Biomedical subjects

Charlotte M Proby

Publications and source records attributed to Charlotte M Proby.

9 recordsLinked to original sources

PubMed2006

Are keratoacanthomas variants of squamous cell carcinomas? A comparison of chromosomal aberrations by comparative genomic hybridization.

Keratoacanthoma (KA) is a benign keratinocytic neoplasm that usually presents as a solitary nodule on sun-exposed areas, develops within 6-8 weeks and spontaneously regresses after 3-6 months. KAs share features such as infiltration and cytological atypia with squamous cell carcinomas (SCCs). Furthermore, there are reports of KAs that have metastasized, invoking the question of whether or not KA is a variant of SCC. To date no reported criteria are sensitive enough to discriminate reliably between KA and SCC, and consequently there is a clinical need for discriminating markers. We screened fresh frozen material from 132 KAs and 37 SCCs for gross chromosomal aberrations by using comparative genomic hybridization (CGH). Forty-nine KAs (37.1%) and 31 SCCs (83.7%) showed genomic aberrations, indicating a higher degree of chromosomal instability in SCCs. Gains of chromosomal material from 1p, 14q, 16q, 20q, and losses from 4p were seen significantly more frequently in SCCs compared with KAs (P-values 0.0033, 0.0198, 0.0301, 0.0017, and 0.0070), whereas loss from 9p was seen significantly more frequently in KAs (P-value 0.0434). The patterns of recurrent aberrations were also different in the two types of neoplasms, pointing to different genetic mechanisms involved in their developments.

Carcinoma, Squamous Cell↗

PubMed2006

Clinicopathologic features of skin cancer in organ transplant recipients: a retrospective case-control series.

BACKGROUND: Non-melanoma skin cancers (NMSCs) are increased in organ transplant recipients, but transplant and immunocompetent squamous and basal cell carcinomas (SCCs, BCCs) have not been compared previously in a single-center study. OBJECTIVE: To compare clinicopathologic features of transplant and immunocompetent NMSCs. METHODS: Consecutive transplant NMSCs (60 SCCs, 100 BCCs) and immunocompetent NMSCs (40 SCCs, 125 BCCs) presenting between 1995-1997. RESULTS: Transplant patients were 15 years younger at time of NMSC diagnosis compared with immunocompetent individuals, and transplant tumors were often more multiple and extracephalic. Spindle cell morphology was more common in transplant SCCs, a superficial component was more common in transplant BCCs, and histologic features of HPV infection were overrepresented in transplant tumors. Outcome was worse for transplant SCCs but not transplant BCCs. LIMITATIONS: Histologic features required to identify HPV infection have not been validated. CONCLUSIONS: These findings have direct implications for clinical care. The increased frequency and distribution of transplant NMSCs underscore the importance of whole-body surveillance. Transplant SCCs, particularly those with diffuse spindle cell change, may require more aggressive management, whereas transplant BCCs do not. Finally, our data support differences in the pathogenesis of transplant NMSC, which may influence future preventive and therapeutic strategies.

Aged↗

PubMed2005

Genomewide single nucleotide polymorphism microarray mapping in basal cell carcinomas unveils uniparental disomy as a key somatic event.

Basal cell carcinoma is the most common human cancer with increasing incidence reported worldwide. Despite the aberrant signaling role of the Hedgehog pathway, little is known about the genetic mechanisms underlying basal cell carcinomas. Towards a better understanding of global genetic events, we have employed the Affymetrix Mapping 10K single nucleotide polymorphism (SNP) microarray technique for "fingerprinting" genomewide allelic imbalance in 14 basal cell carcinoma-blood pair samples. This rapid high-resolution SNP genotyping technique has revealed a somatic recombination event-uniparental disomy, leading to a loss of heterozygosity (LOH), as a key alternative genetic mechanism to allelic imbalances in basal cell carcinomas. A highly conserved LOH region at 9q21-q31 was found in 13 of 14 (93%) basal cell carcinomas. Further statistical and fluorescence in situ hybridization analyses confirmed that the 9q LOH was a result of uniparental disomy in 5 of 13 (38%) basal cell carcinomas. De novo mutations in the Patched 1 gene (PTCH) were found in 9 of 13 (69%) basal cell carcinomas with 9q LOH. A second important locus, containing LOH at 6q23-q27 was found in 5 of 14 (36%) basal cell carcinomas, suggesting that the presence of an additional putative tumor suppressor gene may be contributing to basal cell carcinoma development. This study shows that the rate of 9q LOH in basal cell carcinomas has been previously underestimated. Furthermore, we provide the first evidence that uniparental disomy due to somatic recombination constitutes one of the mechanisms of LOH in basal cell carcinoma tumorigenesis.

