Differential gene expression profiling of matched primary renal cell carcinoma and metastases reveals upregulation of extracellular matrix genes.

Background: The majority of renal cell carcinoma (RCC) studies analyze primary tumors, and the corresponding results are extrapolated to metastatic RCC tumors. However, it is unknown if gene expression profiles from primary RCC tumors differs from patient-matched metastatic tumors. Thus, we sought to identify differentially expressed genes between patient-matched primary and metastatic RCC tumors in order to understand the molecular mechanisms underlying the development of RCC metastases. Patients and methods: We compared gene expression profiles between patient-matched primary and metastatic RCC tumors using a two-stage design. First, we used Affymetrix microarrays on 15 pairs of primary RCC [14 clear cell RCC (ccRCC), 1 papillary] tumors and patient-matched pulmonary metastases. Second, we used a custom NanoString panel to validate seven candidate genes in an independent cohort of 114 ccRCC patients. Differential gene expression was evaluated using a mixed effect linear model; a random effect denoting patient was included to account for the paired data. Third, The Cancer Genome Atlas (TCGA) data were used to evaluate associations with metastasis-free and overall survival in primary ccRCC tumors. Results: We identified and validated up regulation of seven genes functionally involved in the formation of the extracellular matrix (ECM): DCN, SLIT2, LUM, LAMA2, ADAMTS12, CEACAM6 and LMO3. In primary ccRCC, CEACAM6 and LUM were significantly associated with metastasis-free and overall survival (P < 0.01). Conclusions: We evaluated gene expression profiles using the largest set to date, to our knowledge, of patient-matched primary and metastatic ccRCC tumors and identified up regulation of ECM genes in metastases. Our study implicates up regulation of ECM genes as a critical molecular event leading to visceral, bone and soft tissue metastases in ccRCC.

Atypical adenomatous hyperplasia of the prostate: a premalignant lesion?

To better understand genetic alterations in atypical adenomatous hyperplasia (AAH) of the prostate, we examined the prevalence of allelic imbalance at 5 microsatellite polymorphic markers on chromosomes 7q31-35, 8p12-21, 8p22, 8q22.2, and 18q12.2 from 15 patients with AAH. DNA samples were obtained from formalin-fixed paraffin-embedded sections using tissue microdissection. We found allelic imbalance in 7 of 15 (47%) cases of AAH. Genetic changes that commonly occur in early prostatic carcinogenesis and prostate carcinoma are found in AAH. Current data provide evidence of a genetic link between some cases of AAH and carcinoma.

The cell cycle inhibitors p21WAF1 and p27KIP1 are associated with survival in patients treated by salvage prostatectomy after radiation therapy.

We evaluated p27KIP1 and p21WAF1 expression in 52 patients treated by salvage radical prostatectomy and bilateral pelvic lymphadenectomy for biopsy-proven locally persistent or recurrent prostate cancer after external beam radiation therapy. We defined low and high expression based on the median value observed in our sample. Five-year distant metastasis-free survival and cancer-specific survival were 71 and 82%, respectively, for patients with low expression of p21 (< or =5%), compared with 94 and 100%, respectively, for those with high expression of p21 (>5%; P = 0.02 and 0.01, respectively). Five-year distant metastasis-free survival and cancer-specific survival were 71 and 82%, respectively, for patients with low expression of p27 (<50%), compared with 88 and 96%, respectively, for those with high expression of p27 (> or =50%; P = 0.06 and 0.01, respectively). These findings indicate that p21 and p27 expression levels are significant predictors of survival for patients selected for salvage prostatectomy for recurrent prostate cancer.

Postatrophic hyperplasia of the prostate. A histologic mimic of prostatic adenocarcinoma.

