PTEN loss and ERG protein expression are infrequent in prostatic ductal adenocarcinomas and concurrent acinar carcinomas.

BACKGROUND: Prostatic ductal adenocarcinoma is an unusual and aggressive morphologic subtype of prostate cancer. PTEN gene deletion and ERG gene rearrangement are among the most common genomic changes in acinar prostate cancers. Though ductal adenocarcinoma most commonly occurs with synchronous usual-type acinar adenocarcinoma, little is known about the molecular phenotype of these mixed tumors. METHODS: We used genetically validated immunohistochemistry (IHC) assays to assess PTEN and ERG status in a group of 37 surgically treated ductal adenocarcinomas and 18 synchronous acinar adenocarcinomas where we have previously reported ERG gene rearrangement status by fluorescence in situ hybridization (FISH). A group of 34 stage and grade-matched pure acinar adenocarcinoma cases was studied as a control. RESULTS: ERG IHC was highly concordant with ERG FISH results, with 100% (36/36) concordance among ductal adenocarcinomas and 91% (31/34) concordance among 34 pure acinar carcinomas. Similar to previous FISH results, ERG expression by IHC was significantly less common among ductal adenocarcinomas (11% or 4/37) and their synchronous acinar tumors (6% or 1/18) compared to matched pure acinar adenocarcinoma cases (50% or 17/34; P = 0.0005 and 0.002, respectively). PTEN loss by IHC was also less common among ductal adenocarcinomas (18% or 6/34) and their synchronous acinar tumors (22% or 4/18) compared to matched pure acinar carcinomas (50% or 17/34; P = 0.01 and 0.08, respectively). As expected, PTEN loss was enriched among ERG positive compared to ERG-negative tumors in the pure acinar tumor control group (2.5-fold enrichment; P = 0.04) however this was not observed among the ductal adenocarcinomas (1.5 fold enrichment; P = NS). Of ductal adenocarcinomas with an evaluable synchronous acinar component, ERG status was concordant in 94% (17/18) and PTEN status was concordant in 94% (16/17). CONCLUSIONS: Based on PTEN and ERG, ductal adenocarcinomas and their concurrent acinar carcinomas may be clonally related in some cases and show important molecular differences from pure acinar carcinoma.

Actinomycotic endocarditis of the eustachian valve: a rare case and a review of the literature.

Eustachian valve endocarditis caused by Actinomyces species is extremely rare. A literature review revealed only one reported case-caused by Actinomyces israelii in an intravenous drug abuser. Our patient, a 30-year-old woman who at first appeared to be in good health, presented with fever, a large mobile mass on the eustachian valve, and extensive intra-abdominal and pelvic masses that looked malignant. Histopathologic examination of tissue found in association with an intrauterine contraceptive device revealed filamentous, branching microorganisms consistent with Actinomyces turicensis. This patient was treated successfully with antibiotic agents. In addition to presenting a new case of a rare condition, we discuss cardiac actinomycotic infections in general and eustachian valve endocarditis in particular: its predisposing factors, clinical course, sequelae, and our approaches to its management.

Genes associated with prostate cancer are differentially expressed in African American and European American men.

BACKGROUND: Despite more aggressive screening across all demographics and gradual declines in mortality related to prostate cancer (PCa) in the United States, disparities among populations persist. A substantial proportion of African American men (AAM) have a higher overall incidence, earlier age of onset, increased proportion of clinically advanced disease, and increased bone metastases and mortality from PCa compared to European American men (EAM). Limited early evidence indicates that underlying causes for disparities may be observed in tumor-specific gene expression programs. METHODS: This study used microarray-based methods to measure expression levels for 517 genes that were previously associated with PCa in archived formalin-fixed paraffin embedded (FFPE) specimens; testing the hypothesis that gene expression features of functional consequence to cancer distinguish PCa from AAM and EAM. A t test was conducted comparing AAM to EAM expression levels for each probe on the array. RESULTS: Analysis of 639 tumor samples (270 AAM, 369 EAM) showed that 95 genes were overexpressed specifically in PCa from AAM relative to EAM and 132 were overexpressed in PCa from EAM relative to AAM. Furthermore, systems-level analyses highlight the relevant signaling pathways and functions associated with the EAM- or AAM-specific overexpressed gene sets, for example, inflammation and lipid metabolism. CONCLUSIONS: Results here bring further understanding to the potential for molecular differences for PCa in AAM versus EAM. IMPACT: The results support the notion that therapeutic benefits will be realized when targeted treatments are designed to acknowledge and address a greater spectrum of PCa subtypes and molecular distinctions.

Hepatocyte nuclear factor-1ß expression in clear cell adenocarcinomas of the bladder and urethra: diagnostic utility and implications for histogenesis.

