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Context.—: Nephrogenic adenoma (NA) is a common urinary tract lesion typically associated with urothelial disruption, leading to implantation of shed renal tubular cells. NA may demonstrate a spectrum of architectural and cytologic features mimicking urothelial carcinoma (UC), adenocarcinoma (including clear cell adenocarcinoma and prostatic adenocarcinoma), and invasion. However, admixed UC and NA has not been described., Objective.—: To describe cases where the NA was intimately intermixed with UC, potentially mimicking variant differentiation or invasion., Design.—: In 3 health care systems we identified specimens of NA and UC intimately intermixed with each other to the extent that they could mimic a spectrum of one lesion. We assessed patterns of NA and clinical implications of misdiagnosing NA as glandular differentiation of UC., Results.—: There were 4 women and 29 men (median age, 72 years; range, 31-89 years). Twenty-four patients had transurethral resections, 3 had biopsies, and 6 had major resections. Fourteen had noninvasive high-grade papillary UC, 6 had carcinoma in situ, and 11 had invasive high-grade UC. In 2 patients, NA developed in a papillary urothelial neoplasm with extensive denudation. Three patients had fibromyxoid NA infiltrated by invasive UC. Classical NA (n = 30) had tubulopapillary (n = 18), pure tubular (n = 7), or pure papillary architecture (n = 5). In 1 lesion, NA was present in muscularis propria, and 2 lesions involved adventitia. NA could have been misdiagnosed as invasion in 17 of 22 (77%) noninvasive tumors or higher stage in 19 of 33 (58%)., Conclusions.—: NA can be intermingled with high-grade UC, expanding the spectrum of entities that must be considered in the differential diagnosis, as it may mimic glandular or tubular differentiation, invasion, and a higher stage of disease. Misinterpretation of NA in such a setting may incorrectly convey a more aggressive biological potential of cancer to clinicians.

Renal cell tumors with mixed morphology resembling multiple renal cell carcinoma (RCC) subtypes are generally regarded as unclassified RCC. However, occasionally, papillary adenoma or RCC appears admixed with a larger, different tumor histology. We retrieved 17 renal tumors containing a papillary adenoma or papillary RCC component admixed with another tumor histology and studied them with immunohistochemistry and fluorescence in situ hybridization (FISH). Larger tumors were oncocytomas (n = 10), chromophobe RCCs (n = 5), borderline oncocytic tumor (n = 1), and clear cell RCC (n = 1). The size of papillary component ranged from 1 to 34 mm. One tumor was an oncocytoma encircled by a cyst (2.0 cm) with papillary hyperplasia of the lining. The papillary lesions were diffusely cytokeratin 7 positive (17/17), in contrast to "host" tumors. Alpha-methylacyl-coA-racemase labeling was usually stronger in the papillary lesions (13/15). KIT was negative in all papillary lesions and the clear cell RCC and positive in 16/16 oncocytic or chromophobe tumors. Eight of 15 (53%) collision tumors had differing FISH results in the two components. A papillary renal cell proliferation within another tumor is an uncommon phenomenon with predilection for oncocytoma and chromophobe RCC, possibly related to their common entrapment of benign tubules. When supported by distinct morphology and immunohistochemistry in these two components, this phenomenon should be diagnosed as a collision of two processes. A diagnosis of unclassified RCC should be avoided, due to potential misrepresentation as an aggressive renal cancer.

Aims: To develop an immunohistochemical strategy for distinguishing renal oncocytoma (RO) from the eosinophilic variant of chromophobe (ChRCC), and papillary (PRCC) and clear cell (CRCC) renal cell carcinoma containing eosinophilic cytoplasm in core biopsy specimens., Methods and Results: Cluster analysis was performed on immunohistochemical data from 21 RO, 16 ChRCC, 16 CRCC and 20 PRCC patients. A panel of CK7, C-kit, S100A1 and vimentin clustered into four groups. Cluster A (94% ChRCC) expressed C-kit and CK7 and lacked S100A1 and vimentin. Cluster B (95% RO) expressed C-kit, S100A1, focal CK7 (single or small clusters of cells) and lacked vimentin. Cluster C comprised a mixture of PRCC and CRCC with no expression of C-kit or CK7 and variable S100A1 and vimentin. PRCC with strong expression of CK7 clustered into group D. A panel of S100A1 (positive) and focal CK7 expression distinguished RO from ChRCC with 91% sensitivity and 93% specificity. A panel of vimentin (negative) and C-kit (positive) distinguished RO from CRCC with 83% sensitivity and 86% specificity and RO from PRCC with 79% sensitivity and 88% specificity., Conclusions: Hierarchical cluster analysis is an effective approach to analyse high-volume immunohistochemical data to generate an optimal panel in the differential diagnosis of oncocytoma from its mimics., (© 2011 Blackwell Publishing Limited.)

