[Show abstract][Hide abstract] ABSTRACT: A unique renal neoplasm characterized by eosinophilic cytoplasm and solid and cystic growth was recently reported in patients with tuberous sclerosis complex (TSC). We searched multiple institutional archives and consult files in an attempt to identify a sporadic counterpart. We identified 16 morphologically identical cases, all in women, without clinical features of TSC. The median age was 57 years (range, 31 to 75 y). Macroscopically, tumors were tan and had a solid and macrocystic (12) or only solid appearance (4). Average tumor size was 50 mm (median, 38.5 mm; range, 15 to 135 mm). Microscopically, the tumors showed solid areas admixed with variably sized macrocysts and microcysts that were lined by cells with a pronounced hobnail arrangement. The cells had voluminous eosinophilic cytoplasm with prominent granular cytoplasmic stippling and round to oval nuclei with prominent nucleoli. Scattered histiocytes and lymphocytes were invariably present. Thirteen of 16 patients were stage pT1; 2 were pT2, and 1 was pT3a. The cells demonstrated a distinct immunoprofile: nuclear PAX8 expression, predominant CK20-positive/CK7-negative phenotype, patchy AMACR staining, but no CD117 reactivity. Thirteen of 14 patients with follow-up were alive and without disease progression after 2 to 138 months (mean: 53 mo; median: 37.5 mo); 1 patient died of other causes. Although similar to a subset of renal cell carcinomas (RCCs) seen in TSC, we propose that sporadic "eosinophilic, solid, and cystic RCC," which occurs predominantly in female individuals and is characterized by distinct morphologic features, predominant CK20-positive/CK7-negative immunophenotype, and indolent behavior, represents a novel subtype of RCC.
The American journal of surgical pathology 09/2015; DOI:10.1097/PAS.0000000000000508 · 5.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We describe a young male patient with longstanding hypertension, who was diagnosed with primary hyperaldosteronism and treated by an attempted retroperitoneoscopic total unilateral adrenalectomy for a left-sided presumed aldosterone-secreting adenoma. Imaging had shown an unremarkable focal adrenal lesion with normal contralateral adrenal morphology, and histology of the resected specimen showed no adverse features. Post-operatively, his blood pressure and serum aldosterone levels fell to the normal range, but 9 months later, his hypertension recurred, primary aldosteronism was again confirmed and he was referred to our centre. Repeat imaging demonstrated an irregular left-sided adrenal lesion with normal contralateral gland appearances. Adrenal venous sampling was performed, which supported unilateral (left-sided) aldosterone hypersecretion. Redo surgery via a laparoscopically assisted transperitoneal approach was performed and multiple nodules were noted extending into the retroperitoneum. It was thought unlikely that complete resection had been achieved. His blood pressure returned to normal post-operatively, although hypokalaemia persisted. Histological examination, from this second operation, showed features of an adrenocortical carcinoma (ACC; including increased mitoses and invasion of fat) that was assessed as malignant using the scoring systems of Weiss and Aubert. Biochemical hyperaldosteronism persisted post-operatively, and detailed urine steroid profiling showed no evidence of adrenal steroid precursors or other mineralocorticoid production. He received flank radiotherapy to the left adrenal bed and continues to receive adjunctive mitotane therapy for a diagnosis of a pure aldosterone-secreting ACC.
Pure aldosterone-secreting ACCs are exceptionally uncommon, but should be considered in the differential diagnosis of patients presenting with primary aldosteronism.Aldosterone-producing ACCs may not necessarily show typical radiological features consistent with malignancy.Patients who undergo surgical treatment for primary aldosteronism should have follow-up measurements of blood pressure to monitor for disease recurrence, even if post-operative normotension is thought to indicate a surgical 'cure'.Owing to the rarity of such conditions, a greater understanding of their natural history is likely to come from wider cooperation with, and contribution to, large multi-centre outcomes databases.
