Pathological characterization and clinical outcome of penile intraepithelial neoplasia variants: a North American series.

Penile intraepithelial neoplasia (PeIN) is classified as human papillomavirus (HPV)- and non-HPV-related. This classification is associated with distinct morphologic subtypes. The natural history and prognosis of PeIN subtypes are not well known. This study aims to evaluate clinicopathological features, HPV status, and outcome of PeIN subtypes. Eighty-two lesions from 64 patients with isolated PeIN were retrospectively reviewed. Mean age was 59 years. Lesions were multicentric in 34% of patients and affected glans (33%), shaft (26%), and foreskin (20%). Histologically, 22% of patients had coexisting lesions, classified as hybrid and mixed. HPV-related PeIN (97%) included basaloid (59%), warty (8%), warty-basaloid (8%), hybrid (19%) and mixed (3%) types. P16 and HPV positivity occurred in 99% and 82% of lesions, respectively. HPV 16 was more common in basaloid PeIN. Multiple genotypes were detected in 35%, more commonly in hybrid PeIN (P = 0.051). Positive margins occurred in 63% of excisions. PeIN recurred in 48% of excisions and 30% of overall repeated procedures, and progression to invasive carcinoma occurred in 2%. At follow-up, 86% of patients had no evidence of disease and 12% were alive with disease. Lichen sclerosus occurred in non-HPV and HPV-related PeIN (100% and 47%).In conclusion, HPV-related and, more specifically basaloid PeIN were the predominant types and preferentially associated with HPV 16. While PeIN had a high recurrence rate, there was a slow and infrequent progression to invasive or metastatic carcinoma with multimodal treatments. Additional studies are needed to understand biology and natural history of PeIN.

MAGI2 is an independent predictor of biochemical recurrence in prostate cancer.

BACKGROUND: Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 2 (MAGI2) promotes the activity of phosphatase and tensin homolog (PTEN). Recent studies suggest that dysregulation of this signaling pathway has a role in prostate carcinogenesis. Our study aims to determine the prognostic significance of MAGI2 expression in prostate cancer. METHODS: Tissue microarrays from 51 radical prostatectomy cases including benign prostatic tissue, high grade prostatic intraepithelial neoplasia (HGPIN), and adenocarcinoma were constructed. Immunohistochemistry with double staining for MAGI2 and p63 was performed and analyzed by image analysis as percent of analyzed area (%AREA). Multivariable logistic regression was used to correlate MAGI2 expression with clinical outcomes. Generalized Estimating Equations (GEE) with linear and logistic regression was used to correlate MAGI2 with intrapatient histology. RESULTS: MAGI2 %AREA was inversely associated with progression from HGPIN to adenocarcinoma of low to high Gleason score (OR, 0.980; slope, -0.02; P = 0.005) and HGPIN to cancer of any Gleason score (OR, 0.969; P = 0.007). After adjusting for grade, stage, and margin status, MAGI2 %AREA was a significant independent predictor of biochemical recurrence (BCR) (OR, 0.936; 95%CI, 0.880-0.996; P = 0.037; bootstrap P = 0.017). The addition of MAGI2 %AREA to these standard clinical parameters improved accuracy of predicting BCR by 2.9% (91.0% vs 88.1%). CONCLUSIONS: These results reveal that MAGI2 expression is reduced during prostate cancer progression and that retention of MAGI2 signal reduces odds of BCR. The study results further suggest a possible role of MAGI2 in prostate neoplasia. Decreased MAGI2 expression may help predict prostate cancer aggressiveness and provide new insight for treatment decisions and post-operative surveillance intervals.

Core Needle Biopsy and Fine Needle Aspiration Alone or in Combination: Diagnostic Accuracy and Impact on Management of Renal Masses.

