Heparin-binding EGF-like growth factor is an autocrine growth factor for human urothelial cells and is synthesized by epithelial and smooth muscle cells in the human bladder.

The epidermal growth factor receptor (HER1) has been implicated in regenerative growth and proliferative diseases of the human bladder epithelium (urothelium), however a cognate HER1 ligand that can act as a growth factor for normal human urothelial cells (HUC) has not been identified. Here we show that heparin-binding EGF-like growth factor (HB-EGF), an activating HER1 ligand, is an autocrine regulator of HUC growth. This conclusion is based on demonstration of HB-EGF synthesis and secretion by primary culture HUC, identification of HER1 as an activatable HB-EGF receptor on HUC surfaces, stimulation of HUC clonal growth by HB-EGF, inhibition of HB-EGF-stimulated growth by heparin and of log-phase growth by CRM 197, a specific inhibitor of HB-EGF/HER1 interaction, and identification of human urothelium as a site of HB-EGF precursor (proHB-EGF) synthesis in vivo. ProHB-EGF expression was also detected in the vascular and detrusor smooth muscle of the human bladder. These data suggest a physiologic role for HB-EGF in the regulation of urothelial proliferation and regeneration subsequent to mucosal injury. Expression of proHB-EGF is also a feature of differentiated vascular and detrusor smooth muscle in the bladder. Because proHB-EGF is known to be the high affinity diphtheria toxin (DT) receptor in human cells, synthesis of the HB-EGF precursor by human urothelium also suggests the possibility of using the DT-binding sites of proHB-EGF as an in vivo target for the intraluminal treatment of urothelial diseases.

Clinical utility of the percentage of positive prostate biopsies in defining biochemical outcome after radical prostatectomy for patients with clinically localized prostate cancer.

PURPOSE: To determine the clinical utility of the percentage of positive prostate biopsies in predicting prostate-specific antigen (PSA) outcome after radical prostatectomy (RP) for men with PSA-detected or clinically palpable prostate cancer. METHODS: A Cox regression multivariable analysis was used to determine whether the percentage of positive prostate biopsies provided clinically relevant information about PSA outcome after RP in 960 men while accounting for the previously established risk groups that are defined according to pretreatment PSA level, biopsy Gleason score, and the 1992 American Joint Committee on Cancer (AJCC) clinical T stage. The findings were then tested using an independent surgical database that included data for 823 men. RESULTS: Controlling for the known prognostic factors, the percentage of positive prostate biopsies added clinically significant information (P <.0001) regarding time to PSA failure after RP. Specifically, 80% of the patients in the intermediate-risk group (1992 AJCC T2b, or biopsy Gleason 7 or PSA > 10 ng/mL and

Pretreatment nomogram for prostate-specific antigen recurrence after radical prostatectomy or external-beam radiation therapy for clinically localized prostate cancer.

PURPOSE: To present nomograms providing estimates of prostate-specific antigen (PSA) failure-free survival after radical prostatectomy (RP) or external-beam radiation therapy (RT) for men diagnosed during the PSA era with clinically localized disease. PATIENTS AND METHODS: A Cox regression multivariable analysis was used to determine the prognostic significance of the pretreatment PSA level, 1992 American Joint Committee on Cancer (AJCC) clinical stage, and biopsy Gleason score in predicting the time to posttherapy PSA failure in 1,654 men with T1c,2 prostate cancer managed with either RP or RT. RESULTS: Pretherapy PSA, AJCC clinical stage, and biopsy Gleason score were independent predictors (P < .0001) of time to posttherapy PSA failure in patients managed with either RP or RT. Two-year PSA failure rates derived from the Cox regression model and bootstrap estimates of the 95% confidence intervals are presented in the format of a nomogram stratified by the pretreatment PSA, AJCC clinical stage, biopsy Gleason score, and local treatment modality. CONCLUSION: Men at high risk (> 50%) for early (< or = 2 years) PSA failure could be identified on the basis of the type of local therapy received and the clinical information obtained as part of the routine work-up for localized prostate cancer. Selection of these men for trials evaluating adjuvant systemic and improved local therapies may be justified.

Calculated prostate cancer volume greater than 4.0 cm3 identifies patients with localized prostate cancer who have a poor prognosis following radical prostatectomy or external-beam radiation therapy.

