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Summary Knowledge on renal involvement in kidney donors with diabetes, that is, diabetic nephropathy (DN), is limited. During the 7 years (2010-2017), 921 postperfusion biopsies were performed for living donors (14%) or deceased donors (86%). The Renal Pathology Society classification schema for DN (class 0-IV) was used. Biopsies with light microscopic changes of DN (at least class IIa) were selected for study. Eleven biopsies (1.2%) showed DN, all from deceased donors (class IIa in 8, class IIb in 2, and class III in 1 biopsy). The glomerular basement membrane thickness ranged from 439 ± 52 to 725 ± 82 nm. These biopsies also displayed arterionephrosclerosis. They were from 9 deceased donors (fulfilling clinical criteria for acceptance in all, diabetes ;[>6 years] in 8, hypertension in 6, and proteinuria [1+] in all). Follow-up biopsies (5-342 weeks after transplant) showed DN of the same class (7 biopsies), probably progression (1), or progression (3). At follow-up (15-416 weeks), all recipients were alive. One graft was lost at 76 weeks because of progressive DN. The other 10 grafts were functioning, but the serum creatinine reached 2.0 to 2.7 mg/dL in 5 of them. Although diabetes is frequent in kidney donors, donor-related DN is unusual. It is observed only in deceased donors, but the risk factors for its development are not known. Donor-related DN may be stable or progress. Whether it resolves, especially for DN in early phase, remains unknown. It may adversely impact the graft outcome with a magnitude proportional to the severity of the tissue injury in the postperfusion biopsies.

Congo red stain apple-green birefringence under polarized light is the most popular method for detecting amyloid; however, it has limitations. The goal of this study was to evaluate if examination of Congo red stain by fluorescent microscopy (FM) significantly enhances the diagnostic yield. Congo red-stained tissue sections were retrospectively and prospectively examined by light microscopy (LM) with and without polarizer and by FM using the Texas red filter and results by each method compared. Congo red-stained amyloid recognized by LM was unequivocally and easily identified by FM in each of 48 cases. In 22 of them, FM either confirmed the presence of a small amount of amyloid or lead to a definitive diagnosis, which was otherwise missed. Eight cases with Congo red-negative by LM were also negative by FM. In 8 cases with a false-positive Congo red stain, FM still detected the signal in 5, but it was absent in 3 cases. In conclusion, Congo red fluorescence improves the diagnostic yield of LM for both positive and negative cases.

To study the importance of prostatic involvement by transitional cell carcinoma (TCC) in patients with bladder cancer, we examined the entire prostates by whole-mount sections from 214 radical cystoprostatectomy specimens for detailed patterns of involvement by TCC and correlated the results with lymph node metastasis and patients' survival. Prostatic involvement by TCC was detected in 69 (32%) of 214 cases. Among them, 30 (43%) patients had carcinoma in situ (CIS) and the other 39 (57%) were invasive TCC. Carcinoma in situ occurred in either prostatic urethra (n = 6, 20%) or, more commonly, in prostatic ducts/acini (n = 14, 47%), and in a combination of prostatic urethra and ducts (n = 10, 33%). Ten (26%) of the invasive TCC resulted from direct penetration from the primary tumor in the bladder, and the remaining 29 (72%) cases arose from prostatic urethra/ducts, of which 11, 13, and 5 invaded the lamina propria, prostatic stroma, and periprostatic or seminal vesical tissue, respectively. Both prostatic TCC involvement and nodal metastasis were highly significant prognostic factors for patients' survival and the survival significance of prostatic TCC involvement still existed regardless of lymph node status. Furthermore, the presence of prostatic CIS and degrees of prostatic invasion are associated with nodal metastasis and survival. Patients with prostatic CIS or urethral lamina propria invasion had a similar, but higher incidence of lymph node metastasis and lower long-term and 5-year survival than those patients without prostatic involvement. Similarly, prostatic stromal invasion and periprostatic/seminal vesical invasion had a similar, but much higher nodal metastasis and worse survival than patients with only prostatic CIS or urethral lamina propria invasion. In summary, presence of prostatic TCC involvement and levels of involvement are significant prognostic factors in patients with bladder cancer.