PURPOSE: Fine needle aspiration with and without concurrent core needle biopsy is a minimally invasive method to diagnose and assist in management of renal masses. We assessed the pathological accuracy of fine needle aspiration compared to and associated with core needle biopsy and the impact on management. MATERIALS AND METHODS: We performed a single institution, retrospective study of 342 cases from 2001 to 2015 with small and large renal masses (4 or less and greater than 4 cm, respectively). Diagnostic and concordance rates, and the impact on management were analyzed. RESULTS: Adequacy rates for fine needle aspiration only, core needle biopsy only and fine needle aspiration plus core needle biopsy were 21%, 12% and 8% (aspiration vs aspiration plus biopsy p <0.026). In the aspiration plus biopsy group adding aspiration to biopsy and biopsy to aspiration reduced the inadequacy rate from 23% to 8% and from 27% to 8% for a total reduction rate of 15% and 19%, respectively, corresponding to 32 cases (9.3%). Rapid on-site examination contributed to a 22.5% improvement in fine needle aspiration adequacy rates. In this cohort 30% of aspiration only, 5% of biopsy only and 12% of aspiration plus biopsy could not be subtyped (aspiration vs biopsy p <0.0001, aspiration vs aspiration plus biopsy p <0.0127 and biopsy vs aspiration plus biopsy p = 0.06). The diagnostic concordance rate with surgical resection was 99%. Conversion of an inadequate specimen to an adequate one by a concurrent procedure impacted treatment in at least 29 of 32 patients. Limitations include the retrospective design and accuracy measurement based on surgical intervention. CONCLUSIONS: Fine needle aspiration plus core needle biopsy vs at least fine needle aspiration alone may improve diagnostic yield when sampling renal masses but it has subtyping potential similar to that of core needle biopsy only.

New and Emerging Diagnostic and Prognostic Immunohistochemical Biomarkers in Prostate Pathology.

The diagnosis of minimal prostatic adenocarcinoma can be challenging on prostate needle biopsy, and immunohistochemistry may be used to support the diagnosis of cancer. The International Society of Urologic Pathology currently recommends the use of the basal cell markers high-molecular-weight cytokeraratin and p63, and α-methylacyl-coenzyme-A racemase. However, there are caveats associated with the interpretation of these markers, particularly with benign mimickers. Another issue is that of early detection of presence and progression of disease and prediction of recurrence after clinical intervention. There remains a lack of reliable biomarkers to accurately predict low-risk cancer and avoid over treatment. As such, aggressive forms of prostate cancer may be missed and indolent disease may be subjected to unnecessary radical therapy. New biomarker discovery promises to improve early detection and prognosis and to provide targets for therapeutic interventions. In this review, we present the emerging immunohistochemical biomarkers of prostate cancer PTEN, ERG, FASN, MAGI-2, and SPINK1, and address their diagnostic and prognostic advantages and limitations.

Loss of FOXA1 Drives Sexually Dimorphic Changes in Urothelial Differentiation and Is an Independent Predictor of Poor Prognosis in Bladder Cancer.

We previously found loss of forkhead box A1 (FOXA1) expression to be associated with aggressive urothelial carcinoma of the bladder, as well as increased tumor proliferation and invasion. These initial findings were substantiated by The Cancer Genome Atlas, which identified FOXA1 mutations in a subset of bladder cancers. However, the prognostic significance of FOXA1 inactivation and the effect of FOXA1 loss on urothelial differentiation remain unknown. Application of a univariate analysis (log-rank) and a multivariate Cox proportional hazards regression model revealed that loss of FOXA1 expression is an independent predictor of decreased overall survival. An ubiquitin Cre-driven system ablating Foxa1 expression in urothelium of adult mice resulted in sex-specific histologic alterations, with male mice developing urothelial hyperplasia and female mice developing keratinizing squamous metaplasia. Microarray analysis confirmed these findings and revealed a significant increase in cytokeratin 14 expression in the urothelium of the female Foxa1 knockout mouse and an increase in the expression of a number of genes normally associated with keratinocyte differentiation. IHC confirmed increased cytokeratin 14 expression in female bladders and additionally revealed enrichment of cytokeratin 14-positive basal cells in the hyperplastic urothelial mucosa in male Foxa1 knockout mice. Analysis of human tumor specimens confirmed a significant relationship between loss of FOXA1 and increased cytokeratin 14 expression.