PURPOSE: Patients with palpable extraprostatic disease (T3) have a poor prostate-specific antigen (PSA) failure-free (bNED) survival rate after radical prostatectomy (RP) or external-beam radiation therapy (RT). This study was performed to validate or refute the prognostic value of the previously defined calculated prostate cancer volume (cV(Ca)). PATIENTS AND METHODS: For patients with clinically localized disease (T1c,2), a Cox regression multivariable analysis was used to assess the ability of the cV(Ca) value to predict time to posttherapy PSA failure following RP or RT. RESULTS: The cV(Ca) value was a significant predictor (P < or = .0005) of time to posttherapy PSA failure in both an RP and RT data set independent of the one used to derive the cV(Ca)-based clinical staging system. In both RP- and RT-managed patients, estimates of 3-year bNED survival were not statistically different for patients with either T1c,2 disease and a cV(Ca) greater than 4.0 cm3 (RP, 27%; RT, 18%) or T3 disease (RP, 37%; RT, 34%). Despite pathologic T2 disease, the 3-year estimate of bNED survival was at most 51% in RP-managed patients with T1c,2 disease and cV(Ca) greater than 4.0 cm3. CONCLUSION: A cV(Ca) greater than 4.0 cm3 identified patients with T1c.2 disease whose bNED survival was poor after RT or RP despite pathologic T2 disease that suggests the presence of occult micrometastatic disease in many of these patients. Prospective randomized trials to evaluate the impact on survival of adjuvant systemic therapy in these high-risk patients are justified.

Utilizing predictions of early prostate-specific antigen failure to optimize patient selection for adjuvant systemic therapy trials.

PURPOSE: Prostate-specific antigen (PSA) failure within 2 years after radical prostatectomy (RP) has been shown to be a clinically significant predictor of distant failure. This study was performed to estimate 2-year PSA failure rates on the basis of readily available clinical and pathologic factors to identify patients for whom effective adjuvant systemic therapy is needed. PATIENTS AND METHODS: A Cox regression multivariable analysis was used to determine whether the percentage of positive prostate biopsies, PSA level, and the pathologic findings at RP in 1,728 men provided clinically relevant information about PSA outcome after RP. A bootstrapping technique with 2,000 replications was used to provide 95% confidence intervals for the predicted 2-year PSA failure rates, which were determined on the basis of the independent clinical and pathologic predictors of PSA outcome. RESULTS: The independent predictors of time to PSA failure included a percentage of positive prostate biopsies of greater than 34% (P: < or =.009), PSA level greater than 10 ng/mL (P: < or =.01), seminal vesicle invasion (P: =. 02), prostatectomy Gleason score of 8 to 10 (P: =.04), and positive surgical margins (P: =.0001). Predictions of 2-year PSA failure rates and bootstrap estimates of the 95% confidence intervals were arranged in a tabular format, stratified by independent clinical and pathologic predictors of PSA outcome. CONCLUSION: Patients who are most likely to benefit from effective adjuvant systemic therapy after RP can be identified using readily available clinical and pathologic data.

Optimizing patient selection for prostate monotherapy.

PURPOSE: Patients at low risk for prostate-specific antigen (PSA) failure following definitive local therapy are those with PSA of 10 or less, biopsy Gleason Score of 6 or less, and 1992 American Joint Committee on Cancer (AJCC) clinical Stage T1c or T2a. However, low-risk patients managed with radical prostatectomy and found to have prostatectomy Gleason score > or = 3+4 have a less favorable PSA outcome when compared to patients with prostatectomy Gleason score < or = 3+3. This study was performed to determine whether the percentage of positive prostate biopsy cores could predict upgrading from a biopsy Gleason score of 6 or less to a prostatectomy Gleason score > or = 3+4 in low-risk patients to optimize selection for prostate only radiation therapy. METHODS AND MATERIALS: Concordance testing of the biopsy Gleason score and the primary and secondary prostatectomy Gleason grades was performed in 427 prostate cancer patients treated with radical prostatectomy and at low risk for PSA failure. Logistic regression multivariable analysis was performed to test the ability of the established prognostic factors and the percentage of positive prostate biopsies (<34%, 34-50%, >50%) to predict for upgrading from biopsy Gleason score of 6 or less prostatectomy Gleason score > or = 3+4. PSA failure-free survival was reported using the actuarial method of Kaplan and Meier and comparisons were made using a log-rank test. RESULTS: Twenty-nine percent of the 427 study patients were upgraded from a biopsy Gleason score of 6 or less to a prostatectomy Gleason score > or = 3+4. The presence of greater than 50% positive biopsies was the only significant factor for predicting the upgrading from biopsy Gleason score of 6 or less to prostatectomy Gleason score > or = 3+4 on logistic regression multivariable analysis with the variables treated as continuous and categorical. Specifically, upgrading occurred in 26% vs. 59% of patients with 50% or less vs. greater than 50% positive biopsies, respectively. This translated into a 5-year PSA failure-free survival which was significantly higher (92% vs. 62%, p = 0.00001) for men with 50% or less vs. greater than 50% positive prostate biopsies, respectively. CONCLUSION: The presence of greater than 50% positive biopsies was associated with higher rates of pathologic upgrading which translated into lower 5-year PSA failure-free survival following radical prostatectomy (RP). Therefore, the percentage of positive biopsies may be useful in optimizing the selection of low-risk patients for prostate only radiation therapy such as external beam radiation or implant monotherapy.

