Management of uveal melanoma: a consensus-based provincial clinical practice guideline.

INTRODUCTION: Survival in uveal melanoma has remained unchanged since the early 1970s. Because outcomes are highly related to the size of the tumour, timely and accurate diagnosis can increase the chance for cure. METHODS: A consensus-based guideline was developed to inform practitioners. PubMed was searched for publications related to this topic. Reference lists of key publications were hand-searched. The National Guidelines Clearinghouse and individual guideline organizations were searched for relevant guidelines. Consensus discussions by a group of content experts from medical, radiation, and surgical oncology were used to formulate the recommendations. RESULTS: Eighty-four publications, including five existing guidelines, formed the evidence base. SUMMARY: Key recommendations highlight that, for uveal melanoma and its indeterminate melanocytic lesions in the uveal tract, management is complex and requires experienced specialists with training in ophthalmologic oncology. Staging examinations include serum and radiologic investigations. Large lesions are still most often treated with enucleation, and yet radiotherapy is the most common treatment for tumours that qualify. Adjuvant therapy has yet to demonstrate efficacy in reducing the risk of metastasis, and no systemic therapy clearly improves outcomes in metastatic disease. Where available, enrolment in clinical trials is encouraged for patients with metastatic disease. Highly selected patients might benefit from surgical resection of liver metastases.

Risk of second primary malignancies following a diagnosis of cutaneous malignant melanoma or nonmelanoma skin cancer in Alberta, Canada from 1979 to 2009.

BACKGROUND: Recent studies have revealed geographical variations with respect to the risk of second primary malignancies (SPMs) following cutaneous malignant melanoma (CMM) and nonmelanoma skin cancer (NMSC). OBJECTIVES: To provide the largest analysis of the risk of SPM following skin cancers in Canada and to detect associations that may shed light on common pathogeneses between linked malignancies. METHODS: Relative risks for development of SPMs following a diagnosis of CMM or NMSC were calculated via a retrospective analysis of data retrieved from the Alberta Cancer Registry (ACR) from 1979 to 2009. RESULTS: From 1979 to 2009, 85,967 NMSC and 6884 CMM incident cases were recorded in the ACR. In total 19,869 SPMs were identified following a primary NMSC (7709 cutaneous and 12,160 noncutaneous), while 1437 SPMs (908 cutaneous and 529 noncutaneous) followed CMM. Patients with a previous history of skin cancer had a 60% increased risk of developing an SPM compared with those without [observed/expected ratio (O/E) 1.6, 95% confidence interval (CI) 1.6-1.7; P < 0.001]. Thirty and 10 different SPMs were significantly identified to follow a diagnosis of NMSC and CMM, respectively. Patients under the age of 40 years with a prior history of CMM had a marked increased expectancy for SPM [O/E 5.6, 95% CI 4.5-7.0; P < 0.001). CONCLUSIONS: Further studies are warranted to identify environmental and molecular connections among linked cutaneous and noncutaneous malignancies, which may lead to earlier detection of related neoplasms via expanded screening protocols and development of shared treatment regimens. Heightened surveillance for the development of SPMs in patients with CMM under the age of 40 years should be considered.

Trends in incidence of nonmelanoma skin cancers in Alberta, Canada, 1988-2007.

