Stephen M. Bonsib

Practice guidelines for the renal biopsy

Biopsy of the kidney should never be undertaken without careful consideration of the risks vs benefits. Given the importance of a correct diagnosis in the treatment and prognosis of renal disease, the pathological evaluation should use all available modalities. Native kidney biopsies require examination by light microscopy, immunohistochemistry and electron microscopy. The processing of the renal biopsy is complex and requires the support of a fully equipped anatomic pathology laboratory. Technical expertise is required to process the small fragments of tissue and to produce sections of highest quality. The correct diagnosis requires a well-trained renal pathologist with thorough knowledge of not only renal pathology but also renal medicine in order to correlate intricate tissue-derived information with detailed clinical data. In view of the importance and consequences of the pathologic diagnosis, the Renal Pathology Society appointed an Ad Hoc Committee on Practice Guidelines, to define the essential ingredients necessary to provide quality renal pathology diagnoses. This document incorporates the consensus opinions of the committee and the RPS membership at large.

Molecular Genetic Evidence for the Independent Origin of Multifocal Papillary Tumors in Patients with Papillary Renal Cell Carcinomas

Purpose: In patients with papillary renal cell carcinoma, it is not uncommon to find two or more anatomically distinct and histologically similar tumors at radical nephrectomy. Whether these multiple papillary lesions result from intrarenal metastasis or arise independently is unknown. Previous studies have shown that multifocal clear cell renal cell carcinomas express identical allelic loss and shift patterns in the different tumors within the same kidney, consistent with a clonal origin. However, similar clonality assays for multifocal papillary renal cell neoplasia have not been done. Molecular analysis of microsatellite and chromosome alterations and X-chromosome inactivation status in separate tumors in the same patient can be used to study the genetic relationships among the coexisting multiple tumors. Experimental Design: We examined specimens from 21 patients who underwent radical nephrectomy for renal cell carcinoma. All patients had multiple separate papillary lesions (ranging from 2 to 5). Eighteen patients had multiple papillary renal cell carcinomas. Seven had one or more papillary renal cell carcinomas with coexisting papillary adenomas. Genomic DNA samples were prepared from formalin-fixed, paraffin-embedded tissue sections using laser-capture microdissection. Loss of heterozygosity assays were done for six microsatellite polymorphic markers for putative tumor suppressor genes on chromosomes 3p14 (D3S1285), 7q31 (D7S522), 9p21 (D9S171), 16q23 (D16S507), 17q21 (D17S1795), and 17p13 (TP53). X-chromosome inactivation analyses were done on the papillary kidney tumors from three female patients. Fluorescence in situ hybridization analysis was done on the tumors of selected patients showing allelic loss at loci on chromosome 7 and/or chromosome 17. Results: Twenty of 21 (95%) cases showed allelic loss in one or more of the papillary lesions in at least one of the six polymorphic markers analyzed. A concordant allelic loss pattern between each coexisting kidney tumor was seen in only 1 of 21 (5%) cases. A concordant pattern of nonrandom X-chromosome inactivation in the coexisting multiple papillary lesions was seen in two of three female patients. A discordant pattern of X-chromosome inactivation was seen in the tumors of the other female patient. Fluorescence in situ hybridization showed that the majority of tumors analyzed had gains of chromosomes 7 and 17. Two patients had one tumor with chromosomal gain and another separate tumor that did not. Conclusion: Our data suggest that, unlike multifocal clear cell renal cell carcinomas, the multiple tumors in patients with papillary renal cell carcinoma arise independently. Thus, intrarenal metastasis does not seem to play an important role in the spread of papillary renal cell carcinoma, a finding that has surgical, therapeutic, and prognostic implications.