Clinical predictors of upgrading to Gleason grade 4 or 5 disease at radical prostatectomy: potential implications for patient selection for radiation and androgen suppression therapy.

PURPOSE: A survival benefit has been suggested by the Radiation Therapy Oncology Group (RTOG) for the addition of androgen suppression to external beam radiation therapy for patients with locally advanced and high-grade disease. This study was performed to identify clinical factors that predicted high-grade disease at prostatectomy (i.e., Gleason grade 4 or 5) in patients with clinically localized and low-grade disease (i.e., Gleason grades 1-3) at biopsy. These pretreatment factors may allow for the identification of patients likely to derive a survival benefit from the addition of androgen suppression to external beam radiation therapy while awaiting the results of the prospective randomized trials. METHODS AND MATERIALS: Concordance testing of both the primary and secondary biopsy and prostatectomy Gleason grades was performed in 693 patients with clinical Stage T1c, 2 prostate cancer managed with a radical prostatectomy (RP). For the subset of 420 patients with low-grade disease (i.e., Gleason grade < or =3) a logistic regression multivariable analysis was performed to evaluate the ability of the preoperative prostate-specific antigen (PSA), clinical stage, and ultrasound determined prostate gland volume to predict for upgrading to high-grade disease (i.e., Gleason grade 4 or 5). RESULTS: Forty percent of men with low-grade disease at biopsy were found to have high-grade disease at RP. Men who have at least a 50% chance of being upgraded from biopsy Gleason grade < or =3 to prostatectomy Gleason grade > or =4 disease included those with prostate gland volumes < or =75 cm3 and a PSA > 20 ng/ml or a PSA >10 and < or =20 and clinical Stage T2b,2c. For men with prostate gland volumes >75 cm3, only those with both PSA > 20 ng/ml and clinical Stage T2b,2c were at a significant risk of upgrading. CONCLUSION: Until the randomized data become available, clinical factors may be useful in identifying patients with clinically localized prostate cancer who are likely to benefit from combined androgen suppression and external beam radiation therapy.

The impact of the biopsy Gleason score on PSA outcome for prostate cancer patients with PSA < or = 10 ng/ml and T1c,2a: implications for patient selection for prostate-only therapy.

PURPOSE: This study was performed to determine the ability of the biopsy Gleason score, prostate-specific antigen (PSA) level, and the 1992 American Joint Commission on Cancer (AJCC) clinical T-stage for predicting time to postoperative PSA failure for patients with a PSA < or =10 ng/ml and T1c or T2a disease. Specific attention is given to the patient subgroup with biopsy Gleason 3 + 4 vs. 4 + 3. METHODS AND MATERIALS: A concordance map of the biopsy and prostatectomy Gleason grades and a clinical-pathologic correlation of the PSA, biopsy Gleason score, and 1992 AJCC T-stage and pathologic stage were performed. A Cox regression multivariable analysis was used to evaluate the ability of the biopsy Gleason score, PSA, and 1992 AJCC T-stage to predict time to PSA failure for 457 men managed with a radical prostatectomy (RP). RESULTS: The absence of prostatectomy Gleason grade 4 or 5 disease was noted in 71%, 50%, and 11% of patients with biopsy Gleason score 2-6, 3 + 4, and > or =4 + 3 disease respectively while pathologic evidence of seminal vesicle invasion was noted in 2%, 4%, and 17% of these patients respectively. Estimates of 5-year PSA failure-free survival rates were not statistically different for patients with biopsy Gleason score 2-6 vs. 3 + 4 (79% vs. 81%; p = 0.93), but were significantly different for patients having biopsy Gleason score 2-6 vs. 4 + 3 (79% vs. 62%; p = 0.04) or 2-6 vs. 8-10 (79% vs. 18%; p = 0.0001) prostate cancer. CONCLUSION: Based on the pathologic stage and PSA control data following RP, patients with biopsy Gleason 3 + 4 disease and PSA < or =10 ng/ml and 1992 AJCC T1c or T2a disease may be suitable candidates for radiation therapy directed at the prostate only.

