Penile Paget's Disease: A Case Report and Review of the Literature.

Extramammary Paget's Disease (EMPD) is a rare cutaneous, slow growing, intraepithelial adenocarcinoma that can be either primary (intraepithelial arising within the epidermis) or secondary (intraepithelial spread of a visceral carcinoma). Here we present the case of a 63-year-old male with EMPD of the glans penis stemming from underlying urothelial carcinoma. Our treatment decision elected for management with chemotherapy and local treatment with radiation therapy. Subsequent, review of the literature demonstrated a rare disease with a variety of underlying malignancies causing this secondary pathology. Caregivers should be aware of the association of Paget's disease and urothelial cancer and should have a high index of suspicion that erythematous penile lesions may represent Paget's disease and that penile biopsies should be performed early in this setting.

Deleterious effects of calcium channel blockade on pressure transmission and glomerular injury in rat remnant kidneys.

Hypertensive mechanisms are postulated to play a major role in the progressive glomerulosclerosis (GS) after renal mass reduction. But, in contrast to converting enzyme inhibitors, BP reduction by calcium channel blockers, has not provided consistent protection. Radiotelemetric BP monitoring for 7 wk was used to compare nifedipine (N) and enalapril (E) in the rat approximately 5/6 renal ablation model. After the first week, rats received N, E, or no treatment (C). The overall averaged systolic BP in C (173 +/- 7 mmHg) was reduced by both E and N (P < 0.001), but E was more effective (113 +/- 2 vs. 134 +/- 3 mmHg, P < 0.01). GS was prevented by E (2 +/- 1 vs. 26 +/- 5% in C) but not by N (25 +/- 6%). GS correlated well with the overall averaged BP in individual animals of all groups, but the slope of the relationship was significantly steeper in N compared with C+E rats (P < 0.02), suggesting greater pressure transmission to the glomeruli and GS for any given BP. Since autoregulatory mechanisms provide the primary protection against pressure transmission, renal autoregulation was examined at 3 wk in additional rats. Autoregulation was impaired in C rats, was not additionally altered by E, but was completely abolished by N. These data demonstrate the importance of autoregulatory mechanisms in the pathogenesis of hypertensive injury and suggest that calcium channel blockers which adversely affect pressure transmission may not provide protection despite significant BP reduction.

Molecular subtyping of Borrelia burgdorferi sensu lato isolates from five patients with solitary lymphocytoma.

Solitary lymphocytoma is a rare cutaneous manifestation of Lyme borreliosis that has been reported almost exclusively from Europe. This suggests that its etiologic agent may be absent or extremely rare on the North American continent. All three species of B. burgdorferi sensu lato known to be associated with human Lyme borreliosis (B. burgdorferi sensu stricto, B. garinii, and B. afzelii have been isolated in Europe, whereas only B. burgdorferi sensu stricto has been found in North America. This suggests that either B. garinii or B. afzelii might be the etiologic agent of borrelial lymphocytoma. To investigate this hypothesis we characterized five strains of B. burgdorferi sensu lato isolated from lymphocytoma lesions of patients residing in Slovenia. The methods used included: large restriction fragment pattern analysis of restriction enzyme MluI-digested genomic DNA, plasmid profiling, protein profiling, ribotyping using 5S, 16S, and 23S rDNA probes, and polymerase chain reaction amplification of the rrf (5S)-rrl (23S) intergenic spacer region. Molecular subtyping showed that four of the five isolates belonged to the species B. afzelii; however, this species is the predominant patient isolate in Slovenia and, therefore, may not represent a preferential association with lymphocytoma. The fifth isolate appeared to be most closely related to the DN127 genomic group of organisms. Further characterization of the isolate revealed that it possessed a unique molecular "fingerprint." The results not only show that borrelial lymphocytoma can be caused by B. afzelii but also demonstrate an association with another genomic group of B. burgdorferi sensu lato that is present in North America as well.

Identification of three species of Borrelia burgdorferi sensu lato (B. burgdorferi sensu stricto, B. garinii, and B. afzelii) among isolates from acrodermatitis chronica atrophicans lesions.