BACKGROUND: Nonmelanoma skin cancer (NMSC) is the most common malignancy affecting caucasian populations and has been seeing global increases in incidence for decades. OBJECTIVES: The objective of this study was to determine trends in incidence of NMSC in Alberta, Canada from 1988 to 2007. METHODS: A retrospective analysis of patients from Alberta diagnosed with NMSC from 1988 to 2007 inclusive was conducted with data retrieved from the Alberta Cancer Registry (ACR). Sex-, age- and anatomical location-specific incidence rates and trends were examined. RESULTS: From 1988 to 2007, there were 66 192 basal cell carcinomas, 19 959 invasive squamous cell carcinomas (SCC) and 12 494 in situ SCC. ACR coding for the 2007 data was not completed at the time of this study; hence, data from this year were not included in the trend analyses. Incidence of NMSC in women has been stable since 2000 [annual percentage change (APC) 0.08, P = 0.88] and has declined in men since 2001 (APC -1.28, P = 0.026). BCC incidence has been stable since 2000 (APC -0.80, P = 0.09). In situ and invasive SCC also showed a trend towards stabilization in 2000 (APC 0.36, P = 0.77) and 1995 (APC 0.01, P = 0.98), respectively. NMSC primarily affects the elderly and is rarely seen in individuals before the age of 40 years. Although the head and neck region was the location most often involved with NMSC (71.1%), it revealed a stabilizing trend, whereas most other anatomical regions demonstrated an increasing NMSC incidence rate. CONCLUSIONS: NMSC incidence in Alberta has stabilized in women and declined in men. As 95-99% of NMSC occurs in patients aged 40 years or older, and with its increased frequency in traditionally clothed areas, the authors recommend regular complete skin examinations starting at 40 years of age.

Ineffectiveness of sun awareness posters in dermatology clinics.

BACKGROUND: Although sun awareness posters have been used in doctors' offices and clinics for decades to promote sun protective behaviour, there is no evidence of their usefulness. OBJECTIVES: To investigate whether sun awareness posters lead to inquiry of skin cancer and sun protection measures. METHOD: Patients considered at risk for skin cancer seen at a dermatology clinic were randomly asked to complete a questionnaire designed to assess the effectiveness of three different sun awareness posters placed in patient rooms. The posters were selected on the basis of their catchy slogan and eye-appealing images, and included those featuring parental interest, sex appeal and informative advice. RESULTS: Only half of the patients noticed the posters (50.6%). The poster with sex appeal garnered the most attention (67.8%), followed by the informative poster (49.2%) and the parental interest poster (35.8%) (P < 0.001). Although patients who noticed the sun awareness poster inquired about cutaneous cancers and sun protection practices twice as often as those who did not notice the poster, only one-tenth of such inquiries were attributed to the poster ( approximately 5% of the target population). As reported in the questionnaire, the posters themselves were less effective than the advice of physicians in influencing patient attitudes towards sun protection measures. CONCLUSION: Organizations that produce and disseminate posters should consider beyond focus groups when they design their posters and should consider field testing their products to ensure that they are reaching the targeted audience and are having the expected beneficial effect, otherwise their posters are simply decorative.

Differentiation of atypical moles (dysplastic nevi) from early melanomas by dermoscopy.

Several conventional and new dermoscopic criteria are highly specific for diagnosing early melanomas. Until the reliability of the dermoscopic scoring systems has been validated, the presence of any combination of these specific features should elevate the index of suspicion for melanoma and prompt a biopsy to avoid missing this cancer.

Radioiodinated N-[3-(4-morpholino)propyl]-N-methyl-2-hydroxy-5-iodo-3-methylbenzylamine (ERC9): a new potential melanoma imaging agent.

The role of nuclear medicine in the management of patients with malignant melanoma has expanded in recent years with the introduction of lymphoscintigraphy and sentinel lymph node biopsy, intense interest in positron emission tomography (PET) imaging using 2-[18F]fluoro-2-deoxyglucose (18F-FDG) as a tracer, and encouraging reports of several new single-photon-emitting radiopharmaceuticals. While PET imaging with FDG exhibits a high sensitivity for imaging patients with melanoma, specificity may not be as high and access to the technology remains limited. Single-photon emission tomography (SPET) imaging remains standard technology for most nuclear medicine departments. We report a novel radiopharmaceutical--radioiodinated N-[3-(4-morpholino)-propyl]-N-methyl-2-hydroxy-5-iodo-3-methylbenzylamine (ERC9)--which appears to show a sensitivity and specificity that are commensurate with expectations of a radiopharmaceutical for routine clinical imaging. In this phase II trial, 110 patients at risk for recurrence, with suspected recurrence or being restaged have been imaged with this novel tracer, demonstrating an overall sensitivity of 91% and specificity of 89%. The results of our study support a phase III trial to establish the clinical role of ERC9 in staging melanoma patients at presentation who are at high risk for metastasis, or restaging patients with known relapse to assess the extent of their disease, particularly if therapy or enrollment into a clinical trial is being considered.