Perineural invasion is associated with increased relapse after external beam radiotherapy for men with low-risk prostate cancer and may be a marker for occult, high-grade cancer.

PURPOSE: To investigate the risk of postradiotherapy prostate-specific antigen (PSA) failure on the basis of pretreatment risk factors in prostate cancer patients with and without perineural invasion (PNI) in prostate biopsy specimens and to explain the observation that otherwise low-risk patients with PNI experience decreased freedom from PSA failure after external beam radiotherapy (RT). METHODS AND MATERIALS: The study cohort consisted of 381 patients who underwent RT between 1989 and 2000 for clinically localized prostate cancer. A single genitourinary pathologist scored the absence or presence of PNI on all prostate biopsy specimens. Patients were divided into low-, intermediate- and high-risk subgroups on the basis of their 1992 American Joint Committee on Cancer T-stage, pretreatment PSA level, and Gleason score. Cox regression uni- and multivariate analyses were performed to evaluate whether the presence or absence of PNI in the biopsy specimen was a predictor of the time to post-RT PSA failure for patients in each pretreatment risk group. PSA failure was defined using the American Society for Therapeutic Radiology and Oncology consensus definition. Actuarial PSA failure-free survival was estimated using the Kaplan-Meier method, and comparisons were performed using the log-rank test. RESULTS: Cox regression univariate analysis revealed that PNI was a significant predictor of the time to PSA failure in the low-risk (p = 0.04) and high-risk (p = 0.03) cohorts. The 5-year PSA failure-free survival rate was 50% vs. 80% (p = 0.04) in low-risk patients, 70% vs. 75% (p = 0.72) in intermediate-risk patients, and 29% vs. 53% (p = 0.03) in high-risk patients with and without PNI, respectively. Cox regression multivariate analysis within the high-risk group revealed that a PSA level > or =20 ng/mL (p = 0.01) and Gleason score > or =8 (p = 0.02), but not PNI, were the only significant predictors of the time to PSA failure after RT. However, an association was found between the presence of PNI in the needle biopsy specimen and a biopsy Gleason score of 8-10 (p = 0.06). The association was stronger between the presence of PNI in the needle biopsy specimen and a biopsy Gleason score of 7-10 (p = 0. 033). CONCLUSION: A decrement in PSA outcome after RT for low-risk patients with PNI-positive biopsy specimens was found. The association between PNI and high Gleason score provides a possible explanation for the loss of statistical significance of PNI in the Cox regression multivariate analysis of the high-risk cohort. The data suggest that PNI found in the biopsy specimen of an otherwise low-risk patient predicts for occult high-grade disease that is missed owing to the sampling error associated with prostate biopsy. The association between PNI and a high Gleason score argues for the use of more aggressive therapy, such as hormonal therapy with RT and/or dose escalation, in these select patients.

Defining the implant treatment volume for patients with low risk prostate cancer: does the anterior base need to be treated?

PURPOSE: An increased incidence of acute urinary retention has been reported after interstitial prostate radiation therapy when the anterior base of the prostate gland receives 100% of the prescription dose. The frequency of prostate cancer in this location as a function of the pre-treatment prostate specific antigen (PSA), biopsy Gleason score, and 1992 American Joint Commission on Cancer Staging (AJCC) was determined. METHODS AND MATERIALS: One hundred four men treated at the Brigham and Women's Hospital with radical prostatectomy for clinically localized prostate cancer between 1995-1996 comprised the study population. Prostatectomy specimens were whole mounted and the location of each tumor foci enumerated. RESULTS: Of 269 foci of prostate cancer found in 39 low-risk prostate cancer patients (PSA < 10 ng/ml, biopsy Gleason score < or = 6, and 1992 AJCC clinical stage T1c,2a), a single focus (0.37%) was noted in the anterior base. Conversely, 20/355 (5.6%) and 18/251 (7.2%) tumor foci were noted in the anterior base in 43 patients with intermediate risk and 24 patients with high-risk disease, respectively. CONCLUSIONS: A new definition of the treatment volume excluding the anterior base for low-risk prostate cancer patients may be justified.

