Spontaneous metastasis in mouse models of testicular germ-cell tumours.

Testicular germ-cell tumours (TGCTs) are the most common cancer in young men; the incidence is increasing worldwide and they have an unusually high rate of metastasis. Despite significant work on TGCTs and their metastases in humans, absence of a mouse model of spontaneous metastasis has greatly limited our understanding of the mechanisms by which metastatic potential is acquired and on their modes of dissemination. We report a new model of spontaneous TGCT metastasis in the 129 family of mice and provide evidence that these are true metastases derived directly from primary testicular cancers rather than independently from ectopic stem cells. These putative metastases (pMETs) occur at similar frequencies among TGCT-affected males in six genetically distinct TGCT-susceptible strains and were largely found in anatomical sites that are consistent with patterns of TGCT metastasis in humans. Various lines of evidence support their pluripotency and germ-cell origin, including presence of multiple endodermal, mesodermal and ectodermal derivatives as well as cells showing OCT4 and SSEA-1 pluripotency markers. In addition, pMETs were never found in males that did not have a TGCT, suggesting that metastases are derived from primary tumours. Finally, pMETS and primary TGCTs shared several DNA copy number variants suggesting a common cellular and developmental origin. Together, these results provide the first evidence for spontaneous TGCT metastasis in mice and show that these metastases originate from primary TGCTs rather than independently from ectopic stem cells.

Experimental rodent models of prostatitis: limitations and potential.

Prostatitis is a polyetiological inflammation of the prostate gland in men characterized by pelvic pain, irritative voiding symptoms, and sexual dysfunction. Histologically prostatitis is characterized by poly- and mononuclear cell infiltrates (neutrophils, lymphocytes, macrophages and plasma cells) in the stromal connective tissue around the acini or ducts. Prostatitis is an important worldwide health problem in men. The pathogenesis and diagnostic criteria for the condition are obscure, with the result that the development of management programs for this condition has been hindered. Animal model(s) might be useful in elucidating mechanisms involved in the molecular pathogenesis of chronic nonbacterial prostatitis and chronic pelvic pain syndrome. Given that prostatitis might have a multifactorial etiology, several animal models with unique features may prove helpful. This review examines a number of experimental rodent models of prostatitis and evaluates their advantages and limitations.

Altered expression of RET proto-oncogene product in prostatic intraepithelial neoplasia and prostate cancer.

BACKGROUND: The RET proto-oncogene encodes a protein that belongs to the tyrosine kinase growth factor receptor family. Germline point mutations in RET are found in individuals with multiple endocrine neoplasia (MEN) syndromes, and gene rearrangements have been reported in papillary thyroid cancers. We recently identified transcripts of the RET proto-oncogene in human prostate cancer xenografts and prostate cancer cell lines by means of reverse transcription-polymerase chain reaction analyses. The purpose of this study was to investigate Ret protein expression in human prostate tissue. METHODS: Ret protein expression was evaluated immunohistochemically in formalin-fixed, paraffin-embedded whole-prostate sections. The prostate specimens were obtained from 30 patients with prostate cancer after radical prostatectomies. Ret protein expression was compared in tumor foci and benign prostatic tissue. Medullary thyroid carcinoma tissue associated with an MEN syndrome and papillary thyroid cancer tissue served as positive controls. RESULTS: Ret appeared to be overexpressed in high-grade (histopathologically advanced) prostatic intraepithelial neoplasia (PIN) and prostate cancer when compared with its expression level in benign prostatic secretory epithelium. In addition, there was an apparent increase in Ret protein expression with decreased cellular differentiation, i.e., increasing Gleason pattern. CONCLUSION: Expression of the RET proto-oncogene in benign prostatic epithelium, high-grade PIN, and histopathologically advanced prostate cancer suggests that RET may play a role in the growth of both benign and neoplastic prostate epithelial cells.

Chemoprevention of prostate carcinogenesis by alpha-difluoromethylornithine in TRAMP mice.

Development of effective chemopreventive agents for human consumption requires conclusive evidence of their efficacy in animal models that have relevance to human diseases. Transgenic adenocarcinoma mouse prostate (TRAMP) is an excellent model of prostate cancer that mimics progressive forms of human disease inasmuch as 100% of males develop histological PIN by 8-12 weeks of age that progress to adenocarcinoma with distant site metastases by 24-28 weeks of age. In these animals, ornithine decarboxylase (ODC) activity (>3-fold) as well as protein expression (>4-fold) was found to be markedly higher in the dorsolateral prostate as compared with the nontransgenic littermates, suggesting their suitability to determine the chemopreventive effect of alpha-difluoromethylornithine (DFMO), an enzyme-activated irreversible inhibitor of ODC, against prostate cancer. Using male TRAMP mice, we studied the effect of oral consumption of DFMO on development of prostate carcinogenesis and surrogate end point biomarkers related to prostate cancer progression. In two independent experiments, each consisting of 8 animals on test, the cumulative incidence of prostatic cancer development at 28 weeks of age in 16 untreated TRAMP mice was 100% (16 of 16), whereas 94% (15 of 16) and 69% (11 of 16) of the animals exhibited distant site metastases to lymph nodes and lungs, respectively. Oral consumption of 1% DFMO (w/v) in the drinking water to TRAMP mice from 8 to 28 weeks of age resulted in a significant decrease in (a) weight (59%) and volume (66%) of prostate, (b) genitourinary weight (63%), and (c) ODC enzyme activity (52%) in the dorsolateral prostate. Importantly, in none of the DFMO-fed TRAMP mice were any distant metastases to lymph node and lungs observed. Furthermore, DFMO treatment resulted in the marked reduction in the protein expression of proliferation cell nuclear antigen, ODC, and probasin in the dorsolateral prostate. The protein expression of antimetastases markers, i.e., E-cadherin and alpha- and beta-catenin, was found to be restored in DFMO-fed animals as compared with the non-DFMO-fed mice. These chemopreventive effects of DFMO were further confirmed by immunohistochemical analysis of the dorsolateral prostate. Histological analysis of the dorsolateral prostate of DFMO-fed animals displayed marginal epithelial stratification, a small number of cribriform structures, elongated hyperchromatic epithelial nuclei, and a significant increase in apoptotic index. Non-DFMO-fed animals, on the other hand, displayed extensive epithelial stratification with profound cribriform structures accompanied with marked thickening, remodeling, and hypercellularity of the fibromuscular stroma. In nontransgenic littermates fed with DFMO, no significant alterations in the above parameters were evident. These data demonstrate that ODC represents a promising and rational target for chemoprevention of human prostate cancer and that TRAMP mice are excellent models for screening of novel drugs and chemopreventive regimens for potential human use.

Loss of fragile histidine triad expression in colorectal carcinomas and premalignant lesions.

Abnormal expression of the fragile histidine triad (FHIT) candidate tumor suppressor gene has been observed in a variety of human tumors, but little is known about its expression during colorectal tumorigenesis. Sections of 70 aberrant crypt foci (ACF), 55 adenomas, 84 primary colorectal carcinomas, and 13 metastatic lesions were evaluated immunohistochemically for Fhit expression. All normal colonic epithelium showed a strong expression of Fhit; 44% of carcinomas showed a marked loss or absence of Fhit expression. The proportion of carcinomas with reduced expression showed an increasing trend (a) with decreasing differentiation and (b) in tumors with metastases (62%) compared with tumors without metastases (38%). The proportion of metastatic lesions (12 of 13) with reduced expression of Fhit was even greater. Although only a small proportion of ACF and adenomas showed a reduction of Fhit expression, the reduced expression of Fhit was strongly associated with the degree of dysplasia in both ACF (P = 0.0002) and adenomas (P = 0.0085). The findings of reduced expression of Fhit in a small proportion of colonic precancerous lesions and in increased proportions of primary and metastatic colorectal cancers suggest that Fhit plays a role in the development and progression of some colon carcinomas.

Prostate cancer and other xenografts from cells in peripheral blood of patients.

Good models for the investigation of human prostate cancer are few. Cells from approximately 9.2-21 ml of peripheral blood from patients with metastatic prostate cancer or metastatic colon cancer were injected s.c. into nude mice. Prostate cancer from 2 of 11 patients and colon cancer from 1 of 3 patients were found to be growing as metastases in the lungs of the nude mice. To our knowledge, this is the first report of the formation of xenografts from carcinoma cells taken directly from the peripheral blood of patients. Expanding circulating cancer cells with this approach may have important translational applications including: (a) development of models of human cancers; and (b) sampling of cancers from specific patients for novel molecular and therapeutic approaches.

Metabolic syndrome, inflammation and lower urinary tract symptoms: possible translational links.

BACKGROUND: Epidemiological data suggest that lower urinary tract symptoms (LUTSs) may be associated with metabolic syndrome (MetS). Inflammation has been proposed as a candidate mechanism at the crossroad between these two clinical entities. The aim of this review article is to evaluate the role of MetS-induced inflammation in the pathogenesis and progression of LUTS. METHODS: A systematic review was conducted using the keywords 'metabolic syndrome and lower urinary tract symptoms' within the title search engines including PubMed, Web of Science and the Cochrane Library for relevant research work published between 2000 and January 2015. The obtained literature was reviewed by the primary author (QH) and was assessed for eligibility and standard level of evidence. RESULTS: Total of 52 articles met the eligibility criteria. On the basis of database search during the past 15 years and our systematic review of prospective and retrospective cohorts, case-control trials, observational studies and animal data identified a possible link between MetS-induced inflammation and LUTS including BPH, bladder outlet obstruction, overactive bladder, urinary incontinence and other possible urinary tract abnormalities. CONCLUSIONS: There is convincing evidence to suggest that MetS and inflammation could be important contributors to LUTS in men, particularly in the development of BPH. However, the role of MetS-induced inflammation remains unclear in overactive bladder, urinary incontinence and etiology of LUTS progression.

Overexpression of ornithine decarboxylase in prostate cancer and prostatic fluid in humans.

Prostate cancer (PCA), the most commonly diagnosed cancer in males in the United States, is the second leading cause of cancer-related deaths of males in this country. Because of the poor success rate in the treatment of PCA, an intervention at an early stage may reduce the progression of small carcinoma to large metastatic lesion, thereby reducing PCA-related deaths. Concerted efforts are needed to establish mechanism-based approaches to develop: (a) the markers for early detection of the disease as well as toward monitoring the efficacy of treatment(s); and (b) novel chemopreventive strategies against PCA. Using unique samples of pair-matched benign and cancer tissue obtained from the same PCA patient, we showed that ornithine decarboxylase (ODC) activity is significantly (P < 0.001) elevated in PCA (1142 +/- 100; mean +/- SE) than in paired benign tissue (427 +/- 51; mean +/- SE). The immunoblot analysis also showed a significant elevation in the protein expression of ODC in the PCA tissues as compared with the paired benign tissue. Furthermore, our data showed that the ODC activity in the prostatic fluid obtained by a digital rectal massage from the patients with PCA (3847 +/- 162; mean +/- SE) was significantly higher than in the patients with benign prostatic hyperplasia (2742 +/- 167; mean +/- SE) or normal individuals (1244 +/- 67; mean +/- SE). This observation might be of significance because the prostatic fluid could be obtained noninvasively by digital rectal massage. We suggest that ODC could serve as a target for early detection of human PCA as well as for monitoring the efficacy of treatment(s). The development of ODC as a target for novel chemopreventive strategies against PCA is an intriguing possibility.

Atypical small acinar proliferation suspicious for malignancy in prostate needle biopsies: clinical significance in 33 cases.

Prostate needle biopsies occasionally contain an atypical small acinar proliferation (ASAP) that is suspicious for, but not diagnostic of, adenocarcinoma. The histologic features and clinical significance of this finding are unexplored. We evaluated 33 cases of ASAP with at least one follow-up needle biopsy seen at Mayo Clinic from 1993 to 1996. Numerous histologic and clinical features were assessed to determine their predictive value for adenocarcinoma on subsequent biopsy. Mean patient age was 61.6 years (range 45-72). Adenocarcinoma was identified on follow-up biopsy in 15 of 33 patients (45%), with a median follow-up of 9 months (range 1-27). Gleason score varied from 4 to 7 (mean 5.9). Two patients (6%) had subsequent diagnoses of ASAP after one and three repeat biopsies. Digital rectal examination, serum prostate-specific antigen, and a variety of histologic findings were not predictive of cancer on follow-up biopsy. These histologic findings included number of biopsy cores (mean 5.5), number of acini per focus of ASAP (mean 7.9), number of foci (mean one), variation in acinar size, nuclear enlargement (none, 12% of cases; mild, 45%; moderate, 33%; severe, 10%), nucleolar enlargement (none, 27%; mild, 46%; moderate, 27%), luminal mucin (39%), crystalloids (6%), focal chronic inflammation (64%), adjacent atrophy (100%), and adjacent high-grade prostatic intraepithelial neoplasia (PIN) (42%). Stratification of suspicion in cases of ASAP without PIN into three categories ("favor benign, uncertain, and favor carcinoma") was somewhat predictive of subsequent cancer (20%, 25%, and 60% of cases with subsequent cancer, respectively), but the results were not significant. The high predictive value of ASAP for subsequent adenocarcinoma warrants repeat biopsy. No single clinical or pathologic feature appeared to increase the likelihood of subsequent cancer.

Molecular genetic evidence for different clonal origin of components of human renal angiomyolipomas.

Renal angiomyolipoma is a benign neoplasm composed of variable proportions of blood vessels, smooth muscle, and adipose tissue. Smooth muscle, adipose tissue, blood vessels, and adjacent normal kidney tissue were separately microdissected from sections prepared from formalin-fixed, paraffin-processed tissues from angiomyolipomas from 18 women. X chromosome inactivation analysis using the methylation pattern at exon 1 of the human androgen receptor gene on chromosome Xq11-12 was used to study the clonal origin of each component. Nonrandom inactivation of X chromosomes was found in six of the 15 informative tumors. The smooth muscle and adipose tissue showed differing patterns of nonrandom inactivation of X chromosomes in five angiomyolipomas and the same pattern of nonrandom inactivation of X chromosomes in one. Samples from the blood vessels showed random inactivation of X chromosomes in all informative cases. Our data showed that the adipose tissue and smooth muscle cells of renal angiomyolipoma are both monoclonal but may arise independently. The coexistence of tumor subclones with morphologic heterogeneity can lead to the formation of a clinically detectable tumor.

Microvessel density in renal cell carcinoma: lack of prognostic significance.

OBJECTIVES: Microvessel density (MVD) is a significant prognostic factor in many cancers, but its importance has not been evaluated in renal cell carcinoma. The objectives of this study were: (1) to determine the relationship of MVD in renal cell carcinoma to clinical stage, pathologic stage, histologic type, and tumor grade, and (2) to evaluate the role of MVD as a predictor of cancer-specific survival. METHODS: We reviewed the clinical and pathologic findings from 97 consecutive patients 60 years of age and younger with renal cell carcinoma treated at the Mayo Clinic between 1980 and 1982 by radical nephrectomy. Mean follow-up was 7.5 years, and 44 patients (45%) died of renal cell carcinoma. MVD was evaluated immunohistochemically using the labeled streptavidin-biotin-peroxidase method with a monoclonal antibody directed against factor VIII-related antigen. The area of highest MVD within the tumor was selected for review without knowledge of the patient's clinical parameters, and the number of vessels in an x400 field (0.1855 mm2) was counted. RESULTS: Mean MVD was 741.2 vessels/mm2 (standard deviation, 394.3; range, 21.6 to 1078.2). In 49 cases (51%), there were greater than 1,000 vessels/mm2, forming a syncytium that precluded accurate vessel counting. In these cases, we used a value of 1,078 vessels/mm2 for calculations, corresponding to 200 vessels per x400 field. MVD was higher in clear cell than in non-clear cell carcinoma (811.2 versus 529.2 vessel/mm2, respectively; P = 0.007). There was no correlation of MVD and clinical stage, pathologic stage, tumor grade, of cancer-specific survival (all P > 0.05). CONCLUSIONS: MVD is higher in the clear cell pattern of renal cell carcinoma than in non-clear cell patterns. MVD does not correlate with clinical stage, pathologic stage, or grade, and MVD has no predictive value for cancer-specific survival.

Low-grade collecting duct carcinoma of the kidney: report of 13 cases of low-grade mucinous tubulocystic renal carcinoma of possible collecting duct origin.

OBJECTIVES: To assess the nature of a series of unusual low-grade mucin-producing tubulocystic renal cancers diagnosed at the Mayo Clinic since 1985. METHODS: We reviewed the clinical, radiologic, and pathologic features of 13 unusual low-grade renal carcinomas with features most suggestive of collecting duct origin. RESULTS: In 8 cases, the tumor was discovered incidentally. Presenting symptoms in the other 5 patients were similar to those of typical renal carcinoma. Imaging studies and angiography disclosed solid, cystic, or complex masses that were relatively avascular. Pathologic assessment revealed good circumscription, minimal hemorrhage and/or necrosis, minimal tendency to extend beyond the kidney, tubulocystic architecture, a fibrotic interface with adjacent normal renal parenchyma, low nuclear grade, and minimal mitotic activity. Mucin production was noted in all evaluable cases. All tumors expressed keratins AE1/AE3 and/or Cam 5.2. The tumors showed immunoreactivity to antibodies directed against keratin 34 beta E12 (8 of 13 cases), and Ulex Europeus antigen 1 (6 of 10 cases). Follow-up ranged from 12 to 114 months (mean 62). No metastases occurred in 12 patients. One patient died of metastatic carcinoma morphologically identical to the primary renal neoplasm 46 months after his tumor had been misinterpreted as a benign condition. CONCLUSIONS: We believe the tumors described in this article may be of collecting duct origin, representing the low-grade end of a spectrum of cancers arising in collecting duct epithelium.

Optimized microvessel density analysis improves prediction of cancer stage from prostate needle biopsies.

OBJECTIVES: Clinical staging of prostate cancer is inaccurate, often with significant upstaging on final pathologic review. We previously demonstrated the ability to predict extraprostatic extension of cancer by use of the Gleason score and serum prostate-specific antigen (PSA) measurements. Herein we present an interim analysis of data from an ongoing multi-institutional study to determine the predictive power of an enhancement of microvessel density analysis in combination with Gleason score and serum PSA to predict extraprostatic extension. METHODS: We evaluated a total of 186 randomly selected biopsy samples and matched totally embedded radical prostatectomy samples with preoperative PSA concentrations and patient demographics. Gleason score and optimized microvessel density (OMVD) were determined from the needle biopsy samples; pathologic stage was verified by independent review of the radical prostatectomy samples. An automated digital image analysis system measured microvessel morphology and calculated the OMVD in the biopsy samples (Biostage; Bard Diagnostic Sciences, Seattle, Wash). RESULTS: Prediction of extraprostatic extension was increased significantly when OMVD analysis was added to Gleason score and serum PSA concentration (P = 0.003). CONCLUSIONS: Optimized microvessel density analysis significantly increases the ability to predict extraprostatic extension of cancer preoperatively when combined with Gleason score and serum PSA concentration. This method appears to be a useful tool that can assist with treatment decisions in selected patients.

PET imaging of hepatocellular carcinoma with 2-deoxy-2[18F]fluoro-D-glucose, 6-deoxy-6[18F] fluoro-D-glucose, [1-11C]-acetate and [N-methyl-11C]-choline.

AIM: This study was designed to investigate the performance of positron emission tomography (PET) imaging for hepatocellular carcinoma (HCC) on a hepatitis viral infection-induced woodchuck model using existing tracers such as 2-deoxy-2[(18)F]fluoro-D-glucose (2FDG), 6-deoxy-6[(18)F]fluoro-D-glucose (6FDG), [1(-11)C]acetate (acetate) and [N-methyl(-11)C]choline (choline). METHODS: Fourteen woodchucks with HCC were imaged with different radiotracers: 13 (10 with HCC and 3 controls) with 2FDG; 4 (3 with HCC and 1 control) with 6FDG; 13 (10 with HCC and 3 controls) with acetate; 4 (2 with HCC and 2 controls) with choline. The woodchucks were euthanized after imaging experiments and liver tissues were harvested for histology, for enzymatic activities including hexokinase (HK), glucose-6-phosphatase, acetyl-CoA synthetase (ACAS) and choline kinase (CK), and for differential gene expressions between the HCCs and the surrounding hepatic tissues. RESULTS: 2FDG detected 7/13 tumors with a tumor-to-liver uptake ratio (T/L) of 1.36+/-0.13. Five of these HCCs were moderately- or poorly-differentiated. The HK/glucose-6-phosphatase ratio was significantly higher in HCCs compared to the surrounding liver tissues (P=0.05). None of the HCCs imaged with 6FDG were detected by PET (T/L=1.01+/-0.11). Acetate detected 16/17 HCCs (T/L=2.02+/-0.7). ACAS activity was significantly higher in HCCs (P=0.01) and lipids-related genes were found up-regulated. Choline imaging detected all HCCs (T/L=1.63+/-0.34). CK activity was significantly higher in HCCs (P=0.001). CONCLUSIONS: Well-differentiated and some moderately-differentiated HCCs do not uptake 2FDG more than the surrounding liver tissues, but display increased acetate uptake. There is no contrast between HCCs and the surrounding liver tissues on the 6FDG PET images. Despite elevated background signal from the liver, choline uptake seems to be detectable in the HCCs scanned in this study.

The S100 proteins for screening and prognostic grading of bladder cancer.

The S100 gene family, which is composed of at least 24 members carrying the Ca2+ binding EF-hand motif, has been implicated in both intracellular and extracellular functions, including enzyme activities, immune responses, cytoskeleton dynamics, Ca2+ homeostasis, cell growth and cell differentiation. Altered S100 protein levels are associated with a broad range of diseases, including cardiomyopathy, inflammatory and immune disorders, neurodegenerative disorders and cancer. Although the precise role of S100 protein in carcinogenesis is poorly understood, it seems that formation of homo- and hetero-dimers, binding of Ca2+ and interaction with effector molecules are essential for the development and progression of many cancers. Several studies have suggested that S100 proteins promote cancer progression and metastasis through cell survival and apoptosis pathways. In animal models of bladder cancer, several S100 proteins are differentially expressed in bladder tumors relative to normal urothelium. In human bladder cancer, overexpression of S100A4, S100A8 or S100A11 are associated with stage progression, invasion, metastasis and poor survival. This review summarizes these findings and evaluates their implications for human bladder cancer management.

Histogenesis of sarcomatoid urothelial carcinoma of the urinary bladder: evidence for a common clonal origin with divergent differentiation.

The histogenesis of sarcomatoid urothelial carcinoma, a rare neoplasm with bidirectional epithelial and mesenchymal differentiation, has been a matter of controversy. To clarify its origin, we analysed the status of X-chromosome inactivation in sarcomatoid urothelial carcinomas from 10 female patients and examined losses of heterozygosity (LOH) in these specimens and in additional 20 tumours from male patients. Six polymorphic microsatellite markers where genetic alterations occur frequently in early or advanced stages of urothelial carcinomas, including D3S3050, D8S261, IFNA, D9S177, D11S569 and TP53, were investigated in the current study. The identical pattern of non-random X-chromosome inactivation in both carcinomatous and sarcomatous components was identified in five of eight informative female patients, and the remaining three informative cases showed a random, but concordant, pattern of X-chromosome inactivation. The concordant X-chromosome inactivation results in all eight informative cases support the concept of a monoclonal origin of both components of this biphasic neoplasm. Among the tumours demonstrating loss of heterozygosity, high incidences of an identical pattern of allelic loss between carcinomatous and sarcomatous components were identified in genetic alterations associated with early carcinogenesis: 86% at D8S261, 78% at D11S569, 75% at D9S177 and 57% at IFNA. In contrast, concordant LOH patterns were less frequently observed for microsatellites related to advanced carcinogenesis: only 40% at D3S3050 and 40% at TP53. The significant overlap of loss of heterozygosity supports a monoclonal cell origin and suggests that clonal divergence may occur during tumour progression and differentiation. Divergent patterns of discordant allelic loss of microsatellite markers imply that heterogeneous pathogenetic pathways may exist in the evolution of this enigmatic neoplasm.

OCT4: biological functions and clinical applications as a marker of germ cell neoplasia.

Germ cell tumours (GCTs) are a heterogeneous group of neoplasms, which develop in the gonads as well as in extragonadal sites, that share morphological patterns and an overall good prognosis, owing to their responsiveness to current surgical, chemotherapeutic, and radiotherapeutic measures. GCTs demonstrate extremely interesting biological features because of their close relationships with normal embryonal development as demonstrated by the pluripotentiality of some undifferentiated GCT variants. The similarities between GCTs and normal germ cell development have made it possible to identify possible pathogenetic pathways in neoplastic transformation and progression of GCTs. Genotypic and immunophenotypic profiles of these tumours are also useful in establishing and narrowing the differential diagnosis in cases of suspected GCTs. Recently, OCT4 (also known as OCT3 or POU5F1), a transcription factor that has been recognized as fundamental in the maintenance of pluripotency in embryonic stem cells and primordial germ cells, has been proposed as a useful marker for GCTs that exhibit features of pluripotentiality, specifically seminoma/dysgerminoma/germinoma and embryonal carcinoma. The development of commercially available OCT4-specific antibodies suitable for immunohistochemistry on paraffin-embedded specimens has generated increasing numbers of reports of OCT4 expression in a wide variety of gonadal and extragonadal GCTs. OCT4 immunostaining has been shown to be a sensitive and specific marker for seminomatous/(dys)germinomatous tumours and in embryonal carcinoma variants of non-seminomatous GCTs, whether in primary gonadal or extragonadal sites or in metastatic lesions. Therefore, OCT4 immunohistochemistry is an additional helpful marker both in the differential diagnosis of specific histological subtypes of GCTs and in establishing a germ cell origin for some metastatic tumours of uncertain primary. OCT4 expression has also been reported in pre-invasive conditions such as intratubular germ cell neoplasia, unclassified (IGCNU) and the germ cell component of gonadoblastoma. Additionally, OCT4 immunostaining shows promise as a useful tool in managing patients known to be at high risk for the development of invasive GCTs.

