High-resolution profiling of histone h3 lysine 36 trimethylation in metastatic renal cell carcinoma.

Mutations in SETD2, a histone H3 lysine trimethyltransferase, have been identified in clear cell renal cell carcinoma (ccRCC); however it is unclear if loss of SETD2 function alters the genomic distribution of histone 3 lysine 36 trimethylation (H3K36me3) in ccRCC. Furthermore, published epigenomic profiles are not specific to H3K36me3 or metastatic tumors. To determine if progressive SETD2 and H3K36me3 dysregulation occurs in metastatic tumors, H3K36me3, SETD2 copy number (CN) or SETD2 mRNA abundance was assessed in two independent cohorts: metastatic ccRCC (n=71) and the Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma data set (n=413). Although SETD2 CN loss occurs with high frequency (>90%), H3K36me3 is not significantly impacted by monoallelic loss of SETD2. H3K36me3-positive nuclei were reduced an average of ~20% in primary ccRCC (90% positive nuclei in uninvolved vs 70% positive nuclei in ccRCC) and reduced by ~60% in metastases (90% positive in uninvolved kidney vs 30% positive in metastases) (P<0.001). To define a kidney-specific H3K36me3 profile, we generated genome-wide H3K36me3 profiles from four cytoreductive nephrectomies and SETD2 isogenic renal cell carcinoma (RCC) cell lines using chromatin immunoprecipitation coupled with high-throughput DNA sequencing and RNA sequencing. SETD2 loss of methyltransferase activity leads to regional alterations of H3K36me3 associated with aberrant RNA splicing in a SETD2 mutant RCC and SETD2 knockout cell line. These data suggest that during progression of ccRCC, a decline in H3K36me3 is observed in distant metastases, and regional H3K36me3 alterations influence alternative splicing in ccRCC.

Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma.

Antiangiogenic therapy resistance occurs frequently in patients with metastatic renal cell carcinoma (RCC). The purpose of this study was to understand the mechanism of resistance to sunitinib, an antiangiogenic small molecule, and to exploit this mechanism therapeutically. We hypothesized that sunitinib-induced upregulation of the prometastatic MET and AXL receptors is associated with resistance to sunitinib and with more aggressive tumor behavior. In the present study, tissue microarrays containing sunitinib-treated and untreated RCC tissues were stained with MET and AXL antibodies. The low malignant RCC cell line 786-O was chronically treated with sunitinib and assayed for AXL, MET, epithelial-mesenchymal transition (EMT) protein expression and activation. Co-culture experiments were used to examine the effect of sunitinib pretreatment on endothelial cell growth. The effects of AXL and MET were evaluated in various cell-based models by short hairpin RNA or inhibition by cabozantinib, the multi-tyrosine kinases inhibitor that targets vascular endothelial growth factor receptor, MET and AXL. Xenograft mouse models tested the ability of cabozantinib to rescue sunitinib resistance. We demonstrated that increased AXL and MET expression was associated with inferior clinical outcome in patients. Chronic sunitinib treatment of RCC cell lines activated both AXL and MET, induced EMT-associated gene expression changes, including upregulation of Snail and ß-catenin, and increased cell migration and invasion. Pretreatment with sunitinib enhanced angiogenesis in 786-0/human umbilical vein endothelial cell co-culture models. The suppression of AXL or MET expression and the inhibition of AXL and MET activation using cabozantinib both impaired chronic sunitinib treatment-induced prometastatic behavior in cell culture and rescued acquired resistance to sunitinib in xenograft models. In summary, chronic sunitinib treatment induces the activation of AXL and MET signaling and promotes prometastatic behavior and angiogenesis. The inhibition of AXL and MET activity may overcome resistance induced by prolonged sunitinib therapy in metastatic RCC.

Outcome of patients with metastatic renal cell carcinoma treated with targeted therapy without cytoreductive nephrectomy.