Lack of P16ink4a over expression in penile squamous cell carcinoma is associated with recurrence after lymph node dissection.

PURPOSE: There have been conflicting data in studies on the prognostic role of high risk human papillomavirus in penile squamous cell carcinoma. Using P16(ink4a) over expression as a surrogate marker for high risk human papillomavirus, we evaluated high risk human papillomavirus status with respect to various clinical features, including recurrence and overall survival, among others. MATERIALS AND METHODS: P16(ink4a) over expression was evaluated by immunohistochemistry for 119 consecutive patients with penile squamous cell carcinoma. Several variables were recorded including age, stage, histological grade, lymph node status, lymphovascular invasion, metastasis and recurrence. Median followup was 30 months. RESULTS: P16(ink4a) over expression was detected in 49.5% (59 of 119) of samples. There was no significant difference between P16(ink4a) negative and P16(ink4a) positive tumors in terms of stage (p = 0.518), histological grade (p = 0.225), lymphovascular invasion (p = 0.388), overall survival (p = 0.156) or lymph node metastasis (p = 0.748). P16(ink4a) negative tumors were more likely to recur overall (p = 0.04), especially if patients had positive lymph nodes at diagnosis (p = 0.002). CONCLUSIONS: These data suggest that P16(ink4a)/high risk human papillomavirus status is associated with recurrence, especially in patients with positive lymph nodes at diagnosis. Thus, patients with P16(ink4a) negative penile cancer, particularly those with lymph node metastases, may warrant closer observation after surgery.

Plasma Epstein-Barr virus DNA predicts outcome in advanced Hodgkin lymphoma: correlative analysis from a large North American cooperative group trial.

Epstein-Barr virus (EBV) is associated with Hodgkin lymphoma (HL) and can be detected by in situ hybridization (ISH) of viral nucleic acid (EBER) in tumor cells. We sought to determine whether plasma EBV-DNA could serve as a surrogate for EBER-ISH and to explore its prognostic utility in HL. Specimens from the Cancer Cooperative Intergroup Trial E2496 were used to compare pretreatment plasma EBV-DNA quantification with EBV tumor status by EBER-ISH. A cutoff of >60 viral copies/100 µL plasma yielded 96% concordance with EBER-ISH. Pretreatment and month 6 plasma specimens were designated EBV(-) or EBV(+) by this cutoff. Patients with pretreatment EBV(+) plasma (n = 54) had inferior failure-free survival (FFS) compared with those with pretreatment EBV(-) plasma (n = 274), log-rank P = .009. By contrast, no difference in FFS was observed when patients were stratified by EBER-ISH. Pretreatment plasma EBV positivity was an independent predictor of treatment failure on multivariate analyses. At month 6, plasma EBV(+) patients (n = 7) had inferior FFS compared with plasma EBV(-) patients (n = 125), log-rank P = .007. These results confirm that plasma EBV-DNA is highly concordant with EBER-ISH in HL and suggest that it may have prognostic utility both at baseline and after therapy. This trial was registered at www.clinicaltrials.gov as #NCT00003389.

Clonal immunoglobulin DNA in the plasma of patients with AIDS lymphoma.

Immunoglobulin (Ig) gene rearrangements are used to define clonality of suspected B-lineage malignancy in tissue samples. To determine whether such rearrangements could be identified in plasma, we screened plasma from 14 consecutive patients with AIDS-related lymphoma with multiplex Ig primers. Clonally rearranged Ig DNA was detected in plasma from 7 of 14 patients. Patients in whom clonal Ig DNA remained detectable after combination chemotherapy died with lymphoma. Tumor was available from 1 patient, and the IgH amplification products from plasma and tumor were sequenced and confirmed to be identical. Ig DNA rearrangements in plasma may be useful as a lymphoma-specific tumor marker, and failure to clear clonal Ig DNA may identify patients at high risk for failure of standard therapy.