In Europe, at least three species of Borrelia are known to be causative agents of Lyme borreliosis: B. burgdorferi sensu stricto, B. garinii, and B. afzelii. Observable differences in the molecular characteristics of the three species have led to speculation that they may also differ in their pathogenic potential and/or tissue tropisms. Several studies have found an association between the chronic skin manifestation of Lyme borreliosis, acrodermatitis chronica atrophicans, and infection by B. afzelii. We sought to find further evidence for such a correlation by studying the genetic profiles of 22 strains of B. burgdorferi sensu lato derived from 21 patients who presented to the University Medical Center, Ljubljana, Slovenia between 1992 and 1995. Strains were isolated in culture from skin biopsies of acrodermatitis chronica atrophicans lesions; in the case of one patient two separate acrodermatitis chronica atrophicans lesions were cultured. All 21 patients had clinically typical lesions with "classic" histopathology and high IgG antibody titers to B. burgdorferi sensu lato. Strains were characterized and typed by 16S ribosomal RNA-specific polymerase chain reaction and determination of their large restriction fragment patterns using pulsed-field gel electrophoresis of MluI-digested genomic DNA. Of the 22 isolates studied, 17 possessed the highly conserved MLa1 pattern characteristic of B. afzelii. The remaining five isolates possessed large restriction fragment patterns that were typical of B. garinii (MLg2, four isolates from three patients) and B. burgdorferi sensu stricto (MLb2, one isolate). The results of 16S ribosomal RNA-specific polymerase chain reaction were concordant with these species designations. These data show that B. afzelii is the predominant, but not the exclusive, etiologic agent of acrodermatitis chronica atrophicans.

Distribution of the protease inhibitor alpha 1-antichymotrypsin in cerebral and systemic amyloid.

We performed immunocytochemical staining to study the distribution of serum protease inhibitors in cerebral and systemic amyloid deposits. In beta-protein amyloid deposits in Alzheimer's disease, Down's syndrome, age-related cerebral amyloidosis, sporadic cerebral amyloid angiopathy and hereditary cerebral hemorrhage with amyloidosis of Dutch origin, antibody to alpha 1-antichymotrypsin (ACT) stains senile plaques and vascular deposits. Immature plaques or preamyloid deposits, identified by their positive staining for beta-protein and negative staining for Congo red, which represents the earliest recognizable stages of amyloid deposition, are also labeled. We did not detect ACT in other chemically different forms of cerebral and systemic amyloid. None of the other inhibitors in this study, i.e. antithrombin III and alpha 2-macroglobulin, was detected in the amyloid deposits. Neurons and glial cells throughout the central nervous system in normal and amyloid-containing brains also bind ACT antibody. The results emphasize the close association of ACT with one type of cerebral amyloid (beta-amyloid diseases) as well as the failure to detect such an association in other chemically different forms of cerebral and systemic amyloids.

Metanephric adenosarcoma in a young adult: morphologic, immunophenotypic, ultrastructural, and fluorescence in situ hybridization analyses: a case report and review of the literature.

Metanephric neoplasms are uncommon renal tumors that arise in both children and adults. They may be composed of small epithelial cells or benign stroma, or both, and are termed metanephric adenoma, metanephric stromal tumor, or metanephric adenofibroma, respectively. Thus far, these tumors have been known for their benign behavior. We present the case of a 21-year-old woman who developed a neoplasm composed of a renal epithelial component identical to metanephric adenoma combined with a malignant spindle cell sarcoma. The epithelial component was positive for pankeratin AE1/3, whereas the sarcomatous component was negative for epithelial markers and positive for vimentin, CD34, and CD117. No smooth muscle differentiation was apparent in the sarcoma by immunohistochemistry or ultrastructural analysis. By fluorescent in situ hybridization analysis of the sarcomatous component there was monosomy of the X chromosome, but no apparent variation from the normal diploid pattern for chromosomes 3, 7, 12, and 17. We conclude that the spectrum of metanephric neoplasia should be expanded to include malignant stromal variants, and we propose the term "metanephric adenosarcoma" for the present case.

Combined effects of an angiotensin converting enzyme inhibitor and a calcium antagonist on renal injury.