BACKGROUND: Cytoreductive nephrectomy (CN) became a standard procedure in metastatic renal cell carcinoma (mRCC) in the immunotherapy era. Historically, median overall survival (OS) of patients treated with interferon alpha (IFN-α) without CN was 7.8 months. Median OS in patients treated with targeted therapy (TT) without CN is unknown. PATIENTS AND METHODS: We retrospectively reviewed records of patients with mRCC who received TT without CN. Kaplan-Meier methods and Cox regression analysis were used to estimate median OS and identify poor prognostic factors. RESULTS: One hundred and eighty-eight patients were identified. Most patients had intermediate-risk (54.8%) or poor-risk (44.1%) disease. Median OS for all patients was 10.4 months [95% confidence interval (CI) 8.1-12.5]. By multivariable analysis, elevated baseline lactate dehydrogenase and corrected calcium, performance status of two or more, retroperitoneal nodal metastasis, thrombocytosis, current smoking, two or more metastatic sites, and lymphopenia were independent risk factors for inferior OS. Patients with four or more factors had increased risk of death (hazard ratio 8.83, 95% CI 5.02-15.5, P < 0.001) and 5.5-month median OS. Nineteen patients (10.0%) survived for 2+ years. CONCLUSIONS: These data highlight the improved OS of patients with mRCC treated with TT without CN, compared with historical IFN-α treatment, and may guide the design of trials investigating the role of CN in the TT era.

Hsa-miR-9 methylation status is associated with cancer development and metastatic recurrence in patients with clear cell renal cell carcinoma.

The long-term prognosis for clear cell renal cell carcinoma (ccRCC) is dramatically altered by the development of metastatic recurrence. However, there are very few indicators that can predict which patient will develop a recurrence. MicroRNAs regulate many cellular processes and have been shown to be associated with cancer development and recurrence. More recently it has been shown that microRNA genes can be epigenetically modified in cancer, resulting in aberrant silencing of microRNA genes with tumor suppressor functions. In this study, we show that two genes encoding for hsa-miR-9 are significantly hypermethylated in ccRCC tumors compared with adjacent normal tissues (P-value <0.001 for both miR-9-1 and miR-9-3) resulting in decreased expression, and that the methylation of these genes was more significant in DNA obtained from the primary tumor for patients who developed a recurrence (P-value: 0.012 and 0.009 for miR-9-1 and miR-9-3, respectively) than in tumors from nonrecurrent patients. Furthermore, methylation of miR-9-3 was significantly associated with an increased risk of recurrence (hazard ratio: 5.85, 95% confidence intervals: 1.30-26.35) and high methylation levels of either miR-9-1 or miR-9-3 resulted in a significant, nearly 30-month decrease in recurrence-free survival time (P-value: 0.034 and 0.007 for miR-9-1 and miR-9-3, respectively). Our results demonstrate that hsa-miR-9 is involved in the development of ccRCC while also having a role in the development of metastatic recurrence.

Gene and protein expression markers of response to combined antiangiogenic and epidermal growth factor targeted therapy in renal cell carcinoma.

BACKGROUND: Metastatic renal cell carcinoma (mRCC) patients treated with anti-vascular endothelial growth factor (VEGF) therapies demonstrate promising outcomes but not all patients benefit. Factors that predict response remain to be elucidated. PATIENTS AND METHODS: Nephrectomy material from 37 patients with mRCC receiving bevacizumab +/- erlotinib was used for protein and gene expression assessment. Protein lysates were subjected to reverse-phase protein array profiling. RNA extracts were used to carry out gene expression microarray-based profiling. Normalized protein and gene expression data were correlated with overall survival (OS) and progression-free survival (PFS) using univariate Cox hazard model and linear regression. Immunoblotting was carried out to validate the results. RESULTS: High protein levels of AMP-activated protein kinase and low levels of cyclin B1 (CCNB1) were associated with longer OS and PFS. Further validation revealed reduced expression and activation of phosphoinositide 3-kinase (PI3K) pathway components and cell cycle factors in patients with prolonged survival after therapy. Gene expression analysis revealed up-regulation of PI3K- and cell cycle-related pathways in patients with shorter PFS. CONCLUSIONS: The OS and PFS of bevacizumab +/- erlotinib-treated patients with renal cell carcinoma were associated with changes in expression of protein and gene expression markers related to PI3K pathway and cell cycle signaling.

Vaccination of metastatic renal cell carcinoma patients with autologous tumour-derived vitespen vaccine: clinical findings.

