[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.
Full-text · Article · Jan 2016 · The American journal of surgical pathology
[Show abstract][Hide abstract] ABSTRACT: This article reviews the most frequently encountered tumor of the testis; pure and mixed malignant testicular germ cell tumors (TGCT), with emphasis on adult (postpubertal) TGCTs and their differential diagnoses. We additionally review TGCT in the postchemotherapy setting, and findings to be integrated into the surgical pathology report, including staging of testicular tumors and other problematic issues. The clinical features, gross pathologic findings, key histologic features, common differential diagnoses, the use of immunohistochemistry, and molecular alterations in TGCTs are discussed.
No preview · Article · Dec 2015 · Surgical Pathology Clinics
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Up to 50% of patients diagnosed with stage I non-seminomatous germ cell tumors (NSGCT) harbor occult metastases. Patients are managed by surveillance with chemotherapy at relapse or adjuvant treatment up-front. Late toxicities from chemotherapy are increasingly recognised. Based on a potential biological role in germ cells/tumors and pilot data, our aim was to evaluate tumor expression of the chemokine CXCL12 alongside previously proposed markers as clinically useful biomarkers of relapse.
Immunohistochemistry for tumor expression of CXCL12 was assessed as a biomarker of relapse alongside vascular invasion, histology (percentage embryonal carcinoma) and MIB1 staining for proliferationin formalin fixed paraffin-embedded orchidectomy samples from patients enrolled in the Medical Research Council's TE08/22 prospective trials of surveillance in stage I NSGCT.
TE08/TE22 trial patients had a 76.4% 2-year relapse free rate (RFR) and both CXCL12 expression and percentage embryonal carcinoma provided prognostic value independently of vascular invasion (stratified log rank test p=0.006 for both).There was no additional prognostic value for MIB1 staining. A model using CXCL12, percentage embryonal carcinoma and VI defines 3 prognostic groups that were independantly validated.
CXCL12 and percentage embryonal carcinoma both stratify patients' relapse risk over and above vascular invasion alone. This is anticipated to improve the stratification of patients and identify high-risk cases to be considered for adjuvant therapy.
Preview · Article · Oct 2015 · Clinical Cancer Research
[Show abstract][Hide abstract] ABSTRACT: Benign prostatic hyperplasia (BPH) treatments have changed little over many years and do not directly address the underlying cause. Because BPH is characterised by uncontrolled cell growth, the chromosomal telomeres should be eroded in the reported absence or low levels of telomerase activity, but this is not observed. We investigated the telomere biology of cell subpopulations from BPH patients undergoing transurethral resection of prostate (TURP). Measurement of TERC, TERT, and telomerase activity revealed that only the epithelial stem-like and progenitor fractions expressed high levels of telomerase activity (p <. 0.01) and individual enzyme components (p <. 0.01). Telomerase activity and TERT expression were not detected in stromal cells. Telomere length measurements reflected this activity, although the average telomere length of (telomerase-negative) luminal cells was equivalent to that of telomerase-expressing stem/progenitor cells. Immunohistochemical analysis of patient-derived BPH arrays identified distinct areas of luminal hyperproliferation, basal hyperproliferation, and basal-luminal hyperproliferation, suggesting that basal and luminal cells can proliferate independently of each other. We propose a separate lineage for the luminal and basal cell components in BPH. Patient summary: We unexpectedly found an enzyme called telomerase in the cells that maintain benign prostatic hyperplasia (BPH), suggesting that telomerase inhibitors could be used to alleviate BPH symptoms. In benign prostatic hyperplasia (BPH), a small population of basal cells expresses high levels of telomerase. Basal and luminal cells can proliferate independently, implying distinct basal and luminal lineages and suggesting that telomerase-blocking drugs could inhibit epithelial hyperproliferation in BPH.
[Show abstract][Hide abstract] ABSTRACT: Chromosomal rearrangements and fusion genes play important roles in tumor development and progression. Four high-frequency prostate cancer (CaP) specific fusion genes, SDK1:AMACR, RAD50:PDLIM4, CTAGE5:KHDRBS3 and USP9Y:TTTY15 have been reported in Chinese CaP samples through a transcriptome sequencing study. We previously reported that USP9Y:TTTY15 is a transcription-mediated chimeric RNA, which is expressed in both tumor and non-malignant samples, and here we attempted to confirm the existence of the other three fusion genes SDK1:AMACR, RAD50:PDLIM and CTAGE5:KHDRBS3. We detected SDK1:AMACR fusion transcript in 23 of 100 Chinese CaP samples, but did not detect RAD50:PDLIM4 and CTAGE5:KHDRBS3 transcripts in any of those samples. SDK1:AMACR fusion transcript is Chinese CaP specific, which was neither detected in nonmalignant prostate tissues adjacent to cancer from Chinese patient nor in CaP samples from UK patients. However, we did not detect genomic rearrangement of SDK1 gene by fluorescence in situ hybridization analysis, indicating that SDK1:AMACR is also a transcription-mediated chimeric RNA. Quantitative analysis demonstrated that high level AMACR expression was associated with SDK1:AMACR fusion status (P=0.004), suggesting that SDK1:AMACR fusion transcript may promote prostate carcinogenesis through increasing AMACR expression. However, the fusion status was not significantly correlated with any poor disease progression clinical features. The identification of the SDK1:AMACR fusion transcript in CaP cases from China but not from UK further supports our previous observation that different genetic alterations contribute to CaP in China and Western countries, although many genetic changes are also shared. Further studies are required to establish if CaPs with SDK1:AMACR represent a distinct subtype.