The role of phosphoinositide 3-kinase in the sorting and transport of newly synthesized tyrosinase-related protein-1 (TRP-1).

Tyrosinase-related protein-1 (TRP-1) is a 75 kDa type-1 transmembrane glycoprotein localized to the melanosome. The mechanism by which newly synthesized TRP-1 reaches its ultimate destination is currently unknown, but has been speculated to occur via the endosomal pathway. Recently, it has been shown that phosphatidylinositide (PI) 3-kinase is involved in various cellular functions, including regulating the constitutive movement of proteins from one intracellular compartment to another; however, whether PI 3-kinase participates in the trafficking of proteins such as TRP-1 to the melanosome is unknown. In this study we investigate the role of PI 3-kinase on the trafficking of TRP-1 in human melanoma MeWo cells using wortmannin, a potent inhibitor of PI 3-kinase. Our investigations demonstrate that wortmannin interferes with the membrane trafficking of TRP-1 in MeWo cells, and that it specifically results in the redistribution of the protein within a novel vesicular compartment with characteristics of the endosomal and lysosomal compartments [positive for LAMP-1, and partially positive for CD63 and cation-independent mannose 6-phosphate receptors (CI-M6PR)], and is accessible to internalized proteins such as immunoglobulins. Movement within this novel compartment is microtubule and GTPase dependent. These findings have led us to postulate that TRP-1 is sorted from the trans-Golgi network to a compartment in the vicinity of late endosomes, trafficking from which to the melanosome appears to be dependent on PI 3-kinase as it is blocked by wortmannin.

Intracellular vesicular trafficking of tyrosinase gene family protein in eu- and pheomelanosome biogenesis.

The intracellular vesicular trafficking in the melanosome biogenesis (melanogenesis) is reviewed with the incorporation of our own experimental findings. The melanosome biogenesis involves four stages of melanosome maturation, which reflect the transport of structural and enzymatic proteins from Golgi (trans-Golgi network: TGN) to the melanosomal compartment and their organization therein. The major melanosomal proteins include tyrosinase gene family protein (tyrosinase and tyrosinase-related protein; TRP), lysosome-associated membrane protein (Lamp) and gp100 (pmel 17). They are glycosylated in the endoplasmic reticulum, and transported by vesicles from the TGN to the melanosomal compartment. During the formation of transport vesicles, they assemble on the cytoplasmic face of the TGN to select cargo by interacting directly or indirectly with coat proteins. Tyrosinase and TRP-1 possess the dileucine motifs at the cytoplasmic domain, to which adapter protein-3 binds to transport them from the TGN to stage I melanosomes (related to late endosomes) and then to stage II melanosomes. A number of small guanosine triphosphate-binding proteins, including rab 7, appear to be involved in this vesicular transport. Phosphatidyl inositol 3 kinase also regulates this membrane trafficking of melanosomal glycoprotein. Eumelanogenesis is controlled by melanocyte-stimulating hormone, and all three tyrosinase gene family proteins are transported from the TGN to stage II melanosomes that are elliposoidal and contain the structural matrix of filaments/lamellae. In contrast, pheomelanogenesis is primarily regulated by agouti signal protein, and only tyrosinase is transported from stage I melanosomes to stage II melanosomes that are spherical and related to lysosomes. Because of the absence of TRP-1 and TRP-2 in pheomelanogenesis, it may be suggested that tyrosinase is involved in lysosomal degradation after forming dopaquinone, to which the cysteine present in the lysosomal granule binds to form cysteinyldopas that will then be auto-oxidized to become pheomelanin.

Nikolsky's sign: is it 'dry' or is it 'wet'?