[Show abstract][Hide abstract] ABSTRACT: The natural history of prostate cancer is highly variable and difficult to predict accurately. Better markers are needed to guide management and avoid unnecessary treatment. In this study, we validate the prognostic value of a cell cycle progression score (CCP score) independently and in a prespecified linear combination with standard clinical variables, that is, a clinical-cell-cycle-risk (CCR) score.
Paraffin sections from 761 men with clinically localized prostate cancer diagnosed by needle biopsy and managed conservatively in the United Kingdom, mostly between 2000 and 2003. The primary end point was prostate cancer death. Clinical variables consisted of centrally reviewed Gleason score, baseline PSA level, age, clinical stage, and extent of disease; these were combined into a single predefined risk assessment (CAPRA) score. Full data were available for 585 men who formed a fully independent validation cohort.
In univariate analysis, the CCP score hazard ratio was 2.08 (95% CI (1.76, 2.46), P<10(-13)) for one unit change of the score. In multivariate analysis including CAPRA, the CCP score hazard ratio was 1.76 (95% CI (1.44, 2.14), P<10(-6)). The predefined CCR score was highly predictive, hazard ratio 2.17 (95% CI (1.83, 2.57), χ(2)=89.0, P<10(-20)) and captured virtually all available prognostic information.
The CCP score provides significant pretreatment prognostic information that cannot be provided by clinical variables and is useful for determining which patients can be safely managed conservatively, avoiding radical treatment.British Journal of Cancer advance online publication, 23 June 2015; doi:10.1038/bjc.2015.223 www.bjcancer.com.
British Journal of Cancer 06/2015; 113(3). DOI:10.1038/bjc.2015.223 · 4.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
The handling and reporting of testicular tumours is difficult due to their rarity.DesignA survey developed by the European Network of Uro-Pathology (ENUP) and sent to its members and experts to assess the evaluation of testicular germ cell tumoursResults25 experts (E) and 225 ENUP members replied. Areas of disagreement included immaturity in teratomas, reported by 32% (E) but 68% (ENUP). Although the presence of rete testis invasion was widely reported, the distinction between pagetoid and stromal invasion was made by 96% (E) but only 63% (ENUP). Immunohistochemistry was used in more than 50% of cases by 68% (ENUP) and 12% (E). Staging revealed the greatest areas of disagreement. Invasion of the tunica vaginalis without vascular invasion was interpreted as T1 by 52% (E) and 67% (ENUP), but T2 by the remainder. Tumour invading the hilar adipose tissue adjacent to the epididymis without vascular invasion was interpreted as T1: 40% (E), 43% (ENUP), T2: 36% (E), 30% (ENUP) and T3: 24% (E), 27% (ENUP).Conclusions
There is remarkable consensus in many areas of testicular pathology. Significant areas of disagreement included staging and reporting of histologic types, both of which have the potential to impact on therapy.This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: While androgen and androgen receptor (AR) activity have been strongly implicated in prostate cancer development and therapy, the influence of the CAG repeat, which is found within the first exon of the AR gene, on prostate carcinogenesis is still unclear. We investigated the differences in the length of the CAG repeat between prostate cancer patients and controls in the Chinese population as well as between TMPRSS2:ERG fusion positive and negative samples. A general association between prostate cancer and either longer or shorter AR CAG repeat length was not observed in the Chinese population. However, our data suggest that certain CAG repeat lengths may increase or decrease prostate cancer risk. Shorter CAG repeat length was also not shown to be associated with a higher induction rate of TMPRSS2 and ERG proximity, an essential step for TMPRSS2:ERG fusion formation. However, samples with a CAG repeat of 17 were found more frequently in the TMPRSS2:ERG fusion positive than negative prostate cancer cases and mediated a higher rate of androgen-induced TMPRSS2 and ERG co-localisation than AR with longer (24) and shorter (15) CAG repeats. This suggests that 17 CAG repeats may be associated with TMPRSS2:ERG fusion positive prostate cancer, but may have a preventive role for prostate cancer in the Chinese population, which has a low TMPRSS2:ERG fusion frequency. This study suggests that different mechanisms for the association of CAG repeat length polymorphism and prostate cancer exist in different ethnic populations.