The aim of this study was to evaluate the clinical efficacy as determined by time to progression and response rate (RR) of autologous vitespen (formerly HSPPC-96; Oncophage, Antigenics Inc., New York, NY, USA) with and without interleukin-2 (IL-2; Proleukin: Chiron, Emoryville, CA, USA) in stage IV metastatic renal cell carcinoma (RCC) patients undergoing nephrectomy. Eighty-four patients were enrolled on study, and then underwent nephrectomy and harvest of tumour tissue for use in autologous vaccine manufacture. Initial treatment schedule started approximately 4 weeks after surgery and consisted of six injections: once weekly for 4 weeks, then two injections biweekly (vaccines administered at weeks 1, 2, 3, 4, 6, 8), followed by restaging at or around week 10. Patients who had stable or responsive disease continued to receive vaccine, with four more vaccinations biweekly (at weeks 10, 12, 14, 16). Patients who had progressive disease at week-10 evaluation received four consecutive 5-day-per-week courses of 11 x 10(6) U of IL-2 subcutaneously (weeks 10, 11, 12, 13), with four doses of vitespen at 2-week intervals (at weeks 10, 12, 14, 16). At the next evaluation (week 18), patients with a complete response received two further cycles of vitespen (with IL-2 if also received during prior cycle) or until vaccine supply was exhausted. Patients with stable disease or partial response repeated their prior cycle of therapy. Disease progressors who had not yet received IL-2 began IL-2 treatment, and progressors who had already received IL-2 came off study. Of 60 evaluable patients, 2 demonstrated complete response (CR), 2 showed partial response (PR), 7 showed stable disease, and 33 patients progressed. Sixteen patients had unconfirmed stable disease. Two patients who progressed on vaccine alone experienced disease stabilisation when IL-2 was added. Treatment with vitespen did not result in a discernable benefit in the majority of patients with metastatic RCC treated in this study. Use in combination with immunoregulatory agents may enhance the efficacy of vitespen.

Chromophobe renal cell carcinoma: a comparative study of histological, immunohistochemical and ultrastructural features using high throughput tissue microarray.

AIMS: In some cases distinction between chromophobe renal cell carcinoma (CRCC), oncocytoma and clear cell (conventional) renal cell carcinoma (eosinophilic variant) using routine light microscopy remains problematic. The present study investigates the level of agreement in the diagnosis of CRCC, as well as the histological features most frequently used for this diagnosis by two pathologists with a special interest in renal neoplasia. The sensitivity and specificity of immunohistochemical markers in cases with overlapping histological features in the diagnosis of CRCC were also studied. Electron microscopy was performed, as a diagnostic gold standard, on all of the cases. METHODS AND RESULTS: Thirty-two renal tumours with predominantly eosinophilic cytoplasm were reviewed in a blinded fashion by two pathologists. The diagnosis and morphological features used to render each diagnosis were tabulated. Validation of the utility of keratin 7 and 20, epithelial membrane antigen (EMA), vimentin, CD10, parvalbumin, RCC antigen, antimitochondrial antibody and Hale's colloidal iron was performed by the construction of a tissue microarray (TMA) master block. Based on histological criteria alone, overall agreement on the diagnosis of these tumours was reached in 69% of the cases, while there was total disagreement in 12%. In 59% of the cases, total agreement was reached in classifying the case as a CRCC based on histology alone. Kappa statistics for interobserver variability were calculated as only slight agreement (kappa = 0.3). The histological features most frequently associated with a diagnosis of CRCC were accentuated cell borders (87%) and a combination of hyperchromatic wrinkled nuclei (79%) and perinuclear halos (74%). The most sensitive and specific marker for CRCC was parvalbumin (sensitivity 0.91; specificity 1.0). The immunohistochemical profile of EMA+/ vimentin- was useful but had low specificity (sensitivity 0.75; specificity 0.4). CD10 had the highest sensitivity (1.0) but worst specificity (0.25) for CRCC. Keratin 7 had high sensitivity (0.83) but fairly low specificity (0.37) for CRCC. Hale's colloidal iron and the RCC antigen marker were not contributory. Finally, the antimitochondrial antibody was found to be fairly sensitive (0.83) for excluding CRCC. CONCLUSIONS: A small but significant proportion of renal tumours with cells having eosinophilic cytoplasm cannot be classified, even by experienced pathologists, based on histology alone. In these cases it is imperative to use markers with known sensitivity and specificity for the diagnosis of CRCC.

Primary signet-ring cell carcinoma of lung: immunohistochemical study and comparison with non-pulmonary signet-ring cell carcinomas.