Aged↗

PubMed2005

Low-dose retinoids in the prevention of cutaneous squamous cell carcinomas in organ transplant recipients: a 16-year retrospective study.

OBJECTIVE: To evaluate the long-term efficacy of systemic retinoids in reducing the incidence of cutaneous squamous cell carcinomas (SCCs) in organ transplant recipients (OTRs), who are at greatly increased risk of SCCs. DESIGN: A retrospective before-after study of OTRs who had received low-dose systemic retinoids during 1 to 16 years for prevention of SCCs. SETTING: A specialist dermatology clinic for organ transplant recipients at St Bartholomew's and the Royal London Hospital, University of London, London, England. PATIENTS: Thirty-two OTRs with at least 1 histologically proved SCC. INTERVENTIONS: Continuous systemic retinoids at dosages of 0.2 to 0.4 mg/kg per day for a minimum of 12 months. MAIN OUTCOME MEASURES: The mean difference between the number of SCCs developing annually during retinoid treatment and the number during the 12-month pretreatment interval. RESULTS: In 28 continuously treated individuals, the mean number of SCCs in the 12-month pretreatment interval was 2.9. The number of SCCs was significantly reduced, with a mean difference of 1.46 in the first year of treatment (P = .006), 2.20 in the second (P<.001), and 2.14 in the third (P = .02). The numbers of SCCs were also reduced in subsequent years, but this effect was no longer significant because of smaller patient numbers. Six patients in whom retinoid treatment was interrupted subsequently had a significant increase in SCCs. CONCLUSIONS: Low-dose systemic retinoids significantly reduce SCC development in OTRs for the first 3 years of treatment, and this effect may be sustained for at least 8 years, with a generally well-tolerated side-effect profile. Studies are now required to further optimize their use as a chemopreventive strategy in high-risk OTRs.

Adult↗

PubMed2005

Safety and efficacy of 5% imiquimod cream for the treatment of skin dysplasia in high-risk renal transplant recipients: randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To evaluate the safety and efficacy of 5% imiquimod cream for cutaneous dysplasia in high-risk renal transplant recipients. DESIGN: A randomized, blinded, placebo-controlled study comparing treated with control skin. SETTING: A specialist organ transplant dermatology clinic. PATIENTS: Twenty-one high-risk patients with skin cancer with comparable areas of clinically atypical skin on dorsal hands or forearms. INTERVENTIONS: Imiquimod or placebo (randomly assigned) applied 3 times a week for 16 weeks to 1 dorsal hand or forearm, with 8 months of follow-up. At week 16, biopsy samples were collected from pre-assigned sites in the treatment and control areas and were examined for dysplasia. MAIN OUTCOME MEASURES: The proportion of patients showing reduced numbers of viral and keratotic lesions and reduced histological severity of dysplasia in the treatment vs control areas at week 16, serum creatinine levels, and tumors developing in the study sites. RESULTS: Fourteen patients receiving imiquimod and 6 receiving placebo completed the study. Seven patients using imiquimod (1 taking placebo) had reduced skin atypia, 7 using imiquimod (none taking placebo) had reduced viral warts, and 5 using imiquimod (1 taking placebo) showed less dysplasia histologically. In 1 year, fewer squamous skin tumors arose in imiquimod-treated skin than in control areas. Renal function was not adversely affected. CONCLUSIONS: Topical 5% imiquimod cream seems to be safe on skin areas up to 60 cm2 in renal transplant recipients. It may be effective in reducing cutaneous dysplasia and the frequency of squamous tumors developing in high-risk patients. Larger studies are required to confirm these results.

Acitretin↗

PubMed2005

Human papillomavirus gene expression in cutaneous squamous cell carcinomas from immunosuppressed and immunocompetent individuals.

Epidermodysplasia verruciformis (EV)-type human papillomavirus (HPV) DNA have been detected by PCR in squamous cell carcinomas (SCC) from both organ transplant recipients (OTR) and immunocompetent individuals. Their role in skin cancer remains unclear, and previous studies have not addressed whether the viruses are transcriptionally active. We have used in situ hybridization to investigate the transcriptional activity and DNA localization of HPV. EV-HPV gene transcripts were demonstrated in four of 11 (36%) OTR SCC, one of two (50%) IC SCC, and one of five (20%) OTR warts positive by PCR. Viral DNA co-localized with E2/E4 early region gene transcripts in the middle or upper epidermal layers. Non-EV cutaneous HPV gene transcripts were demonstrated in one of five (20%) OTR SCC and four of 10 (40%) OTR warts. In mixed infections transcripts for both types were detected in two of six (33%) cases. Our results provide evidence of EV-HPV gene expression in SCC; although only a proportion of tumors were positive, the similarly low transcriptional activity in warts suggests this is an underestimate. These observations, together with emerging epidemiological and functional data, provide further reason to focus on the contribution of EV-HPV types to the pathogenesis of cutaneous SCC.