Background: Insulin-like growth factor-II mRNA-binding protein 3 (IMP-3 ), a member of the insulin-like growth factor mRNA-binding protein family, is expressed in several human malignancies, including melanomas. However, the expression of IMP-3 has not been explored in melanoma in situ, various histologic subtypes of invasive melanomas and atypical Spitz tumors., Methods: IMP-3 immunostain was performed in 157 melanocytic lesions., Results: Nearly all benign (8/8), dysplastic (8/8) and Spitz nevi (8/9) were negative for IMP-3. Focal IMP-3 positivity was observed in 5/12 melanoma in situ and 4/15 superficial melanomas (Breslow depth 1 mm) and 25/52 metastatic melanomas demonstrated strong IMP-3 staining. IMP-3 expression differs significantly between non-desmoplastic melanomas (superficial and deep) and benign or dysplastic or Spitz nevi (p = 0.0427, respectively). Four of 23 desmoplastic melanomas expressed IMP-3 , which was significantly different from deep melanomas (p = 0.0109). IMP-3 stained 7 of 10 atypical Spitz tumors. The difference between atypical Spitz tumors and Spitz nevi was statistically significant (p = 0.0256)., Conclusion: A malignant circumstance, such as non-desmoplastic melanoma or atypical Spitz tumor, can be inferred when IMP-3 is expressed, suggesting potential diagnostic value of IMP-3 in melanocytic lesions.

Nested urothelial carcinoma (UC) is a rare histologic variant of UC, characterized by deceptively bland histologic features resembling von Brunn's nests but usually with a poor outcome. In our experience, this variant is frequently misclassified or underrecognized as its clinicopathologic spectrum is not well defined. In addition, its relationship to usual UC and response to traditional bladder cancer management are largely unknown. Herein we report the largest series to date of 30 UC cases with pure or predominant nested morphology to identify its associated histopathologic findings, clinical outcome, and immunophenotype. Patient age ranged from 41 to 83 years (average, 63 years) with a male-female ratio of 2.3:1. The architectural pattern of the nested component ranged from a predominantly disorderly proliferation of discrete, small, variably sized nests (90%) to focal areas demonstrating confluent nests (40%), cordlike growth (37%), and cystitis cystica-like areas (33%) to tubular growth pattern (13%). The deep tumor-stroma interface was invariably (100%) jagged and infiltrative. Despite overall banal cytology, tumor nests demonstrated focal random cytologic atypia (90%) and focal high-grade cytologic atypia centered within the base of the tumor (40%). The tumor stroma ranged from having minimal stromal response to focally desmoplastic and myxoid. A component of usual UC was present in 63% of cases. The nested component demonstrated an immunophenotype identical to usual UC, with CK7, CK20, p63, and CK903 expression in 93%, 68%, 92%, and 92% of cases, respectively. At resection, all but 1 case demonstrated invasive carcinoma-9% into lamina propria, 4% into muscularis propria, 65% into perivesical fat, and 17% into adjacent organ(s). When compared with pure high-grade UC, nested UC was associated with muscle invasion at transurethral resection (31% versus 70%; P < .0001), extravesical disease at cystectomy (33% versus 83%; P < 0.0001), and metastatic disease (19% versus 67%; P < .0001). Follow-up was available on 29 patients (97%) with a median of 12 months (range, 1-31 months) of follow-up; 3 (10%) died of disease, 16 (55%) are alive with persistent or recurrent disease, and 10 (34%) are alive without disease. Response to neoadjuvant chemotherapy was observed in 2 (13%) of 15 patients. Nested UC seen either in pure form or with a component of usual UC had similarly unfavorable outcomes (P = .78). Increased awareness and familiarity with the clinicopathologic spectrum is critical for confident recognition and adequate management of this very aggressive variant of UC., (Copyright 2010 Elsevier Inc. All rights reserved.)