Signet-ring cell carcinoma (SRCC) of lung is a rare variant of pulmonary adenocarcinoma. In view of this rarity, the question of whether an SRCC is primary pulmonary or metastatic arises frequently because the majority of SRCCs seen in lung are metastatic tumors having arisen in stomach, colon, or breast. On routine histologic examination it is difficult to distinguish between pulmonary SRCC from SRCC metastasizing from other organs. Thyroid transcription factor-1 (TTF-1) is a homeodomain-containing transcription factor that is almost exclusively expressed in thyroid and pulmonary epithelial cells. TTF-1 expression has been demonstrated in various neoplasms of lung; however, the expression of TTF-1 in SRCCs has not been investigated so far. In the present study, using an immunoperoxidase staining procedure on paraffin sections, we investigated the expression of TTF-1, cytokeratin 7, cytokeratin 20, and villin (a specific marker expressed in tumors of the digestive tract, renal proximal tubules, and hepatic bile ducts) in 32 SRCCs from various organs (17 lung, 5 breast, 5 stomach, and 5 colon). Fourteen (82.4%) of 17 pulmonary SRCCs exhibited TTF-1 positivity, whereas none of the SRCCs of other organs were positive for TTF-1. A cytokeratin profile (CK7+/CK20-) was identified in 94.1% of pulmonary SRCC, and although it differed from the profile exhibited in colonic SRCCs (CK7-/CK20+), a similar profile was seen in breast SRCCs and some SRCCs arising in the stomach. Villin was identified in 29.4% of pulmonary SRCCs and 20% (one case) arising in the breast. Although the pattern of villin immunostaining exhibited by nondigestive tract SRCCs (cytoplasmic) differed from those of digestive tract SRCCs (membranous), distinguishing between the two groups based on their pattern of immunostaining alone would be difficult. The results of this study indicate that TTF-1 is expressed in a high percentage of pulmonary SRCCs and is very specific and that TTF-1 would be extremely valuable in distinguishing pulmonary SRCCs from those arising in other organs.

Concurrent angiomyolipoma and renal cell neoplasia: a study of 36 cases.

Little is known about the association of angiomyolipoma and adult renal-cell neoplasia. We studied the clinicopathologic features of 36 patients with concurrent angiomyolipoma and renal-cell neoplasia from the consultation and surgical pathology files of nine institutions. HMB-45 immunoreactivity was analyzed in both neoplasms. Twenty-five sporadic cases of patients with angiomyolipoma and renal-cell neoplasia and 11 cases of patients with tuberous sclerosis, as defined by Gomez' criteria, had mean ages of 59 and 53 years, respectively, and female-male ratios of 2:1 and 5:1, respectively. The mean size of the angiomyolipomas was 1 cm in the sporadic cases and 3 cm in those patients with tuberous sclerosis (medians: 0.5 and 3 cm, respectively, P =.002). The mean sizes of the renal-cell neoplasms were 5 cm in sporadic cases and 6 cm in patients with tuberous sclerosis (medians: 4 and 5 cm, respectively; P =.88). In both clinical settings, angiomyolipoma was more commonly the incidental tumor. Clear-cell (conventional) renal-cell carcinoma was the most common renal-cell neoplasm in both groups of patients, accounting for approximately two thirds of the tumors. In patients with tuberous sclerosis, 27% of renal-cell neoplasms were oncocytomas, compared with 8% in sporadic cases (P =.15). Papillary neoplasia, chromophobe, and collecting-duct renal-cell carcinoma were found only in sporadic cases. All of the 22 renal-cell neoplasms studied were negative for HMB-45, whereas all 25 angiomyolipomas studied were positive.

Tumor stage, vascular invasion and the percentage of poorly differentiated cancer: independent prognosticators for inguinal lymph node metastasis in penile squamous cancer.

PURPOSE: We determine if histopathological factors of the primary penile tumor can stratify the risk of the development of inguinal lymph node metastases. MATERIALS AND METHODS: Clinical records of 48 consecutive patients with squamous cell carcinoma of the penis who underwent resection of the primary lesion and either inguinal lymph node dissection or were observed for signs of recurrence (median followup 59 months) were reviewed. Parameters examined included pathological tumor stage, quantified depth of invasion and tumor thickness, histological and nuclear grade, percentage of poorly differentiated cancer in the primary tumor, number of mitoses and presence or absence of vascular invasion. Variables were compared in 18 lymph node positive and 30 lymph node negative cases. RESULTS: Pathological tumor stage, vascular invasion and presence of greater than 50% poorly differentiated cancer were the strongest predictors of nodal metastasis on univariate and multivariate regression analyses. None of 15 pT1 tumors exhibited vascular invasion or lymph node metastases. Of 33 patients with pT2 or greater tumors 21 (64%) had vascular invasion and 18 (55%) had metastases. Only 4 of 25 patients (15%) with 50% or less poorly differentiated cancer in the penile tumor had metastases compared with 14 of 23 patients (61%) with greater than 50% poorly differentiated cancer (p = 0.001). No other variables tested were significantly different among the patient cohorts. CONCLUSIONS: Pathological stage of the penile tumor, vascular invasion and greater than 50% poorly differentiated cancer were independent prognostic factors for inguinal lymph node metastasis. Prophylactic lymphadenectomy in compliant patients with pT1 lesions without vascular invasion and 50% or less poorly differentiated cancer does not appear warranted.