The clinical utility of the percent of positive prostate biopsies in predicting biochemical outcome following external-beam radiation therapy for patients with clinically localized prostate cancer.

PURPOSE: An investigation was performed of the clinical utility of the percent of positive prostate biopsies in predicting prostate-specific antigen (PSA) outcome following external-beam radiation therapy (RT) for men with PSA-detected or clinically palpable prostate cancer. METHODS AND MATERIALS: A Cox regression multivariable analysis was used to determine whether the percent of positive prostate biopsies provided clinically relevant information about PSA outcome following external beam RT in 473 men while accounting for the previously established risk groups based on the pretreatment PSA level, biopsy Gleason score, and the 1992 American Joint Commission on Cancer (AJCC) clinical T stage. RESULTS: Controlling for the known prognostic factors, the percent of positive prostate biopsies added clinically significant information (p = 0.02) regarding time to PSA failure following RT. Specifically, 76% of the patients in the intermediate risk group (1992 AJCC T(2b) or biopsy Gleason 7 or PSA > 10 ng/mL and < or = 20 ng/mL) could be classified into either an 30% or 85% 5-year PSA control cohort using the preoperative prostate biopsy data. CONCLUSION: The previously validated stratification of PSA outcome following radical prostatectomy (RP) using the percent of positive prostate biopsies in intermediate-risk patients is also clinically significant for men treated with external beam RT. The percent positive prostate biopsies should be considered in conjunction with the PSA level, biopsy Gleason score, and 1992 AJCC clinical T stage when counseling patients with newly diagnosed and clinically localized prostate cancer about PSA outcome following RP or external beam RT.

Optimizing patient selection for dose escalation techniques using the prostate-specific antigen level, biopsy gleason score, and clinical T-stage.

PURPOSE: Ideal candidates for 3D dose escalation conformal radiation or external beam + implant therapy are identified on the basis of the prostate-specific antigen (PSA) level, biopsy Gleason score, and the 1992 American Joint Commission Cancer (AJCC) clinical T-stage. METHODS AND MATERIALS: The pathologic findings of 1742 men with clinical stage T1c,2 prostate cancer managed with a radical prostatectomy (RP) between 1990 and 1998 were subjected to a logistic regression multivariable analysis. The endpoints examined included pathologic organ-confined (OC), specimen-confined (SC), and margin (M) or seminal vesicle (SV) positive disease. SC disease was defined as extracapsular extension (ECE) with a negative surgical margin. The clinical factors tested included PSA level, biopsy Gleason score, and the 1992 AJCC clinical T-stage. PSA failure-free (bNED) survival was calculated according to the method of Kaplan and Meier. RESULTS: Significant negative predictors of pathologic OC-disease or positive predictors of M+ or SV+ disease included a PSA > 10 ng/ml (p<0.0001), biopsy Gleason score < or =7 (p< or =0.0004), and > or =T2b disease (p< or =0.03). Only biopsy Gleason score 7 (p = 0.0006) and PSA 10-15 ng/ml (p = 0.04) were significant predictors of SC disease. The estimates of 5-year bNED survival were 80%, 62%, and 35% (p<0.0001) for patients having a low, intermediate, or high likelihood of having M+ or SV+ disease respectively. CONCLUSIONS: Patients most likely to derive a survival benefit from the improved local control possible using dose escalation techniques were those who had both a low risk of having occult micrometastatic disease (<25% M+ or SV+) and a reasonable likelihood of remaining disease-free after RP (>50% 5-year bNED). These patients included those having T1c, 2a, PSA > 10-15 ng/ml, and biopsy Gleason < or =6 or T1c, 2a, 2b, PSA < or =10 ng/ml, and biopsy Gleason < or =7 prostate cancer.

Benign atypical vascular lesions of the lip. A study of 12 cases.

We present 12 cases of benign atypical vascular lesions of the lip with cytologic or architectural features that raised microscopically the possibility of angiosarcoma. The patterns encountered in these lesions, sometimes in combination, were the following: lobular capillary hemangioma in five cases; intravascular papillary endothelial hyperplasia in five cases; epithelioid hemangioma in four cases; and acquired progressive lymphangioma in one case.