Nikolsky's signs refers to the ability to induce peripheral extension of a blister as a consequence of applying lateral pressure to the border of an intact blister. Although initially used in reference to the pemphigus group of blistering dermatoses, a positive Nikolsky's sign can be seen in other bullous diseases such as toxic epidermal necrolysis and staphylococcus scalded skin syndrome. Appreciating whether the blister is 'wet' or 'dry' at the site of a positive Nikolsky's signs may have both diagnostic and prognostic significance which I illustrate with several clinical cases. Lastly, I review the significance of a positive Nikolsky's sign.

Vulvitis circumscripta plasmacellularis (Zoon's vulvitis) associated with autoimmune polyglandular endocrine failure.

Vulvitis circumscripta plasmacellularis (Zoon's vulvitis) is a distinct clinicopathological entity which presents as a shiny, atrophic, erythematous plaque of the vulva. It is an idiopathic condition with characteristic clinical and histological findings that generally occur in isolation of other medical disorders. We report a 36-year-old woman with vulvitis circumscripta plasmacellularis associated with polyglandular endocrine failure and circulating autoimmune antibodies. The association between Zoon's vulvitis and these autoimmune conditions raises the possibility that Zoon's vulvitis may be an autoimmune disorder.

Risk of developing multiple primary cutaneous melanomas in patients with the classic atypical-mole syndrome: a case-control study.

The classic atypical-mole syndrome (CAMS) and/or a history of malignant melanoma (MM) increases the risk for multiple melanomas. Case notes of 118 CAMS and 173 control patients, each with a history of MM, were reviewed for the occurrence of second primary MMs. The mean (+/-SD) age at diagnosis of the first MM was 38.8 +/- 12.8 and 48.9 +/- 14.7 years (P < 0.001) for CAMS cases and controls, respectively. Thirty-two of 118 CAMS and 18 of 173 controls developed second primary MMs, for a cumulative 10-year life-table risk of 35.5% and 17.0%, respectively (P < 0.0001). The mean number of months from the time of diagnosis of the first to the second MM was 33.9 +/- 41.8 and 58.6 +/- 57.3 months for the CAMS and controls, respectively (P = 0.08). In both cohorts the second MMs were significantly thinner, compared with the first MMs. The relative risk (RR) for developing second MMs for CAMS patients was 3.2. The RR for the CAMS cohort compared with a matched population from the United States Statistics, Epidemiology. End Results data base was 337, and for the controls, the RR was 84. All patients with MMs are at significant risk for developing multiple MMs: the risk is greater for patients with CAMS. Periodic total cutaneous examinations are indicated for life in an attempt to identify new MMs when they are thin.

Multiple pigmented follicular cysts: a subtype of multiple pilosebaceous cysts.

Pigmented follicular cyst is a rare disorder which typically presents as a pigmented papule on the head or neck and which, histologically, exhibits terminally differentiated, pigmented hair shafts in an epidermoid cyst. We report a 22-year-old man with the multiple variant of this disorder. Clinically he had numerous brown-blue to flesh-coloured, domed-shaped papules, on the anterior chest and abdomen, of 10 years duration. Histologically, hybrid cysts exhibiting trichilemmal and epidermoid keratinization were seen. The cysts contained numerous pigmented, terminally differentiated hair shafts and, embedded in the wall of one cyst, was a sebaceous gland. The condition of multiple pigmented follicular cysts, is thought to represent a distinct subtype within the spectrum of multiple pilosebaceous cystic disorders.

Induction of melanogenesis during the various melanoma growth phases and the role of tyrosinase, lysosome-associated membrane proteins, and p90 calnexin in the melanogenesis cascade.