Sarcomatoid differentiation in renal cell carcinoma: a study of 101 cases.

Sarcomatoid renal cell carcinoma is not a distinct histologic entity and represents high-grade transformation in different subtypes of renal cell carcinoma. It is not known whether any particular histologic type has a predilection for sarcomatoid change or whether the primary histologic type of renal carcinoma undergoing sarcomatoid change affects prognosis. Of 952 consecutively histologically subtyped renal cell carcinomas, the incidence of sarcomatoid differentiation was 8% in conventional (clear cell) renal carcinoma, 3% in papillary renal carcinoma, 9% in chromophobe renal carcinoma, 29% in collecting duct carcinoma, and 11% in unclassified renal cell carcinoma. One hundred one renal cell carcinomas with sarcomatoid change were studied, and clinicopathologic parameters were correlated with outcome. The mean age of patients was 60 years (range, 33-80 years), and the male-to-female ratio was 1.6:1. The median tumor size was 9.2 cm (range, 3-25 cm). The primary histologic subtype of the carcinoma component was conventional (clear cell) renal carcinoma in 80 cases, papillary renal carcinoma in eight, chromophobe renal carcinoma in seven, collecting duct carcinoma in two, and unclassified renal cell carcinoma in four. The sarcomatoid component resembled fibrosarcoma in 54 cases, malignant fibrous histiocytoma in 44, undifferentiated sarcoma (not otherwise specified) in three with focal rhabdomyosarcomatous component in two of them. The spindled elements accounted for 1% to 99% of the sampled tumor (median, 40%; mean 45%). The histologic grade of the spindled elements was intermediate to high in 92 cases and low in nine cases. Most cases were TNM stages III and IV (seven stage I, six stage II, 63 stage III, and 25 stage IV). Follow-up was available in 88 patients; 61 (69%) patients died of disease and had a median survival time of 19 months. Distant metastases, most frequently to the lungs, were documented in 51 (66%) of 77 patients who had available clinical information regarding distant metastasis. The disease-specific survival rate was 22% and 13% after 5 and 10 years, respectively, compared with a cohort of renal cell carcinomas without sarcomatoid change with a 5-and 10-year disease-specific survival of 79% and 76%, respectively. Kaplan-Meier survival analysis showed that tumors with high TNM stage (p = 0.0027), at least 50% sarcomatoid component (p = 0.0453), and angiolymphatic invasion (p = 0.0282) were associated with decreased survival rates. The primary histologic subtype of the carcinoma component and the type and grade of the sarcomatoid component did not affect survival. In a Cox proportional hazard regression model, TNM stage appeared to be the only significant variable in predicting outcome among renal cell carcinomas with sarcomatoid change (p = 0.018; risk ratio, 6.984 and 8.439). Compared with a cohort of renal cell carcinomas without sarcomatoid change, sarcomatoid tumors tended to present at a more advanced stage (p = 0.0001). Also, when adjusted for stage, necrosis, and tumor size, patients with tumors with sarcomatoid differentiation had a worse prognosis than did patients with tumors without sarcomatoid change (p = 0.0001). In conclusion, sarcomatoid change in renal cell carcinoma portends a worse prognosis. Because tumors with even a small component of sarcomatoid change may have an adverse outcome, this finding, when present, should be noted in the surgical pathology report.

Intravesical adipose tissue: a quantitative study of its presence and location with implications for therapy and prognosis.

