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Biomedical subjects

P Harnden

Publications and source records attributed to P Harnden.

At least 19 recordsLinked to original sources
PubMed2006

Retroperitoneal metastatic squamous cell carcinoma of the tonsil (with elevated beta human chorionic gonadotrophin): a misdiagnosis as extra-gonadal germ cell tumour.

Head and neck cancers usually spread first to the regional lymph nodes but rarely may metastasize to distant sites. Metastasis to distant lymph node groups is a rare event. Furthermore, delayed multiple metastases without local recurrence is relatively uncommon. A case of retroperitoneal metastasis from a squamous cell carcinoma of the tonsil, secreting beta human chorionic gonadotrophin (beta-hCG), is reported. A 58-year-old man had undergone a tonsillectomy and chemo-radiotherapy for squamous cell carcinoma of the left tonsil and 13 months later presented with non-specific abdominal pain. The serum beta-hCG levels were high and an abdominal ultrasound scan revealed hydronephrosis on the left side. A computed tomography scan demonstrated para-aortic retroperitoneal lymphadenopathy. The patient underwent an open lymph node biopsy. The initial pathological analysis was interpreted as extra-gonadal germ cell tumour and the patient received chemotherapy. A subsequent review was consistent with a metastatic squamous cell carcinoma of the tonsil, as immunohistochemical studies showed positive staining for epithelial membrane antigen and cytokeratins 5/6 but a negative reaction to placental alkaline phosphatase. Following this, the chemotherapy regimen was changed; however, a restaging scan demonstrated progression, and the patient died from aspiration pneumonia secondary to alcohol intoxication. To our knowledge, this is the first reported case of retroperitoneal metastasis from a squamous cell carcinoma of the tonsil, secreting beta-hCG and causing hydronephrosis. This case highlights the necessity of using clinical, histological, immunohistological and ultrastructural examination to establish precise diagnosis and to avoid inappropriate treatment.

Carcinoma, Squamous Cell↗
PubMed2006

A UK-based investigation of inter- and intra-observer reproducibility of Gleason grading of prostatic biopsies.

AIMS: The frequency of prostatic core biopsies to detect cancer has been increasing with more widespread prostate specific antigen (PSA) testing. Gleason score has important implications for patient management but morphological reproducibility data for British practice are limited. Using literature-based criteria nine uropathologists took part in a reproducibility study. METHODS: Each of the nine participants submitted slides from consecutive cases of biopsy-diagnosed cancer assigned to the Gleason score groups 2-4, 5-6, 7 and 8-10 in the original report. A random selection of slides was taken within each group and examined by all pathologists, who were blind to the original score. Over six circulations, new slides were mixed with previously read slides, resulting in a total of 47 of 81 slides being read more than once. RESULTS: For the first readings of the 81 slides, the agreement with the consensus score was 78% and overall interobserver agreement was kappa 0.54 for Gleason score groups 2-4, 5-6, 7, 8-10. Kappa values for each category were 0.33, 0.56, 0.44 and 0.68, respectively. For the 47 slides read more than once, intra-observer agreement was 77%, kappa 0.66. The study identified problems in core biopsy interpretation of Gleason score at levels 2-4 and 7. Patterns illustrated by Gleason as 2 tended to be categorized as 3 because of the variable acinar size and unassessable lesional margin. In slides with consensus Gleason score 7, 13% of readings were scored 6 and in slides with consensus 6, 18% of readings were scored 7. CONCLUSIONS: Recommendations include the need to increase objectivity of the Gleason criteria but limits of descriptive morphology may have to be accepted.

Biopsy↗
PubMed2006

A study of Gleason score interpretation in different groups of UK pathologists; techniques for improving reproducibility.

AIMS: To test the effectiveness of a teaching resource (a decision tree with diagnostic criteria based on published literature) in improving the proficiency of Gleason grading of prostatic cancer by general pathologists. METHODS: A decision tree with diagnostic criteria was developed by a panel of urological pathologists during a reproducibility study. Twenty-four general histopathologists tested this teaching resource. Twenty slides were selected to include a range of Gleason score groups 2-4, 5-6, 7 and 8-10. Interobserver agreement was studied before and after a presentation of the decision tree and criteria. The results were compared with those of the panel of urological pathologists. RESULTS: Before the teaching session, 83% of readings agreed within +/- 1 of the panel's consensus scores. Interobserver agreement was low (kappa = 0.33) compared with that for the panel (kappa = 0.62). After the presentation, 90% of readings agreed within +/- 1 of the panel's consensus scores and interobserver agreement amongst the pathologists increased to kappa = 0.41. Most improvement in agreement was seen for the Gleason score group 5-6. CONCLUSIONS: The lower level of agreement among general pathologists highlights the need to improve observer reproducibility. Improvement associated with a single training session is likely to be limited. Additional strategies include external quality assurance and second opinion within cancer networks.