Clusters of atrophic prostatic acini that display proliferative epithelial changes are referred to as postatrophic hyperplasia (PAH). PAH is histologically similar to adenocarcinoma and may cause diagnostic confusion. Despite the importance of distinguishing PAH from carcinoma, the last systematic study of this lesion was reported > 40 years ago, and many contemporary pathologists are unfamiliar with this lesion. We reviewed 100 consecutive whole-mount radical prostatectomy specimens removed for carcinoma to determine the incidence of PAH. In addition, 11 prostatic needle biopsy specimens with PAH were evaluated to further characterize the lesion in limited specimens. PAH was identified in 18 radical prostatectomies (18%), including 10 unicentric and eight multicentric cases. It was found exclusively in the peripheral zone in all but two cases, which had additional involvement of the transition zone. PAH consisted of a microscopic lobular cluster of small acini with irregular atrophic-appearing contours lined by cuboidal cells with mild nucleomegaly and micronucleoli; mildly enlarged nucleoli were focally present in 39% of cases. Within the small acinar cluster, a larger dilated acinus was usually present centrally, which was lined by flattened to cuboidal epithelial cells. The basal cell layer at the periphery of each acinus was invariably present but often inconspicuous. Immunohistochemical staining for high-molecular-weight keratin (antibody 34 beta E12) showed the presence of an intact basal cell layer in seven of 10 cases and a focally fragmented basal cell layer in three other cases. PAH was associated with patchy chronic inflammation in 16 of 18 prostatectomy cases; stromal changes were present in all cases, ranging from smooth atrophy to dense sclerosis with compression of acini. No intraluminal basophilic mucin was identified, but two needle biopsies showed PAH with focal mucinous metaplasia. Crystalloids were not seen in any case. Focal partial acinar involvement by high-grade prostatic intraepithelial neoplasia was present in adjacent acini in two cases. Adjacent acini also invariably showed typical changes of atrophy. In the needle biopsy specimens, PAH showed the same features as those in prostatectomies, but often only a portion of the lesion was sampled. PAH is distinguished from carcinoma by its characteristic architecture, intact or fragmented basal cell layer, inconspicuous or mildly enlarged nucleoli, and adjacent acinar atrophy with stromal fibrosis or smooth muscle atrophy. Distinguishing PAH from carcinoma is most difficult in needle biopsy specimens in which only a portion of the lesion is sampled, and awareness of this entity assists in this distinction.

Diagnosis of prostate cancer in needle biopsies after radiation therapy.

Interpretation of postirradiation needle biopsies is a major diagnostic challenge for the pathologist because of substantial radiation-induced changes in benign and malignant prostatic tissue. Reports that have systematically evaluated the histopathologic findings in postirradiation needle biopsies are limited. In this study, we evaluated 46 histologic features in 29 postirradiation needle biopsy specimens from 29 patients. All patients had recurrent cancer on needle biopsies after external beam radiation, and all subsequently underwent salvage radical prostatectomy and bilateral pelvic lymphadenectomy. Patient age ranged from 57 to 78 years (mean, 61 years). The interval from radiation therapy to biopsy ranged from 1.0 to 17 years (mean, 3.9 years). Histologic features that were helpful in the diagnosis of cancer after radiation therapy included infiltrative growth, perineural invasion, intraluminal crystalloids, blue mucin secretions, the absence of corpora amylacea, and the presence of coexistent high-grade prostatic intraepithelial neoplasia. Benign glands usually showed nuclear enlargement (86%) and prominent nucleoli (50%), and therefore, these cytologic features alone were not reliable for the diagnosis of cancer after irradiation. Postirradiation needle biopsies underestimated the prostatectomy Gleason grade in 35% of cases and overestimated it in 14% of cases; these results were similar to published reports from patients not receiving radiation therapy. There was a major discrepancy in degree of radiation effect between radical prostatectomy and biopsies. Moderate or severe radiation effect on cancer was present in 48% of needle biopsy specimens, whereas 94% of radical prostatectomy specimens had no or minimal radiation effect on cancer when the areas with the least amount of radiation effect were chosen for quantification. These findings indicate that quantification of radiation effect in needle biopsy specimens was inaccurate and potentially misleading. Conversely, Gleason grade in postirradiation needle biopsy specimens appeared to provide useful predictive information and should be reported.