Fungi are important etiologic agents of sinusitis. However, features of fungal sinusitis including the histologic spectrum, diagnostic mishaps, incidence, and fungal types have not been systematically studied. From 1996 through 2001, a total of 788 surgical pathology sinus specimens from 384 cases was retrieved. Fungal sinusitis was diagnosed in 58 specimens (7%) from 47 cases (12%). Four histologic categories of fungal sinusitis were identified: (1) allergic fungal sinusitis in 34 cases (copious mucin, abundant eosinophils, Charcot-Leyden crystals (so-called allergic mucin), with rare noninvasive fungal hyphae); (2) mycetoma/fungus ball in 11 cases (tightly packed fungal hyphae without allergic mucin or tissue invasion); (3) chronic invasive fungal sinusitis in 1 case (tissue granulomas with fungal hyphae); and (4) acute fulminant fungal sinusitis in 1 case (fungal vascular invasion). The diagnosis was initially missed in 16/34 (47%) cases of allergic fungal sinusitis despite typical features; incorrect classification was noted in 47% of cases. Sixty-seven percent of cases had positive fungal cultures, dematiaceous fungi being the most common. Allergic fungal sinusitis accounted for the majority of fungal sinusitis. Although misdiagnosis or incorrect classification is rather frequent for fungal sinusitis, awareness of the distinctive morphologic features of this entity may prevent these errors.

Light chain crystal deposition disease is a rare and poorly characterized entity that can be confused with a number of different conditions, depending on where the disease process is manifested. The present study explored the role of ultrastructural immunogold labeling in the diagnosis of this condition. Seven cases of light chain crystal deposition (kappa light chain-related) are reported. Immunohistochemistry and immunofluorescence techniques play a rather limited role in the evaluation of these cases, as a result of the inability to detect monoclonal kappa light chains in association with the crystalline structures or high background staining. Ultrastructural labeling is the method of choice to fully characterize these cases. However, surgical pathologists must learn to recognize the findings associated with this condition to avoid misdiagnosis. If the diagnosis is at least suspected, then a complete hematologic workup may identify the underlying plasma cell dyscrasia. It must be emphasized that in some patients the plasma cell dyscrasia does not become clinically manifested until years after the diagnosis of light chain crystal deposition.

Renal biopsy specimens from patients with systemic lupus erythematosus (SLE) rarely show changes that are pathogenetically and morphologically unrelated to SLE. The morphology and behavior of these nonlupus nephritides are not well known. Two hundred fifty-two renal biopsies performed on 224 patients with SLE collected from 3,036 native kidney biopsies performed between 1975 and 1998 were reviewed, and those that showed nonlupus nephritides (index biopsies) were selected for studies. Thirteen biopsy specimens with nonlupus nephritides were identified in 13 patients, who belonged to 3 clinically distinct groups. Group I included 6 patients in whom SLE was diagnosed at the time of index biopsies. The index biopsies in these patients showed focal segmental glomerusclerosis (FSGS; 3 cases), Immunoglobulin (Ig) M nephropathy (1 case), and thin basement membrane disease (1 case). The diagnostic features for FSGS included segmental sclerosis involving at least 1 glomerulus, absence of lupus nephritis or other conditions that may cause nonspecific segmental sclerosis of glomeruli such as ischemia or nephrosclerosis, and nephrotic-range proteinuria. There was uniform, global, diffuse and marked thinning of the glomerular basement membrane in the case of thin basement membrane disease. Group II included 3 patients in whom SLE was diagnosed 2 to 9 years before the time of index biopsies and SLE was active at the time of biopsy. The index biopsies in these patients showed FSGS (2 cases) and hypertensive nephrosclerosis (1 case). Group III included 4 patients in whom SLE was diagnosed 5 to 36 years before the time of index biopsies and SLE was inactive at the time of biopsy. The index biopsies in these patients showed 1 case each of amyloidosis, FSGS, hypertensive nephrosclerosis, and allergic acute tubulointerstitial nephritis. Previous renal biopsies, performed in 5 patients, showed IgM nephropathy (1 case), diffuse proliferative lupus GN (1 case), focal proliferative lupus GN (1 case), and mesangial proliferative lupus GN (2 cases). Follow-up biopsies, performed in 3 patients, confirmed the diagnosis of FSGS (2 cases) and hypertensive nephrosclerosis (1 case) noted in the index biopsies. Nonlupus nephritides may occasionally be encountered in SLE patients, regardless of clinical or serologic disease activity. These renal lesions display a broad morphologic spectrum in which FSGS seems most frequent. Renal biopsy plays a crucial role in identifying these lesions, which may have prognostic and therapeutic implications distinct from those of lupus nephritis.