American Journal of Cancer Research 12/2014; 4(6):886-96. · 4.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Active surveillance (AS) is an important management option for men with low-risk, clinically localized prostate cancer. The clinical parameters for patient selection and definition of progression for AS protocols are evolving as data from several large cohorts matures. Vital to this process is the critical role pathologic parameters play in identifying appropriate candidates for AS. These findings need to be reproducible and consistently reported by surgical pathologists. This report highlights the importance of accurate pathology reporting as a critical component of these protocols.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 10/2014; 465(6). DOI:10.1007/s00428-014-1668-5 · 2.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We investigated if methylation of candidate genes can be useful for predicting prostate cancer (PCa) specific death.
Methylation of PITX2, WNT5a, SPARC, EPB41L3 and TPM4 was investigated in a 1:2 case-control cohort comprising 45 men with cancer of Gleason score ≤7 who died (cases), and 90 men who were alive or died of other causes with survival time longer than the cases (controls). A univariate conditional logistic regression model was fitted by maximizing the likelihood of DNA methylation of each gene versus the primary end point.
A 10% increase in methylation of PITX2 was associated with PCa related death with OR 1.56 (95% CI: 1.17-2.08; p = 0.005).
Our study strengthens prior findings that PITX2 methylation is useful as a biomarker of poor outcome of PCa and in addition we also suggest that it may be particularly useful in men with low Gleason score.
Biomarkers in Medicine 10/2014; 8(9):1143-50. DOI:10.2217/bmm.14.41 · 2.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Prostate cancer has a variable clinical behaviour with frequently unpredictable outcome. DNA methylation plays an important role in determining the biology of cancer but prognostic information is scanty. We assessed the potential of gene-specific DNA methylation changes to predict death from prostate cancer in a cohort of untreated men in the UK.
This was a population-based study in which cases were identified from six cancer registries in Great Britain. DNA was extracted from formalin-fixed paraffin wax-embedded transurethral prostate resection tissues collected during 1990-96 from men with clinically-localised cancer who chose not to be treated for at least 6 months following diagnosis. The primary end point was death from prostate cancer. Outcomes were determined through medical records and cancer registry records. Pyrosequencing was used to quantify methylation in 13 candidate genes with established or suggested roles in cancer. Univariate and multivariate Cox models were used to identify possible predictors for prostate cancer-related death.
Of 367 men, 99 died from prostate cancer during a median of 9.5 years follow-up (max = 20). Univariately, 12 genes were significantly associated with prostate cancer mortality, hazard ratios ranged between 1.09 and 1.28 per decile increase in methylation. Stepwise Cox regression modelling suggested that the methylation of genes HSPB1, CCND2 and DPYS contributed objective prognostic information to Gleason score and PSA with respect to cancer-related death during follow-up (p = 0.006).
Methylation of 13 genes was analysed in 367 men with localised prostate cancer who were conservatively treated and stratified with respect to death from prostate cancer and those who survived or died of other causes. Of the 13 genes analysed, differential methylation of HSPB1, CCND2 and DPYS provided independent prognostic information. Assessment of gene-methylation may provide independent objective information that can be used to segregate prostate cancers at diagnosis into predicted behavioural groups.