Phase II study of everolimus in metastatic urothelial cancer.

UNLABELLED: What's known on the subject? and what does the study add?: No recent advances have been made in the treatment of patients with advanced bladder cancer and, to date, targeted therapies have not resulted in an improvement in outcome. The mammalian target of rapamycin pathway has been shown to be up-regulated in bladder cancer and represents a rational target for therapeutic intervention. In the present phase II study of everolimus, one near-complete response, one partial response and several minor responses suggest that everolimus possesses biological activity in a subset of patients with bladder cancer. To maximize benefit from targeted agents such as everolimus, the preselection of patients based on molecular phenotype is required. OBJECTIVE: To assess the efficacy and tolerability of everolimus in advanced urothelial carcimoma (UC). PATIENTS AND METHODS: The present study comprised a single-arm, non-randomized study in which all patients received everolimus 10 mg orally once daily continuously (one cycle = 4 weeks). In total, 45 patients with metastatic UC progressing after one to four cytotoxic agents were enrolled between February 2009 and November 2010 at the Memorial Sloan-Kettering Cancer Center. The primary endpoints were 2-month progression-free survival (PFS) and the safety of everolimus, with the secondary endpoint being the response rate. A Simon minimax two-stage design tested the null hypothesis that the true two month PFS rate was ≤ 50%, as opposed to the alternative hypothesis of ≥ 70%. RESULTS: The most common grade 3/4 toxicities were fatigue, infection, anaemia, lymphopaenia, hyperglycaemia and hypophosphataemia. There were two partial responses in nodal metastases, with one patient achieving a 94% decrease in target lesions and remaining on drug at 26 months. An additional 12 patients exhibited minor tumour regression. There were 23 of 45 (51%) patients who were progression-free at 2 months with a median (95% CI) PFS of 2.6 (1.8-3.5) months and a median (95% CI) overall survival of 8.3 (5.5-12.1) months. No clear association was observed between mammalian target of rapamycin pathway marker expression and 2-month PFS. CONCLUSIONS: Although everolimus did not meet its primary endpoint, one partial response, one near-complete response and twelve minor regressions were observed. Everolimus possesses meaningful anti-tumour activity in a subset of patients with advanced UC. Studies aiming to define the genetic basis of everolimus activity in individual responders are ongoing.

Targeted Mutational Analysis of Cortisol-Producing Adenomas.

CONTEXT: Somatic gene mutations have been identified in only about half of cortisol-producing adenomas (CPAs). Affected genes include PRKACA, GNAS, PRKAR1A, and CTNNB1. OBJECTIVE: This work aims to expand our understanding of the prevalence of somatic mutations in CPAs from patients with overt Cushing syndrome (OCS) and "subclinical" mild autonomous cortisol excess (MACE), with an immunohistochemistry (IHC)‒guided targeted amplicon sequencing approach using formalin-fixed paraffin-embedded (FFPE) tissue. METHODS: We analyzed FFPE adrenal tissue from 77 patients (n = 12 men, 65 women) with either OCS (n = 32) or MACE (n = 45). Using IHC for 17α-hydroxylase/17,20-lyase (CYP17A1) and 3ß-hydroxysteroid dehydrogenase (HSD3B2), we identified 78 CPAs (32 OCS CPAs and 46 MACE CPAs). Genomic DNA was isolated from the FFPE CPAs and subjected to targeted amplicon sequencing for identification of somatic mutations. RESULTS: Somatic mutations were identified in 71.8% (56/78) of the CPAs. While PRKACA was the most frequently mutated gene in OCS CPAs (14/32, 43.8%), somatic genetic aberrations in CTNNB1 occurred in 56.5% (26/46) of the MACE CPAs. Most GNAS mutations were observed in MACE CPAs (5/7, 71.4%). No mutations were observed in PRKAR1A. In addition to the known mutations, we identified one previously unreported mutation in PRKACA. Two patients with MACE harbored 2 adjacent tumors within the same adrenal gland - one patient had 2 CPAs, and the other patient had a CPA and an aldosterone-producing adenoma (identified by IHC for aldosterone synthase). CONCLUSION: A comprehensive FFPE IHC-guided gene-targeted sequencing approach identified somatic mutations in 71.8% of the CPAs. OCS CPAs demonstrated a distinct mutation profile compared to MACE CPAs.