Papillary renal cell carcinoma. Histology and immunohistochemistry.

Papillary renal cell carcinoma (RCC) is an uncommon subtype of RCC that has distinctive gross, histologic, and cytogenetic features, but for which only limited immunohistochemistry data have been reported. We compared 36 papillary RCCs and five renal cell adenomas with 19 non-papillary (clear cell and granular) RCCs using a variety of antibodies to keratin and carcinoembryonic antigen (CEA). Papillary tumors were often multifocal and associated with coexistent adenomas, whereas nonpapillary tumors generally lacked these features. Low-grade papillary RCCs demonstrated three occasionally overlapping histologic patterns (typical, trabecular, and sclerotic), whereas high-grade tumors were characterized by an admixture of many patterns. Immunohistochemically, 100% (36 of 36 cases) of the papillary tumors were positive for AE1/AE3, and 92% (33 of 36 cases) were positive for callus keratins; only 3% (one of 36 cases) stained for 34BE12, and 11% (four of 36 cases) weakly stained for CEA. The five renal cell adenomas were likewise positive for AE1/AE3 (five of five cases) and callus (five of five cases) keratins. In contrast, 85% (16 of 19 cases) of the nonpapillary tumors stained for AE1/AE3, but only 5% (one of 19 cases) stained for callus; none (0/19) stained for 34BE12, and 10% (2/19) weakly stained for CEA. The consistent expression of callus keratins by papillary RCCs and renal cell adenomas underscores the close relation of these lesions, providing additional evidence for their oncological distinction from nonpapillary RCCs.

Metastatic metanephric adenoma in a child.

Metanephric adenoma is a recently characterized renal tumor that generally occurs in adults and has an excellent prognosis. To date, only one atypical metanephric adenoma has been reported to metastasize. The authors report a case of typical metanephric adenoma that arose in the left kidney of a 7-year-old girl that was associated with metastases to the para-aortic, hilar, and aortic bifurcation lymph nodes. The tumor was 9.5 cm and was composed entirely of epithelial elements arranged in tubules, short papillae, and glomeruloid bodies with scattered psammoma bodies. No atypia and only rare mitotic activity were present. Immunohistochemically, the tumor was negative for epithelial membrane antigen, negative for keratin AE1, and focally positive for both keratin CAM5.2 and cytokeratin 7. Tumor cytogenetics revealed a normal diploid karyotype, and disomy of chromosomes 7 and 17 was confirmed by fluorescence in situ hybridization. The authors conclude that tumors with histologic, immunohistochemical, and genetic features characteristic of typical metanephric adenoma can present with metastatic disease.

Clear cell sarcoma of soft parts: report of a case primary in the kidney with cytogenetic confirmation.

Clear cell sarcoma of soft parts (CCSSP), also known as malignant melanoma of soft parts, is an aggressive tumor that usually presents in soft tissue and very rarely in small bowel. We report a case arising in the kidney of a 20-year-old man which was difficult to distinguish from Wilms' tumor. The tumor metastasized to the liver and lungs, and the patient died of disseminated disease 5 years after his initial presentation. Both the primary and metastatic tumors were composed predominantly of spindle cells with occasional more epithelioid areas that were inconsistently arranged in nests. In both primary and metastatic sites, the tumor surrounded and entrapped normal epithelial elements, mimicking the biphasic appearance of Wilms' tumor. The tumor cells, however, were positive for S-100 protein and HMB45 and negative for keratin and CD99, and cytogenetic analysis revealed a clonal abnormality, translocation t(12;22)(q13;q12), characteristic of CCSSP. This result was verified by fluorescence in situ hybridization on paraffin-embedded tissue, which demonstrated EWS gene-region rearrangement. CCSSP joins a growing list of tumors that typically arise in soft tissue (PNET, solitary fibrous tumor, and infantile/congenital fibrosarcoma), but can also present in the kidney and may be confused with primary renal tumors. Awareness of this possibility and the use of ancillary studies. including immunohistochemistry, cytogenetic analysis, and fluorescence in situ hybridization, are important for accurate diagnosis.

Use of antibodies to RCC and CD10 in the differential diagnosis of renal neoplasms.