BACKGROUND: Angiotensin converting enzyme inhibitors have uniformly been shown to prevent the development both of proteinuria and of glomerulosclerosis in rats with a remnant kidney. Conversely, dihydropyridine calcium antagonists (DCA) have failed to demonstrate such a benefit in spite of causing an equivalent reduction in blood pressure. OBJECTIVE: To test the hypothesis that concomitant administration of an angiotensin converting enzyme inhibitor and a DCA would lead to a smaller increase both in proteinuria and in glomerulosclerosis relative to that caused by administration of a DCA alone at similar levels of blood pressure. METHODS: Experiments were carried out using Sprague-Dawley rats that had been subjected to five-sixths renal ablation. Animals were allocated randomly to one of four groups: control (no treatment), amlodipine (A rats), benazepril (B rats), or a combination of benazepril and amlodipine (B + A rats). We implanted intraperitoneal sensors for telemetric monitoring of the animal's blood pressure. Other parameters measured at baseline included proteinuria and inulin clearance. After approximately 7 weeks all of the parameters were remeasured and animals killed for morphologic assessment of the kidney. RESULTS: The B + A rats had lower levels of proteinuria than did the rats in group A (21 +/- 12 mg/day for B + A rats versus 59 +/- 24 mg/day for A rats, P < 0.05). The degree of glomerulosclerosis in the B + A rats was also reduced markedly compared with that in A rats (12 +/- 4% for B + A rats versus 43 +/- 12% for A rats, P < 0.05). Moreover, the results on proteinuria and glomerulosclerosis of B + A rats were similar to those for B rats. These differences could not be explained totally in terms of differences in blood pressure control (144 +/- 12 mmHg in A rats versus 132 +/- 13 mmHg in B + A rats, NS). CONCLUSION: The results were consistent with the observation that a combination of benzepril and amlodipine provides additional protection against renal injury compared with that provided by amlodipine alone. The mechanism for this benefit is not known.

Human polyoma virus-associated interstitial nephritis in the allograft kidney.

BACKGROUND: Asymptomatic polyoma virus infection documented by urine cytology or serology is well known, but the clinical course of biopsy-proven interstitial nephritis is not well defined. METHODS: Twenty-two cases were identified by histology, immunostaining, in situ hybridization, electron microscopy, or polymerase chain reaction. RESULTS: The clinical features mimicked acute rejection (n=19), chronic rejection with incidental diagnosis at nephrectomy (n=2), or drug toxicity (n=1). Histology showed homogenous intranuclear inclusions. In situ hybridization showed BK virus (BKV) to be the predominant species, but polymerase chain reaction documented JC virus co-infection in one of five cases so tested. Electron microscopy in seven cases showed 20-51-nm virions. The two cases diagnosed at nephrectomy received no therapy. Initial antirejection therapy in 12 cases led to clearance of the virus in 1/12 (8%), partial therapeutic response in 3/12 (25%), and graft loss in 8/12 (67%) cases. The last recorded creatinine in patients with functional grafts ranged from 1.9 to 7.0 (median: 4.5) mg/dl, 0.4-45 (median: 4.0) months after initial diagnosis. The remaining eight cases treated by reduction of immunosuppression at the outset have been free of graft loss for 0.2-10.0 (median: 4.8) months since diagnosis, and clearance of virus has been documented in three of six (50%) cases. The serum creatinine in these patients is 1.7-6.0 (median: 2.4) mg/dl, 0.2-10 (median: 4.8) months after diagnosis. Follow-up biopsies performed 1-23.5 months after diagnosis show chronic allograft nephropathy. CONCLUSIONS: Polyoma virus tubulo-interstitial nephritis-associated graft dysfunction usually calls for judicious decrease in immunosuppression and monitoring for acute rejection. Development of methods to serially quantify the viral load in individual patients could potentially improve clinical outcome.

Transjugular renal biopsy in patients with liver disease.