BMC Cancer 09/2014; 14(1):655. DOI:10.1186/1471-2407-14-655 · 3.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Abstract Chromosomal rearrangements and fusion genes play important roles in tumor development and progression. Four high-frequency prostate cancer-specific fusion genes were recently reported in Chinese cases. We attempted to confirm one of the fusion genes, USP9Y-TTTY15, by reverse transcription PCR, but detected the presence of the USP9Y-TTTY15 fusion transcript in cancer samples, nonmalignant prostate tissues, and normal tissues from other organs, demonstrating that it is a transcription-induced chimeric RNA, which is commonly produced in normal tissues. In 105 prostate cancer samples and case-matched adjacent nonmalignant tissues, we determined the expression level of USP9Y-TTTY15 and a previously reported transcription-induced chimeric RNA, SLC45A3-ELK4. The expression levels of both chimeric RNAs vary greatly in cancer and normal cells. USP9Y-TTTY15 expression is neither higher in cancer than adjacent normal tissues, nor correlated with features of advanced prostate cancer. Although the expression level of SLC45A3-ELK4 is higher in cancer than normal cells, and a dramatic increase in its expression from normal to cancer cells is correlated with advanced disease, its expression level in cancer samples alone is not correlated with any clinical parameters. These data show that both chimeric RNAs contribute less to prostate carcinogenesis than previously reported.
Omics A Journal of Integrative Biology 09/2014; 18(10). DOI:10.1089/omi.2014.0042 · 2.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Members of the International Society of Urological Pathology (ISUP) participated in a half-day consensus conference to discuss guidelines and recommendations regarding best practice approaches to use of immunohistochemistry (IHC) in differential diagnostic situations in urologic pathology, including bladder, prostate, testis and, kidney lesions. Four working groups, selected by the ISUP leadership, identified several high-interest topics based on common or relevant challenging diagnostic situations and proposed best practice recommendations, which were discussed by the membership. The overall summary of the discussions and the consensus opinion forms the basis of a series of articles, one for each organ site. This Special Article summarizes the overall recommendations made by the four working groups. It is anticipated that this ISUP effort will be valuable to the entire practicing community in the appropriate use of IHC in diagnostic urologic pathology.
American Journal of Surgical Pathology 08/2014; 38(8):1017-1022. DOI:10.1097/PAS.0000000000000254 · 5.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The judicious use of immunostains can be of significant diagnostic assistance in the interpretation of testicular neoplasms when the light microscopic features are ambiguous. A limited differential diagnosis by traditional morphology is required for the effective use of immunohistochemistry (IHC); otherwise, the inevitable occurrence of exceptions to anticipated patterns will lead to "immunoconfusion." The diagnosis of tumors in the germ cell lineage, the great majority of primary tumors of the testis, has been considerably facilitated over the past decade by IHC directed at developmentally important nuclear transcription factors, including OCT4, SALL4, SOX2, and SOX17, that are mostly restricted to certain tumor histotypes. In conjunction with other markers, a specific diagnosis can be achieved in most instances through a panel of 3 or 4 immunostains and often fewer. IHC among tumors in the sex cord-stromal group may produce a significant proportion of false-negative cases until more sensitive and equally specific markers are validated. The negativity of these tumors for the IHC stains used for germ cell tumors is key in the important distinction of neoplasms in these 2 general categories. In this review, the International Society of Urological Pathologists (ISUP) provides diagnostic guidelines in the form of algorithms to assist practicing pathologists confronting a differential diagnostic question concerning a testicular neoplasm. The goal of ISUP is to anticipate commonly encountered differential diagnoses and recommend an efficient and limited pattern of IHC stains to resolve the question.
The American journal of surgical pathology 05/2014; 38(8). DOI:10.1097/PAS.0000000000000233 · 5.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: There is a lack of biomarkers to predict outcome with targeted therapy in metastatic clear cell renal cancer (mccRCC). This may be because dynamic molecular changes occur with therapy.
To explore if dynamic, targeted-therapy-driven molecular changes correlate with mccRCC outcome.
Multiple frozen samples from primary tumours were taken from sunitinib-naïve (n=22) and sunitinib-treated mccRCC patients (n=23) for protein analysis. A cohort (n=86) of paired, untreated and sunitinib/pazopanib-treated mccRCC samples was used for validation. Array comparative genomic hybridisation (CGH) analysis and RNA interference (RNAi) was used to support the findings.
Three cycles of sunitinib 50mg (4 wk on, 2 wk off).
Reverse phase protein arrays (training set) and immunofluorescence automated quantitative analysis (validation set) assessed protein expression.