The histogenesis of clear cell adenocarcinoma of the bladder/urethra is uncertain. Hepatocyte nuclear factor-1ß is a homeodomain protein that has been reported to be frequently overexpressed in ovarian clear cell adenocarcinoma in comparison with rare or no expression in other types of epithelial ovarian tumors. We assessed the expression of hepatocyte nuclear factor-1ß in a series of 18 clear cell adenocarcinomas of the bladder and urethra and compared it with that of invasive high-grade transitional/urothelial carcinoma (n = 35); adenocarcinomas of the bladder, urethra, and paraurethral glands (n = 21); as well as nephrogenic adenomas of the bladder (n = 8). Staining intensity and extent were evaluated using a 4-tiered grading system (0-3). A case was considered positive for hepatocyte nuclear factor-1ß if 10% or more of tumor cells showed at least weak nuclear staining or if any moderate or strong nuclear staining was observed. All 18 clear cell adenocarcinomas exhibited nuclear staining in at least 50% of tumor cells (16 strong, 1 moderate, and 1 weak with focal strong nuclear staining) in comparison with positive nuclear staining (moderate) in 1 of 21 bladder adenocarcinoma, 1 of 35 invasive high-grade transitional/urothelial carcinoma (weak to moderate staining), and 2 of 8 nephrogenic adenomas (1 weak and 1 moderate to strong staining). We concluded that hepatocyte nuclear factor-1ß is a useful marker in differentiating clear cell adenocarcinomas of the bladder/urethra from invasive high-grade transitional/urothelial carcinoma and other types of bladder adenocarcinomas and to a lesser extent from nephrogenic adenomas. Hepatocyte nuclear factor-1ß is of no diagnostic utility in discriminating primary bladder/urethral clear cell adenocarcinomas from metastatic clear cell adenocarcinomas of the female genital tract to the bladder/urethra. From a histogenesis standpoint, although the expression of hepatocyte nuclear factor-1ß in both gynecologic and urologic tract clear cell adenocarcinomas may point to a Müllerian derivation/differentiation, this immunohistochemical evidence is insufficient to completely exclude an urothelial association.

Clear cell adenocarcinoma of the bladder and urethra: cases diffusely mimicking nephrogenic adenoma.

Although clear cell adenocarcinoma have been described focally mimicking nephrogenic adenoma, we have identified a subset of clear cell adenocarcinoma that diffusely resembles nephrogenic adenoma (nephrogenic adenoma-like clear cell adenocarcinoma). Twelve classic clear cell adenocarcinomas of the bladder and urethra and 7 nephrogenic adenoma-like clear cell adenocarcinomas were compared to 10 nephrogenic adenomas. Classic clear cell adenocarcinomas and nephrogenic adenoma-like clear cell adenocarcinomas comprised 4 men and 15 women. The following features were seen in classic clear cell adenocarcinomas: nephrogenic adenoma-like clear cell adenocarcinomas: predominantly solid pattern (7/12:0/7), marked nuclear pleomorphism (7/12:1/7), prominent nucleoli (5/12:1/7), clear cytoplasm in 50% or greater of tumor (7/12:0/7), and necrosis (8/12:3/7), although the necrosis in nephrogenic adenoma-like clear cell adenocarcinomas was often focal and intraluminal. Both patterns of clear cell adenocarcinomas showed prominent hobnail features, although more pronounced in nephrogenic adenoma-like clear cell adenocarcinomas. Muscularis propria invasion was seen in 5 of 9 classic clear cell adenocarcinomas and 6 of 6 nephrogenic adenoma-like clear cell adenocarcinomas, where evaluable. Classic clear cell adenocarcinoma was associated with urothelial carcinoma (n = 2) and endometriosis (n = 1). The Ki-67 rate in clear cell adenocarcinomas ranged from 10% to 80% compared with 0% to 5% in nephrogenic adenoma. The following antibodies were not helpful in distinguishing nephrogenic adenoma-like clear cell adenocarcinoma from nephrogenic adenoma: CD10, estrogen receptor, p63, high-molecular-weight cytokeratin, and alpha-methylacyl coenzyme-A racemase. PAX2 expression was more frequent in nephrogenic adenoma (89%) compared to both patterns of clear cell adenocarcinoma (29%-32%). The key features discriminating between nephrogenic adenoma-like clear cell adenocarcinoma and nephrogenic adenoma include occasional clear cells, more prominent pleomorphism especially hyperchromatic enlarged nuclei, and extensive muscular invasion. Presence of mitoses and a high rate of Ki-67 expression in lesions resembling nephrogenic adenoma require clinical correlation, close follow-up, and repeat biopsy with more extensive sampling.

TMPRSS2-ERG gene fusions are infrequent in prostatic ductal adenocarcinomas.

Ductal adenocarcinoma of the prostate is an unusual subtype that may be associated with a more aggressive clinical course, and is less responsive to conventional therapies than the more common prostatic acinar adenocarcinoma. However, given its frequent association with an acinar component at prostatectomy, some have challenged the concept of prostatic ductal adenocarcinoma as a distinct clinicopathologic entity. We studied the occurrence of the TMPRSS2-ERG gene fusion, in 40 surgically resected ductal adenocarcinoma cases, and in their associated acinar component using fluorescence in situ hybridization. A group of 38 'pure' acinar adenocarcinoma cases matched with the ductal adenocarcinoma group for pathological grade and stage was studied as a control. Compared with the matched acinar adenocarcinoma cases, the TMPRSS2-ERG gene fusion was significantly less frequently observed in ductal adenocarcinoma (45 vs 11% of cases, P=0.002, Fisher's exact test). Here, of the ductal adenocarcinoma cases with the gene fusion, 75% were fused through deletion, and the remaining case was fused through translocation. The TMPRSS2-ERG gene fusion was also rare in the acinar component of mixed ductal-acinar tumors when compared with the pure acinar adenocarcinoma controls (5 vs 45%, P=0.001, Fisher's exact test). In 95% of the ductal adenocarcinoma cases in which a concurrent acinar component was analyzed, there was concordance for presence/absence of the TMPRSS2-ERG gene fusion between the different histologic subtypes. In the control group of pure acinar adenocarcinoma cases, 59% were fused through deletion and 41% were fused through translocation. The presence of the TMPRSS2-ERG gene fusion in some cases of prostatic ductal adenocarcinoma supports the concept that ductal adenocarcinoma and acinar adenocarcinoma may be related genetically. However, the significantly lower rate of the gene fusion in pure ductal adenocarcinoma cases underscores the fact that genetic and biologic differences exist between these two tumors that may be important for future therapeutic strategies.