Humans↗
PubMed2004

A surgical model of composite cystoplasty with cultured urothelial cells: a controlled study of gross outcome and urothelial phenotype.

OBJECTIVES: To study the outcome of composite cystoplasty using cultured urothelial cells combined with de-epithelialized colon or uterus in a porcine surgical model, using appropriate controls, and to characterize the neo-epithelium created by composite cystoplasty. MATERIALS AND METHODS: Urothelial cells were isolated and propagated in vitro from open bladder biopsies taken from nine female minipigs. Cohesive sheets of confluent urothelial cells were transferred to polyglactin carrier meshes and sutured to de-epithelialized autologous colon in four animals and de-epithelialized autologous uterus in five. These composite segments were then used for augmentation cystoplasty. Conventional colocystoplasty, de-epithelialized colocystoplasty and sham operations were carried out in six control animals. After killing the animals at approximately 90 days the bladders were removed for examination and immunohistochemical analysis, using a panel of antibodies against cytokeratins and urothelial differentiation-associated antigens. RESULTS: Macroscopically, the bladders augmented with composite segments derived from uterine muscle had no evidence of shrinkage or contracture. Histological analysis showed that in four of five composite uterocystoplasties, the neo-urothelium was stratified and had a transitional morphology, although in some areas coverage was incomplete. Immunohistochemical analysis showed evidence of squamous differentiation in both native and augmented segments. All composite and de-epithelialized colonic segments showed significant contraction with poor urothelial coverage, reflecting the unsuitability of the thin-walled porcine colon for de-epithelialization. CONCLUSIONS: The functional and macroscopic outcome of bladder augmentation with a composite derived from cultured urothelium and de-epithelialized smooth muscle of uterine origin endorses the feasibility of composite cystoplasty.

Animals↗
PubMed2004

Bladder cancer in patients with spinal cord injuries.

OBJECTIVE: To evaluate the age-standardized incidence rate of bladder cancer in patients with spinal cord injury (SCI) and the overall risk for this population. PATIENTS AND METHODS: We reviewed 1334 patients with SCI whose dates of SCI, or first attendance at our centre, were between 1940 and 1998. The length of follow-up was calculated for each patient and age-specific incidence rates of bladder cancer calculated using 5-year age bands. This was used to calculate the overall incidence rate, using direct standardization with the European standard population. The cancers were analysed histochemically to characterize the phenotype. RESULTS: The 1324 patients contributed a total of 12 444 person-years of follow-up. There were four cases of bladder cancer, giving an age-standardized incidence rate of 30.7 per 100 000 person-years. Histochemistry showed areas were positive for cytokeratin 14, which was also positive in the undifferentiated areas. Immunohistochemical staining was positive for cytokeratin 14 and consistently negative for cytokeratin 20, suggesting a pure squamous phenotype. CONCLUSIONS: The age-standardized incidence of invasive bladder cancer in patients in our SCI unit is not statistically different from that of the general population. However, the incidence of invasive bladder cancer in the present study appears to be lower than that reported in other series. Histochemical analysis confirmed a squamous cell phenotype in these tumours.

Adult↗
PubMed2003

Increased incidence of renal parenchymal carcinoma in the Northern and Yorkshire region of England, 1978-1997.

Kidney cancer remains relatively rare, but incidence and mortality rates are reported to be rising steadily across the world. To determine if such increases were occurring in the UK, we examined the rates of incidence and mortality in different histological subtypes of kidney cancer in the Northern and Yorkshire region of England. Details of all 8741 cases diagnosed between 1978 and 1997 were extracted from the population-based Northern and Yorkshire Cancer Registry. For all types of tumour, both incidence and mortality rates increased over the study period. Overall age-standardised incidence rates increased by 86% for renal parenchymal carcinoma (RPC) (80% for males, 90% for females) from 2.8 to 5.2 cases per 100000 (3.8-6.8 male, 2.0-3.8 female). There were incidence increases in all age groups, all Carstairs index groups and in both urban and rural populations. Although increased incidental detection of kidney tumours by improved investigational techniques may account for some of this rise, we believe it unlikely that it accounts for all of the increase observed. Potential aetiological causes for the increased rates include hypertension, smoking, a diet lacking fruit and vegetables, analgesic use and, particularly, obesity.

Adult↗
PubMed2001

Role of p53 in the responses of human urothelial cells to genotoxic damage.

Loss of p53 function is a feature of many types of malignancy, including transitional-cell carcinoma (TCC), where it is associated with high-grade lesions and the development of muscle-invasive disease. Genotoxic agents used as part of the treatment strategy may contribute to tumour progression by inducing further non-lethal DNA damage in surviving cells. To determine the role of p53 in cellular responses to genotoxic agents, we used cultured normal human urothelial (NHU) cells and NHU cells with disabled p53 function. Mitomycin C and gamma-radiation caused normal cells to undergo an extended period of cell-cycle arrest, followed by complete recovery of proliferative potential. In contrast, cells with disabled p53 function, whether karyotypically normal (HU-E6 cells) or post-crisis with karyotypic abnormalities (HU-E6P cells), underwent extensive apoptosis. Overall survival was dose-dependent, and surviving HU-E6 cells from low-dose treatments showed clonal karyotypic abnormalities. These findings demonstrate that p53 status is a crucial factor in determining the ability of urothelial cells to survive DNA damage and suggest caution in the use of genotoxic treatments for low-grade tumours as our data imply that malignancies that have not yet lost p53 function will show the same "repair-and-recovery" response as normal cells.

Alkylating Agents↗
PubMed2001

Identification of genes involved in human urothelial cell-matrix interactions: implications for the progression pathways of malignant urothelium.

Interactions between epithelial cells and the extracellular matrix are central to tissue homeostasis and have a dynamic role in tissue remodeling and repair. Regulation of these pathways is balanced by positive and negative feedback elements, many of which have been implicated in the pathways of malignant progression. We have used differential display to identify genes that are up-regulated in normal human urothelial cells in response to exposure to extracellular matrix proteins (Matrigel) in vitro. This approach has identified genes that have key roles in cell-cell and cell-matrix interactions and that have been implicated in the progression of carcinomas of urothelial or other epithelial cell origins. One confirmed but unknown differentially expressed sequence was used to isolate a full-length gene, MIG-C4, from a human urothelial cDNA library. This gene was found to encode a novel urokinase plasminogen-activator receptor-like member of the Ly-6 family of glycosyl-phosphatidylinositol-anchored glycoproteins, and was identified as the human homologue of the rat metastasis-associated C4.4A gene. By in situ hybridization, MIG-C4 was expressed variably in normal urothelium and intensely in the tumor component of some noninvasive superficial lesions and in invasive and metastatic urothelial cancers. Thus, our approach has identified previously nonimplicated gene products involved in normal urothelium-matrix interactions that could be tumor-invasion or suppressor-gene targets in the development of invasive and metastatic tumor phenotypes.

Amino Acid Sequence↗
PubMed2001

The role of the histopathologist in the management of testicular germ cell tumour in adults.

In the last 20--30 years the availability of effective chemotherapy and more accurate clinical staging has greatly improved the prognosis for patients with testicular germ cell tumours. Initially, such treatment appeared to diminish the role of histopathology to the distinction between seminoma and nonseminomatous germ cell tumour (NSGCT) in the primary specimen. However, histopathology has evolved as a prognostic tool indicating the risk of relapse in various defined clinical contexts thereby facilitating therapeutic decisions. The clinical emphasis has been on quality of life and reduction of therapy both in terms of the number of patients treated and the number of chemotherapy courses given to each patient. The treatment of adult testicular germ cell tumours may differ between countries but protocols are established. Therefore it is appropriate to discuss the role of histopathology during this era of relative therapeutic stability.

Adult↗
PubMed1999

Expression of cytokeratin 20 redefines urothelial papillomas of the bladder.

BACKGROUND: Most non-invasive urothelial tumours of the bladder are diagnosed as papillary carcinomas in accordance with the WHO classification and because the identification of papillomas is difficult by routine histology; some patients are therefore misdiagnosed. This practice is associated with psychological morbidity for the patient and may also skew cancer statistics. Cytokeratin 20 (CK20) is a sensitive marker of urothelial differentiation. We investigated whether this marker could be used in the identification of urothelial papillomas and used the rate of recurrence as an indicator to assess the biological behaviour of such tumours. METHODS: In a prospective study, immunocytochemistry for CK20 was done on tumours of all patients who presented for the first time with non-invasive papillary bladder tumours. We classified the expression pattern of CK20 as normal or abnormal at the time of initial diagnosis. We recorded time to first biopsy-proven recurrence or length of follow-up when no recurrence was observed. FINDINGS: Of 58 consecutive patients, ten had tumours with a normal pattern of CK20 expression. No patients developed further tumours during the follow-up (median 18 [range 13-28] months). By contrast, 30 (73%) of the 41 evaluable patients with tumours that showed abnormal CK20 expression developed further tumours; the median time to a second tumour was 6 (2-24) months. The only factor that had a significant effect on the outcome of patients in terms of recurrence was expression of CK20 (p<0.0001). INTERPRETATION: Normal urothelial differentiation, as evidenced by a normal pattern of CK20 expression, is retained in a proportion of non-invasive papillary urothelial tumours and thus justifies use of the term urothelial papilloma. A large-scale study is needed to investigate the outcome of patients with such tumours.

Adult↗
PubMed1999

Urinary concentrations of the soluble adhesion molecule E-cadherin and total protein in patients with bladder cancer.

Reduced expression of the adhesion molecule E-cadherin has been associated with increased invasiveness and poorer survival in patients with bladder cancer. We have examined soluble E-cadherin (sE-cadherin) and total protein concentrations in urine from patients with bladder cancer (n = 34), non-neoplastic benign urological diseases (n = 14) and healthy controls (n = 21) to determine their diagnostic and prognostic significance. Soluble E-cadherin concentrations of the cancer group were significantly higher (P < 0.001) than those of the controls but the benign group was not significantly different from either the cancer group or the controls. When sE-cadherin concentrations were adjusted for creatinine, similar but more statistically significant results were obtained and the benign group was significantly elevated compared with the controls (P < 0.01). No differences were apparent between the invasive (pT1-4) and non-invasive (pTa) cancers. Urinary total protein concentrations in the cancer group were significantly higher than the controls (P < 0.001) and the benign group (P < 0.05) although no difference was seen between the benign group and patients with non-invasive (pTa) cancer or between the benign group and controls. When expressed as the protein/creatinine index, results were similar but more statistically significant and a significant difference was seen between invasive and non-invasive cancers (P < 0.01). Only the protein/creatinine index correlated significantly with stage of the tumour (P < 0.01). It is concluded that urinary sE-cadherin measurements are of no greater value than urinary total protein.

Adult↗
PubMed1999

Immunophenotype of transitional metaplasia of the uterine cervix.

Transitional, glandular, and squamous epithelia show distinctive patterns of expression of cytokeratins 13, 17, 18, and 20. Furthermore, some markers, such as cytokeratin (CK) 20 and the asymmetric unit membrane, are related to terminal urothelial differentiation, their expression limited to superficial and occasional intermediate cells. In this study, seven cases fulfilling the morphologic criteria of transitional metaplasia of the uterine cervix were investigated with these markers to determine whether there was evidence of true urothelial-type differentiation in these lesions. Results were consistent and showed clear differences between the squamous, glandular, and metaplastic transitional areas of the cervix. In particular, the expression of CK13, CK17, and CK18 in the metaplastic areas was identical to the pattern observed in normal urothelium. However, full urothelial differentiation was not observed, as CK20 and asymmetric unit membrane were never expressed in the transitional metaplasia. Based on these findings, the term of immature transitional metaplasia would be a more accurate description of this entity.

Aged↗
PubMed1999

Cytokeratin expression patterns in normal and malignant urothelium: a review of the biological and diagnostic implications.

The cytokeratins are the intermediate filament proteins characteristic of epithelial cells. In human cells, some 20 different cytokeratin isotypes have been identified. Epithelial cells express between two and ten cytokeratin isotypes and the consequent profile which reflects both epithelial type and differentiation status may be useful in tumour diagnosis. The transitional epithelium or urothelium of the urinary tract shows alterations in the expression and configuration of cytokeratin isotypes related to stratification and differentiation. In transitional cell carcinoma, changes in cytokeratin profile may provide information of potential diagnostic and prognostic significance. The intensification of immunolabelling with some CK8 and CK18 antibodies may underly an active role in tumour invasion and foci of CK17-positive cells may represent proliferating populations. Loss of CK13 is a marker of grade and stage and de novo expression of CK14 is indicative of squamous differentiation and an unfavourable prognosis. However, perhaps the most important recent finding is the demonstration that a normal CK20 expression pattern is predictive of tumour non-recurrence and can be used to make an objective differential diagnosis between transitional cell papilloma and carcinoma. This review will consider cytokeratin expression in urothelium and discuss the application of cytokeratin typing to the diagnosis and prognosis of patients with TCC.

Biomarkers↗