FOXA1 repression drives lineage plasticity and immune heterogeneity in bladder cancers with squamous differentiation.

Cancers arising from the bladder urothelium often exhibit lineage plasticity with regions of urothelial carcinoma adjacent to or admixed with regions of divergent histomorphology, most commonly squamous differentiation. To define the biologic basis for and clinical significance of this morphologic heterogeneity, here we perform integrated genomic analyses of mixed histology bladder cancers with separable regions of urothelial and squamous differentiation. We find that squamous differentiation is a marker of intratumoral genomic and immunologic heterogeneity in patients with bladder cancer and a biomarker of intrinsic immunotherapy resistance. Phylogenetic analysis confirms that in all cases the urothelial and squamous regions are derived from a common shared precursor. Despite the presence of marked genomic heterogeneity between co-existent urothelial and squamous differentiated regions, no recurrent genomic alteration exclusive to the urothelial or squamous morphologies is identified. Rather, lineage plasticity in bladder cancers with squamous differentiation is associated with loss of expression of FOXA1, GATA3, and PPARG, transcription factors critical for maintenance of urothelial cell identity. Of clinical significance, lineage plasticity and PD-L1 expression is coordinately dysregulated via FOXA1, with patients exhibiting morphologic heterogeneity pre-treatment significantly less likely to respond to immune checkpoint inhibitors.

Circulating clonotypic B cells in classic Hodgkin lymphoma.

Although Hodgkin and Reed-Sternberg (HRS) cells are B lymphoid cells, they are unlike any normal cells of that lineage. Moreover, the limited proliferative potential of HRS cells belies the clinical aggressiveness of Hodgkin lymphoma (HL). More than 20 years ago, the L428 HL cell line was reported to contain a small population of phenotypic B cells that appeared responsible for the continued generation of HRS cells. This observation, however, has never been corroborated, and such clonotypic B cells have never been documented in HL patients. We found that both the L428 and KM-H2 HL cell lines contained rare B-cell subpopulations responsible for the generation and maintenance of the predominant HRS cell population. The B cells within the HL cell lines expressed immunoglobulin light chain, the memory B-cell antigen CD27, and the stem cell marker aldehyde dehydrogenase (ALDH). Clonal CD27(+)ALDH(high) B cells, sharing immunoglobulin gene rearrangements with lymph node HRS cells, were also detected in the blood of most newly diagnosed HL patients regardless of stage. Although the clinical significance of circulating clonotypic B cells in HL remains unclear, these data suggest they may be the initiating cells for HL.

Androgen receptor coactivator p44/Mep50 in breast cancer growth and invasion.

Hormones and their receptors play an important role in the development and progression of breast carcinoma. Although the primary focus has been on oestrogen and oestrogen receptor (ER), androgen, androgen receptor (AR) and its coactivator(s) have been implicated in tumorigenesis of breast carcinoma and warrant further investigation. AR coactivator p44/Mep50 is identified as a subunit of methylosome complex and lately characterized as an AR coactivator that enhances AR mediated transcription activity in a ligand dependent manner. In prostate cancer, p44 is expressed in the nucleus of benign epithelia and translocated into the cytoplasm in cancer cells. Furthermore, nuclear expression of p44 inhibits prostate cancer growth. In this report, we examined the expression and function of p44 in breast cancer. In addition to being an AR coactivator, p44 also functions as an ER coactivator. In contrast to findings in prostate cancer, the expression of p44 shows strong cytoplasmic expression in morphologically normal terminal ductal lobular units, while nuclear p44 is observed in both ductal carcinoma in situ and invasive carcinoma. Further, overexpression of nuclear-localized p44 stimulates proliferation and invasion in MCF7 breast cancer cells in the presence of oestrogen and the process is ERα dependent. These findings strongly suggest that p44 plays a role in mediating the effects of hormones during tumorigenesis in breast.