Chronic tubulointerstitial injury (CTI) including tubular atrophy and interstitial fibrosis represents one major determinant for the progression of chronic renal disease regardless of cause. Although peritubular capillaries (PTCs) are essential to maintain the normal structure and function of renal tubules, little is known about the role of PTCs in the development of CTI. The integrity of PTCs seems to be regulated by growth factors. Vascular endothelial cell growth factor (VEGF) has recently been recognized as a potent regulator of angiogenesis, vascular survival, and vascular permeability. Knowledge of the role of VEGF in renal disease is still rudimentary, and its role in CTI has not been explored. We analyzed the morphologic changes of PTCs and correlated them with other morphologic parameters of CTI in 32 human kidneys with various types of chronic tubulointerstitial disease. The VEGF expression was immunohistochemically evaluated. Compared with normal kidney, PTC loss (41% to 55% of control) and reduced size of PTCs (55% to 88% of control) were noted in kidneys with CTI. The PTC density was positively correlated with the proximal tubular density (r = 0.66, P < .0001), proximal tubular size (r = 0.54, P < .001), and negatively correlated with interstitial volume (r = −0.84, P < .0001). Compared with normal kidney, where podocytes were the only cell type that constantly expressed VEGF, an interesting pattern of increased VEGF expression by renal tubules, especially morphologically intact or hypertrophic ones, was shared by all cases with CTI. Loss of VEGF in sclerotic glomeruli was noted. PTC injury is pathogenetically linked to tubular atrophy, tubular loss, and interstitial fibrosis in human kidneys with CTI and might be a key factor for the progression of chronic tubulointerstitial disease. The characteristic and uniform pattern of altered VEGF expression in kidneys with CTI may result from ischemia induced by PTC loss and represent a protective mechanism against further PTC injuries. HUM PATHOL 31:1491-1497.

Clear cell papillary renal cell carcinoma (CCP-RCC) has recently been recognized as a distinct subtype of renal cell carcinoma (RCC) due to its unique morphologic, immunohistochemical, and genetic features and indolent clinical behavior. However, the incidence of this tumor in a nephrectomy series for renal mass has not been fully investigated. Twelve cases of CCP-RCC were identified from a total of 290 consecutive partial (n = 137) or radical nephrectomies (n = 153) for RCC from 2010 to 2012 in our hospital. In this series, CCP-RCC was the fourth most common (4.1%) kidney tumor following clear cell (conventional) (70%), papillary (16.6%), and chromophobe (5.9%) RCCs. The average age of the CCP-RCC patients was 58.2 years (range, 18-81 years), with an equal sex distribution. Four cases (33.3%) were associated with end-stage renal disease. Of the 12 CCP-RCCs, 9 presented as solitary tumors; 2 coexisted with clear cell RCC; and 1 with papillary RCC. The average size of tumors was 2.5 cm (range, 0.8-6.0 cm). All tumors were pT1 (10 pT1a and 2 pT1b). Two cases were initially misclassified as clear cell RCC. Strong positive cytokeratin 7 stain and negative stains with α-methylacyl-CoA racemase and RCC marker differentiate CCP-RCC from low-grade clear cell RCC with similar histologic features. We conclude that CCP-RCC is a common renal neoplastic entity, representing the fourth most common (4.1%) RCC. It can be easily misclassified due to its overlapping features with low-grade clear cell RCC. In equivocal cases, immunohistochemical stains with a small panel of markers (cytokeratin 7, α-methylacyl-CoA racemase, RCC marker, or CD10) are warranted in making the correct histologic classification.

