Merkel cell carcinoma in Western Australia: a population-based study of incidence and survival.

BACKGROUND: Merkel cell carcinoma (MCC) is an uncommon but aggressive cutaneous skin cancer. Even with the appropriate treatment, MCC is prone to recurrence, and metastases are common. Exposure to ultraviolet radiation has been suggested as contributing towards the development of MCC. MCC has not been extensively investigated in Australia, even though Australia has the highest incidence of sun-related cancers in the world. OBJECTIVES: To describe the demographics and determine trends of incidence and survival of MCC cases in Western Australia (WA). METHODS: All reported invasive cases of MCC incident between 1 January 1993 and 31 December 2007 were extracted from the WA Cancer Registry. Age-adjusted incidence rates for MCC were calculated using direct standardization to the U.S. standard 2000 population. Cause-specific survival was investigated using Kaplan-Meier and Cox proportional hazards analysis. results: Two hundred and fifteen cases were confirmed by pathological review as being definite cases of MCC. Patients were mainly males (65%) and elderly (median age 77 years). Standardized age-adjusted incidence rates were higher in men (1·0/100,000) than in women (0·63/100,000) and higher in older ages (15·5/100,000 in the 85+year age group) than younger ages (0·1/100,000 in the 30-34 year age group). Five-year cause-specific survival was 64%. CONCLUSIONS: Incidence of MCC in WA is the highest reported in the literature. In addition, MCC has worse survival than melanoma. The high rates and demographic and anatomical distribution are consistent with sun exposure playing a causal role.

Local recurrence of melanoma.

Local recurrence (LR) of cutaneous malignant melanoma (CMM) is a controversial issue, especially in regard to recommendations for margins of excision of primary CMM. Factual evidence in support of the belief that wider margins of excision decrease the risk of local recurrence is meagre, but recommendations for adjusting margins of excision according to tumour thickness are still presented. The histological features of LR indicate that two mechanisms are involved: (1) persistent growth of incompletely excised primary melanoma, and (2) local metastasis. The second group comprises the most common form of LR and is associated with a poor prognosis, indicating that it is a manifestation of systemic disease. The morphological features and the prognostic implications of LR indicate that many are due to haematogenous rather than lymphatic metastasis alone and, therefore, are not preventable by wider excisions beyond complete excision of the primary tumour itself. The concept that most LRs are metastases is consistent with the failure of wide margins of excision to prevent LR. The higher risk of LR associated with greater tumour thickness is associated with the increased risk of metastasis from the thicker tumours, not with the extent of excision. The resolution of the controversy regarding the primary surgical treatment of CMM depends on the recognition by pathologists and clinicians alike that the two types of LR have diagnostic microscopic features and that they have entirely different implications for prognosis.

Clinical and histologic features of level 2 cutaneous malignant melanoma associated with metastasis.

BACKGROUND: Metastatic melanoma developing in patients with a level 2 primary cutaneous malignant melanoma (CMM) is rare but has been reported in studies with follow-up periods ranging up to 15 years. The objective of this study was to investigate level 2 CMM associated with metastasis in a population-based retrospective study. METHODS: In this retrospective population-based study, all level 2 CMMs associated with metastases were identified in Western Australia during 1982-1989 and were followed up to the end of 1996. RESULTS: Pathology reports of 2834 patients were examined. Of these, 1716 had a CMM of maximum tumor thickness 1 mm or less recorded on the pathology report. Of these, 67 had a metastatic melanoma reported on follow-up. Histologic review of these 67 cases under blind conditions identified 5 cases with a level 2 primary CMM followed by metastasis without another primary CMM. All these level 2 CMM showed established regression. Eight other patients were identified with a level 2 CMM, metastatic melanoma, and another primary CMM of at least level 3 invasion. These subsequent primaries occurred before the metastasis had been reported. CONCLUSIONS: These findings suggest that metastasis from level 2 CMM without regression is very rare, if it occurs at all.

The repopulation of murine Langerhans cells after depletion by mild heat injury.