HMGA2: a biomarker significantly overexpressed in high-grade ovarian serous carcinoma.

Ovarian carcinoma consists of a group of histologically heterogeneous diseases involving distinct tumorigenic pathways. High-grade papillary serous carcinoma of the ovary is commonly associated with p53 mutations. HMGA2, an oncofetal protein, is found to be overexpressed in ovarian cancer. To study the function of HMGA2 in ovarian cancer, it is important to know which subtypes of ovarian cancer are associated with HMGA2 overexpression. In this study, we collected six different types of ovarian cancer and examined HMGA2 expression by immunohistochemistry, along with HMGA1, p53 and Ki-67. We found that HMGA2 overexpression was significantly higher in high-grade papillary serous carcinoma (64%) and carcinosarcoma (60%) than in other types of ovarian cancers (7-23%). HMGA2 overexpression was moderately associated with dominant p53 mutations (R=0.51). In addition, the microRNA in situ analysis revealed that let-7b, the HMGA2-negative regulators, were significantly lost in high-grade serous carcinoma. Our findings suggest that HMGA2 is an important molecular change significantly related to high-grade papillary serous carcinoma and is less common in other histological types of ovarian cancer.

Development of multiple adrenal myelolipomas after trauma-induced adrenal haemorrhage.

Adrenal myelolipomas represent a benign neoplasm with known associations with many chronic diseases, 21-hydroxylase deficiency and cancer. However, the aetiology of adrenal myelolipomas remains unknown. Here, we present a case of a patient with image-proven bilateral adrenal haemorrhages caused by trauma with the subsequent development of bilateral adrenal myelolipomas several years later. Resection and pathological analysis of left adrenal gland confirmed the presence of multiple adrenal myelolipomas. Our case strongly suggests that trauma was the inciting event that led to the formation of these lesions.

Genetic Characteristics of Aldosterone-Producing Adenomas in Blacks.

Somatic mutations have been identified in aldosterone-producing adenomas (APAs) in genes that include KCNJ5, ATP1A1, ATP2B3, and CACNA1D. Based on independent studies, there appears to be racial differences in the prevalence of somatic KCNJ5 mutations, particularly between East Asians and Europeans. Despite the high cardiovascular disease mortality of blacks, there have been no studies focusing on somatic mutations in APAs in this population. In the present study, we investigated genetic characteristics of APAs in blacks using a CYP11B2 (aldosterone synthase) immunohistochemistry-guided next-generation sequencing approach. The adrenal glands with adrenocortical adenomas from 79 black patients with primary aldosteronism were studied. Seventy-three tumors from 69 adrenal glands were confirmed to be APAs by CYP11B2 immunohistochemistry. Sixty-five of 73 APAs (89%) had somatic mutations in aldosterone-driver genes. Somatic CACNA1D mutations were the most prevalent genetic alteration (42%), followed by KCNJ5 (34%), ATP1A1 (8%), and ATP2B3 mutations (4%). CACNA1D mutations were more often observed in APAs from males than those from females (55% versus 29%, P=0.033), whereas KCNJ5 mutations were more prevalent in APAs from females compared with those from males (57% versus 13%, P<0.001). No somatic mutations in aldosterone-driver genes were identified in tumors without CYP11B2 expression. In conclusion, 89% of APAs in blacks harbor aldosterone-driving mutations, and unlike Europeans and East Asians, the most frequently mutated aldosterone-driver gene was CACNA1D. Determination of racial differences in the prevalence of aldosterone-driver gene mutations may facilitate the development of personalized medicines for patients with primary aldosteronism.