Atheroemboli-associated polyps of the sigmoid colon.

Atheroemboli-associated inflammatory type polyps localized to a portion of the sigmoid colon occurred in a 68-year-old diabetic man presenting with a 2-year history of bloody diarrhea and abdominal pain. The patient underwent segmental resection of the sigmoid colon. The specimen contained 15 polyps ranging from 0.3 to 1.9 cm in greatest dimension, localized to an 8-cm length of sigmoid colon. The polyps had an edematous submucosa with a superficially ulcerated mucosa. Microscopically, arterioles within the submucosa of the polyps contained organized atheroemboli. The overlying mucosa was largely replaced by granulation tissue, with foci of coagulation necrosis present in residual mucosa. The remainder of the bowel was unremarkable. The histologic diagnosis of atheroembolization to the gastrointestinal tract is difficult, requiring the inclusion of submucosa with atheroemboli in the biopsy tissue. Ischemic ulcers and erosions as well as inflammatory polyps related to atheroemboli may require deeper biopsy for etiologic diagnosis.

Natural history of urothelial dysplasia of the bladder.

Urothelial dysplasia is the putative precursor of urothelial carcinoma in situ (CIS) and invasive urothelial carcinoma of the urinary tract. Urothelial dysplasia is frequently identified in patients with urothelial CIS and cancer. However, very little is known about the clinical presentation and natural history of urothelial dysplasia in the absence of urothelial CIS or invasive cancer. The authors studied 36 patients with isolated urothelial dysplasia at the Mayo Clinic between 1969 and 1984. None of these patients had previous or concurrent urothelial CIS or invasive cancer, and none received treatment for dysplasia. The histopathologic features of urothelial dysplasia were examined, and long-term clinical follow-up was obtained. Progression was defined as the development of urothelial CIS or carcinoma. The male-to-female ratio was 2.6:1, and the mean patient age at the time of diagnosis was 60 years (range 25-79). Urothelial dysplasia has a predilection for the posterior wall. Eleven patients had urinary irritative symptoms, 10 had hematuria, 3 had both irritative symptoms and hematuria, and 12 were found to have dysplasia incidentally. The mean follow-up was 8.2 years (range 0.1-25.5). Seven (19%) of 36 patients developed biopsy-proven progression, including 4 with CIS and 3 with invasive cancer, and 1 of them died of bladder cancer. The intervals from diagnosis to progression ranged from 6 months to 8 years (mean 2.5 years). One of the remaining 29 patients had positive cytologic results 2.5 years after the initial diagnosis of dysplasia. The authors conclude that urothelial dysplasia is a significant risk for the development of CIS and invasive urothelial carcinoma, and patients with urothelial dysplasia should be followed up closely.

Metanephric adenoma, nephrogenic rests, and Wilms' tumor: a histologic and immunophenotypic comparison.