We have developed a model of focal Langerhans cell depletion by mild heat injury and used it to investigate the mechanisms of Langerhans cell repopulation in the injured epidermis. The possibility whether repopulation occurred by recruitment of precursor cells from the circulation or dermis or, alternatively, by migration from the surrounding normal epidermis into the injured area was considered. Repopulation was studied by evaluating the pattern of Langerhans cell reappearance and calculating the rate of change in the density. Heat injury followed by whole-body irradiation with shielding of the injured skin was used to assess repopulation in the absence of bone marrow precursors. Using tritiated thymidine autoradiography, we also investigated whether the newly arrived Langerhans cells (be they from circulating precursors or surrounding normal epidermis) actually divide. The results showed that heat injury completely eliminated the Langerhans cells within the area delineated by the injury. Two hours after injury, the Langerhans cells were fragmented and 2 days later, they could not be detected. Regeneration of the epidermis occurred 2 days after injury and Langerhans cells reappeared scattered somewhat sparsely in the centre of the lesion on day 3. These cells were small and slender, bearing one or two short dendrites. As the dendrites increased in number and in length, the cells became similar morphologically and phenotypically to normal Langerhans cells. The rate of repopulation increased dramatically between days 5 and 7 and reached normal density on day 11. The pattern of Langerhans cell repopulation in the injured area and the lack of repopulation in the irradiated animals indicated that repopulation occurs by immigration of precursors from the circulation or dermis. There was no indication of migration of Langerhans cells from surrounding normal epidermis. Lastly, the newly arrived Langerhans cells failed to divide at the site of injury.

The pathogenesis of local recurrence of melanoma at the primary excision site.

Local recurrence of melanoma at the primary excision site may imply that the primary excision was incomplete or 'inadequate', and that the recurrence was due to retained primary melanoma cells or occult microsatellites in the adjacent tissue. Pathologists frequently report these tumours in the scar as recurrent or residual melanoma, without further qualification, apparently without considering the possibility that they may be metastases and manifestations of systemic disease. In this study, 17 of 19 cases of locally recurrent melanoma at the primary excision site showed the histological features of metastasis rather than residual incompletely excised primary melanoma. Because the prevention of local recurrence is the main reason given in recommendations for wide excision of melanoma beyond complete excision of the primary tumour itself, it is essential that surgeons and pathologists should classify these neoplasms precisely as either persistent incompletely excised primary melanoma or metastatic melanoma.

The steady-state turnover of murine epidermal Langerhans cells.

We have investigated the steady-state turnover of murine epidermal Langerhans cells (LCs) using an X-irradiation model, 3H-thymidine autoradiography and cultured epidermal sheet explants, and by assessing the LC population in normal mice. The LC density after whole-body irradiation without any cutaneous shielding was not significantly different from that in skin shielded during whole-body irradiation (P > 0.05), indicating that the additional irradiation to the skin did not contribute to a decrease in LC density. In both instances, the LC number gradually decreased in a linear fashion. The results indicate that epidermal LCs continuously leave the epidermis and are continually replaced by circulating precursor cells from the bone marrow at a steady rate. Autoradiographic studies after a pulse injection of 3H-thymidine showed a labelling index of 0.013%, indicating that local mitosis is not an important contributor to the maintenance of the epidermal LC population. Although local X-irradiation resulted in temporary reduction of LC density, epidermal sheet explant culture obtained immediately after local X-irradiation showed no difference in LC density as compared with control unirradiated skin, indicating that the decrease in LC density was not due to significant LC destruction. From these data, we calculated that the half-life of murine LCs in the epidermis is approximately 9 days.

The morphological features of locally recurrent melanoma and cutaneous metastases of melanoma.

Local recurrence of melanoma at the primary excision site usually implies that the primary excision was incomplete or "inadequate" and that the recurrence was attributable to retained primary melanoma cells or occult melanoma metastases in the adjacent tissue. Pathologists frequently report these tumors in the scar as recurrent or residual melanoma, apparently without considering the possibility that they may be local metastases and manifestations of systemic disease. In this study of 72 cases, we have shown that the morphological features of locally recurrent melanoma, excluding persistent incompletely excised primary melanoma, and cutaneous metastases of melanoma were identical. Because the prevention of local recurrence is the main reason for wide excision of melanoma beyond complete excision of the primary tumor itself, it is essential that pathologists should classify these neoplasms precisely as either persistent incompletely excised primary melanoma or metastatic melanoma.

Necrobiotic xanthogranuloma with paraproteinaemia.

A 51-year-old woman developed multiple periorbital nodules. The subsequent demonstration of IgG lambda paraproteinaemia and the histological features of necrobiotic xanthogranulomatous inflammation confirmed the clinical diagnosis of necrobiotic xanthogranuloma with paraproteinaemia.

Differential expression of epidermal growth factor receptor in melanocytic tumours demonstrated by immunohistochemistry and mRNA in situ hybridization.

Differential expression of the epidermal growth factor receptor (EGFR) has been reported in melanocytic lesions. To evaluate these differences in EGFR expression in melanocytic tumours, formalin-fixed, paraffin embedded sections from 33 benign melanocytic neoplasms and 77 cutaneous melanomas were analysed for EGFR protein and mRNA expression using immunohistochemistry and mRNA in situ hybridization. The majority of benign and malignant lesions expressed EGFR at both protein and mRNA levels. In 7% (7/100) samples, mRNA but not protein expression was observed. Overall, a higher proportion of cells expressed EGFR protein in malignant lesions compared with benign lesions (P = 0.06), and the intensity of mRNA expression was higher in the malignant tumours (P < 0.001). No significant differences in EGFR protein or mRNA expression with tumour progression within the malignant lesions were seen. These results indicate that EGFR mRNA and protein expression is common to benign and malignant melanocytic lesions, and that an overall increase in expression is associated with malignant transformation. However, differential EGFR expression between in situ melanomas and invasive or metastatic lesions was not observed.

p16 and p21WAF1 protein expression in melanocytic tumors by immunohistochemistry.

To determine whether variation in the level of expression of p16 and p21WAF1 (p21) is associated with critical stages in cutaneous melanoma development or progression, the expression of these antigens was analyzed by immunohistochemistry in 110 benign and malignant melanocytic lesions. Differential expression of p16 protein has been reported in cutaneous melanocytic lesions, with loss of expression associated with the invasive stage of tumor development. Expression of p16 was seen in 31 of 35 benign melanocytic tumors (89%), 11 of 12 in situ melanomas (92%), 19 of 38 invasive primary melanomas (50%), and 16 of 25 metastatic melanomas (64%). There was a significant difference in the expression level of p16 observed in in situ versus invasive primary melanomas (p = 0.006), which is consistent with loss of normal p16 activity occurring in association with malignant tumor invasion. Overall, p21 levels were found to be low or undetectable in the majority of benign lesions, with greater p21 expression seen in malignant tumors. p21 was expressed in 28% of nevi, 60% of in situ melanomas, 61% of invasive melanomas, and 48% of metastatic melanomas. Among primary invasive tumors, the frequency of p21 expression increased with level of invasion (p < 0.01) and with increasing thickness (p < 0.01). However, differences in p21 expression were not clearly related to a particular stage of melanoma development.

Case-control study of sun exposure and squamous cell carcinoma of the skin.

We conducted a case-control study of sun exposure and squamous cell carcinoma (SCC) of the skin within a population-based, longitudinal study of skin cancer. Cases had histopathologically confirmed SCC. Subjects were interviewed about their lifetime sun exposure, including exposure to the site of the SCC (sites for controls were assigned randomly). Analysis was restricted to 132 cases and 1,031 controls born in Australia and with no ancestors from southern Europe. The total site-specific exposure was strongly related to risk of SCC; the odds ratio increased to a maximum of 3.3 at 65,000 hr of exposure before falling slightly. Site-specific exposure during childhood and adolescence was more strongly associated with SCC than exposure during adulthood. An intermittent pattern of weekly sun exposure was not associated with SCC and the odds ratios for hours of exposure on vacation were close to unity. The number of blistering sunburns to the site was positively associated with SCC. Use of sunscreens and hats showed inconsistent effects. Sun exposure, especially during childhood and adolescence, increases the risk of SCC. The pattern of exposure appears to be unimportant, despite the association with sunburn, which may simply be an indicator of the skin's sensitivity to sunlight.

Demographic characteristics, pigmentary and cutaneous risk factors for squamous cell carcinoma of the skin: a case-control study.