Roles for the stem cell associated intermediate filament Nestin in prostate cancer migration and metastasis.

The intermediate filament protein Nestin identifies stem/progenitor cells in adult tissues, but the function of Nestin is poorly understood. We investigated Nestin expression and function in common lethal cancers. Nestin mRNA was detected in cell lines from small cell lung, and breast cancers, and particularly elevated in cell lines derived from prostate cancer metastases. Whereas the androgen-independent lines PC3, 22RV1, and DU145 all expressed Nestin transcripts under standard culture conditions, the androgen-dependent line LnCaP expressed Nestin only on androgen withdrawal. We confirmed associations of Nestin expression, androgen withdrawal, and metastatic potential by immunohistochemical analysis of samples from 254 prostate cancer patients. Cytoplasmic Nestin protein was readily identifiable in prostate cancer cells from 75% of patients with lethal androgen-independent disease, even in cancer sampled from the prostate itself. However, Nestin expression was undetectable in localized androgen-deprived tumors and in metastases without prior androgen deprivation. To address its function, we reduced Nestin levels with short hairpin RNAs, markedly inhibiting in vitro migration and invasion in prostate cancer cells but leaving cell growth intact. Nestin knockdown also diminished metastases 5-fold compared with controls despite uncompromised tumorigenicity at the site of inoculation. These results specify a function for Nestin in cell motility and identify a novel pathway for prostate cancer metastasis. Activity of this pathway may be selected by the extraprostatic environment or, as supported by our data, may originate within the prostate after androgen deprivation. Further dissection of this novel Nestin migration pathway may lead to strategies to prevent and neutralize metastatic spread.

The role of P501S and PSA in the diagnosis of metastatic adenocarcinoma of the prostate.

BACKGROUND: Adenocarcinoma of the prostate can present as metastatic carcinoma with no known primary. Prostatic origin can be confirmed in most of these cases by immunohistochemistry for prostate-specific antigen (PSA) and prostate-specific acid phosphatase. In a small subset of high-grade prostate carcinomas, both markers are negative and therefore are not helpful for confirming prostatic origin. Recently, novel marker proteins that are preferentially expressed in prostate tissue were identified. One such marker is P501S or prostein, a 553-amino acid protein that is localized to the Golgi complex. It is expressed in both benign and neoplastic prostate tissues, but not in any other normal or malignant tissue examined to date. Owing to its apparent specificity, prostein may be a good marker to demonstrate prostatic origin in metastatic prostate cancer. DESIGN: Five-micron sections of a tissue microarray were subjected to immunohistochemistry with a monoclonal mouse anti-P501S (clone 10E3, Dako, Carpintera, CA) antibody and a monoclonal mouse anti-PSA (clone ER-PR8, Dako, Carpintera, CA) antibody. The tissue microarray contains 78 cases of metastatic prostatic adenocarcinoma, 20 cases of primary prostatic adenocarcinoma, and 20 cases of benign prostate tissue from the peripheral zone as well as samples of benign brain, pancreas, kidney, thyroid, testis, skeletal muscle, and fibroconnective tissue. RESULTS: Similar staining (intensity and extent) was identified for both markers in the majority of metastatic tumors (11 distant sites, 42 pelvic lymph nodes), in all 20 primary tumors and in all benign prostate and nonprostate tissues. The P501S stain had perinuclear cytoplasmic (Golgi) distribution even in poorly differentiated tumors and metastases. Two distant metastases were negative for PSA but retained focal weak positivity for P501S. Two other distant metastases were weakly PSA positive, but strongly P501S positive. Metastases in the pelvic lymph nodes were positive for both markers in 53 cases and 1 lymph node metastasis was strongly PSA positive but P501S negative. In summary, 67 of the 69 cases (97%) of metastatic prostate carcinomas were PSA positive, whereas 68 of the 69 cases showed at least focal weak reactivity for P501S (99%). None of the tumors were negative for both markers. CONCLUSIONS: Immunohistochemistry for P501S is a sensitive and highly specific marker for identifying prostate tissue. The large majority of metastatic prostatic adenocarcinomas are P501S positive (99%). A small subset of metastatic prostatic adenocarcinoma shows significant differences in staining intensity and extent for PSA and P501S and, therefore, combined use of these markers may result in increased sensitivity for detecting prostatic origin.

Solitary fibrous tumor on needle biopsy and transurethral resection of the prostate: a clinicopathologic study of 13 cases.

