +/- 3702 mg/day pre-transplant to 550 + 918 at 3 weeks (p < 0.0001) and continued to decline until 1 year post-transplant (472 +/- 1116, p < 0.0001 vs. 3 weeks). Proteinuria greater than 3000 mg/day was present in 48 patients (42%) pre-transplant, in 1 patient (1%) at 3 weeks and in 4 patients (4%) at 1 year. Surveillance graft biopsies were done at 1 year in 93% of patients. Proteinuria > or = 1500 mg/day and/or an absolute increase in proteinuria > 500 mg/day after 3 weeks post-transplant was associated with allograft glomerular pathology. In conclusion, pre-transplant proteinuria, even when high grade, declines rapidly after transplantation. Failure to decline or persistence of proteinuria greater than 1500 mg/day is indicative of allograft pathology.

Kidney transplant function and histological clearance of virus following diagnosis of polyomavirus-associated nephropathy (PVAN).

Polyomavirus-associated nephropathy (PVAN) is managed by reduced immunosuppression with or without antiviral therapy. Data from 55 patients with biopsy-proven PVAN were analyzed for adverse outcomes and influence of baseline variables and interventions. During 20+/-11 months follow-up, the frequencies of graft loss, major and any functional decline were 15%, 24% and 38%, respectively. Repeat biopsies were performed in 45 patients with persistent PVAN in 47%. Low-dose cidofovir, IVIG and cyclosporine conversion were used in 55%, 20% and 55% of patients. No single intervention was associated with improved outcome. Of the variables examined, only degree of interstitial fibrosis at diagnosis was associated with kidney function decline. In contrast, donor source, interstitial fibrosis, proportion of BKV positive tubules and plasma viral load at diagnosis were all associated with failure of histological viral clearance. This retrospective, nonrandomized analysis suggests that: (i) Graft loss within 2 years of PVAN diagnosis is now uncommon, but ongoing functional decline and persistent infection occur frequently. (ii) Low-dose cidofovir, IVIG and conversion to cyclosporine do not abrogate adverse outcomes following diagnosis. (iii) Fibrosis at the time of diagnosis predicts subsequent functional decline. Further elucidation of the natural history of PVAN and its response to individual interventions will require prospective clinical trials.

Radiofrequency ablation of the kidney: acute and chronic histology in porcine model.

OBJECTIVES: To our knowledge, the chronic histopathologic effects of radiofrequency ablation (RFA) of renal parenchyma have not been extensively documented. In this study, we report the light and electron microscopic features of renal RFA in acute and chronic porcine models. METHODS: Eleven animals underwent renal RFA of the lower pole kidney bilaterally. RFA was performed laparoscopically in 6 acute animals and percutaneously in 5 chronic animals. Acute animals were killed immediately following surgery. One chronic animal each was killed on postoperative day 3, 7, 14, 30, and 90. Histopathologic evaluation of all renal tissue specimens was carried out with light and electron microscopy. RESULTS: Acutely, the renal radiolesion appeared as a yellowish white, well-circumscribed, necrotic area on gross examination, with evidence of extensive coagulative necrosis and marked inflammation on microscopic examination. From day 1 through 90, light and electron microscopy revealed evidence of progressive, irreversible cell death and necrosis with diminishing inflammatory response in the glomeruli, tubules, and renal interstitium. RFA lesions underwent gradual spontaneous resorption of the necrotic area with ultimate autoamputation. CONCLUSIONS: RFA results in necrosis of the ablated renal parenchyma.

Invasive carcinoid tumor of the heart.

Carcinoid tumors have been described in almost every organ and may affect virtually every body system. Cardiac involvement manifesting as right-sided valvular disease is characteristic of the carcinoid syndrome; however, direct myocardial involvement is unusual. We present a case of an invasive carcinoid tumor whose primary manifestation was myocardial invasion.

Giant cell reparative granuloma of the petrous temporal bone: a case report and literature review.

Giant cell reparative granuloma (GCRG) is an unusual, benign bone lesion that most commonly affects the maxilla and mandible; skull involvement is rare. The etiology is uncertain but may be related to trauma. GCRG is difficult to distinguish from giant cell tumor of the bone and has a lower recurrence rate. Thirteen reports of temporal bone GCRG in 11 patients have been reported. One report of a petrous GCRG in a 3-year-old girl has been identified. A 38-year-old male presented with a 2-year history of fullness in his left ear, ipsilateral hearing loss, and intermittent cacosmia. Computed tomography and magnetic resonance imaging revealed a large left-sided anterior temporal extradural mass. The patient underwent a left frontotemporal craniotomy and resection of a left temporal fossa tumor that involved the petrous and squamous parts of the temporal bone. The patient's post-operative course was uneventful, except for increased hearing loss secondary to opening of the epitympanum. Follow-up at one month revealed no other problems. Histopathology of the specimen was consistent with a giant cell reparative granuloma.

Laparoscopic and percutaneous radiofrequency ablation of the kidney: acute and chronic porcine study.

OBJECTIVES: The chronic effects of renal radiofrequency ablation are unknown. Herein, we investigate the anatomic and physiologic sequelae of laparoscopic and percutaneous renal radiofrequency ablation in acute and chronic porcine models. METHODS: Our study comprised two phases-an acute phase and a chronic phase. In the acute phase, bilateral laparoscopic renal radiofrequency ablation was performed in 6 animals (12 renal units), which were euthanized immediately after surgery. In the chronic study, bilateral percutaneous renal radiofrequency ablation was performed in 5 animals (10 renal units). One animal each was euthanized at postoperative day 3, 7, 14, 30, and 90. RESULTS: Ultrasound-monitored laparoscopic (n = 12) and percutaneous (n = 10) radiofrequency ablations of the lower pole of the kidney were technically successful in each instance. No intraoperative complications occurred. In the survival experiments, the radiolesions showed gradual spontaneous resorption and ultimate renal autoamputation, while maintaining pelvocalyceal integrity as confirmed by ex vivo retrograde ureteropyelogram. Serum creatinine and hematocrit remained stable in all survival animals. Postoperative complication occurred in 1 chronic animal with nonobstructive small bowel dilation at autopsy. CONCLUSIONS: Laparoscopic and percutaneous renal radiofrequency ablation are technically feasible. The anatomic and physiologic sequelae of renal radiosurgery are favorable. Improved techniques of real-time monitoring of the evolving renal radiolesion are necessary.