Because stage and grade of renal cell carcinoma (RCC) sometimes fail to predict the patient's outcome, additional prognostic predictors are needed. Apoptosis is a process of programmed cell death seen in both normal and neoplastic tissues, which has been shown to have prognostic significance in some tumor types. Forty-seven RCCs were studied for size, grade, stage, apoptosis, and proliferation. Fragmented DNA, a hallmark of apoptosis, was detected in situ by a process in which the fragmented DNA was labeled with a biotinylated nucleotide, which, in turn, was detected by an avidin-biotin-peroxidase labeling system. The proliferating tumor cells were detected by immunostaining with the MIB-1 antibody. The apoptotic index and proliferation index of each RCC were expressed as the number of tumor cells undergoing apoptosis and proliferation per 1,000 tumor cells. For grade I to IV RCCs, the median proliferative index was 13, 41, 119, and 143; the median apoptotic index was 8, 12, 39, and 73. For stage I to IV RCCs, the median proliferative index was 21, 34, 70, and 144; the median apoptotic index was 8, 9, 20, and 69. There was a statistically significant correlation of tumor grade, stage, and size with both proliferative index and apoptotic index. There was a statistically significant correlation between proliferation index and apoptotic index. In conclusion, apoptosis can be easily and reliably recognized by the in situ end labeling of fragmented DNA and may help predict the outcome of RCC.

Papillary cystadenoma of the epididymis is an uncommon benign lesion that may occur sporadically or as a manifestation of von Hippel-Lindau (VHL) disease. Neither immunohistochemical studies nor molecular genetic analyses of the VHL gene have been reported previously for this lesion. The authors describe two cases of clear cell papillary cystadenoma of the epididymis, both of which were initially confused with metastatic renal cell carcinoma. Both lesions showed positive immunohistochemical staining for low and intermediate molecular weight keratins (Cam 5.2 and AE1/AE3), EMA, vimentin, alpha 1-antitrypsin, and alpha 1-antichymotrypsin. Each was negative for CEA. Because clear cell papillary cystadenoma is similar to renal cell carcinoma histologically, and because both occur as components of the von Hippel-Lindau disease complex, the authors analyzed both cases for the presence of mutations in the VHL gene. A somatic VHL gene mutation was detected in one of the two tumors by polymerase chain reaction followed by single-strand conformation polymorphism analysis. Direct sequencing revealed a cytosine to thymine transition at nucleotide 694, resulting in the replacement of an arginine with a stop codon after the sixth amino acid of exon 3. As the VHL gene is believed to function as a tumor suppressor gene, VHL gene mutations may play a role in the initiation of tumorigenesis in sporadic cystadenomas of the epididymis.

Prostate tissue samples from patients with prostatic carcinoma (PC) and/or benign prostatic hyperplasia (BPH) were examined for expression of transforming growth factor- β 1 (TGF- β 1 ) using an immunohistochemical technique. Tissues were stained with CC and LC antisera, which react with extracellular and intracellular TGF- β 1 , respectively. All PC and BPH tissues showed positive extracellular staining; however, CC-immunoreactive material was significantly more extensive in PC compared with BPH, the average positively staining areas being 59% and 26%, respectively. This differential staining pattern was evident in cases in which areas of PC were located adjacent to areas of BPH. LC staining was identified exclusively intracellularly involving both stromal and epithelial cells in cases of PC as well as BPH. However, while stromal cell staining was more pronounced in BPH, epithelial cell staining tended to be more extensive and more intense in PC. The findings suggest that TGF- β 1 may be biologically important in the development of PC and BPH.

T3 renal cell carcinoma (RCC) is a heterogeneous group of tumors that are substaged based on perirenal or sinus fat invasion, adrenal invasion, and renal vein invasion. To evaluate whether the extent of fat invasion (minimal versus extensive) and direct adrenal gland invasion, renal vein invasion with or without concurrent fat invasion has a similar prognosis, we retrospectively reviewed 198 T3N0/NxM0 RCCs in a single academic tertiary hospital. Fat invasion was subdivided as minimal (or =5 mm into the fat) or extensive (5 mm) invasion. Direct adrenal invasion was defined as contiguous involvement of ipsilateral adrenal gland. Among the 198 T3 RCCs, minimal and extensive fat invasions were identified in 57 and 61 cases, respectively; renal vein invasion and direct adrenal invasion were seen in 66 and 14 cases. The patients' average age was 62.9 years, and 145 patients were male and 53 were females. The 2-year and 5-year survival rates were 85% and 56% for minimal fat invasion, 76% and 70% for extensive fat invasion, and 55% and 32% for renal vein invasion, respectively. There was no difference of survival in patients with T3b (renal vein invasion) RCC stratified by presence or absence of concurrent fat invasion. The 2-year and 5-year survival rates for adrenal invasion were 31% and 21%, respectively, which was significantly worse than that of fat or renal vein invasion. Multivariate analysis showed that nuclear grade, sarcomatoid differentiation, and subgrouping of pT3 RCC (fat invasion, renal vein invasion, and adrenal invasion) remained independent predictors of patient's overall survival. In conclusion, our study shows that T3 RCCs with minimal or extensive perinephric fat invasion has a similar prognosis and is significantly more favorable than that of renal vein invasion regardless of presence or absence of concurrent fat invasion. In contrast, tumors with adrenal gland invasion carry a far worse prognosis than perinephric fat or renal vein invasion and thus supporting a separate stage category.

