Cellular cohesion as a prognostic factor in malignant melanoma: a retrospective study with up to 12 years follow-up.

Malignant melanomas have a high metastatic potential. Although the depth of tumour invasion is the single most important histological prognostic factor, in clinical practice this correlation is frequently challenged. In this study, we assessed the cohesion of malignant melanocytes in the dermal component of all primary melanomas in vertical growth phase with tumour thickness >0.76 mm diagnosed in our Department between 1990 and 1995. The rationale behind this morphological evaluation was based on the hypothesis that a change in the adhesion molecule profile of melanoma cells may manifest visually discrete changes in the way that cells group together in dermal aggregates. We used a dyscohesion score based on the proportion of invasive tumour occupied by dyscohesive neoplastic cells and assessed its clinical significance by correlating it with the incidence of recurrence, regional and distant metastases and survival of the patients. Follow-up was up to 12 years. We found that the degree of melanoma cell dyscohesion was associated with the probability of local recurrence or metastasis. This correlation was particularly significant when dyscohesion involving an area smaller than 25% (dyscohesion score 1) of the dermal component was compared to dyscohesion involving a larger area (scores 2-4). Melanomas in the latter group had significantly increased likelihood of recurrence or metastasis (P<0.025, log-rank test). This was particularly the case in T1-T3 melanomas (P<0.005). Similarly, T1-T3 melanomas with dyscohesion score 1 had a significantly higher survival rate (P<0.025). In the same cohort, both disease-free survival and survival were not significantly correlated to thickness, probably due to the limited number of cases. Finally, we showed that extent of dyscohesion was independent of Breslow thickness or tumour regression. We believe that estimation of melanoma cell dyscohesion is a reliable histological prognostic factor that may be appropriate in clinical practice.

The conventional autopsy in modern medicine.

In many countries, including the UK, where relatives' consent is required, clinical autopsy rates (i.e. autopsies other than those required by law) have been declining since the 1950s. In the UK, even in teaching hospitals, the clinical autopsy rate has fallen to only 10% of deaths or less. At this rate of decline, clinical autopsies - and the pathologists who perform them - face extinction. The future practice of medicine will be blind to the many adverse consequences of clinical actions or omissions. The reasons for this decline are manifold and these have to be addressed if autopsy is to stand a chance of survival. The future of autopsy lies in promoting public support for autopsies, in some cases adapting the autopsy to address specific questions, thus making more effective use of information from autopsies. Only by ensuring that the next generation of doctors have experienced the powerful educational benefit of examining the body after death will the importance of autopsy to modern medicine be understood.

A longitudinal study of the effect of subcutaneous estrogen replacement on bone in young women with Turner's syndrome.

It is desirable that young women with primary ovarian failure achieve normal peak bone mass to reduce the subsequent risk of osteoporosis, and that there are management strategies to replace bone that is already lost. While estrogen (E2) is generally considered to prevent bone loss by suppressing bone resorption, it is now recognized that estrogen also exerts an anabolic effect on the human skeleton. In this study, we tested whether estrogen could increase bone mass in women with primary ovarian failure. We studied the mechanism underlying this by analyzing biochemical markers of bone turnover and iliac crest biopsy specimens obtained before and 3 years after E2 replacement. Twenty-one women with Turner's syndrome, aged 20-40 years, were studied. The T scores of bone mineral density at lumbar spine and proximal femur at baseline were -1.4 and -1.1, respectively. Hormone replacement was given as subcutaneous E2 implants (50 mg every 6 months) with oral medroxy progesterone. Serum E2 levels increased incrementally from 87.5 pM at baseline to 323, 506, 647, and 713 pM after 6 months and 1, 2, and 3 years of hormone replacement therapy (HRT), respectively. The bone mineral density at the lumbar spine and proximal femur increased after 3 years to T scores of -0.2 and -0.4, respectively. The cancellous bone volume increased significantly from 13.4% to 18.8%. There was a decrease in activation frequency, but the active formation period was increased by HRT. There was a significant increase in the wall thickness from 33.4 microm at baseline to 40.9 microm after 3 years of HRT, reflecting an increase in bone formed at individual remodeling units. Although there was an early increase in biochemical markers of bone formation, these declined thereafter. Our results show that estrogen is capable of exerting an anabolic effect in the skeleton of young women with Turner's syndrome and low bone mass.

Malignant and noninvasive skin tumours in renal transplant recipients.