Metanephric adenoma (MA) is a renal tumor that is generally detected in adults and occasionally in children. These tumors usually behave in a benign fashion. Although the histogenesis of MA is unclear, a morphologic similarity to Wilms' tumor (WT) complex exists. Six cases of MA, five cases of childhood WT (CWT), two cases of adult WT (AWT), and four cases of treated MWT and/or nephrogenic rests (MWT/NR), with paraffin blocks available for use, were retrieved from the surgical pathology files of the Mayo Clinic. Clinical information was extracted from the medical record. Immunoperoxidase stains for WT1, AE1, CK7, CD57, CD56, and desmin were performed on paraffin sections from all cases. All six cases of MA were strongly and diffusely positive with antibodies to WT1 and CD57 and focally positive with antibodies to CK7. Three cases showed focal faint staining in <5% of the cells with keratin AE1. Stains for CD56 and desmin were negative. All seven cases of WT, including five CWT and two AWT, were strongly and diffusely positive with WT1 in the blastema and epithelium but showed only weak focal positivity in stromal cells. Six cases were diffusely positive for CD56 and one case showed focal positivity. Keratin AE1 was positive in one case of AWT and focally positive in the other AWT. The blastema of all cases of WT were negative for desmin, CK7, and CD57, although staining for keratin AE1, CD56, and CD57 was seen in maturing tubules of CWT cases. Of the five CWT cases, two had associated NR and two showed maturing WT after treatment. The areas of NR and maturing WT were histologically similar to MA and were composed of small tubules with uniform nuclei with no mitotic activity, scant cytoplasm, and focal calcifications. All four cases of maturing WT/NR were positive for WT1 and focally positive for CD57, CK7, and AE1. Stains for CD56 and desmin were negative except in foci of residual blastema, which stained for CD56 but lacked CD57 and CK7 staining. Five cases each of renal cell carcinoma, papillary renal cell carcinoma, and oncocytoma were negative for WT1. Two of five cases of chromophobe carcinoma showed very weak staining present in <10% of tumor nuclei. Metanephric adenoma is histogenetically related to WT and is morphologically and immunophenotypically identical to maturing WT and nephrogenic rests.

Serous borderline tumor of the paratestis: a report of seven cases.

We report the clinical, morphologic, immunophenotypic, and ploidy findings of seven cases of serous borderline tumor of the paratestis. Mean patient age was 56 years (range, 14-77 years), and the clinical presentation was that of a testicular mass. Tumors ranged in size from 1 to 6 cm (mean, 3.5 cm). Six tumors arose from the tunica albuginea, and two of these tumors were intratesticular. One tumor arose from the tunica vaginalis. Serous borderline tumor of the paratestis is histologically identical to its ovarian counterpart. The tumors were cystic with numerous intracystic blunt papillae lined by stratified epithelial cells with minimal to mild cytologic atypia. Psammoma bodies were present in two cases. In all cases, the neoplastic cells stained strongly and diffusely for cytokeratin 7, estrogen receptor, and CD15, and six of seven cases were positive for progesterone receptor and MOC-31. The cells did not stain for cytokeratin 20, carcinoembryonic antigen, calretinin, and HER2/neu. Proliferative activity, as assessed by MIB-1 staining, ranged from 1.3% to 10% (mean, 5.5%). Five of six tumors were diploid, and one was tetraploid. Patients were treated by radical orchiectomy and followed up from 4 months to 18 years (mean, 48 months; median, 8.5 months). No recurrences or metastases occurred. Serous borderline tumor of the paratestis is morphologically and immunophenotypically identical to ovarian serous borderline tumor. To date, no serous borderline tumor of the paratestis reported in the literature or in our series has recurred or metastasized after resection.

Leydig cell tumor of the testis: a clinicopathologic, DNA content, and MIB-1 comparison of nonmetastasizing and metastasizing tumors.