A renal biopsy of a 57-year-old man with nephrotic syndrome revealed marked glomerular deposition of Congo red-positive, bire-fringent material characteristic for amyloid. Ultrastructurally, however, this material is composed of nonbranching, haphazardly arranged fibrils of approximately three times the thickness of typical amyloid fibrils. To our knowledge, there has been no report of such a finding, and this unique case enlarges the morphologic spectrum of renal fibrillosis.

Serous surface carcinoma (SSC) of the peritoneum is defined as a primary tumor histologically indistinguishable from serous carcinoma of the ovary, diffusely involving the peritoneal surface but sparing or only superficially invading the ovaries. In this study of 22 cases of SSC, it was found that the main clinical manifestations of SSC were abdominal pain and enlargement. In most cases, SSC evenly involved the entire mesothelial surface but rarely was predominant in or even limited to the pelvis. It frequently invaded the submesothelium, but deep invasion into abdominal and pelvic organs or local metastasis was rare, and distant metastasis was not seen at presentation. Microscopically, SSC was a high-grade tumor frequently showing high mitotic rate, psammomas bodies, and necrosis. The tumor was usually contiguous with hyperplastic mesothelium on either ovarian surface or other locations. Tumor cells in all cases except one showed cytoplasmic or surface neutral or acidic mucin or both. Tumor cells stained positive for keratin (100% of cases), epithelial membrane antigen (100%), Leu-M1 (45%), B72.3 (85%), vimentin (35%), and carcinoembryonic antigen (25%). Electron microscopic studies of six cases showed epithelial differentiation in each. Seven patients (32%) were alive with no clinical disease at 3 to 31 months, one patient (4%) was alive with extensive local disease at 24 months, 11 patients (50%) died almost exclusively of local recurrence at 1 to 70 months, and three patients (14%) died of operative complications. It is concluded that SSC arises from peritoneal mesothelium but has epithelial phenotype. It can be morphologically differentiated from other conditions with similar laparotomy findings, such as malignant mesothelioma, benign papillary mesothelioma, cystic mesothelioma, and benign or borderline peritoneal serous tumors. The prognosis of SSC is poor, and most patients die of uncontrollable local disease.

We present 2 cases of mixed epithelial and stromal tumor of the kidney with sarcomatous transformation. One patient was a 53-year-old woman who presented with macroscopic hematuria. The resected tumor involved the right renal parenchyma, measuring 13.0 × 8.0 × 4.0 cm, and extended to perirenal adipose tissue. The second patient was a 56-year-old woman who presented with right flank colic pain. The tumor measured 6.0 × 5.5 × 4.0 cm, with an intact capsule at the upper pole. Both tumors showed a well-circumscribed, multilocular, cystic, and focally solid mass. Sections of both tumors revealed benign and malignant components. The benign component consisted of multilocular cysts and fibrous stroma with a focally ovarian stromalike component. The malignant component in both cases was predominantly composed of undifferentiated cellular spindle cell sarcoma with frequent mitoses. One case showed additional heterologous malignant elements, including rhabdomyosarcomatous, chondrosarcomatous, and focal carcinomatous components. We report 2 additional cases of sarcomatous transformation in mixed epithelial and stromal tumor of the kidney.

Primary central nervous system lymphomas (PCNSLs) represent malignant non-Hodgkin's B-cell lymphomas confined to the central nervous system. Recent years have brought a dramatic increase in the frequency of PCNSL in the immunocompromised and immunocompetent populations. Cryoglobulins are cold-precipitable immunoglobulins associated with a number of infectious, autoimmune, and neoplastic disorders. Although it is known that patients with hematologic malignancies (eg, B-cell lymphomas, chronic lymphocytic leukemia, plasma cell dyscrasias) may have cryoglobulinemias and cryoglobulin deposition in several organs (eg, kidney, liver skin, blood vessels, peripheral nervous system), PCNSL associated with cryoglobulin deposition has not been previously described. This report demonstrates localized cryoglobulin deposition within the tumor bed in an immunocompetent patient with PCNSL.