Background. Transplant recipients require immunosuppression to prevent graft rejection. This conveys an increased risk of malignancy, particularly skin tumours. There is a need for up-to-date data for the South of England. Method. Pathology records were reviewed for 709 kidney transplant recipients on immunosuppression at our hospital from 1995 to 2008. Skin tumours were recorded/analysed. Results. Mean age at transplant was 46 years. Mean length of follow-up was 7.2 years and total follow-up was 4926 person-years. 53 (7.5%) patients (39/458 (8.5%) males and 14/251 (5.6%) females) developed ≥1 skin malignancy. Cumulative incidences of 4.0%, 7.5%, and 12.2% were observed for those with <5, <10, and ≥10 years follow-up, respectively. The rate was 45 tumours per 1000 person-years at risk. Additionally, 21 patients (3.0%) only had noninvasive tumours. 221 malignant skin tumours were found: 50.2% were SCCs, 47.1% BCCs, and 2.7% malignant melanomas. Mean years to first tumour were 5.8. Mean number of tumours per patient was 4, with mean interval of 12 months. Conclusions. Despite changes in transplantation practice during the time since the last data were published in this region, these findings are similar to previous studies. This adds to the evidence allowing clinicians to inform patients in this region of their risk.

Malignancy without immortality? Cellular immortalization as a possible late event in melanoma progression.

Cell senescence is a permanent growth arrest following extended proliferation. Cultured cancer cells including metastatic melanoma cells often appear immortal (proliferate indefinitely), while uncultured benign nevi (moles) show senescence markers. Here, with new explantation methods, we investigated which classes of primary pigmented lesions are typically immortal. Nevi yielded a few proliferating cells, consistent with most nevus cells being senescent. No nevus culture (0/28) appeared immortal. Some thin and thick melanoma cultures proved immortal under these conditions, but surprisingly few (4/37). All arrested cultures displayed three senescence markers in some cells: ß-galactosidase, nuclear p16, and heterochromatic foci/aggregates. However, melanoma cultures also showed features of telomeric crisis (arrest because of ultrashort telomeres). Moreover, crisis markers including anaphase bridges were frequent in uncultured vertical growth-phase (VGP) melanomas. Conversely, all immortal melanoma cultures expressed telomerase reverse transcriptase and telomerase, showing aneuploidy. The findings suggest that primary melanomas are typically precrisis, with immortalization/telomere maintenance as a late event.

Dominantly inherited cutaneous small-vessel lymphocytic vasculitis maps to chromosome 6q26-q27.

Outside the context of hereditary deficiencies of complement and IgA, Mendelian inherited predisposition to small vessel lymphocytic vasculitis (SVLV) has rarely been documented. Here we report a large, multigenerational family segregating symmetrical cutaneous SVLV affecting the cheeks, thighs and hands. In all affected family members the disease presented in early infancy and there was no evidence for an association with systemic disease. Skin biopsy of lesions showed a lymphocytic vasculitis with red blood cell extravasation. Complementary studies, with extensive investigation focused on dysfunction of the immunological system were negative. The pattern of inheritance of SVLV in the family was compatible with an autosomal dominantly acting disease gene with incomplete penetrance. To localize the disease causing gene in the family a genome-wide linkage search was conducted using a high-density SNP array. Haplotype construction and analysis of recombination events permitted the minimal interval defining the disease locus to be refined to a 4.7 Mb region on chromosome 6q26-q27. The genes CCR6 and GPR31, which map to the linked region represent plausible candidates for the disease on the basis of their biological function. Extensive screening of both genes by mutational analysis failed to identify a deleterious mutation in the family.

WASp deficiency in mice results in failure to form osteoclast sealing zones and defects in bone resorption.

No defects related to deficiency of the Wiskott-Aldrich Syndrome protein (WASp) have been described in osteoclasts. Here we show that there are significant morphologic and functional abnormalities. WASp-null cells spread over a much larger surface area and are highly polykaryotic. In their migratory phase, normal cells assemble clusters of podosomes behind their leading edges, whereas during the bone resorptive phase multiple podosomes are densely aggregated in well-defined actin rings forming the sealing zone. In comparison, WASp-null osteoclasts in either phase are markedly depleted of podosomes. On bone surfaces, this results in a failure to form actin rings at sealing zones. Complementation of WASp-null osteoclasts with an enhanced green fluorescent protein (eGFP)-WASp fusion protein restores normal cytoarchitecture. These structural disturbances translate into abnormal patterns of bone resorption both in vitro on bone slices and in vivo. Although physiologic steady-state levels of bone resorption are maintained, a major impairment is observed when WASp-null animals are exposed to a resorptive challenge. Our results provide clear evidence that WASp is a critical component of podosomes in osteoclasts and indicate a nonredundant role for WASp in the dynamic organization of these actin structures during bone resorption.