Although transjugular renal biopsy has been used extensively in Europe, experience with its use in the United States has been limited. We report 25 patients who underwent both transjugular liver and renal biopsies in the same sitting and 4 patients who underwent only a transjugular renal biopsy. All 29 patients had both liver disease and renal abnormalities. Each patient was also believed to have a relative or absolute contraindication to a percutaneous renal biopsy (usually in the form of a bleeding abnormality). Transjugular renal biopsy yielded a quantity of tissue sufficient for diagnosis in all but 1 patient. The mean number of glomeruli obtained per biopsy was 19.4 +/- 12.2 (SD). Pathological diagnoses found were tubular injury in 5 patients, membranoproliferative glomerulonephritis in 5 patients, nephrosclerosis in 3 patients, diabetic nephropathy in 2 patients, immunoglobulin A (IgA) nephropathy in 2 patients, minimal change disease in 2 patients, end-stage renal disease in 2 patients, nonspecific changes in 1 patient, early glomerulosclerosis in 1 patient, tubular atrophy only in 1 patient, and normal renal histological characteristics in 4 patients. One patient with suspected IgA nephropathy had no histological diagnosis established because of a lack of glomeruli in the biopsy specimen. There were no instances of major bleeding from the perirenal area; however, a small perirenal hematoma was identified in 3 patients by postbiopsy computed tomography or sonography. Thus, based on our experience, transjugular renal biopsy appears to be a safe and effective procedure for establishing a histological diagnosis and is an attractive alternative biopsy method for patients with advanced liver disease and contraindications to conventional percutaneous renal biopsy.

The changing concepts of amyloid.

The first issue of the Archives of Pathology & Laboratory Medicine, published 75 years ago, contained an article by Richard Jaffé on the experimental induction of amyloidosis in mice. This publication was one of a series of milestones that have marked our ongoing and evolving concept of amyloidosis, beginning with the first description by Virchow more than a century ago. Since that time, scientific understanding of amyloidogenesis has expanded through the involvement of newly developed techniques, such as biochemical analysis, electron microscopy, and molecular genetics. As a result of these investigations, it is now known that amyloidoses comprise an entire family of sporadic, familial and/or inherited, degenerative, and infectious disease processes, linked by the common theme of abnormal protein folding and deposition. This article seeks to provide a synopsis of the present state of our knowledge with regard to these disorders, including current terminology, classification, major clinical syndromes, and diagnosis.

Mixed epithelial and stromal tumor of the kidney: preliminary immunohistochemical and electron microscopic studies of the epithelial component.

Mixed epithelial and stromal tumor of the kidney is a rare biphasic tumor composed of cysts and tubules embedded in the spindle cell stroma. Although the histogenesis of this tumor is unknown, it has been proposed that both components of the tumor, i.e., stromal and epithelial, are neoplastic. The authors report preliminary immunohistochemical and electron microscopic studies of the epithelial component from one case of a typical, benign, mixed epithelial, and stromal tumor of the kidney. In this study, some tubules showed positivity for proximal, while others showed positivity for distal, nephron immunomarkers. By electron microscopy, some tubules had features of proximal tubular epithelium, while other tubules had features of the loop of Henle (thin segments). The authors believe that in a benign tumor such morphologic heterogeneity is inconsistent with neoplastic proliferation. Therefore, they postulate that in mixed epithelial and stromal tumor of the kidney the tubules are entrapped rather than neoplastic. Additional studies are needed to address this issue and electron microscopy should play a significant role in this process.

Molecular characterization of Borrelia spp. isolates from greater metropolitan Chicago reveals the presence of Borrelia bissettii. Preliminary report.

Lyme Disease in the US is concentrated in three endemic areas: the Northeast, the upper mid-West, and the Pacific coast. In the mid-West, the range of Lyme disease has expanded to include large parts of Wisconsin and Minnesota. Despite its proximity to the mid-Western focus, Illinois, so far, has not been considered an endemic area. However, more recent data suggest that this situation may be changing. Also, the extent of borrelial diversity in the mid-West remains largely unexplored. Here, we present preliminary results on the molecular characterization of Borrelia isolates from rodents captured in Cook and Lake Counties, both of which are parts of the greater metropolitan Chicago area in Illinois. We investigated the rodent reservoir present in forested areas of suburban Chicago in order to determine the frequency of infection with the Lyme disease agent(s) by culture isolation of Borrelia spirochetes (Picken et al., unpublished). Rodent isolates of Borrelia were identified to the species level by genetic characterization. In total, 19 isolates were obtained over 3 years from NW Cook Co. and Lake Co. Pulsed-field gel electrophoretic analysis of Mlul digested DNA from these isolates showed macrorestriction patterns similar to that of the Californian isolate, strain DN127 (PF type I), New York isolate strain 25015 (PF type II), or a variant of the latter (PF type III). Sequence data generated from the rrf(5S)-rrl(23S) intergenic spacer region of the ribosomal RNA gene cluster confirmed the identity of all the Chicago isolates studied to date as B. bissettii. These strains are unlike our previous Borrelia isolates from NW Illinois and Wisconsin. In addition, there was a predominant association of B. bissettii infection with pratal rodent species such as Microtus pennsylvanicus and Zapus hudsonius. The relationship of this novel enzootic focus to the established mid-Western endemic focus of Lyme disease remains to be elucidated. The geographic range and reservoir diversity of this organism may have hitherto been underestimated.