The majority of renal neoplasms can be distinguished on the basis of histologic examination alone; however, there are morphologic similarities between clear cell renal carcinoma and chromophobe cell carcinoma, as well as between the granular/eosinophilic variants of these tumors and renal oncocytoma. Only a limited number of histochemical markers are available to aid in the differential diagnosis of these neoplasms. Hale's colloidal iron usually yields strong, diffuse cytoplasmic staining of chromophobe cell carcinomas whereas clear cell carcinomas are generally negative; however, interpretation of this stain is not always straightforward. By immunohistochemistry, vimentin is detectable in most clear cell carcinomas and is absent from most chromophobe cell tumors and oncocytomas, but reliance on a single antibody can be misleading. In this report we examine the use of commercially available monoclonal antibodies to RCC and CD10 in the differential diagnosis of common renal tumors. Eighty-five percent of clear cell carcinomas (53 of 62) had detectable surface membrane staining for RCC, and 94% (58 of 62) were positive for CD10. Papillary carcinomas were likewise strongly positive for RCC and CD10 in nearly all cases (13 of 14 each). In contrast, all 19 chromophobe cell carcinomas examined were completely negative for surface membrane staining with both of these markers. Oncocytomas were also negative for RCC (0 of 9), but CD10 was detectable in some cases (3 of 9). These results suggest that the presence of surface membrane staining for RCC and CD10 may be used to confirm a diagnosis of suspected clear cell or papillary renal carcinoma. Chromophobe cell carcinomas should be negative for both markers. The absence of RCC staining may also be helpful in the diagnosis of renal oncocytoma.

Solid variants of papillary (chromophil) renal cell carcinoma: clinicopathologic and genetic features.

Papillary renal cell carcinomas (RCCs) traditionally have been defined histologically as tumors with at least 50% true papillae. However, these tumors also have characteristic immunohistochemical and genetic features that separate them from other RCCs. We identified six tumors composed of solid sheets of cells without true papillae but that otherwise resembled papillary RCCs, which we feel represent solid variants of papillary RCCs. All six tumors were primary lesions of the kidney, all were strongly reactive for epithelial membrane antigen, cytokeratin 7, and callus keratin, and all were negative for the high molecular weight keratin antibody 34BE12. Four of four tumors tested showed trisomies for chromosome 7, chromosome 17, or both by either cytogenetic analysis or fluorescence in situ hybridization. Four cases were composed of solid sheets of cells containing distinct micronodules that in some cases resembled abortive papillae. The cells composing the micronodules had abundant eosinophilic cytoplasm, open chromatin, and in some cases prominent nucleoli. The intervening cells had similar nuclei, but the amount of cytoplasm was variable. In three of these micronodular cases, multiple tumors diffusely replaced the kidney; in the fourth case two typical clear cell RCCs and a typical papillary RCC were also present in the same kidney, but the micronodular tumor was unifocal. The two remaining cases were solitary tumors consisting of solid sheets of cells forming ill-defined tubules. These cells had scant clear cytoplasm and small round to elongate nuclei with occasional nuclear grooves but only rare small nucleoli. Limited follow-up has shown no evidence of disease in any patient thus far. The differential diagnosis includes "renal adenoma," renal adenomatosis, metanephric adenoma, and clear/granular cell RCC. We conclude that solid variants of papillary RCCs lack true papillae but have characteristic histologic, immunohistochemical, and genetic features.

Papillary (chromophil) renal cell carcinoma: histomorphologic characteristics and evaluation of conventional pathologic prognostic parameters in 62 cases.