One of the least commonly encountered spindle cell tumors seen on prostatic needle biopsy or transurethral resection (TUR) of the prostate is solitary fibrous tumor (SFT). We studied 13 cases of SFTs identified on either prostate needle biopsy (n=9) or TUR of the prostate (n=4). Mean patient age at diagnosis was 63 years (range: 46 to 75 y; median: 65 y). Twelve men presented with urinary tract symptoms and 1 patient was biopsied during work-up of bone metastases. Ten cases were SFTs originating in the prostate, 2 cases arose between the prostate and rectum extending into the prostate (n=2), and 1 case was a pelvic mass without infiltration of the prostate. In 9 cases, a complete tumor resection was attempted by cystoprostatectomy (n=2), radical prostatectomy (n=4), pelvic exenteration (n=2), or pelvic tumor resection (n=1). Enucleation (n=1) and TUR (n=1) were performed in 2 other cases. Tumor sizes ranged from 8.5 to 15 cm in 7 radically resected cases. Mitotic rates were 3 to 5 per 10 high power fields in 5 cases, with the remaining cases having either rare (n=4) or no mitoses (n=4). Seven cases demonstrated areas of necrosis. Based on a combination of increased cellularity, mitotic activity, necrosis, nuclear pleomorphism, and infiltrativeness, 4 prostatic SFTs were malignant, 4 were benign, and 2 were borderline. Of the 3 non-prostatic SFTs, 1 was malignant and 2 were borderline. All tumors but 1 were immunoreactive for CD34 (n=12). Material for additional immunohistochemistry was available for the majority of cases with positive stains for Bcl-2 (11/11), CD99 (7/10), beta-catenin (5/10), and c-kit (0/11). Three SFTs demonstrated >or=10% p53 immunoreactivity including 1 tumor with 50% positivity; and 3 cases had Ki-67 rates of >or=20%. Although all SFTs were initially clinically considered to be of prostatic origin, some of the cases arose in the pelvis with secondary involvement of the prostate. Approximately 50% of prostatic SFTs were malignant. Even in the prostatic and nonprostatic SFTs with no overt malignant features, sometimes it was necessary to remove the prostate and in some instances the adjacent organs because of the large size of the tumors. SFTs must be differentiated from other spindle cell neoplasms of the prostate especially from gastrointestinal stromal tumors that may arise from the rectal wall with invasion of the prostate or from the region between the rectum and the prostate.

Immunohistochemical antibody cocktail staining (p63/HMWCK/AMACR) of ductal adenocarcinoma and Gleason pattern 4 cribriform and noncribriform acinar adenocarcinomas of the prostate.

Overexpression of alpha-methylacyl coenzyme A racemase (AMACR) in combination with absence of basal cell markers [ie, p63 and high molecular weight cytokeratin (HMWCK)] is typical of classic acinar prostatic adenocarcinoma. We studied the expression and diagnostic utility of p63/HMWCK/AMACR immunohistochemical cocktail staining in ductal adenocarcinoma and cribriform Gleason pattern 4 acinar prostate cancer and compared it to noncribriform Gleason pattern 4 acinar prostate cancer. One to 4 representative formalin-fixed paraffin-embedded archival tissue blocks from 62 radical prostatectomy specimens harboring prostate cancer of ductal (n=51), cribriform Gleason pattern 4 acinar (n=27), and noncribriform Gleason pattern 4 acinar adenocarcinoma (n=48) were included in this study. Immunohistochemistry was performed using a triple stain of AMACR, p63, and HMWCK. Only staining that was moderate or strong was considered positive. The percentage of staining intensity and the presence of occasional basal cells positive with p63/HMWCK were recorded in each histologic type of prostatic adenocarcinoma. Seventy-seven percent of ductal prostatic adenocarcinoma, 67% of cribriform acinar prostatic carcinoma, and 81% of noncribriform acinar prostatic carcinoma showed positive staining for AMACR. There was no statistically significant difference between AMACR staining among the 3 histologic types, although there was a trend for noncribriform acinar prostatic carcinoma to have greater expression of AMACR than cribriform acinar prostatic carcinoma (P=0.07). Staining was often heterogeneous, varying in staining intensities within the same histologic type of carcinoma. Basal cells were detectable by p63 and HMWCK in a patchy fashion in 31.4% (16/51) of ductal and 29.6% (8/27) of cribriform acinar carcinomas compared with 2.1% (1/48) of noncribriform acinar carcinomas. In summary: (1) the majority of prostatic ductal and cribriform acinar carcinomas strongly expressed AMACR, however, subpopulations of these prostatic carcinoma were either completely negative or only weakly positive; (2) AMACR staining was often heterogeneous in intensity in the same histologic type of tumor, even within the same case; (3) patchy basal cell staining in noncribriform acinar prostatic carcinoma is rare. In contrast, remnants of basal cells identified by p63/HMWCK were seen in a patchy fashion in a significant minority of both ductal and cribriform acinar prostatic adenocarcinoma, which most likely represents intraductal spread of tumor.

Expression of CDX2 in benign tissue and adenocarcinoma of the prostate.