Leydig cell tumors of the testis are rare and account for a small proportion of testicular neoplasms. The objective of this study was to identify clinical and morphologic features predictive of metastasis in a large series of Leydig cell tumors, and to determine whether ploidy or proliferative activity were predictive of malignancy. Thirty cases of Leydig cell tumor of the testis (23 tumors that had not metastasized and 7 that had metastasized) were studied. Clinical history and follow-up were collected in all cases. The morphologic features examined included tumor size, mitotic index (mitotic figures/10 high-power fields), necrosis, angiolymphatic invasion, cell type, tumor-testicle interface, presence of extension beyond the testicular parenchyma, and presence of lipochrome and Reinke crystals. Most patients (93%) had a testicular mass. Patients with Leydig cell tumors that metastasized were diagnosed at a mean age of 62 years (range, 39-70 years) compared with 48 years (range, 9-79 years) in patients with nonmetastasizing tumors (p = 0.25). Leydig cell tumors that metastasized were significantly larger than nonmetastasizing tumors (mean, 4.7 versus 2.6 cm, respectively; p = 0.008), and had a significantly higher mitotic index (mean, 13.9 versus 1.9, respectively; p < 0.0001). Metastasizing Leydig cell tumors were significantly associated with atypical mitotic figures (p < 0.0001), nuclear variation (p = 0.0025), necrosis (p < 0.0001), angiolymphatic invasion (p = 0.009), infiltrative margins (p < 0.0001), high grade (p = 0.0004), and invasion into rete testis, epididymis, or tunica (p = 0.001) when compared with nonmetastasizing tumors. There was no significant difference between metastasizing and nonmetastasizing tumors in regard to cell type, lipochrome content, presence of Reinke crystals, or nuclear inclusions. All Leydig cell tumors that metastasized and 7 of 18 (38.9%) nonmetastasizing tumors were DNA aneuploid by static image analysis (p = 0.02). Metastasizing Leydig cell tumors had a significantly higher mean MIB-1 activity of 18.6% (range, 5.8-33.6) compared with 1.2% (range, 0.04-8.2) in nonmetastasizing tumors (p = 0.001). In this study, the presence of cytologic atypia, necrosis, angiolymphatic invasion, increased mitotic activity, atypical mitotic figures, infiltrative margins, extension beyond the testicular parenchyma, DNA aneuploidy, and increased MIB-1 activity were significantly associated with metastatic behavior in Leydig cell tumors.

Cancer volume of lymph node metastasis predicts progression in prostate cancer.

Clinical outcome is variable in prostate cancer patients with regional lymph node metastasis. We studied 269 patients who had regional lymph node metastasis at the time of radical retropubic prostatectomy and bilateral pelvic lymphadenectomy at the Mayo Clinic between January 1987 and December 1992. Two hundred fifty-three (94%) patients received androgen deprivation therapy within 90 days of radical prostatectomy. Patients ranged in age from 47 to 79 years (median, 67 years). Median follow-up was 6.1 years (range, 0.3-10.5 years). Nodal cancer volume (size) was measured by the grid-counting method. Cox proportional hazards models were used to determine the impact of numerous clinical and pathologic findings on systemic progression-free survival. Systemic progression was defined as the presence of distant metastasis documented by biopsies or radiographic examinations (abdominal computerized tomography, plain radiographs, or bone scan). Five-year progression-free survival was 90%. In predicting systemic progression using Cox multivariate analysis, only nodal cancer volume added significantly to the model containing the primary cancer variables (Gleason score, cancer volume, and DNA ploidy). The relative hazard rate for a doubling in nodal cancer volume was 1.6 (95% confidence interval, 1.3 to 2.0; p < 0.0001). Spearman rank analysis showed a correlation between nodal cancer volume and Gleason score of the primary cancer, the number of positive nodes, the aggregate length of metastases, and the largest nodal cancer diameter (correlation efficient = 0.37, 0.63, 0.96, and 0.95, respectively). Our data indicate that nodal cancer volume was the most significant nodal determinant of progression to distant metastasis in lymph node-positive prostate cancer patients. We recommend that the diameter of the largest metastasis be evaluated in patients with metastases, because this is a more powerful predictor of patient outcome than current methods, which recommend mere counting of the number of positive nodes.

Prevalence and distribution of prostatic intraepithelial neoplasia in salvage radical prostatectomy specimens after radiation therapy.

High-grade prostatic intraepithelial neoplasia (PIN) is the most likely precursor of prostate cancer. The effect of radiation therapy (RT) on the prevalence of PIN is uncertain. We studied 86 patients who underwent salvage radical prostatectomy after irradiation failure at the Mayo Clinic. The prevalence, volume, multicentricity, spatial proximity to cancer, and architectural patterns of PIN were evaluated. High-grade PIN was identified in 53 (62%) of 86 prostatectomy specimens. Multiple architectural patterns were usually observed, including tufting in 87%, micropapillary in 66%, cribriform in 38%, and flat in 17%. The mean volume of PIN was 0.12 cm3 (range, 0.05-1.20 cm3). PIN was usually multicentric (70%), with a mean number of PIN foci of 2.5 (range, 1-10). Ninety-four percent of PIN foci were located within 2 mm of invasive cancer. There was no correlation between PIN and pathologic stage, surgical margin, tumor size, DNA ploidy, post-RT Gleason score, time interval from RT to biopsy-proven recurrence, postoperative prostate-specific antigen level, distant metastasis-free survival, or cancer-specific survival. Our examination of salvage radical prostatectomy specimens indicated that the prevalence and extent of PIN appeared to be reduced after RT compared to published studies of prostatectomies without prior RT.