Carcinoma, Squamous Cell↗

PubMed2004

p16INK4a and p14ARF tumor suppressor genes are commonly inactivated in cutaneous squamous cell carcinoma.

The p16(INK4a) and p14(ARF) tumor suppressor genes (TSGs) are encoded within the CDKN2A locus on chromosome 9p21 and function as cell cycle regulatory proteins in the p53 and RB pathways. Inactivation of these genes by genetic and epigenetic changes has been described in some human cancers, but their importance in cutaneous squamous cell carcinoma (SCC) has not been established. Our detailed examination of 40 cutaneous SCC revealed loss of heterozygosity of 9p21 markers in 32.5% of cases. Mutational analysis confirmed five point mutations in four of 40 SCCs. These mutations changed the amino acid sequence of p16(INK4a) in four tumors and p14(ARF) in three tumors. Promoter methylation of p16(INK4a) and p14(ARF) was detected in 13 of 36 (36%) and 16 of 38 (42%) cases, respectively. Absent protein expression was confirmed by immunohistochemistry in 13 of 16 (82%) of the tumors with biallelic inactivating events. Overall, the frequency of 9p21 alterations was 76% and for both p16(INK4a) and p14(ARF), promoter methylation is the commonest mechanism of gene inactivation. Alterations at this locus were significantly more common in tumors from immunocompetent compared with immunosuppressed individuals. These data confirm the importance of inactivation of p16(INK4a) and p14(ARF) TSGs in the pathogenesis of cutaneous SCCs.

Carcinoma, Squamous Cell↗

PubMed2003

High frequency and diversity of cutaneous appendageal tumors in organ transplant recipients.

BACKGROUND: Recipients of organ transplant who are immunosuppressed are at greatly increased risk of nonmelanoma skin cancers compared with the general population, but their risk of appendageal tumors is unknown. OBJECTIVE: Our aim was to conduct a systematic examination of cutaneous appendageal tumors arising in recipients of organ transplants compared with individuals who were immunocompetent (ICP). METHODS: We conducted a retrospective, clinicopathologic analysis of consecutive appendageal tumors arising in 650 recipients of organ transplants and in the general population of approximately 605,000 people served by our institution. RESULTS: Between 1993 and 1998, 231 appendageal tumors were identified in 211 individuals; 23 tumors were found in 21 of 650 patients undergoing transplant (3%), 10 in individuals with other immunosuppressive conditions, 3 in 2 patients with Muir-Torre syndrome, and 195 in 178 apparently ICP. In addition to the increased frequency of appendageal tumors among recipients of transplants, malignant tumors were overrepresented (43% of transplant tumors vs 4% in ICP; P <.0001) as were tumors of sebaceous origin (30% vs 6%; P <.0001). CONCLUSIONS: Recipients of organ transplant who are immunosuppressed have a greatly increased risk of cutaneous appendageal tumors compared with apparently ICP. In addition, their tumors are more likely to be malignant and of sebaceous origin.

Adult↗

PubMed2002

Human papillomaviruses and non-melanoma skin cancer.

Epidemiological and experimental studies have overwhelmingly confirmed human papillomaviruses as important causal agents in anogenital carcinogenesis. A role for human papillomaviruses has also been proposed in a diverse range of other malignancies, and particular interest has focused on non-melanoma skin cancer, the commonest malignancy in fair-skinned populations worldwide. Although the evidence for this is considerably less convincing than for anogenital cancer, important epidemiological and functional data have emerged over the past year that have furthered our understanding of the possible contribution of human papillomaviruses to skin cancer. Epidemiological human papillomavirus DNA detection studies have shown associations with non-melanoma skin cancer, but have also emphasized the ubiquity of epidermodysplasia verruciformis human papillomavirus types in normal skin, hair follicles and benign hyperproliferative disorders, as have seroepidemiological approaches. Functional investigations have demonstrated mechanistically relevant interactions between the virus and ultraviolet radiation, host cytokines and cellular proteins including p53 and the pro-apoptotic protein Bak. Taken together, these data have advanced our understanding of the contribution of human papillomaviruses to malignant transformation in cutaneous keratinocytes, but further research is required before a causal association between human papillomaviruses and skin cancer is reliably confirmed.

Basal Cell Carcinoma↗