Dense deposit disease is not a membranoproliferative glomerulonephritis

Dense deposit disease (first reported in 1962) was classified as subtype II of membranoproliferative glomerulonephritis in the early 1970s. Over the last 30 years, marked differences in etiology and pathogenesis between type I membranoproliferative glomerulonephritis and dense deposit disease have become apparent. The sporadic observation that dense deposit disease can be seen with markedly different light microscopy appearances prompted this study. The goal was to examine a large number of renal biopsies from around the world to characterize the histopathologic features of dense deposit disease. Eighty-one cases of dense deposit disease were received from centers across North America, Europe and Japan. Biopsy reports, light microscopy materials and electron photomicrographs were reviewed and histopathologic features scored. Sixty-nine cases were acceptable for review. Five patterns were seen: (1) membranoproliferative n=17; (2) mesangial proliferative n=30; (3) crescentic n=12; (4) acute proliferative and exudative n=8 and (5) unclassified n=2. The age range was 3–67 years, with 74% in the range of 3–20 years; 15% 21–30 years and 11% over 30 years. Males accounted for 54% and females 46%. All patients with either crescentic dense deposit disease or acute proliferative dense deposit disease were between the ages of 3 and 18 years. The essential diagnostic feature of dense deposit disease is not the membranoproliferative pattern but the presence of electron dense transformation of the glomerular basement membranes. Based upon this study and the extensive data developed over the past 30 years, dense deposit disease is clinically distinct from membranoproliferative glomerulonephritis and is morphologically heterogeneous with only a minority of cases having a membranoproliferative pattern. Therefore, dense deposit disease should no longer be regarded as a subtype of membranoproliferative glomerulonephritis.

Renal lymphatics, and lymphatic involvement in sinus vein invasive (pT3b) clear cell renal cell carcinoma: a study of 40 cases

Although renal sinus vein invasion is the most common site of extrarenal involvement in clear cell renal cell carcinoma (CC), CC also spreads by lymphatics. As cortical lymphatics drain into the sinus, some involved sinus structures may be lymphatics, not veins. This possibility was investigated with podoplanin, a specific lymphatic endothelial marker, in 40 CC with sinus vein invasion. Ten blocks of uninvolved kidney, serving as controls, showed lymphatics within the adventitia of midcortical intralobular arteries. Lymphatics became more numerous and enlarged with progression towards the medulla. No lymphatics were among glomeruli or within the medulla unless associated with inflammation. The largest lymphatics occurred within the sinus, and were also noted within pelvic muscularis, and media of large veins. Intralymphatic tumor was observed and divided into two Groups. Group 1 (four cases) involved lymphatics within the invasive edge of tumors lacking a pseudocapsule. The lymphatics were small (0.045–0.19u2009mm), irregularly shaped, often incomplete, and contained single cells or small clusters of tumor cells. Group 2 (four cases) involved sinus lymphatics separate from tumor. One case each also involved adventitial lymphatics of an intralobular artery, the muscularis of the renal pelvis, and media of a muscular vein. The intralymphatic tumor in Group 2 often appeared discohesive, not endothelial cell invested, and larger than in Group 1 (0.4–0.5u2009mm). Conversely, tumor within muscular veins was cohesive, contained a capillary plexis, and was endothelial cell invested. In conclusion, intralymphatic tumor can be demonstrated in CC. Lymphatic involvement is less frequent than venous involvement and involves smaller structures. The potential for lymphatic spread may not be equal among involved lymphatics. Small peritumoral lymphatics may be destined for destruction by tumor growth. However, involved lymphatics within sinus and associated with renal pelvis, are likely sources for lymphatic spread and lymph node metastases.

Renal veins and venous extension in clear cell renal cell carcinoma.