Immunoglobulin light chains and the kidney: an overview.

Monoclonal immunoglobulins and free immunoglobulin light chains are produced by plasma cells as a result of their clonal expansion in plasma cell dyscrasia. These proteins are pivotal in the development of pathologic and clinical symptoms of plasma cell dyscrasia and renal manifestations are frequently the presenting and leading features of this process. The spectrum of pathology associated with monoclonal light chains includes light-chain cast nephropathy and tissue deposits derived from the monoclonal light chain, ie, amyloid derived from the light chains and nonamyloidotic light chain deposition disease. The main diagnostic features, differential diagnosis, and pathogenesis are briefly reviewed.

beta 2-Microglobulin amyloidosis: illustrative cases.

Patients on long-term dialysis tend to develop amyloidosis derived from beta 2-microglobulin. Serum levels of this protein rise in renal insufficiency and remain high in patients on dialysis. The distribution of amyloid deposits in such patients as well as tissue diagnosis, immunohistochemistry, and electron microscopic features are briefly discussed.

Characterization of renal amyloid derived from the variable region of the lambda light chain subgroup II.

Amyloid fibrils were extracted from the kidney of a patient (CHE) shown to have tetramers and dimers of a monoclonal lambda light chain in his serum, and whose bone marrow cells in short-term culture synthesized these forms and a smaller lambda fragment of approximately 10,000 to 12,000 daltons. Biochemical and serologic analysis of a fraction of a size (obtained from amyloid fibrils extracted from the kidney) similar to that synthesized by the bone marrow cells revealed a light chain fragment corresponding to the amino terminal end of the variable region of the lambda light chain subgroup II. The presence of similarly sized short fragments of lambda light chain in both the synthesized and deposited protein suggests that aberrant synthesis and/or proteolytic degradation may play a pathogenetic role in the process of amyloidogenesis.

Primary amyloidosis A. Immunohistochemical and biochemical characterization.

Primary "idiopathic" amyloidosis is usually related to immunoglobulin light chain (AL) associated with immunocytic dyscrasias, while secondary "reactive" amyloidosis (AA) is related to serum amyloid A protein (SAA) and typically occurs with chronic inflammation, malignancy, or familial Mediterranean fever. In the present study, amyloid fibril protein extracted from frozen and paraffin-embedded tissue from a patient (CAR) with primary systemic amyloidosis proved to be AA protein by immunohistochemical, immunochemical, and amino terminal sequence. Extracts from both frozen and formalin-fixed paraffin-embedded kidney and spleen yielded similar monomers and dimers of the AA protein. The additional high-molecular-weight bands and a distinct 12,000-dalton fragment in the amyloid protein extracted from the formalin-fixed paraffin-embedded lung suggest that different processing of proteins, ie, by polymerization and/or degradation, may occur in different organs.

Post-transplantation lymphoproliferative disorder of the NK-cell type: a case report and review of the literature.

Post-transplantation lymphoproliferative disorders (PTLDs) are primarily B-cell disorders that are thought to be Epstein-Barr virus (EBV) driven and that can occur months to years after solid organ or bone marrow transplantation. A small percentage of cases have also been shown to be T-cell phenotype, but a PTLD of NK-cell type has not been previously described. We report here the case of a renal transplant recipient in whom a clinically aggressive, histologically monomorphic PTLD developed that was documented to be of an NK-cell phenotype according to paraffin section and flow cytometric immunophenotyping. Molecular-genetic analysis showed the PTLD to contain germline immunoglobulin heavy, kappa light chain, and T-cell receptor beta and gamma genes. Studies for EBV failed to demonstrate the presence of viral infection in tumor cells. Clinical follow-up showed a rapidly fatal course. To our knowledge, this is the first reported case of an EBV-negative PTLD of true NK-cell type.