Numerous studies have claimed that CDX2 is relatively specific and sensitive in establishing a gastrointestinal origin in metastatic tumors of unknown origin. We have recently seen 2 cases of prostatic adenocarcinoma (PCa) on needle biopsies with diffuse strong nuclear staining for CDX2 sent for consultation. One case was a prostatic duct adenocarcinoma in a man with a prostate-specific antigen (PSA) value of 327 ng/mL, and the other was a PCa with a Gleason score (GS) of 4 + 4 = 8 in a man with a PSA value of 15 ng/mL. An adenocarcinoma with GS 3 + 3 = 6 from the contralateral side did not express CDX2. Because documented examples of this phenomenon are rare, we investigated the immunoexpression of CDX2, using tissue microarrays (TMAs). Three slides of TMAs were used to stain 708 tissue samples (0.6 mm in diameter) containing either benign or malignant prostate tissue, as well as control tissues from various anatomical sites including colon. In total, 195 samples of primary PCa with GS of 6 (n = 41), 7 (n = 21), and 8 (n = 8); 195 samples of benign prostate tissue; and 185 samples of metastatic PCa were studied. Of 70 radical prostatectomy specimens examined for PCa in TMAs, 4 (5.7%) were positive for CDX2, showing Gleason score of 6 (n = 3) and Gleason score of 7 (n = 1). Focal moderate positive staining was seen in benign prostate tissue in 7 (11.7%) of 60 radical prostatectomy specimens. None of the metastatic PCa expressed CDX2. CDX2 may uncommonly be focally expressed in benign prostatic glands. Staining in PCa is less common and appears independent of GS and is usually patchy and focal and of lesser intensity than in colonic tissue. However, rarely strong and diffuse staining may be seen. Positive CDX2 staining in high-grade prostate cancer (ductal, cribriform, and solid) may be confused with secondary carcinoma of colonic origin. Routine histopathology, positive PSA immunostaining, and clinical findings can help confirm the correct diagnosis.

Spindle cell lesions of the adult prostate.

Prostatic spindle cell lesions are diagnostically challenging and encompass a broad array of benign and malignant processes. A subset of these lesions arises only within the prostate and generally represents entities that originate from the prostate epithelium or stroma, such as sclerosing adenosis, sarcomatoid carcinoma, stromal tumors of uncertain malignant potential (STUMP), and stromal sarcoma. Another subset of spindle cell tumors that involve the prostate are also found at other sites and include solitary fibrous tumor, leiomyosarcoma, and neural lesions among others. Finally, tumors may secondarily involve the prostate yet present as primary prostatic processes, as is evident with several cases of gastrointestinal stromal tumors (GIST). The utility of ancillary studies, including immunohistochemistry, is often limited and the main criteria for diagnosis are the morphologic findings by routine H&E stain. This review addresses the various entities that may present as spindle cell tumors within the adult prostate and discusses the functional aspects of the differential diagnosis of these lesions.

Gastrointestinal stromal tumors (GISTs) on prostate needle biopsy: A clinicopathologic study of 8 cases.

Gastrointestinal stromal tumors (GISTs) are typically not included in the differential diagnosis of spindle cell tumors seen on prostate needle biopsy. However, their recognition is critical due to their unique clinical management. We report the rare phenomenon of 8 cases of GISTs diagnosed on prostate needle biopsy. The mean patient age at diagnosis was 53.6 years (range: 42 to 65 years). Tumors variably presented with rectal fullness, urinary obstructive symptoms, and abnormal digital rectal examination. Four tumors were resected. One of these cases was shown to be primary in the rectum without prostatic involvement. The second case extensively involved the prostate but its epicenter was in the rectal muscularis propria. The third case was an encapsulated mass separated by a thin fibrous capsule from the prostate. The fourth case was a perirectal mass that underwent local excision. Four lesions have not been resected. On the basis of imaging studies, one seemed to be a prostatic mass, however, additional imaging investigations showed the mass to be separate from the prostate. Three cases have not yet been studied radiographically. Tumors measured 1.0, 1.7, 5.4, 7.0, 7.4, and 8.5 cm. The sizes of 2 recently diagnosed tumors remain undetermined. Histologically, all 8 GISTs showed spindled cells with a fascicular growth pattern. Additional histologic findings included focal epithelioid features (n = 3), necrosis (n = 3), mitotic rates of >5 per 50 high-power field (n = 2), and cytologically malignant features (n = 3). CD117/c-kit was diffusely positive in all 8 cases and CD34 in 7/8 cases. In all cases studied, stains for S100, desmin, and smooth muscle actin were negative. Two patients were treated with imatinib mesylate. One underwent radical prostatectomy after reduction in tumor size after imatinib administration. Another patient was treated with imatinib for several months with complete tumor response and no residual tumor seen in a subsequent local excision. Rectal or extraintestinal GIST can result in a clinical impression of a prostatic lesion. One should consider CD117/c-kit in the immunohistochemical panel to exclude GIST before diagnosing a solitary fibrous tumor, leiomyosarcoma, or specialized prostatic stromal tumor on prostate needle biopsy.

Pleomorphic giant cell adenocarcinoma of the prostate: report of 6 cases.