Ploidy analysis by flow cytometry and fluorescence in situ hybridization in hydropic placentas and gestational trophoblastic disease.

Placentas with hydropic change may be hydropic degeneration (HD) or gestational trophoblastic disease (GTD), partial (PM) or complete (CM) hydatidiform mole. The separation of HD from PM and PM from CM by histological findings may be problematic in some cases and can be clarified with ploidy analysis. Fluorescence in situ hybridization (FISH) using a probe to chromosome 7 (D7Z1) was applied to tissue cut from paraffin blocks from 10 histologically representative cases each of HD, PM, and CM on which ploidy had been previously confirmed by flow cytometry from paraffin embedded tissue. Villous stromal cells and nonproliferative trophoblast were examined for number of signals/cell and percentage of cells/placenta with three hybridization signals. The mean number of hybridization signals/cell was HD 1.14; PM 1.79; and CM 1.17, with statistical significance between HD and PM (P < .0001), and PM and CM (P < .0001). The mean percentage of cells/placenta with three hybridization signals was HD 1.10%, PM 23.1%, and CM 2.11%, with statistical significance between HD and PM (P < .0001), and PM and CM (P < .0001). In addition, there was no overlap in the mean percentage of cells with three hybridization signals between HD and PM, and PM and CM. Chromosome 2 probe (D2Z1) was applied to tissues that had three chromosome 7 signals to exclude trisomy, and in all cases three signals were present confirming triploidy in PM. FISH can identify diploid and triploid hydropic placentas in paraffin-embedded tissue to assist in differentiating HD from PM, and PM from CM.

The focus of "atypical glands, suspicious for malignancy" in prostatic needle biopsy specimens: incidence, histologic features, and clinical follow-up of cases diagnosed in a community practice.

This study was undertaken to determine retrospectively the prevalence and histologic features of the atypical foci that are suspicious for but are not diagnostic of a malignancy in contemporary prostate needle biopsy specimens reported in a community practice. Histologic features were examined in detail to identify features that prevented an unequivocal diagnosis of carcinoma. Of 1,009 prostate needle biopsy specimens obtained between January 1, 1993, and August 1, 1995, the diagnosis of an atypical focus suspicious for malignancy was made in 48 (4.8%). In review of the biopsy specimens diagnosed as benign, an additional 7 cases (0.7%) were identified. The following histologic features were identified in 54 cases: enlarged nucleoli, 54 (100%); enlarged nuclei, 45 (83%); intraluminal eosinophilic secretions, 40 (74%); infiltrative growth, 37 (68%); small acinar proliferation, 37 (68%); intraluminal basophilic mucin, 23 (42%); amphophilic cytoplasm, 18 (33%); high-grade prostatic intraepithelial neoplasia, 17 (31%); and crystalloids, 12 (22%). Corpora amylacea were not identified. The foci contained from 1 to 67 acini (mean, 20.7). Although each atypical focus showed most of the features of adenocarcinoma, an unequivocal diagnosis of malignancy was not given owing to four features: the small size of the focus, the small number of cells with enlarged nucleoli, the clustered growth pattern, and the presence of high-grade prostatic intraepithelial neoplasia within many of the foci. At initial examination, 36 of 41 patients (83%) had an elevated serum concentration of prostate-specific antigen (mean, 10 ng/mL), and 20 (49%) had abnormal findings on a digital rectal examination. Twenty-five patients (46%) underwent additional sampling of the prostate, and 15 of these (60%) were found to have adenocarcinoma; the remaining 30 patients did not undergo a subsequent biopsy. Patients with subsequent cancer had higher mean serum concentrations of prostate-specific antigen and change in concentrations of prostate-specific antigen than those whose repeat biopsy results were negative; no other clinical or histologic differences were observed between these two groups. To the community pathologists in this study, the lack of prominent nucleoli, the small size of the focus, clustered acini, and/or adjacent high-grade prostatic intraepithelial neoplasia prevented an unequivocal diagnosis of malignancy. If a prostate needle biopsy specimen is reported as containing an atypical focus suspicious for malignancy, a subsequent biopsy is warranted given the high predictive value for adenocarcinoma.