Purpose: The clinical under staging of T1 bladder cancer potentially delays therapy and undermines survival. In this study we evaluated clinicopathological features to aid in the identification of patients with clinical T1 bladder cancer at risk for under staging., Materials and Methods: We identified patients diagnosed with clinical T1 bladder cancer who underwent cystectomy within 4 months. Muscularis propria was present and uninvolved in initial biopsies or patients had a re-staging biopsy with muscle [corrected] present. Under staging was defined as pT2 or greater, N+ or M+ disease at radical cystectomy. A logistic regression multivariable model was used for the risk of under staging. Overall survival was assessed using the Kaplan-Meier method., Results: Of 95 patients 26 (27%) had under staged disease. Median followup was 24 months. Compared to accurately staged cases under staged cases were more likely to have muscularis mucosae invasion (54% vs 19%, p = 0.001), mixed histology (42% vs 17%, p = 0.02) and urethral involvement (31% vs 10%, p = 0.03). In a multivariable model muscularis mucosae invasion increased the odds of under staging 9-fold (95% CI 1.5-54.5, p = 0.01). The cumulative association of these risk factors increased the odds of under staging 20-fold (95% CI 1.8-217, p = 0.0029). Median overall survival (years) was lower in patients with under staged disease (1.4 vs 10.6, p <0.001), those with muscularis mucosae invasion (2.2 vs 6.5, p = 0.04) and those with urethral involvement (25th percentile 0.8 vs 2.0, p = 0.01)., Conclusions: Under staging adversely impacts survival. Muscularis mucosae invasion, urethral involvement and mixed histology cumulatively increase the risk of under staging, and may be valuable in counseling patients regarding early, aggressive intervention.

This article provides comprehensive review of benign diseases and neoplastic conditions of the penis. It describes and provides representative images of clinical, key pathologic features and ancillary techniques to aid in differential diagnoses. It examines these diseases from the epidemiologic standpoint, looks at environmental and genetic factors, and outlines the new histologic entities for penile neoplasms with distinct outcomes and clinical behavior that have been proposed in recent years., (Copyright © 2009 Elsevier Inc. All rights reserved.)

Introduction: Interleukin (IL)-17 plays an important role in the pathogenesis of rheumatoid arthritis and the mouse model collagen-induced arthritis (CIA). Interferon(IFN)-gamma and IL-4 have been shown to suppress Th17 development in vitro, but their potential immunoregulatory roles in vivo are uncertain. The goals of this study were to determine the relationship between Th17 responses and disease severity in CIA and to assess regulation of IL-17 by endogenous IFN-gamma and IL-4., Methods: DBA1/LacJ mice were immunized with type II collagen in complete Freund's adjuvant (CFA) to induce arthritis, and treated with neutralizing antibody to IFN-gamma and/or IL-4. Systemic IL-17, IFN-gamma, and IL-4 were measured in serum. At the peak of disease, cytokine production was measured by ELISA of supernatants from spleen, lymph node and paw cultures. Paws were also scored for histologic severity of arthritis., Results: Joint inflammation was associated with a higher ratio of systemic IL-17/IFN-gamma. Neutralization of IFN-gamma accelerated the course of CIA and was associated with increased IL-17 levels in the serum and joints. The IFN-gamma/IL-4/IL-17 responses in the lymphoid organ were distinct from such responses in the joints. Neutralization of IL-4 led to increased arthritis only in the absence of IFN-gamma and was associated with increased bone and cartilage damage without an increase in the levels of IL-17., Conclusions: IL-4 and IFN-gamma both play protective roles in CIA, but through different mechanisms. Our data suggests that the absolute level of IL-17 is not the only determinant of joint inflammation. Instead, the balance of Th1, Th2 and Th17 cytokines control the immune events leading to joint inflammation.

gamma-H2AX is a marker of activated DNA damage and is overexpressed in many malignancies and their precursor lesions. Previous studies have demonstrated the expression of gamma-H2AX in melanoma and dysplastic nevus, but its diagnostic and prognostic utility in a full range of melanocytic lesions has not been fully studied. In the current study, we investigated gamma-H2AX expression in a total of 162 melanocytic lesions. We found that gamma-H2AX was observed at higher levels (percentage and intensity of staining) in melanoma in situ (12/13), primary cutaneous melanoma (32/33; with the exception of desmoplastic melanoma), and metastatic melanoma (58/62), which was statistically different from that in benign nevus (7/9), dysplastic nevus (6/10), and Spitz nevus (5/9) considered together (P < .0001). Of note, desmoplastic melanoma (20/26) demonstrated weak or negative gamma-H2AX staining. The expression of gamma-H2AX did not show significant correlation with many melanoma prognostic factors, including Breslow depth, mitotic rate, and sentinel lymph node status. Except for desmoplastic melanoma, no difference in gamma-H2AX levels was observed among various melanoma subtypes. The overexpression of gamma-H2AX in melanoma as opposed to nevus indicates its possible role in melanomagenesis. Based on the overlap in subsets of nevi and melanomas, the potential clinical utility of this antibody remains uncertain until further studies have been carried out in a larger cohort of melanocytic lesions, including borderline cases.