Pleomorphic tumors with giant cells have been described in a variety of primary sites. However, only a few cases have been described among prostatic carcinomas with only 1 on diagnostic biopsy material. Five cases were retrieved from the consultation files of one of the authors. One of the cases was retrieved from the surgical pathology files at our institute. Patient ranged in age from 59 to 76 years (mean=65.8 y). The diagnosis was made on needle biopsy (n=3), urethral biopsy (n=1), transurethral resection (n=1), or radical prostatectomy (n=1). In all cases, giant, bizarre, anaplastic cells were present. In 4 of the cases, marked pleomorphism occupied 5% of the specimen, with 20% and 70% bizarre giant cells in the other 2 cases. In one case, the bizarre cells had atypical mitotic figures, with other cases showing no mitoses in the markedly pleomorphic cells. In addition to the pleomorphic giant cell component, multiple coexistent histologic components were seen including Gleason score 9 conventional prostate cancer (n=6), small cell carcinoma (n=1), squamous carcinoma (n=1), and prominent ductal adenocarcinoma differentiation with intraductal spread (n=1). Immunohistochemically, 4 cases were for negative for prostate-specific antigen in the giant cells, 1 had 5% staining, and the other had 50% positivity in the giant cells. Staining for prostate-specific antigen in the conventional prostate carcinoma component was 1%, 5%, 20%, 50%, 100%, and 100%. The bizarre giant cells were strongly positive for cytokeratins AE1/AE3 and/or Cam 5.2 (n=3). Two cases had a history of conventional prostate cancer 4 years before the giant cell component, 1 treated with Lupron and the other with radiation. Follow-up after diagnosis of the giant cell component: Case 1: dead in 1 year of disease; Case 2: progressive metastases in 2 years; Case 3: alive at 1 year with disease; Case 4: large perineal recurrence after brachytherapy at 3 years; Case 5: radical prostatectomy with extraprostatic extension and seminal vesicle invasion; and Case 6: alive at 3 months, free of disease. Conventional prostate cancer, even when very high grade, typically consists of cells with relatively uniform nuclei. Our study expands the histology described in prostate cancer to include in very rare cases with prominent pleomorphism and bizarre giant cells. This giant cell component heralds a particularly aggressive clinical outcome.

Specialized stromal tumors of the prostate: a clinicopathologic study of 50 cases.

Specialized stromal tumors of the prostate encompass stromal sarcoma and stromal tumors of uncertain malignant potential (STUMP). As a result of their relative rarity and lack of long-term follow-up, the prognosis of STUMP is unclear. We studied 50 cases of STUMP and stromal sarcoma with regard to their clinical presentation and follow-up. Patients ranged in age from 27 to 83 years (mean 58 years). The major presenting signs and symptoms were urinary obstructive symptoms (n=25), abnormal digital rectal exam (n=15), hematuria (n=7), hematospermia (n=1), and rectal dysfunction/fullness (n=3). An elevated prostate-specific antigen was either the sole or a compounding rationale for initial urologic examination and prostate biopsy in a subgroup of patients (n=11). The histology in the 36 cases of STUMP not associated with sarcoma were as follows: 25 composed of stroma with scattered cytologically atypical cells associated with benign glands; 8 resembling glandular-stromal hyperplasia but with hypercellular stroma; 6 with extensive myxoid stroma; and 1 with phyllodes pattern. Four of these cases had mixed patterns. Seven cases of STUMP were associated with sarcoma, either concurrently or subsequently. In another 7 cases, pure sarcomas were encountered: 3 low grade (LG) and 4 high grade (HG). In 19 STUMPs, the location of the lesion was determinable: 10 cases arose in the peripheral zone, 7 cases were located in the transition zone, and 2 cases seemed to involve both zones. In 3 of these cases, tumors were adherent to the rectum at the time of resection. There was no evidence of progression of disease for 14 STUMPs after biopsy, TUR, or enucleation where follow-up ranged from 0.3 to 14 years (mean 4.9 years). Five cases of STUMP showed local tumor growth: 1 case increased in size from 6 to 7.5 cm in 3 years and 4 cases recurred frequently necessitating multiple TURs of the prostate (n=2, n=3, n=3, n=3) over 1.1, 2, 7, and 8 years, respectively. Fourteen patients with STUMP underwent radical prostatectomy (RP) soon after diagnosis; of these, 12 were organ confined where the tumor size ranged from 0.7 to 7.5 cm (mean 2.7 cm); 2 cases with a history of a 28 g TUR and a 275 g enucleation showed no residual tumor in the RP specimen. Three cases were lost to follow-up. The histologic subtypes of STUMP did not correlate with the clinical behavior or likelihood of being associated with sarcoma. Two of the LG sarcomas locally invaded around the seminal vesicle, yet all of the LG sarcomas with follow-up were free of disease at 3, 13, 24, 25, 30, and 36 months. Of the 6 HG sarcomas with follow-up, 3 were free of disease at 3, 17, and 72 months. One man was alive with metastasis to the lung 10 months after RP, 1 man was alive at 280 months with multiple metastases, and another died of disease at 115 months. STUMPs can recur frequently, occur at a young age, often involve the peripheral zone where they can be adherent to the rectum requiring its removal, and can be associated with stromal sarcoma. Although STUMPs can be histologically misdiagnosed as nodular hyperplasia, it is important to recognize that these are neoplasms with unique local morbidity and malignant potential. Whereas LG stromal sarcomas can locally invade, HG sarcomas can metastasize and lead to death.

Implants of noninvasive papillary urothelial carcinoma in peritoneum and ileocolonic neobladder: support for "seed and soil" hypothesis of bladder recurrence.

OBJECTIVES: To explore the underlying mechanism of tumor regrowth in cases of noninvasive urothelial carcinoma that recur in unusual anatomic locations. METHODS: The pathology files of our institution and the consult service of one of us were searched for cases of noninvasive nonmetastatic urothelial carcinoma with involvement of unusual anatomic sites. Cases in which the mode of spread included direct spread to the adjacent tissue and lymphovascular metastases were excluded. Medical history, including presenting symptoms, and follow-up data were obtained. RESULTS: Two cases of noninvasive urothelial carcinoma were identified. One had presented as an implant in the peritoneal investment of the bladder dome and the other as multiple implants growing on the benign surface of the colonic mucosa of an orthotopic neobladder distant from the anastomosis site. Both cases had initially presented as noninvasive papillary urothelial carcinoma of the renal pelvis. Although the urinary bladder was free of neoplastic changes at nephroureterectomy, both patients also developed several papillary tumors within the bladder shortly after the removal of the kidney. CONCLUSIONS: After clinicopathologic correlation, the mode of tumor spread in these cases was best explained by the "seeding/implantation" theory. The urothelial tumor cells in each of these cases demonstrated the ability to implant themselves not only in the urothelium of the bladder but also in the colonic mucosa of a constructed neobladder and on the peritoneal surface.