The 2002 TNM formulation defines a pT3b tumor as one that ‘extends into the renal vein or its segmental (muscle containing) branches.’ This definition elicits uncertainty when veins with little muscle are involved or the relationship to the main renal vein is unknown. The diameter and medial thickness of 10 normal renal venous systems were studied and compared to sinus veins involved in 54 pT3b clear cell renal cell carcinomas (CC). All tumors were grossly examined and sampled for histology by the author. An immunoperoxidase cocktail containing CD 31 and actin, Masson trichrome and elastic stains were employed to aid identification of intravenous tumor. The venous dissections showed variable numbers of primary and secondary divisions with substantial overlap in diameter and medial thickness. The medial thickness decreased with each proximal division and ranged from being nonexistent to being thick. Study of the 54 pT3b CC revealed that the initial phase of extrarenal extension involved large caliber veins draining the primary tumor. With extensive venous involvement, tumor invaded through the vein wall into sinus fat or demonstrated retrograde venous extension into adjacent cortex. Correlation between gross and histology revealed that most nodules of tumor within the sinus fat contained evidence of pre-existing veins. The following observations were made: (1) the diameter of a sinus vein or the quantity of muscle is a poor indicator of vein segment or relationship to the main renal vein; therefore, the wording used to define pT3b should be clarified; (2) extrarenal spread in CC begins with intravenous extension whereas sinus fat invasion is usually secondary; (3) retrograde venous extension occurs in cases with massive renal vein involvement; and (4) nodules within the sinus fat usually represent venous involvement.

Imaging Glomeruli in Renal Biopsy Specimens

Glomerular capillary loops are complex vascular filters composed of interdigitating podocytes and fenestrated endothelial cells with an intervening proteoglycan-rich extracellular matrix. This arrangement is crucial to maintaining the filtration barrier but renders the glomerulus difficult to analyze by conventional two-dimensional histochemical techniques. When pathologic lesions distort glomerular architecture, its complex morphology is even more challenging to interpret. Fortunately, recent advances in microscopes and computer software now enable glomerular enthusiasts to dissect this complex structure with finer detail. In this review we explore the application of new methodologies such as two-photon microscopy that optimize three-dimensional, multicolor imaging and single-cell segmentation of glomerular components.

Pathologic Characteristics of Exophytic Renal Masses

OBJECTIVEnPathologic grade is an important prognostic factor for renal-cell carcinoma (RCC). The objective of this study was to determine if there is any association of radiologic characteristics with pathologic grade and type of small renal tumors.nnnPATIENTS AND METHODSnWe retrospectively reviewed the records of 500 patients who underwent extirpative renal surgery. Fifty-one patients met the inclusion criteria of solitary RCC <6 cm and adequate radiologic imaging available for review. The axial images with the largest area of tumor growing into the kidney were evaluated by a single radiologist to determine the percent of tumor that was exophytic.nnnRESULTSnNine patients had tumors that were >67% exophytic, and 42 patients had tumors <67% exophytic. There is a statistically significant difference in the mean Fuhrman grade for these 2 groups (1.78 v 2.25, P < 0.01). The distribution of histologic subtype was as follows: 34 patients with clear cell, 15 with papillary, and one each with chromophobe and unclassified tumors. Papillary RCC comprised 78% (7 of 9) of tumors that were >67% exophytic and 15% (3 of 20) that were <33% exophytic. The relative risk of a >67% exophytic tumor being papillary v nonpapillary is 4.1.nnnCONCLUSIONSnExophytic renal tumors are more likely to be of lower pathologic grade and of the papillary RCC subtype when compared with endophytic renal tumors. A larger prospective study is required to confirm these findings and determine the implications. This information may be useful when small tumors are being considered for watchful waiting or ablative therapies.

Crystal-Associated Nephropathy in Patients With Brushite Nephrolithiasis

Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana; Methodist HospitalInstitute for Kidney Stone Disease, Indianapolis, Indiana; Nephrology Section, University of Chicago, Chicago, Illinois; Departmentof Histology, Jinzhou Medical College, Jinzhou, Liaoning, Peoples Republic of China; Department of Pathology, IndianaUniversity School of Medicine, Indianapolis, Indiana; Department of Chemistry and Biochemistry, Miami University, Oxford, Ohio;and Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada