Paraneoplastic cerebellar ataxia due to burnt-out testicular germ cell tumour?
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Cerebellar Ataxia↗
Biomedical subjects
Alex Freeman
Publications and source records attributed to Alex Freeman.
The role of magnetic resonance imaging in the local staging of penile cancer.
OBJECTIVES: To assess the accuracy of magnetic resonance imaging (MRI) as a local staging technique in penile cancer and its role in selecting patients for conservative surgical management. METHODS: Fifty-five men diagnosed with invasive penile carcinoma on biopsy were locally staged with the use of MRI. Prostaglandin E1 (alprostadil) was injected into the corpora to induce an artificial erection. Radiologic staging was compared against final histopathologic stage of the tumour. Sensitivity, specificity, and kappa agreement values were calculated for each tumour stage. Additionally, corpora cavernosa involvement was reviewed in 20 consecutive cases and suitability for conservative surgery assessed. RESULTS: A good correlation between radiologic and histologic staging was achieved with an overall kappa value of 0.75 (p<0.001). Stage-specific sensitivities and specificities were calculated: T1 (85%; 83%), T2 (75%; 89%), and T3 (88%; 98%). MRI accurately predicted corpora cavernosa invasion in all cases of pathologically proven disease. These patients were selected to undergo partial penectomy. There were no complications using this imaging technique. CONCLUSIONS: This study demonstrates that penile MRI is highly accurate in the local staging of penile cancer. Associated improvements in surgical planning allow the provision of conservative surgical treatments over more radical procedures.
Adult↗
Adult leydig cell tumors of the testis caused by germline fumarate hydratase mutations.
CONTEXT: Leydig cell tumors (LCTs) are the most common non-germ-cell neoplasms of the testis. LCTs are often hormonally active and can result in precocious virilization or in adult feminization. We identified an LCT in an affected individual from a kindred with hereditary leiomyomatosis and renal cell cancer (HLRCC) and a germline fumarate hydratase (FH) mutation (N64T). OBJECTIVE: Our objective was to investigate the role of FH mutations in predisposition to LCTs. DESIGN: We tested for pathogenic effects of the N64T mutation and screened an additional 29 unselected adult LCTs for FH alterations. We also tested these LCTs for mutations in two genes, the LH/choriogonadotropin receptor (LHCGR) and the guanine nucleotide-binding protein alpha (GNAS) that had been implicated in LCT tumorigenesis. RESULTS: No mutations were found in GNAS, and one tumor had a LHCGR somatic substitution. In addition to the HLRCC case with the N64T germline FH mutation, we identified one other LCT with a previously unreported FH mutation (M411I). Both LCTs from these patients showed loss of the wild-type FH allele. Immunohistochemical and in situ hybridization analyses demonstrated activation of the hypoxia/angiogenesis pathway not only in the tumors belonging to the FH mutation carriers but also in several other mutation-negative LCTs. CONCLUSIONS: Our study shows that some LCTs are caused by FH mutations and represents one of the first reports of germline mutations in any type of adult testicular tumor.
Base Sequence↗
A prospective study of 100 cases of penile cancer managed according to European Association of Urology guidelines.
OBJECTIVE: To prospectively assess the outcome of patients treated according to the European Association of Urology (EAU) guidelines on the management of penile cancer, a system originally based on retrospective series. PATIENTS AND METHODS: Between 2002 and 2005, 100 consecutive patients (median age 62 years) with penile cancer were treated at one institution; all were categorized and treated according to EAU guidelines. Data were analysed using the z-test, with significance defined as P < 0.05. RESULTS: Survival curves were limited to those with >12 months of follow-up (mean 29); the survival of the whole group was 92%. Of men with palpable nodes, 72% had lymph node involvement, whereas 18% of those with impalpable nodes who had lymphadenectomy according to the guidelines had lymph node disease. The grade of the primary tumour was more predictive than T stage for lymph node involvement and survival. The 3-year disease-specific survival for N0, N1 and N2 disease was 100%, 100% and 73%, respectively, and survival at 12 months for N3 disease was 67%. The median survival for those with metastases was 3 months. CONCLUSION: The overall survival of men with penile cancer is high, with a clear benefit for early lymphadenectomy in men with positive nodal disease. However, the current EAU guidelines are limited in predicting those patients with micrometastatic disease, with the result that 82% of patients undergo unnecessary prophylactic lymphadenectomy. There is a need to identify more accurate molecular markers for predicting lymph node disease, or the role of novel staging techniques must be assessed.
Adult↗
Comparison of the zones of the human prostate with the seminal vesicle: morphology, immunohistochemistry, and cell kinetics.
BACKGROUND: The prostate contains three glandular zones (central, peripheral, transition) with widely differing susceptibilities to cancer and benign prostatic hyperplasia (BPH). Most of the prostate is derived from urogenital sinus, but the central zone may be derived from Wolffian duct, in common with the seminal vesicles (SV). The peripheral zone is the most frequent site of cancer and the transition zone is the almost exclusive site of BPH. METHOD: We compared the histology and immunohistochemistry of the SV with those of the prostate zones in order to identify differences associated with susceptibility to disease or different embryological origins. Sections from the prostates of nine organ donors (aged 15-36) were stained for tissue-specific markers, antigens previously shown to stain differentially between the zones and markers of cell proliferation and cell death. RESULTS: Neuroendocrine cells were absent from the SV and significantly fewer neuroendocrine cells were seen in the central zone compared to the peripheral zone. Most of the SV epithelium stained for lactoferrin, compared to approximately one-third of central zone and only 2% of peripheral zone epithelial cells. The proliferative index of the central zone was approximately 50% lower and the incidence of apoptotic cells approximately half that of the peripheral and transition zones. CONCLUSIONS: The central zone has features in common with both the SV and the other zones of the prostate. The higher incidence of proliferative diseases in the transition and peripheral zones may be associated with the higher rate of cell turnover observed in these zones.
Adolescent↗
Tumour markers for managing men who present with metastatic prostate cancer and serum prostate-specific antigen levels of <10 ng/mL.
OBJECTIVE: To define immunohistochemical features of the primary cancers that might help in the differential diagnosis and monitoring of treatment in men presenting with metastatic prostate cancer and low serum levels of prostate-specific antigen (PSA), who can be difficult to diagnose and manage. PATIENTS AND METHODS: Paraffin blocks of prostate biopsies were obtained for 33 patients presenting with untreated metastatic prostate cancer and serum PSA levels of <10 ng/mL. Sections were immunostained for PSA, prostatic acid phosphatase (PAP), prostate-specific membrane antigen (PSMA), androgen receptor (AR), chromogranin A and CD 56. RESULTS: The combined Gleason scores were 8-10 in 25 men (76%) and 6 or 7 in the other eight (24%). Morphologically, there were no neuroendocrine features. PSA immunostaining was equivocal in 12 (36%) cases and in a further 19 (58%) was strong but focal and could be missed on biopsy sampling. PSMA was expressed in 90% of cases, and staining was widely distributed in nine of the 12 in which PSA staining was equivocal. There was strong AR expression in 30 (91%) cases and it was present in areas where PSA was absent. CONCLUSION: In this patient group, immunohistochemical assessments of PSMA and AR are potentially useful as diagnostic markers.
Antigens, Surface↗
What surgical resection margins are required to achieve oncological control in men with primary penile cancer?
OBJECTIVE: To evaluate the surgical excision margin required for local oncological control in primary penile cancers, as patients with penile cancer who undergo radical amputation suffer marked psychological, functional and cosmetic sequelae, and although organ-sparing surgery has improved the quality of life of these men, the optimum surgical excision margin to achieve oncological control is unknown. PATIENTS AND METHODS: In all, 51 patients (mean age 61 years) diagnosed with squamous cell carcinoma of the penis between May 2000 and December 2004 were selected for treatment with conservative surgical techniques. All patients were staged before surgery using magnetic resonance imaging. Histopathological features of the tumours, including type, grade, stage and distance from the surgical excision margin, were evaluated. All patients were followed in the outpatient department according to European Association of Urology guidelines. RESULTS: The median (range) follow-up of the men was 26 (2-55) months. Patients were treated by wide localized excision (nine), glans excision (26) and partial penectomy (16). The histopathological review included the analysis of 102 surgical margins (deep and skin) with 49 (48%) measured within 10 mm of the tumour edge and 92 (90%) within a <20-mm resection margin. Three patients (6%) had tumour involvement at the surgical margin and had further surgery. During follow-up two patients (4%) developed local tumour recurrence and were treated successfully with partial penectomy. CONCLUSION: A traditional 2-cm excision margin is unnecessary for treating squamous cell carcinoma of the penis. Conservative techniques, involving excision margins of only a few millimetres, appear to offer excellent oncological control.
Adult↗
P2X3-immunoreactive nerve fibres in neurogenic detrusor overactivity and the effect of intravesical resiniferatoxin.
OBJECTIVES: The ATP-gated purinergic receptor P2X3 is expressed by small diameter sensory neurons and has been identified in normal and neurogenic human bladder suburothelial fibres. Animal models have shown that ATP is released by the urothelium during bladder distension, suggesting a mechanosensory role for P2X3 receptors in normal bladder function. Successful treatment of spinal neurogenic detrusor overactivity (NDO) with intravesical resiniferatoxin (RTX), which partly acts on suburothelial C fibres, provides evidence for the emergence of a C fibre-mediated spinal reflex. The aim of this study was to investigate the possible role of P2X3-positive innervation in this pathological voiding reflex by comparing suburothelial P2X3 immunoreactivity of controls and in patients with NDO before and after intravesical RTX. METHODS: Bladder biopsies were obtained from 8 controls and 20 patients with refractory NDO enrolled in a trial of intravesical RTX. P2X3 nerve fibre density and intensity were studied in the specimens by immunohistochemistry. RESULTS: P2X3-IR nerve fibres were significantly increased in patients with NDO compared to controls (p=0.014). Thirteen patients had pre- and post-RTX biopsies available for immunohistochemistry; 5 of them responded clinically and 8 were non-responders. In the 5 patients who responded to RTX, there was a significant decrease in P2X3-positive fibres (p=0.032), whereas in non-responders, P2X3-IR nerve fibre density did not change significantly. CONCLUSIONS: In patients with NDO, the numbers of P2X3-IR nerve fibres were increased in the suburothelium. There was a significant decrease in P2X3 immunoreactivity in responders to RTX, indicating a potential pathophysiological role for the P2X3 expressing fibres.
Diterpenes↗
Minichromosome maintenance protein in myxofibrosarcoma.
Histopathological assessment of myxofibrosarcoma may be difficult, especially on the basis of a small core biopsy, which enables only a crude evaluation of grade and prognosis. We have tested the hypothesis that determination of cell cycle state may assist in the diagnostic assessment of myxofibrosarcoma. We have studied 51 cases of high-grade (n=20), intermediate-grade (n=21), and low-grade (n=10) myxofibrosarcomas, as well as nine cases of benign myxoma. Cell cycle state within tumors was determined by immunostaining for the recently described marker minichromosome maintenance protein 2 (MCM2), together with Ki67. Labelling indices for both markers were correlated with tumor grade, mitotic index, and time to first recurrence. The MCM2 labelling indices were significantly higher than the Ki-67 labelling indices. Both indices showed a significant correlation with the mitotic index and both showed significant increases with increasing grade of myxofibrosarcoma. The MCM2 labelling index (but not the Ki67 labelling index) showed a significant inverse exponential correlation with the time to first recurrence. Myxoid and cellular areas showed no difference in the MCM2 and Ki-67 labeling index, suggesting that clinically useful information could be obtained from any component of a myxofibrosarcoma sampled in a needle biopsy and/or cytological specimen. We therefore suggest that assessment of cell cycle state may be a useful diagnostic adjunct in the histopathological assessment of myxofibrosarcoma, by enabling more accurate determination of grade and prediction of outcome.
Adult↗
Anaplastic lymphoma kinase (ALK 1) staining and molecular analysis in inflammatory myofibroblastic tumours of the bladder: a preliminary clinicopathological study of nine cases and review of the literature.
Inflammatory myofibroblastic tumours (IMFT) may arise at any anatomical site, including lung, soft tissues, retroperitoneum and bladder. Although morphologically similar, these lesions encompass a spectrum of entities with differing aetiology, ranging from reactive/regenerative proliferations to low-grade neoplasms with a risk of local recurrence, but no significant metastatic potential. Vesical IMFT usually presents as a polypoid mass with a pale firm cut surface and can be of considerable size, mimicking a malignant tumour clinically and radiologically. Its good outcome, however, warrants conservative surgical excision, emphasising the importance of identification and distinction from malignant tumours of the bladder that may require more radical surgery and/or adjuvant therapy. We conducted a preliminary retrospective, comparative immunocytochemical study of 20 bladder tumours, including nine IMFTs, five spindle cell (sarcomatoid) carcinomas, two rhabdomyosarcomas, two leiomyosarcomas and two neurofibromas. The results confirmed IMFT positivity for smooth muscle actin, desmin and cytokeratin in 78-89% cases, resulting in potential confusion with sarcomatoid carcinoma or leiomyosarcoma. In contrast, cytoplasmic anaplastic lymphoma kinase (ALK 1) staining was present in eight IMFT (89%), but was not seen in any other lesion examined. The ALK 1 staining was confirmed by fluorescence in situ hybridisation, with translocation of the ALK gene present in 15-60% tumour cells in four of six IMFT examined, but not in four cases of sarcomatoid carcinoma or three of leiomyosarcoma. In conclusion, ALK 1 staining may be of value in the distinction of vesical IMFT from morphologically similar entities, and often reflects ALK gene translocations in these lesions.
Actins↗
Tissue microarrays in urology.
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Disease Progression↗
Differential expression of CD44 during human prostate epithelial cell differentiation.
CD44 is a polymorphic transmembrane glycoprotein that binds hyaluronan and growth factors. Multiple isoforms of the protein can be generated by alternative splicing but little is known about the expression and function of these isoforms in normal development and differentiation. We have investigated the expression of CD44 during normal prostate epithelial cell differentiation. A conditionally immortalized prostate epithelial cell line, Pre2.8, was used as a model system. These cells proliferate at 33C but at 39C stop dividing and undergo changes consistent with early stages of cell differentiation. During the differentiation of these cells, the expression of the CD44 isoform v3-v10 was upregulated. Two layers of epithelial cells can clearly be distinguished in the human prostate, a basal layer expressing keratins 5/14 and a luminal layer expressing keratins 8/18. In prostate tissue the v3-v10 isoform was found predominantly in basal cells but also in keratin 14-negative, keratin 19-positive cells intermediate between the two layers. CD44 v3-v10 was also expressed in other keratin 14-negative prostate tissues, the ejaculatory ducts and prostatic urethra. Therefore, CD44 v3-v10 may be important as a cell surface marker for differentiating cells in the prostate epithelium.
Cell Differentiation↗
Clinical features of patients who present with metastatic prostate carcinoma and serum prostate-specific antigen (PSA) levels < 10 ng/mL: the "PSA negative" patients.
BACKGROUND: Although < 1% of men present with prostate-specific antigen (PSA)-negative prostate carcinoma, in that they have serum PSA levels much lower than the tumor burden would suggest, such patients represent a management dilemma. To the authors' knowledge, little information exists in the literature regarding patterns of disease and response to treatment. The authors wished to define the clinical features of this patient group. METHODS: The British Association of Urological Surgeons Cancer Registry 2000 and 2001 data bases were used to identify the clinical features and outcome of 33 men with metastatic prostate carcinoma who presented with serum PSA levels < 10 ng/mL. Clinical notes and histopathology were reviewed for each patient. RESULTS: Seventeen patients (51%) presented with urinary symptoms and/or pelvic pain, 6% with cachexia and 21% with bone pain. Characteristic bone metastases were present in 81% of patients, similar to the presentation of men with high serum PSA levels. Hypercalcemia was a feature in 9% of patients. Visceral metastases were present in two patients. The median response duration to first-line hormone manipulation was 7 months. No responses were seen in 11 of 13 patients who received second-line hormones or to any third-line treatment. Three of 5 patients who received chemotherapy responded but developed recurrent disease within 8 weeks of treatment cessation. The median overall survival was 12 months. CONCLUSIONS: The presentation of patients with treatment-naïve PSA-negative metastatic prostate carcinoma is similar to that of patients with high serum PSA levels, but their median survival and response duration to first-line hormone therapy are of much shorter duration. Second-line hormone therapy is ineffective, but early chemotherapy may be beneficial. Hypercalcemia is a particular feature in this group of patients.
Aged↗
Looking after doctor patients.
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Anxiety↗
"Doctors in Difficulty": a way forward?
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Humans↗
Pathologic quiz case: a 93-year-old woman with an enlarged and tender left breast. Histiocytoid variant of lobular breast carcinoma.
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Aged↗
Analysis of minichromosome maintenance proteins as a novel method for detection of colorectal cancer in stool.
Colorectal cancer is a common disease, and more reliable screening methods are needed for early detection. We aim to develop a non-invasive, stool-based assay that can identify colorectal cancer by detection of minichromosome maintenance protein 2 (MCM2) expression in colonocytes retrieved from the faecal surface. We devised a cell line model to investigate methods and conditions for optimum colonocyte retrieval. In our clinical evaluation study, MCM2-positive cells were retrieved from 37 of 40 patients with symptomatic colorectal cancer, but from none of 25 healthy control individuals. These results suggest that immunocytochemical analysis of retrieved colonocytes might enable accurate detection of colorectal cancer in stool.
Adenocarcinoma↗