Polyoma virus-associated cellular changes in the urine and bladder biopsy samples: a cytohistologic correlation.

Polyoma (BK) virus-type cellular changes are occasionally reported in urine specimens, yet rarely detected in histologic sections of bladder biopsies. A total of 762 predominantly voided urine specimens with a cytologic diagnosis of polyoma virus-type change were retrieved from the cytopathology files of the Johns Hopkins Hospital over a 15-year period (1988-2003). Biopsies were available for 33 cases (29 patients) following or preceding the urinary cytology (mean interval, 210 days). The biopsies originated primarily from bladder (n=31) with one biopsy each from renal pelvis and urethra. Representative paraffin blocks were chosen from each case for immunoperoxidase staining with SV40 large T antigen. There were 22 males and 7 females with an age range of 34 to 79 years (mean, 64.7 years). The histologic diagnoses of the 33 tissue biopsies were: benign urothelium (n=9), urothelial carcinoma (n=21) and 1 case each of dysplasia, small cell carcinoma, and chronic lymphocytic leukemia involving lamina propria of the bladder. Only 3 of 33 biopsies on hematoxylin-stained sections showed morphologic changes of polyoma virus, which lacked sufficient tissue to perform immunohistochemistry for SV40 large T antigen (LTag). Immunohistochemical staining for LTag was positive in 7 cases. Only 2 cases showed strong/diffuse and moderate/focal staining for LTag with both representing invasive high-grade urothelial carcinoma (where no inclusions were seen on hematoxylin and eosin-stained sections) and both demonstrating positive immunostaining for p53. One of these 2 cases was from an organ transplant recipient and the other from a patient with no known immunosuppression. Our data lead to the following conclusions: 1) cytology appears to be more sensitive than histology in detecting cells with polyoma virus; 2) cytohistologic discordance might be due to: a) polyoma (BK) virus infected cells are shed from the tissue and collected in the urine; b) polyoma virus changes may be focal and not sampled in directed tissue biopsies; c) polyoma virus changes may originate from sites in the genitourinary tract other than the bladder; d) the lack of a "gold standard" to confirm the cytologic diagnoses of polyoma virus; and e) the discordance in time between the biopsy and cytology specimens in the current retrospective study. 3) Because some cytologically benign cases of polyoma virus were associated with malignant biopsies, careful morphologic evaluation is required to avoid false-negative urinary cytology samples. This investigation further examined the immunohistochemical staining pattern for SV40 LTag and p53 in noninvasive low-grade papillary urothelial carcinoma using a tissue microarray constructed from bladder biopsies of 79 randomly selected patients. Weak LTag staining was present in occasional neoplastic urothelial cells of 2 patients. The staining was present in only one of four samples from each tumor (0.63%; 2 of 316 tumor spots), which further illustrates the patchy and focal presence of virion containing cells. p53 staining in these two spots was also patchy and confined to rare nuclei.

Prostate needle biopsies containing prostatic intraepithelial neoplasia or atypical foci suspicious for carcinoma: implications for patient care.

PURPOSE: We identified information critical for patient treatment on prostate needle biopsies diagnosed with prostatic intraepithelial neoplasia or atypical foci suspicious for carcinoma. MATERIALS AND METHODS: A search was performed using the MEDLINE database and referenced lists of relevant studies to obtain articles addressing the significance of finding PIN or atypical foci suspicious for carcinoma on needle biopsy. RESULTS: There were certain results concerning PIN. 1) Low grade PIN should not be documented in pathology reports due to poor interobserver reproducibility and a relatively low risk of cancer following re-biopsy. 2) The expected incidence of HGPIN on needle biopsy is between 5% and 8%. 3) Although the diagnosis of HGPIN is subjective, interobserver reproducibility for its diagnosis is fairly high among urological pathologists, and yet only moderate among pathologists without special expertise in prostate pathology. 4) The median risk recorded in the literature for cancer following the diagnosis of HGPIN on needle biopsy is 24.1%, which is not much higher than the risk reported in the literature for repeat biopsy following a benign diagnosis. 5) The majority of publications that compared the risk of cancer in the same study following a needle biopsy diagnosis of HGPIN to the risk of cancer following a benign diagnosis on needle biopsy show no differences between the 2 groups. 6) Clinical and pathological parameters do not help stratify which men with HGPIN are at increased risk for a cancer diagnosis. 7) A major factor contributing to the decreased incidence of cancer following a diagnosis of HGPIN on needle biopsy in the contemporary era is related to increased needle biopsy core sampling, which detects many associated cancers on initial biopsy, such that re-biopsy, even with good sampling, does not detect many additional cancers. 8) It is recommended that men do not need routine repeat needle biopsy within the first year following the diagnosis of HGPIN, while further studies are needed to confirm whether routine repeat biopsies should be performed several years following a HGPIN diagnosis on needle biopsy. There were certain results concerning atypical glands suspicious for carcinoma. 1) An average of 5% of needle biopsy pathology reports are diagnosed as atypical glands suspicious for carcinoma. 2) Cases diagnosed as atypical have the highest likelihood of being changed upon expert review and urologists should consider sending such cases for consultation in an attempt to resolve the diagnosis as definitively benign or malignant before subjecting the patient to repeat biopsy. 3) Ancillary techniques using basal cell markers and AMACR (alpha-methyl-acyl-coenzyme A racemase) can decrease the number of atypical diagnoses, and yet one must use these techniques with caution since there are numerous false-positive and false-negative results. 4) The average risk of cancer following an atypical diagnosis is approximately 40%. 5) Clinical and pathological parameters do not help predict which men with an atypical diagnosis have cancer on repeat biopsy. 6) Repeat biopsy should include increased sampling of the initial atypical site, and adjacent ipsilateral and contralateral sites with routine sampling of all sextant sites. Therefore, it is critical for urologists to submit needle biopsy specimens in a manner in which the sextant location of each core can be determined. 7) All men with an atypical diagnosis need re-biopsy within 3 to 6 months. CONCLUSIONS: It is critical for urologists to distinguish between a diagnosis of HGPIN and that of atypical foci suspicious for cancer on needle biopsy. These 2 entities indicate different risks of carcinoma on re-biopsy and different recommendations for followup.