Case of reversible diabetes mellitus in the setting of benign Pheochromocytoma.

Pheochromocytomas have been shown to impair glucose tolerance and, rarely, to precipitate overt diabetes mellitus. We report here a case of a large pheochromocytoma in a woman with a recent diagnosis of diabetes mellitus that proved difficult to control despite high-dose insulin therapy who had complete resolution of her hyperglycemia following adrenalectomy. Her dramatic presentation demonstrates the need to consider this etiology in patients with new-onset insulin resistance and hypertension.

TPX2 as a prognostic indicator and potential therapeutic target in clear cell renal cell carcinoma.

OBJECTIVES: Our aims were to determine if targeting protein for Xklp2 (TPX2) is correlated with clear cell renal cell carcinoma (ccRCC) histology and oncologic outcomes using The Cancer Genome Atlas (TCGA) and an institutional tissue microarray (TMA). METHODS: Clinicopathological data obtained from the TCGA consisted of 415 samples diagnosed with ccRCC. A TMA was constructed from tumors of 207 patients who underwent radical nephrectomy for ccRCC. TPX2 expression by immunohistochemistry on TMA was assessed by a genitourinary pathologist. Clinical data were extracted and linked to TMA cores. TPX2 and Aurora-A mRNA coexpression were evaluated in the TCGA cohort. Overall survival (OS), cancer-specific survival, and recurrence-free survival (RFS) were analyzed using the Kaplan-Meier method and log-rank statistics. Univariate and multivariate analyses were conducted using Cox proportional hazard models. RESULTS: Median follow-up time for the TCGA cohort was 3.07 years. Aurora-A and TPX2 mRNA coexpression were significantly correlated (Pearson correlation = 0.918). High TPX2 mRNA expression was associated with advanced stage, metastasis, poor OS, and RFS. Median follow-up time for the TMA cohort was 5.3 years. Elevated TPX2 protein expression, defined as greater than 75th percentile staining intensity, was identified in 47/207 (22.7%) patients. Increased TPX2 immunostaining was associated with poor OS (P = 0.0327, 53% 5-year mortality), cancer-specific survival (P<0.01, 47.8% 5-year cancer-specific mortality), RFS (P = 0.0313, 73.6%, 5-year recurrence rate), grade, T stage, and metastasis. Multivariate analysis demonstrated elevated expression served as an independent predictor of RFS (hazard ratio = 3.62 (1.13-11.55), P = 0.029). CONCLUSIONS: We show TPX2, a regulator of Aurora-A, is associated with high grade and stage of ccRCC, and is an independent predictor of recurrence. Future studies are warranted testing its role in ccRCC biology, and its potential as a therapeutic target.

Primary Carcinoid Tumor of the Renal Pelvis Arising From Intestinal Metaplasia: An Unusual Histogenetic Pathway?

OBJECTIVES: Primary carcinoid tumor of the renal pelvis is a rare neoplasm with few cases reported in the literature. Here we present the clinical and histopathologic findings of a primary carcinoid tumor arising in the left renal pelvis of a horseshoe kidney in a 61-year-old female patient. MATERIALS AND METHODS: Pathologic features were evaluated with standard hematoxylin and eosin sections and immunohistochemical studies. A literature review was performed to place our case in context to previous reports. RESULTS: The tumor was associated with intestinal metaplasia with high-grade dysplasia and neuroendocrine hyperplasia. Molecular testing for microsatellite instability and loss of heterozygosity were negative. CONCLUSIONS: This report portrays a unique presentation of carcinoid tumor arising from intestinal metaplasia of the pelvic urothelium, and supports its histogenesis from urothelial intestinal metaplasia and neuroendocrine hyperplasia.