Differential expression between sunitinib-naïve and treated samples was seen in 30 of 55 proteins (p<0.05 for each). The proteins B-cell CLL/lymphoma 2 (BCL2), mutL homolog 1 (MLH1), carbonic anhydrase 9 (CA9), and mechanistic target of rapamycin (mTOR) (serine/threonine kinase) had both increased intratumoural variance and significant differential expression with therapy. The validation cohort confirmed increased CA9 expression with therapy. Multivariate analysis showed high CA9 expression after treatment was associated with longer survival (hazard ratio: 0.48; 95% confidence interval, 0.26-0.87; p=0.02). Array CGH profiles revealed sunitinib was associated with significant CA9 region loss. RNAi CA9 silencing in two cell lines inhibited the antiproliferative effects of sunitinib. Shortcomings of the study include selection of a specific protein for analysis, and the specific time points at which the treated tissue was analysed.
CA9 levels increase with targeted therapy in mccRCC. Lower CA9 levels are associated with a poor prognosis and possible resistance, as indicated by the validation cohort.
Drug treatment of advanced kidney cancer alters molecular markers of treatment resistance. Measuring carbonic anhydrase 9 levels may be helpful in determining which patients benefit from therapy.
European Urology 05/2014; 66(5). DOI:10.1016/j.eururo.2014.04.007 · 13.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Genomic changes affecting tumour suppressor genes are fundamental to cancer. We applied SNP array analysis to a panel of testicular germ cell tumours to search for novel tumour suppressor genes and identified a frequent small deletion on 6q25.3 affecting just one gene; ZDHHC14. The expression of ZDHHC14, a putative protein palmitoyltransferase with unknown cellular function, was decreased both at RNA and protein levels in testicular germ cell tumours. ZDHHC14 expression was also significantly decreased in a panel of prostate cancer samples and cell lines. Through next generation sequencing of the ZDHHC14 genomic locus we discovered several mutations in both cancer types. Inducible overexpression of ZDHHC14 led to reduced cell viability and increased apoptosis through the classic caspase-dependent pathway. Finally, we confirmed our in vitro findings of the tumour suppressor role of ZDHHC14 in a mouse xenograft model, showing that overexpression of ZDHHC14 inhibits tumourigenesis. Thus we have identified a novel tumour suppressor gene that is commonly downregulated in testicular germ cell tumours and prostate cancer, as well as given insight into the cellular functional role of ZDHHC14, a potential protein palmitoyltransferase that may play a key protective role in cancer.
The Journal of Pathology 04/2014; 234(1). DOI:10.1002/path.4327 · 7.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It is not known how uropathologists currently report histopathological features of prostate biopsies such as core length, tumor extent, perineural invasion, and non-tumor-associated features such as inflammation and hyperplasia in needle biopsies. A web-based survey was distributed among 661 members of the European Network of Uropathology. Complete replies were received from 266 pathologists in 22 European countries. Total core lengths were reported by 64 %. The numbers of cores positive for cancer was given by 79 %. Linear cancer extent was reported by 81 %, most often given in millimeters for each core (53 %) followed by the estimation of percentage of cancer in each core (40 %). A gap of benign tissue between separate cancer foci in a single core would always be subtracted by 48 % and by 63 % if cancer foci were minute and widely separated. Perineural invasion was reported by 97 %. Fat invasion by tumor was interpreted as extraprostatic extension by 81 %. Chronic and active/acute inflammation was always reported by 32 and 56 % but only if pronounced by 54 and 39 %, respectively. While most (79 %) would never diagnose benign prostatic hyperplasia on needle biopsy, 21 % would attempt to make this diagnosis. Reporting practices for prostate biopsies are variable among European pathologists. The great variation in some methodologies used suggests a need for further international consensus, in order for retrospective data to be comparable between different institutions.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 03/2014; 464(5). DOI:10.1007/s00428-014-1554-1 · 2.65 Impact Factor