Exacerbation of endometriosis as a result of premenopausal tamoxifen exposure.

A 41-year-old woman with a history of endometriosis had breast carcinoma diagnosed and treated with tamoxifen. A pelvic mass was subsequently diagnosed and observed on serial ultrasonographic examinations to increase in size. At surgery extensive endometriosis was found. Exacerbation of endometriosis by tamoxifen may become more common as tamoxifen is used more frequently to reduce the risk of breast cancer among premenopausal women.

Testicular juvenile capillary hemangioma: conservative management with frozen-section examination. A case report.

Juvenile capillary hemangioma, an exceptionally rare benign neoplasm, seen in an 18-year-old patient, was managed in an unorthodox fashion. The patient insisted on a conservative approach to the management of his tumour. In an effort to comply with his wishes, frozen-section examination of the tumour was carried out. The astute observations of the pathologist who recognized the juvenile capillary hemangioma made possible a conservative surgical excision and testicular repair. The case illustrates some of the difficulties that may be encountered in the successful management of testicular tumours.

Chromophobe renal cell carcinoma: a comparative study of histological, immunohistochemical and ultrastructural features using high throughput tissue microarray.

AIMS: In some cases distinction between chromophobe renal cell carcinoma (CRCC), oncocytoma and clear cell (conventional) renal cell carcinoma (eosinophilic variant) using routine light microscopy remains problematic. The present study investigates the level of agreement in the diagnosis of CRCC, as well as the histological features most frequently used for this diagnosis by two pathologists with a special interest in renal neoplasia. The sensitivity and specificity of immunohistochemical markers in cases with overlapping histological features in the diagnosis of CRCC were also studied. Electron microscopy was performed, as a diagnostic gold standard, on all of the cases. METHODS AND RESULTS: Thirty-two renal tumours with predominantly eosinophilic cytoplasm were reviewed in a blinded fashion by two pathologists. The diagnosis and morphological features used to render each diagnosis were tabulated. Validation of the utility of keratin 7 and 20, epithelial membrane antigen (EMA), vimentin, CD10, parvalbumin, RCC antigen, antimitochondrial antibody and Hale's colloidal iron was performed by the construction of a tissue microarray (TMA) master block. Based on histological criteria alone, overall agreement on the diagnosis of these tumours was reached in 69% of the cases, while there was total disagreement in 12%. In 59% of the cases, total agreement was reached in classifying the case as a CRCC based on histology alone. Kappa statistics for interobserver variability were calculated as only slight agreement (kappa = 0.3). The histological features most frequently associated with a diagnosis of CRCC were accentuated cell borders (87%) and a combination of hyperchromatic wrinkled nuclei (79%) and perinuclear halos (74%). The most sensitive and specific marker for CRCC was parvalbumin (sensitivity 0.91; specificity 1.0). The immunohistochemical profile of EMA+/ vimentin- was useful but had low specificity (sensitivity 0.75; specificity 0.4). CD10 had the highest sensitivity (1.0) but worst specificity (0.25) for CRCC. Keratin 7 had high sensitivity (0.83) but fairly low specificity (0.37) for CRCC. Hale's colloidal iron and the RCC antigen marker were not contributory. Finally, the antimitochondrial antibody was found to be fairly sensitive (0.83) for excluding CRCC. CONCLUSIONS: A small but significant proportion of renal tumours with cells having eosinophilic cytoplasm cannot be classified, even by experienced pathologists, based on histology alone. In these cases it is imperative to use markers with known sensitivity and specificity for the diagnosis of CRCC.