Cytokeratin expression in seminoma of the human testis.

We studied cytokeratin (CK) expression immunohistochemically in 64 seminomas using a panel of commercially available antikeratin antibodies and tested for association of CK expression with patient age, tumor size, stage, and outcome. Seventeen embryonal carcinomas were compared with seminoma. CK7, CAM 5.2, AEI/AEIII, and wide-spectrum screening keratin (WSK) were positive in 41%, 30%, 36%, and 36% of the seminomas, respectively. CK20 and high-molecular-weight keratin (HMWK) were negative in all cases. CD30, placental alkaline phosphatase (PLAP), and epithelial membrane antigen (EMA) were positive in 6%, 100%, and 2% of cases, respectively. There were no differences in patient age, stage, tumor size, or outcome between CK-positive and CK-negative seminomas. CK7, CAM 5.2, AEI/AEIII, and WSK were positive in 100%, 88%, 94%, and 88% of embryonal carcinomas, respectively. CK20 and HMWK were negative in all cases. CD30, EMA, and PLAP were positive in 100%, 12%, and 76%, respectively. CKs are present in seminoma, and their presence is not associated with a difference in patient age, stage, or outcome. In cases such as small needle biopsy specimens, CK and CD30 stains may be useful in separating seminoma from embryonal carcinoma.

Juxtaglomerular cell tumor: a clinicopathologic study of four cases and review of the literature.

We studied 4 new cases of juxtaglomerular cell tumor and compared their morphologic and immunohistochemicalfeatures with 2 renal hemangiopericytomas and 5 cutaneous glomus tumors. The juxtaglomerular tumors were resectedfrom 2 males and 2 females (mean age at diagnosis, 23 years). Three patients manifested with severe hypertension. Tumors ranged from 2.2 to 8.0 cm and were well circumscribed. The tumors consisted of solid sheets and nodules of variably sized tumor cells with round, oval, and spindled nuclei alternating with edematous microcystic foci. Nuclear atypia, present in all tumors, was a prominent feature in 2. Mitotic activity was not identified. All cases showed hemorrhage, numerous mast cells, and thick-walled blood vessels. Unusual features included coagulative tumor necrosis, a hemangiopericytoma-like vascular pattern, and hyalinized stroma. All tumors were immunoreactive for CD34 and actin. Ultrastructural analysis revealed the presence of rhomboid-shaped renin protogranules. Patients were treated by partial or radical nephrectomy and followed up for 14 to 48 months. There were no recurrences or metastases. The characteristic clinical and morphologic features of juxtaglomerular cell tumor permit distinction from renal hemangiopericytoma and other renal tumors.

Grading and staging of bladder carcinoma in transurethral resection specimens. Correlation with 105 matched cystectomy specimens.