No preview · Article · Sep 2015 · International Journal of Clinical and Experimental Medicine
[Show abstract][Hide abstract] ABSTRACT: Isolation of circulating tumor cells (CTCs) from peripheral blood has the potential to provide a far easier "liquid biopsy" than tumor tissue biopsies, to monitor tumor cell populations during disease progression and in response to therapies. Many CTC isolation technologies have been developed. We optimized the Parsortix system, an epitope independent, size and compressibility-based platform for CTCs isolation, making it possible to harvest CTCs at the speed and sample volume comparable to standard CellSearch system. We captured more than half of cancer cells from different cancer cell lines spiked in blood samples from healthy donors using this system. Cell loss during immunostaining of cells transferred and fixed on the slides is a major problem for analyzing rare cell samples. We developed a novel cell transfer and fixation method to retain >90% of cells on the slide after the immunofluorescence process without affecting signal strength and specificity. Using this optimized method, we evaluated the Parsortix system for CTC harvest in prostate cancer patients in comparison to immunobead based CTC isolation systems IsoFlux and CellSearch. We harvested a similar number (p = 0.33) of cytokeratin (CK) positive CTCs using Parsortix and IsoFlux from 7.5 mL blood samples of 10 prostate cancer patients (an average of 33.8 and 37.6 respectively). The purity of the CTCs harvested by Parsortix at 3.1% was significantly higher than IsoFlux at 1.0% (p = 0.02). Parsortix harvested significantly more CK positive CTCs than CellSearch (p = 0.04) in seven prostate cancer patient samples, where both systems were utilized (an average of 32.1 and 10.1 respectively). We also captured CTC clusters using Parsortix. Using four-color immunofluorescence we found that 85.8% of PC3 cells expressed EpCAM, 91.7% expressed CK and 2.5% cells lacked both epithelial markers. Interestingly, 95.6% of PC3 cells expressed Vimentin, including those cells that lacked both epithelial marker expression, indicating epithelial-to-mesenchymal transition. CK-positive/Vimentin-positive/CD45-negative, and CK-negative/Vimentin-positive/CD45-negative cells were also observed in four of five prostate cancer patients but rarely in three healthy controls, indicating that Parsortix harvests CTCs with both epithelial and mesenchymal features. We also demonstrated using PC3 and DU145 spiking experiment that Parsortix harvested cells were viable for cell culture.
[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.
Full-text · Article · Jun 2015 · British Journal of Cancer
[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.
No preview · Article · Dec 2014 · American Journal of Cancer Research
[Show abstract][Hide abstract] ABSTRACT: Objectives
To determine the outcome of an expanded cohort of patients with relapsed germ cell tumors (GCT) treated with a salvage chemotherapy regimen consisting of irinotecan, paclitaxel and oxaliplatin (IPO) and assess the role of IPO as an alternative to standard cisplatin-based chemotherapy regimens in this setting.Patients and methodsThe results of 72 consecutive patients were reviewed retrospectively. IPO was used either as a second-line treatment (n=29), of which 20 patients subsequently received high-dose chemotherapy (HDCT), or third-line (n=43), of which 32 patients proceeded to HDCT.ResultsThe 2-year PFS and 3-year OS rates for the whole cohort were 30.2% (95%CI 17.3-40.5%) and 33.4% (95%CI: 20.1-43.8 %) respectively. CR was achieved in 3%, m-ve PR in 41%, m+ve PR in 18%, SD in 17% and PD in 20%. In the second-line setting, the 2-year PFS rate was 43.5% (95%CI: 21.7-60.8%) and 3-year OS 49.1% (95%CI: 24.2-65.1%). In the third-line setting, the 2-year PFS rate was 21.0% (95%CI 9.5-35.4%) and the 3-year OS rate was 23.9% (95%CI 11.7-38.2).According to the current international prognostic factor study group criteria for first relapse for the high and very high risk group the 2 year PFS rates were 50% and 30% respectively. There were 2 treatment related deaths from IPO, and 4 from HDCT. Grade 3 or 4 toxicities included neutropenia (35%), thrombocytopenia (18%), infection (15%), diarrhea (11%) and lethargy (8%). ConclusionsIPO offers an effective, well-tolerated, non-nephrotoxic alternative to cisplatin-based salvage regimens for patients with relapsed GCT. It appears particularly useful in high risk patients and for those in whom cisplatin is ineffective or contra-indicated.
No preview · Article · Nov 2014 · BJU International
[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.
No preview · Article · Oct 2014 · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin
[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.
Full-text · Article · Oct 2014 · Biomarkers in Medicine