Diagnosing metastatic renal cell carcinoma (RCC) by fine-needle aspiration (FNA) can be challenging. Existing antibodies supporting a diagnosis of RCC, including CD10 and RCC-Ma, have problems with specificity and interpretation. In this report, we evaluate the use of two newer immunostains, PAX-2 and gamma-H2AX, which to our knowledge have not been studied in FNA material, in the diagnosis of metastatic RCC and in comparison with RCC-Ma. 29 cases of metastatic RCC were identified as well as a TMA of an additional 30 RCC cases. In the case cohort, RCC-Ma in a membranous pattern of staining identified 15/27 (56%) metastatic RCC, although interpretation was made difficult in many cases due to focality of staining and non-specific cytoplasmic staining. PAX-2 stained 23/29 (79%) of tumors in a nuclear stain, most strongly. Gamma-H2AX stained 19/26 (73%) of metastatic RCC strongly in a nuclear stain. In the TMA, strong, diffuse nuclear staining with gamma-H2AX was present in 22/30 RCC (73%). If weak staining was also included as positive, 26/30 (87%) were positive. PAX-2 stained RCC TMA with a lower percentage at 56%, including weaker staining intensity. Both PAX-2 and gamma-H2AX demonstrated patchy staining of normal renal tubules, PAX-2 to a greater extent. Both PAX-2 and gamma-H2AX are sensitive markers for the diagnosis of metastatic RCC, with improved ease of interpretation when compared with RCC-Ma. A combination of all 3 markers identified 87% of cases, and failure to stain for both PAX-2 and gamma-H2AX suggests against, but does not disprove, a diagnosis of RCC.

The differential diagnosis of metastatic renal cell carcinoma (RCC) includes, although is not limited to, hepatocellular carcinoma (HCC) and adrenocortical carcinoma (ACC) due to overlapping morphology. Immunohistochemical markers, including RCC marker (RCC-Ma) have been employed with varying success in the differential diagnosis of RCC. Our preliminary tissue microarray study demonstrated that gamma-H2AX, an antibody that specifically reacts with phosphorylated histone H2AX, stained many primary RCC strongly and did not stain HCC or ACC, prompting us to evaluate its utility in these tumors and to compare it with RCC-Ma. Seventy-one cases of metastatic RCC, 18 HCC, and 21 ACC were stained with gamma-H2AX and RCC-Ma and the sensitivity and specificity of each marker was compared. RCC-Ma demonstrated a membranous pattern of staining in 70% of RCC cases (50/71), and none of the ACC or HCC (100% specificity for RCC). Nuclear staining by gamma-H2AX had a similar sensitivity of 70% for RCC but a lower specificity of 77%, as it was seen in 1 of 18 HCC (5%) and 8 of 21 (38%)ACC. In metastatic RCC, 83% (39/47) of tumors with a higher nuclear grade stained with gamma-H2AX, compared with 46% (11/24) of low nuclear grade (equivalent of Fuhrman 2 and lower) tumors. RCC-Ma had a similar rate of staining in low and high-grade tumors, 75% (18/24) and 68% (32/47), respectively. More importantly, of RCCs that were negative for RCC-Ma, 14 of 21 (67%) were positive for gamma-H2AX. The results suggest gamma-H2AX is a useful adjunct in diagnosis of metastatic RCC when RCC-Ma is negative and in higher grade RCC, which are often a diagnostic challenge. A nuclear pattern of staining of gamma-H2AX has a comparable sensitivity with RCC-Ma, and the interpretation is easier and more reliable. RCC-Ma is 100% specific for RCC, but only when a membranous pattern of staining is interpreted as positive.

MUM1 is a member of the interferon regulatory factor family of transcription factors. It is normally expressed in plasma cells, late B cells, and activated T cells, and has been described in several B-cell malignancies. Although its expression has been reported in some T-cell neoplasms, the full range and character of expression have not been explored. We studied 58 cases of T-cell lymphoproliferative lesions, including systemic and cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis (LyP), mycosis fungoides (MF), MF with large cell transformation, and Sézary syndrome (SS). Nearly all cutaneous (5/5) and systemic anaplastic large cell lymphomas (4/5) were positive for MUM1, mainly in the large cell population. Similarly, 12 of 16 types A and C LyP showed MUM1 reactivity in greater than 50% of the large cells. Focal MUM1 staining was seen in 3 type B LyP, mostly in reactive lymphoid cells. All 9 MF with large cell transformation expressed MUM1 in large cells, where it paralleled CD30 expression. In comparison, most MF (11/12) were MUM1 negative. Interestingly, all SS cases (8/8) were MUM1 positive, 3 of which demonstrated diffuse staining. There was a significant difference in MUM1 expression between MF and SS groups as well as between MF and large cell transformation of MF groups (P < .001 for both). In summary, MUM1 is not helpful in separating different types of CD30-positive lymphoproliferative disorders. Potentially, MUM1 could serve as an adjunct marker for SS and/or large cell transformation of MF.