We compared the grading and staging of transurethral resection of the bladder (TURB) and cystectomy specimens for 105 patients who underwent radical cystectomy for urothelial carcinoma between 1980 and 1984. Of 105 patients, 96% underwent cystectomy within 100 days of TURB (median interval, 10 days). Grading was performed according to the 1998 World Health Organization/International Society of Urologic Pathology grading system and staging according to the 1997 TNM classification. Histologic grade was low-grade, 13; high-grade, 92 in TURB specimens; low-grade, 17; high-grade, 88 in cystectomy specimens. Pathologic stage was Ta, 15; T1, 55; and T2, 35 in TURB specimens; Ta, 5; T1, 19; T2, 19; T3, 46; and T4, 16 in cystectomy specimens. Histologic grade at TURB was associated with pathologic stage at cystectomy (P < .001). When all advanced-stage (muscle-invasive) carcinomas (pT2 or more) were considered together, 55 patients were understaged by TURB, 4 had higher stage in TURB than in cystectomy, and 46 were the same stage as by cystectomy. Forty-three of 55 patients with stage T1 carcinoma at TURB had advanced-stage carcinoma at cystectomy, including 34 who had extravesicular extension (pT3 or more). We found pathologic understanding by TURB occurs in a significant number of patients with bladder cancer; the newly proposed grading system predicted final pathologic stage.

Urothelial carcinoma of the bladder with choriocarcinomatous differentiation A report of two cases and review of the literature.

Urothelial carcinoma with choriocarcinomatous differentiation is a rare morphologic variant of bladder cancer, and only a limited number of cases have been reported. We present two cases of bladder cancer with choriocarcinomatous features that had different outcomes. The clinical and pathologic features are reviewed to better understand the natural history of this malignant neoplasm. The histologic features of the tumor were compared between the two cases. Immunoperoxidase staining was performed on the tumor cells with polyclonal beta human chorionic gonadotropin (ß-hCG) antibody. A comprehensive literature search revealed an additional 25 confirmed cases, which are summarized in this presentation. Of the 27 patients, only 3 patients were reported to be alive without evidence of disease after treatment. The majority presented with invasive tumors and had a mean survival of 12 months after diagnosis. Chemotherapy, radiation, or radical surgery in advanced stages did not improve survival. Choriocarcinoma in visceral organs usually occurs with high-grade carcinomas and we believe that it is best considered dedifferentiation of the tumor. Urothelial carcinoma with choriocarcinomatous differentiation is an extremely aggressive tumor, and in the rare patient with early stage disease and normal to moderately elevated serum ß-hCG levels, long-term survival can be achieved with radical surgery.

Classification and pathology of testicular germ cell and sex cord-stromal tumors.

Germ cell tumors of the testis are the most frequent testicular neoplasms, with seminoma predominating. The pathologist must be able to discriminate between seminoma and nonseminomatous germ cell tumors as well as sex cord-stromal tumors and metastatic lesions. Appropriate therapy and accurate prognostic information are dependent on the proper classification of testicular neoplasia. Characteristic histologic features, serum markers, and immunohistochemistry are helpful in this regard. Sex cord-stromal tumors comprise a small minority of testicular neoplasms. It remains critically important not to confuse these neoplasms with testicular germ cell or metastatic tumors, and, again, recognition of the characteristic histologic features, immunohistochemical findings, and clinical information is diagnostic. The urologist can provide the pathologist with key clinical information in the attempt to make a correct diagnosis.

Focal microsatellite mutations in relatives with prostatic adenocarcinoma.

Instability of short tandem repeat sequences, microsatellite instability (MI), has been reported to play an important role in the tumorigenesis of various adenocarcinomas, including prostatic adenocarcinoma. Although prostate cancer is not widely recognized as a heriditary cancer, familial clustering is well known. To investigate the frequency of microsatellite instability in familial prostatic adenocarcinomas we analyzed archival tumor tissue from seven paired first degree relatives with prostatic adenocarcinoma. Twelve dinucleotide, nine trinucleotide, six tetranucleotide repeats and the CAG repeat of the androgen receptor gene were screened for MI. Solitary mutations were observed in four separate cases (28.6%) and widespread somatic alterations were not identified. No statistical correlation to pathological characteristics was determined. Our data indicate that microsatellite instability is an uncommon phenomenon in prostatic adenocarcinoma within first degree relatives. Those changes present appear to manifest as focal mutations in contrast to the more global changes seen in MI.