Several unsettled histogenetic, nosologic and diagnostic considerations for renal epithelial tumors may have ultrastructural ramifications. Yet, a comprehensive electron microscopic study of renal epithelial neoplasms, in light of the recent classification, is not available. The ultrastructural findings from fifty-five renal epithelial neoplasms [31 clear cell renal cell carcinomas (RCC), 11 papillary RCC, 5 chromophobe RCC, 3 sarcomatoid RCC and 5 oncocytomas] were correlated with their light microscopic appearance. Clear cell RCC showed long microvilli similar to the brush border of the normal proximal tubules, with abundant cytoplasmic lipid and glycogen. Papillary RCC showed variably sized microvilli, and small amounts of cytoplasmic lipid, but no glycogen. Chromophobe RCC showed many cytoplasmic vesicles and abnormal mitochondria, with rare short and stubby microvilli. Renal oncocytoma showed many mitochondria with a few vesicles in the apical portion of the cytoplasm and rare short and stubby microvilli. The eosinophilic cell variants of clear cell RCC, papillary RCC and chromophobe RCC showed ultrastructural features similar to those of their respective prototypes, except for an increased numbers of mitochondria in the cytoplasm. One sarcomatoid clear cell RCC showed skeletal muscle differentiation. Two types of cytoplasmic inclusions, i.e. hyaline globules and granules similar to those in the Paneth cells (PC-like granules) were identified only in clear cell RCC, which displayed distinctive ultrastructural features. The current EM study demonstrates distinctive ultrastructural features of renal epithelial neoplasms. The findings lend additional support to the current classification of the pertinent tumor types, facilitate the differential diagnoses, and provide insights into the possible histogenesis of renal epithelial neoplasms.

Cell adhesion molecules mediate cell-cell and cell-matrix interactions, and they are thought to play an important role in tumor invasion and metastasis. Altered expression of integrins and CD44 in renal cell carcinoma has been recently demonstrated, but an association with invasive or metastatic behavior has not been reported. We examined very late activation (VLA) integrin and CD44 expression in 37 renal cell carcinomas and correlated adhesion molecule expression with multiple histological and clinical parameters. Most tumors exhibited positive staining for VLA3 (81%). Approximately one third of the tumors stained positively for VLA6 and CD44, and fewer (27%) were positive for VLA2. Only a few tumors were positive for VLA4 (8%) and VLA5 (14%). Most of the tumors exhibiting positive staining showed a combination of membranous and cytoplasmic staining patterns. Low-grade tumors positive for VLA6 showed a tendency for basilar staining of the tumor cells, whereas high-grade tumors exhibited diffuse cytoplasmic staining. All tumors exhibiting weak or strong positive staining for VLA4 or VLA5 showed extrarenal invasion or were known to have developed metastases at the time of nephrectomy. All tumors strongly positive for VLA2 or CD44 showed invasion beyond the renal capsule or metastases. In contrast to a previous study, no association was observed between positive staining and tumor grade. Nor were tumor size, architectural pattern, cell type, or DNA ploidy found to be associated with particular staining patterns. Although many of the invasive tumors showed no difference in VLA integrin or CD44 expression compared with tumors confined to the kidney, increased expression in some of them suggests that these cell adhesion molecules may contribute to the invasive or metastatic phenotype.

Tissue samples from patients with carcinoma of the prostate of various Gleason grades were examined for the frequency of apoptotic bodies. Apoptotic bodies were scored by morphometric methods using hematoxylin-eosin (HE)-stained sections from surgical specimens of prostate cancer. Non-neoplastic prostate tissue adjacent to foci of cancer showed a very low frequency of apoptotic bodies. Significantly larger numbers of apoptotic bodies were observed in the areas of carcinoma than in the non-neoplastic control tissues, regardless of Gleason grade. Interestingly, a positive correlation was noted between apoptotic bodies and increasing Gleason grade. The positive correlation suggests that increased programmed cell death is a feature of the increasing malignant potential that is associated with higher Gleason grade in prostate cancer.