Accurate pathologic staging of carcinomas of the urinary bladder involves assessment of invasion by the tumor into the bladder wall and beyond into perivesical soft tissue. The presence of tumor within perivesical soft tissue implies pathologic stage pT3 (AJCC/UICC system, 1997). In traditional textbooks of histology, anatomy, pathology, and in the literature, other than a single case report and a brief reference in another paper, there is no information on the presence of adipose tissue in the lamina propria or muscularis propria of the urinary bladder. Nine hundred forty-three sections from 139 cystectomy specimens were evaluated for the presence, location, and quantity of adipose tissue within the lamina propria and muscularis propria. The histology of the perivesical soft tissues and the nature of its delineation from muscularis propria were also analyzed. Adipose tissue was seen within the lamina propria in 53% (74 of 139) of cystectomies and in 17.6% (166 of 943) of the examined sections. It was located predominantly in the deep lamina propria (at or below the muscularis mucosae) in 81.1% (60 of 74) of the cystectomies and in 91% (151 of 166) of the sections. Within the lamina propria it was predominantly seen as small localized aggregates in 92% (153 of 166) of sections. All cases showed adipose tissue within the muscularis propria. Adipose tissue was identified within the superficial (inner) muscularis propria in 54% (512 of 943) of sections and was predominantly in small aggregates in 80.5% (412 of 512) of sections. It was in moderate to abundant quantities within the deep (outer) muscularis propria in 60.7% (572 of 943) of sections. The perivesical soft tissue was almost exclusively composed of adipose tissue with variable vascularity. Delineation of the perivesical adipose tissue from the deep (outer) muscularis propria was typically indistinct because muscle bundles of the latter haphazardly merged with the perivesical adipose tissue. Based on these findings, we conclude that adipose tissue is frequently present in the lamina propria and muscularis propria of the urinary bladder wall, and is usually scant in the former location and frequently abundant in the latter. Awareness of the high frequency of adipose tissue within the urinary bladder wall has prognostic and therapeutic implications. In transurethral resection of bladder tumor (TURBT) specimens, misinterpretation of tumor infiltrating adipose tissue within lamina propria (pT1) as perivesical soft tissue involvement (pT3) may potentially result in unwarranted aggressive management. Substaging of muscle invasive tumors should be performed in cystectomy specimens only, because the junction of muscularis propria and the perivesical adipose tissue is typically ill-defined. Muscularis propria adipose tissue in TURBT specimens may be erroneously assumed to be perivesical adipose tissue, potentially leading to overstaging of the primary tumor.

Villous adenoma of urinary tract: a common tumor in an uncommon location.

The presence of colonic-type epithelium in the urinary tract is not an uncommon occurrence, but tumors derived from it are rare. Tumors arising from colonic-type epithelium, including villous adenoma and adenocarcinoma, have been reported in the renal pelvis, ureter, urinary bladder, and urethra. Villous adenomas of the urinary tract are rare, being most common in the urinary bladder, followed by the urethra. Morphologic features of these tumors are similar to those of the colonic adenomas. The largest published series of villous adenomas of the urinary tract was a study of 23 patients. This study is reviewed and other reports on villous adenomas of the urinary tract are discussed.

Benign tumors and tumor-like lesions of the adult kidney. Part II: Benign mesenchymal and mixed neoplasms, and tumor-like lesions.

In this review article the benign tumors and tumor-like lesions of the adult kidney are discussed. The incidence of benign renal tumors is low, especially when compared to renal cell carcinomas, as most are detected incidentally or at autopsy. Some of these tumors, as their names imply, are unique to the kidney, e.g., renal adenoma, metanephric adenoma, renal oncocytoma, nephrogenic adenofibroma, mesoblastic nephroma, capsuloma, juxtaglomerular cell tumor, renomedullary interstitial cell tumor (medullary fibroma), cystic nephroma, cystic partially differentiated nephroblastoma, and cystic hamartoma of the renal pelvis, while others, such as angiomyolipoma, leiomyoma, hemangioma, lipoma, etc., are not unique to the kidney and show similar morphologic features in the other sites they affect. Of the tumor-like lesions, xanthogranulomatous pyelonephritis, malakoplakia, and renal cysts are the most common. The other entities, such as fibroepithelial polyp, are rare, most having been the topic of case reports. In Part I of this paper the benign epithelial tumors of the kidney were previously discussed. This paper (Part II) is devoted to the benign mesenchymal tumors, mixed mesenchymal and epithelial tumors, and the tumor-like lesions.

Prognostic significance of the 1997 TNM classification of renal cell carcinoma.