A 31-year-old woman was incidentally found to have a large right adrenal mass by computed tomography imaging and underwent a workup that included endocrinological evaluation and positron emission tomography imaging. Laboratory results revealed the mass to be non-functioning. Imaging studies revealed a 9-cm heterogeneous mass that was not FDG avid. Because of concern for adrenal cortical carcinoma, the patient underwent a successful right adrenalectomy. Pathology examination demonstrated an 11-cm circumscribed mass consisting of uniform spindle cells without nuclear pleomorphism, necrosis, or mitotic activity. The diagnosis of leiomyoma was supported by a panel of immunohistochemical stains. Adrenal leiomyomas have been reported in the literature, although most are small and not preoperatively suspicious for malignancy. This case illustrates that benign tumors such as leiomyomas, when large and heterogeneous on imaging, can clinically mimic adrenal cortical carcinomas and should be included in the differential diagnosis of adrenal incidentalomas.

Recurrent gene fusions between the androgen-regulated gene TMPRSS2 and the ETS family transcription factors ERG, ETV1, and ETV4 have been identified in the majority of prostate adenocarcinomas (PCA). PCA is often multifocal with histologic heterogeneity of different tumor foci. As TMPRSS2 is a common 5' partner of ETS gene fusions, we monitored TMPRSS2 rearrangement by fluorescence in situ hybridization (FISH) to study the origin and molecular basis of multifocal PCA heterogeneity. TMPRSS2 rearrangement was evaluated by FISH on a tissue microarray representing 93 multifocal PCAs from 43 radical prostatectomy resections. Overall, 70% (30 of 43) of the cases showed TMPRSS2 rearrangement, including 63% through deletion (loss of the 3' TMPRSS2 signal), 27% through translocation (split of 5' and 3' TMPRSS2 signals), and 10% through both mechanisms in different tumor foci. Of the 30 TMPRSS2 rearranged cases, 30% showed concordance in all tumor foci, whereas 70% were discordant in at least one focus. In TMPRSS2 rearranged cases, the largest (index) tumor was rearranged 83% of the time. Pathologic stage, size, or Gleason grade of the multifocal PCA did not correlate with overall TMPRSS2 rearrangement. Our results suggest that multifocal PCA is a heterogeneous group of diseases arising from multiple, independent clonal expansions. Understanding this molecular heterogeneity is critical to the future development and utility of diagnostic and prognostic PCA biomarkers.

Objectives: The histologic classification of bladder tumors remains an important predictor of treatment response and patient outcome, with pure nonurothelial tumors associated with poorer outcome compared with pure urothelial carcinoma (UC). Little, however, is known about the significance of UC with divergent (mixed) histologic features at transurethral resection of bladder tumor (TURBT). This study examined the incidence, pathologic spectrum, and clinical significance of this phenomenon., Methods: The histologic patterns of 448 consecutive TURBT and 295 subsequent cystectomy specimens from this subgroup were analyzed. The type of divergent tumor differentiation observed in the mixed histologic type cases was categorized and quantified. Pure non-UC cases were excluded. Various clinicopathologic parameters were compared between the mixed histologic type and pure UC cohorts., Results: UC with mixed histologic features was identified in 25% of all TURBT specimens and was uniformly (100%) high grade and invasive (99%). The most common mixed histologic components were squamous (40%) and glandular (18%). Eleven percent of cases had multiple mixed histologic types. Compared with the pure high-grade UC, UCs with mixed histologic features were associated with muscle invasion at TURBT (chi-square test, P <0.001) and with extravesical disease at cystectomy (chi-square test, P = 0.0001). The presence of mixed histologic features at TURBT was an independent predictor of extravesical disease in a multivariate logistic model (P = 0.007). However, it was not significant for disease-specific survival in the univariate (P = 0.17) or multivariate (P = 0.68) models., Conclusions: The results of our study have shown that the presence of mixed histologic features at TURBT indicates locally aggressive disease. Patients with mixed histologic features might benefit from an aggressive multimodality treatment strategy.