We conducted a case-control study of squamous cell carcinoma of the skin (SCC) in a cohort of people followed from 1987 to 1994. Subjects were residents of Geraldton, Western Australia, who were between 40 and 64 years of age in 1987. On 2 occasions, in 1987 and 1992, dermatologists examined participants for skin cancers. Subjects were also asked on several occasions about skin cancers that they had had treated. Migrants to Australia had reduced risks of SCC. Furthermore, people who migrated to Australia early in life or, equivalently, lived in Australia for a long time had a higher risk than immigrants who arrived later in life or more recently. People who had southern European ancestry had a much lower risk of SCC than other subjects, most of whom were of British or northern European origin. Among Australian-born subjects of British or northern European ancestry, the skin's sensitivity to sunlight was strongly associated with SCC. The pigmentary traits of hair colour, eye colour and skin colour showed weaker associations. The degree of freckling on the arm was strongly predictive of risk. The risk of SCC increased strongly with increasing evidence of cutaneous solar damage and was most strongly associated with the number of solar keratoses. Our results show that sensitivity to sunlight and high levels of exposure to sunlight are important determinants of the risk of SCC.

Prognostic significance of MIB-1 proliferative activity in thin melanomas and immunohistochemical analysis of MIB-1 proliferative activity in melanocytic tumors.

Metastasis from thin melanomas is rare and unpredictable. In order to assess the prognostic value of the proliferation marker, MIB-1, immunohistochemical staining was evaluated in a retrospective case-control study of 11 thin melanomas with documented metastasis and 11 control tumors that failed to metastasize. Tumors selected were < 1-mm thick and were individually matched for tumor thickness, date of excision, and patient age and sex. Analysis of MIB-1 expression as both a mean and a maximum level for the case and control groups revealed no association with metastasis. Wilcoxon's matched-pairs signed-rank test had p-values of 0.45 for the maximum values and 0.79 for the mean values. For the 11 thin melanomas that metastasized, there was a weak, yet statistically insignificant, correlation between the proportion of cells positive for MIB-1 and the length of the relapse-free period [Spearman's correlation coefficient = 0.20 for the maximum level (p = 0.56) and 0.19 for the mean level (p = 0.58)]. These results suggest that MIB-1 expression may be of limited value as a prognostic marker for increased risk of metastasis in patients with thin melanomas. MIB-1 immunohistochemistry was also performed on 25 benign and 70 malignant paraffin-embedded melanocytic tumors to evaluate the level of MIB-1 expression at different stages of tumor progression. A progressive increase in MIB-1 expression was seen from benign tumors through to primary melanomas, with the highest level seen in metastatic melanomas. Within the group of primary melanomas, the MIB-1 score was shown to correlate significantly with tumor thickness and Clark's level of invasion (Spearman's correlation coefficient = 0.71 for level and 0.77 for thickness).

Incidence of non-melanocytic skin cancer in Geraldton, Western Australia.

To measure the rate at which non-melanocytic skin cancers develop, we conducted a population-based, longitudinal study in Geraldton, Western Australia. Subjects were residents of Geraldton, Western Australia, who were between 40 and 64 years of age and registered on the electoral roll in 1987. In 1987 and again in 1992, dermatologists examined participants for skin cancers. They examined all skin areas, apart from those covered by underwear or hair. Subjects were asked about skin cancers that they had had treated between the 2 surveys. When all skin cancers were counted, the incidence rates of basal cell carcinoma were 3,379 per 100,000 person-years in women and 7,067 per 100,000 in men; those of squamous cell carcinoma were 501 per 100,000 in women and 775 per 100,000 in men. Sixteen percent of men and 14% of women developed at least one basal cell carcinoma; 2.8% of men and 2.2% of women had at least one squamous cell carcinoma. Most incident skin cancers were diagnosed at the second examination. More than half of the subjects who had a skin cancer at the first examination developed another. Squamous cell carcinomas occurred almost exclusively on parts of the body that are usually exposed. Basal cell carcinomas were common on the head, neck and trunk but not on the forearms and backs of hands. A quarter of people with a skin cancer on an exposed site also had one on the trunk. Our results show that skin cancer is extremely common in this population and frequently undiagnosed. Multiple skin cancers occur commonly, and skin cancers on exposed sites often are associated with skin cancers on less exposed sites.

Local recurrence of melanoma.

The precise classification of local recurrence of melanoma as either persistent incompletely excised primary melanoma or metastasis, is essential to the assessment of the efficacy of the treatment and prognosis, and to the logical conclusion of the debate about margins of excision for melanoma.