PURPOSE: The TNM classification of renal cell carcinoma was recently revised in 1997. The most significant change from the previous edition (1987) is an increase in the size cutoff between T1 and T2 tumors from 2.5 to 7.0 cm. We compared the 1997 and 1987 TNM staging classifications in predicting patient outcome. MATERIALS AND METHODS: A total of 381 patients who underwent nephrectomy for renal cell carcinoma at our hospital between 1968 and 1994 were identified. Mean patient age was 61 years (range 15 to 89) and mean followup was 64.5 months. All pathological slides were re-reviewed in uniform manner and staged using the 1987 and 1997 TNM classifications. The impact of numerous pathological factors and each staging classification on disease specific survival and freedom from progression were statistically analyzed, and Kaplan-Meier survival curves were generated and compared. RESULTS: The 1997 TNM classification resulted in a redistribution of 170 cases previously classified as stage II (T2N0M0) to stage I (T1N0M0) under the new system. Both classifications were strong predictors of survival on univariate and multivariate analyses, and essentially equivalent in the ability to predict patient outcome. However, comparison of survival curves on Kaplan-Meier life tables revealed better separation of survival for stage I (T1N0M0) and stage II (T2N0M0) cases under the 1997 TNM classification, with survival for TNM stage I essentially remaining unchanged. CONCLUSIONS: The 1997 TNM classification of renal cell carcinoma appears to be equivalent to the previous classification in predicting outcome but permits better stratification of cases according to survival and, therefore, may have improved clinical usefulness.

Postatrophic hyperplasia of the prostate gland: a detailed analysis of its morphology in needle biopsy specimens.

Postatrophic hyperplasia is a histologic pattern showing atrophic and hyperplastic glands, sometimes with a small acinar configuration. Because distinction from small acinar carcinoma may be challenging, particularly in needle biopsy specimens, we studied 56 needle biopsy specimens containing 68 foci to ascertain the morphologic spectrum of postatrophic hyperplasia. All foci showed a distinct lobular small acinar proliferation with varying proportions of atrophic and hyperplastic glands. Gland size was typically variable, predominantly of small caliber but occasionally of intermediate to larger caliber. Round, oval, elongated, slitlike and stellate glands were seen. The nuclei were generally regular without hyperchromasia, with rare small nucleoli seen in 10 (15%) foci. The cytoplasm was variable, ranging from scant in atrophic glands to moderate or abundant and clear or occasionally eosinophilic in hyperplastic glands. An irregular internal gland contour was noted in glands with features of both atrophy and hyperplasia. Basal cells were apparent by light microscopy in most foci, although their distribution within foci and between foci varied. This finding was confirmed in all 26 cases studied with the high molecular weight cytokeratin immunohistochemical stain (34betaE12). Associated pathology included adenocarcinoma (12%), high-grade prostatic intraepithelial neoplasia (3%), atrophy distinct from foci of postatrophic hyperplasia (55%), and atypical adenomatous hyperplasia (2%). Adjunctive features of cancer were not seen in any of the foci of postatrophic hyperplasia. Familiarity with the histologic features of postatrophic hyperplasia will allow its confident separation from cancer, especially in limited biopsy material.

Benign tumors and tumor-like lesions of the adult kidney. Part I: Benign renal epithelial neoplasms.

The spectrum of renal neoplasms has expanded in recent years. Although most of the work taking place in this field has concerned malignant neoplasms of the kidney, there have been significant improvements in our knowledge of benign renal tumors and tumor-like lesions, especially in renal cell adenoma, renal oncocytoma, and renal angiomyolipoma. Awareness and knowledge of these benign lesions is important because they are often included in the differential diagnoses of malignant tumors, with which they may be confused both clinically and pathologically. The authors review the topic of benign renal neoplasms and tumor-like lesions that occur in adults, emphasizing some of the newly described aspects of these lesions.

Primary, pure, large-cell neuroendocrine carcinoma of the urinary bladder.

We report what to our knowledge is the first case in the English-language literature of a primary, pure, undifferentiated large-cell neuroendocrine carcinoma of the urinary bladder. To date, only one case of a large-cell neuroendocrine carcinoma was reported, and it was associated with an adenocarcinoma most likely of urachal origin. On the other hand, slightly more than 100 cases of undifferentiated small-cell carcinoma of the urinary bladder were reported, approximately one-half of which were associated with poorly differentiated transitional-cell carcinoma of the conventional type. The patient in our case was a 73-year-old man with a history of prostatic cancer treated with radiation therapy. He presented with hematuria, leading to the discovery of a solitary tumor on the dorsal wall of the urinary bladder. A diagnosis of large-cell neuroendocrine carcinoma was made, supported by immunohistochemical reactivity for chromogranin, neuron-specific enolase, and synaptophysin; a variety of other hormonal markers of neuroendocrine tumors were negative. The radical cystoprostatectomy and bilateral pelvic lymphadenectomy specimen showed a transmurally invasive tumor, without regional lymph node metastases. The patient died 2 months after surgery, and the autopsy revealed disseminated metastases histologically identical to the urinary bladder neoplasm. Awareness of the occurrence of large-cell neuroendocrine carcinoma of the urinary bladder seems to be important because of the possible aggressive outcome associated with this tumor and because of differential diagnostic considerations, which include malignant lymphoma and metastasis from another primary, especially in tumors occurring in a pure form.