Risk of prostate cancer on first re-biopsy within 1 year following a diagnosis of high grade prostatic intraepithelial neoplasia is related to the number of cores sampled.

PURPOSE: We determined the influence of the extent of needle biopsy sampling on the detection rate of cancer on first biopsy within 1 year following a diagnosis of HGPIN. MATERIALS AND METHODS: We identified 791 patients with HGPIN on the initial biopsy who had a followup biopsy within 1 year of their diagnosis. The mean interval from diagnosis of HGPIN to re-biopsy was 4.6 months. In the initial biopsy with HGPIN, 323 men had 8 or more cores (median 10, range 8 to 26) and 332 men had 6 core biopsies. RESULTS: In the 6 core initial sampling group, the risk of cancer on re-biopsy was 20.8% compared to only 13.3% following an initial 8 core or more sampling (p = 0.011). With 6 core biopsies for both the initial and re-biopsy the risk of cancer was 14.1% (group 1). With an initial 6 core biopsy and 8 core or more biopsy on followup, the risk of cancer was 31.9% (group 2). With 8 core or more biopsy sampling for both initial and repeat biopsies, the risk for cancer was 14.6% (group 3). The differences between groups 1 and 3 as compared to group 2 were statistically significant (p = 0.001 and p <0.0001, respectively). CONCLUSIONS: With relatively poor sampling (6 cores) on the initial biopsy, associated cancers are missed resulting in only HGPIN on the initial biopsy, and with relatively poor sampling on re-biopsy there is also a relatively low risk of finding cancer on re-biopsy (group 1). With poor sampling on the initial biopsy and better sampling on re-biopsy, some of these initially missed cancers are detected on re-biopsy yielding a higher detection of cancer (group 2). Sampling more extensively on the initial biopsy detects many associated cancers, such that when only HGPIN is found they often represent isolated HGPIN. Therefore, re-biopsy even with good sampling does not detect many additional cancers (group 3). Our study demonstrates that the risk of cancer on biopsy within 1 year following a diagnosis of HGPIN (13.3%) is not that predictive of cancer on re-biopsy if good sampling (8 or more cores) is initially performed. For patients diagnosed with HGPIN on extended initial core sampling, a repeat biopsy within the first year is unnecessary in the absence of other clinical indicators of cancer.

Urothelial carcinoma with rhabdoid features: report of 6 cases.

Extrarenal rhabdoid tumors have been described in a variety of primary sites with only rare case reports of urothelial carcinomas with rhabdoid features in the literature. In this report, we describe the clinicopathologic characteristics, including clinical follow-up on 6 cases of urothelial carcinoma with prominent rhabdoid features. Four cases were retrieved from the consultation files of one of the authors and 2 were retrieved from the surgical pathology files at our institution. The patients were all men, with ages ranging from 53 to 86 years (mean, 66.5 years). Patients initially presented with hematuria or obstructive symptoms. The sites included bladder (n = 4) and renal pelvis (n = 2). All cases had a prominent rhabdoid component (mean, 60%), ranging from 40% to 80%. In addition to the rhabdoid component, multiple coexistent histological components were seen, including in situ urothelial carcinoma (carcinoma in situ) and high-grade papillary urothelial carcinoma (n = 2), poorly differentiated carcinoma with small-cell features (n = 1), sarcomatoid (n = 2), and a myxoid component (n = 2). All cases in this series had focal or diffuse positive staining with one or more cytokeratin markers (epithelial membrane antigen, CAM 5.2, AE1/AE3). Of the 6 patients, 4 were treated initially with surgery (radical cystoprostatectomy, n = 2; radical nephrectomy, n = 2). Of 6 patients, 2 died within 1 month, whereas a third patient died within 4 months. The remaining 3 patients were alive at 3, 3, and 9 months after diagnosis. The histological and immunohistochemical findings in this study serve to broaden the morphological spectrum of urothelial carcinomas with prominent rhabdoid features and add further evidence as to their poor prognosis.