For more than two decades, papillary renal cell carcinoma has been recognized as a possible distinct clinicopathologic subtype of renal cell carcinoma (RCC). However, the histologic criteria for its diagnosis and the clinical outcome are still debated. In an attempt to clarify the diagnostic criteria and resolve issues pertaining to biologic potential, we have evaluated the histologic spectrum of 62 papillary RCCs and assessed significance of conventional pathologic prognostic parameters (Fuhrrman's nuclear grade [NG], pathologic stage [Robson and TNM], tumor size, multifocality, necrosis, and foam cells) and correlated these with outcome. The mean age of patients was 61.8 years (range 22-83), and males were more commonly affected (1.8:1). Grossly, most tumors were well circumscribed, averaged 6.7 cm in size (range 1.8-18), and were predominantly localized to the renal poles (polar vs. mid-renal, 3:1). Multifocality was a prominent feature (24 cases), and in three cases tumors were bilateral. Microscopically, papillary RCCs were predominantly papillary or tubulopapillary, often with a thick fibrous capsule, foam cells, necrosis, hemorrhage, and multifocality. Thirty-five percent of these tumors were low grade (NG I and II) and 65% high grade (NG III and IV). Sixteen of these tumors presented in a higher stage (stages III and IV), and the overall stage correlated with NG (chi 2, p = 0.009). Tumors were further distinguished by cytoplasmic features: eosinophilic (42%), basophilic (34%) and mixed (24%). Eosinophilic tumors were predominantly high grade, and basophilic tumors low grade (chi 2, p = 0.000). A mean follow-up of 57 months showed progression (metastasis, recurrence, or death due to disease) in 21%, whereas 63% were free of disease. Eleven percent died of unrelated causes, and 5% were lost to follow-up. Kaplan-Meier survival analysis showed that both high NG and stage were strongly associated with decreased survival (p = 0.0000 each), as were decreased foam cell (p = 0.0025) and vascular invasion (p = 0.0002). Comparison of 196 reported cases of papillary RCC, including the current series, with reported large series of conventional RCC indicates that papillary RCC usually presents at an early stage, and stage I (Robson) papillary RCC has better 5 year survival rates (87%-100%) than does RCC of the same stage (65-75%). The overall 5 years survival rate for papillary carcinoma (82-90%) was also higher than that of conventional RCC (44-54%). In a Cox proportional hazard regression model, TNM stage appeared to be the only significant variable (p = 0.0000, hazard ratio 10.1) in predicting outcome among papillary RCC. Based on this experience, we conclude that (a) papillary RCC is a malignant tumor, with a tendency to present at a lower stage, but with a distinct potential for progression and aggressive behavior; (b) stratification of these tumors according to cell type, amount of foam cells, presence or absence of vascular invasion, nuclear grade, and pathologic stage provides useful prognostic information; (c) the better 5-year survival rate of papillary RCC (overall and for stage I tumors) compared with that of conventional RCC suggests that it is a tumor with lower malignant potential. Thus, histologic subcategorization of a renal carcinoma as papillary RCC appears to have prognostic implications.

Renal cell carcinomas in children and young adults: increased incidence of papillary architecture and unique subtypes.

Renal cell carcinomas in children and young adults are rare, and the pathologic features of these tumors have not been well described. We reviewed 24 renal cell carcinomas in children and young adults ages 6 to 29 years, 14 of whom were younger than 18 years of age. Fourteen were female. In 19 (79%) of 24 cases, the tumor met histologic criteria for papillary renal cell carcinoma, with at least 50% papillary architecture. Four of the remaining five cases were typical clear cell tumors in patients known to have von Hippel Lindau syndrome, and one case was of chromophobe type. In the papillary tumors, calcifications, high nuclear grade, extracapsular extension (American Joint Commission on Cancer stage T3), and lymph node metastases were common. Among these papillary tumors, four distinct histologic patterns could be identified. Collecting duct-like tumors (two cases) involved the large collecting ducts, were multifocal and predominantly papillary, and had focal tubular and solid areas. These tumors were reactive for epithelial membrane antigen (EMA) and keratins, including CK7, but negative for Ulex europeaus and high molecular weight keratin 34BE12. Voluminous cell tumors (four cases) were composed of cells with extremely voluminous clear cytoplasm and, although predominantly papillary, had areas that also resembled clear cell tumors. These tumors were reactive for keratins AE1/AE3 but were otherwise negative for all other keratins, EMA, and U. europeaus. One of these tumors showed an X;7 translocation. Adult type tumors (12 cases) resembled papillary tumors of adults. These tumors were reactive for EMA and keratins, including CK7, and all but one were negative for U. europeaus and keratin 34BE12. This last case had trisomies of chromosomes 7, 16, 17, and 20. The final neuroendocrinelike case was multifocal, organoid, and composed of nests of small cells in a neuroendocrinelike pattern. Three of 13 patients were alive with disease at last follow-up, and three additional patients died of disease, all within 2 years. Progression was highly associated with lymph node involvement at the time of resection. We conclude that the clinicopathologic features of renal cell carcinomas in children and young adults differ from those arising in older adults. These tumors are characteristically high-grade, high-stage, papillary tumors with numerous calcifications, and several subtypes can be identified based on histologic, immunohistochemical, and cytogenetic features. Some subtypes appear to be unique to this age group.