Immunohistochemical expression of retinoblastoma and p53 tumor suppressor genes in prostatic intraepithelial neoplasia: comparison with prostatic adenocarcinoma and benign prostate.

Mutational alterations involving the p53 and retinoblastoma (RB) tumor suppressor genes are implicated in the oncogenesis of a variety of tumors. Their role in the pathogenesis of prostatic adenocarcinoma remains to be fully elucidated, and their detection in high-grade prostatic intraepithelial neoplasia (HG-PIN) has not been closely examined. We studied the immunohistochemical expression of RB and p53 proteins in HG-PIN, benign prostate, and prostatic adenocarcinoma from 25 radical prostatectomy specimens. Formalin-fixed, paraffin-embedded tissue sections pretreated with antigen retrieval in citrate buffer were stained with anti-RB antibody RB-WL-1 and anti-p53 antibody DO-7. RB immunoreactivity was present in all of the cases in the foci of HG-PIN, benign prostate, and prostatic adenocarcinoma. Mutant p53 protein was detected in 56% of HG-PIN, 72% of prostatic adenocarcinomas, and 20% of benign prostatic glands. A multivariate analysis of variance showed an overall difference in p53 immunoreactivity between HG-PIN, benign prostate, and prostatic adenocarcinoma (P < .001). There was a statistically significant difference between immunoreactivity of the benign prostate and of HG-PIN (P < .001) and between the immunoreactivity of benign prostate and prostatic adenocarcinoma (P < .001). The immunoreactivities of HG-PIN and prostatic adenocarcinoma were not statistically different (P = .3). These data suggest that RB loss might not play a role in initiation of all cases of prostatic adenocarcinoma. The p53 immunoreactivity in HG-PIN was significantly different from that found in benign prostate and was similar to that of prostatic adenocarcinoma. This is in keeping with the putative premalignant character of HG-PIN.

Comparative analysis of the nuclear proliferative index (Ki-67) in benign prostate, prostatic intraepithelial neoplasia, and prostatic carcinoma.

High-grade prostatic intraepithelial neoplasia (HG-PIN) lies in the morphologic continuum between benign and carcinomatous prostate, but its status as a neoplastic precursor remains only putative. We measured nuclear proliferative activity using MIB-1 antibody to further characterize the cell kinetics of HG-PIN and to assess its relationship to prostatic adenocarcinoma. We studied 36 specimens from randomly selected patients who underwent radical prostatectomies for prostatic adenocarcinoma. Sections of formalin-fixed, paraffin-embedded tissue pretreated by a citric acid monohydrate antigen retrieval method were immunostained with the mouse monoclonal antibody MIB-1, which detects the Ki-67 antigen in formalin-fixed tissue. The Ki-67 antigen is expressed by non-G0 proliferating cells and has been used to assess cellular proliferative activity. A maximum of either 20,400 x fields or 100 positively stained nuclei in benign glands, areas of HG-PIN, and adenocarcinoma were counted to obtain an immunohistologic proliferation index for each case. For benign prostate, HG-PIN, and adenocarcinoma, the mean positivity was 0.4 +/- 0.42 cells per field (range, 0-2), 2.5 +/- 3.79 cells per field (range, 0-16.6), and 13.8 +/- 15.05 cells per field (range, 0.25-73.66), respectively. Using a Kruskall-Wallis analysis of variance (chi 2 = 58, P < 0.05) and the t test for dependent samples, we found that the mean Ki-67 antigen expression significantly differs between histologic categories (P < 0.01, all three comparisons). In addition, the proliferative index consistently increased along the continuum from benign to malignant. We conclude that the MIB-1 proliferative index of HG-PIN lies between that of benign and carcinomatous prostate, supporting the assertion that HG-PIN is a biologic intermediate in the multistep process of transformation into carcinoma.