Melanin biosynthesis (melanogenesis) is a metabolic pathway exclusively expressed by melanocytes and melanoma cells, and is often altered and/or markedly elevated in the latter cells. The changes in melanogenesis may be responsible for some of the clinical and histopathological features unique to melanoma. Melanogenesis may also contribute to the malignant transformation of melanoma precursors (i.e., atypical moles [or dysplastic nevi]) to melanoma as seen in patients with the familial atypical multiple-mole-melanoma (FAMMM) syndrome. However, it does not appear to affect the multi-step growth phases of melanoma cells from radial to vertical and lastly metastatic growth phases. Within the melanosomal compartment, eu- and pheomelanin pigments are synthesized. Both tyrosinase and lysosome-associated membrane protein (LAMP) gene products play important roles in this process. A coordinated interaction between these two gene family products is required for melanogenesis to occur properly. p90 calnexin is a new melanosome-associated molecule that is presumed to function as a melanogenesis chaperone by controlling the assembly and folding of glycoprotein intermediates of tyrosinase and LAMP gene families.

Management of cutaneous malignant melanoma by dermatologists of the American Academy of Dermatology. I. Survey of biopsy practices of pigmented lesions suspected as melanoma.

BACKGROUND: The incidence of malignant melanoma (MM) has rapidly increased during the past five decades. Relatively little information is available on whether the role of the dermatologist has increased concomitantly in the surgical management of this cancer. OBJECTIVE: Our purpose was to learn how members of the American Academy of Dermatology (AAD) treat patients with lesions highly suspected as being MM and how the management of these patients may have changed over the past decade. This, the first of a two-part series, concerns biopsies. METHODS: The data for the study were collected by means of a questionnaire that was sent to all members of the AAD practicing in the United States (N = 7412). RESULTS: A total of 2991 valid questionnaires were returned, a response rate of 40%. The majority of respondents (89% in 1982; 90% in 1992) stated that they performed the biopsies of pigmented lesions suspected of being MMs. Excisional biopsy was the preferred technique (58% in 1982; 68% in 1992). The type of biopsy and who performed the initial biopsy of a suspected MM were associated with the following factors: (1) the number of years in practice, (2) the type of practice, and (3) whether the dermatologist subsequently performed the definitive surgery for the MM. Regional variations in biopsy practices were also noted. CONCLUSION: Most AAD dermatologists who responded to the questionnaire perform the biopsies of lesions highly suspected of being MM. During the last decade an increasing proportion of dermatologists are performing excisional biopsies rather than other types of biopsies for such lesions.

Management of cutaneous malignant melanoma by dermatologists of the American Academy of Dermatology. II. Definitive surgery for malignant melanoma.

BACKGROUND: During the past few decades there has been increasing interest and training in dermatologic surgery. OBJECTIVE: Our purpose was to determine to what extent members of the American Academy of Dermatology (AAD) are involved in the surgical management of patients with malignant melanomas (MMs), comparing 1982 with 1992. METHODS: Members of the AAD practicing in the United States (N = 7412) were sent a questionnaire that surveyed their role in the definitive treatment of patients with MMs and the surgical margins of normal-appearing skin that they used or recommended for melanomas of various thicknesses. RESULTS: Sixty-four percent of the respondents stated that they performed the definitive surgery for in situ melanoma in 1992, a 14% increase from 1982. Although a significantly greater percentage of dermatologists were performing the definitive surgery for invasive melanoma in 1992 (28%) compared with 1982 (14%), the majority continued to refer their patients to surgical colleagues for definitive treatment. There has been a narrowing of surgical margins recommended or used for melanomas of all thicknesses. In addition, regional differences of the role of the dermatologist in surgical management of patients with MM were observed. CONCLUSION: An increasing proportion of dermatologists are involved in the surgical management of patients with MMs. Most dermatologists appear to be in accord with the guidelines for surgical margins currently recommended in the literature.

Case-control study of melanocytic nevi on the buttocks in atypical mole syndrome: role of solar radiation in the pathogenesis of atypical moles.

BACKGROUND: It is not known why melanocytic nevi (MN) become dysmorphic (atypical) in patients with the atypical mole syndrome (AMS). A complex origin for acquired MN has been postulated. Genetic predisposition, solar radiation, and/or the formation of a sun-induced circulating mitogenic factor may contribute to the formation of MN. OBJECTIVE: This study was undertaken to help elucidate the pathogenesis of atypical MN in patients with AMS. METHODS: The number of common and atypical MN was determined for a defined sun-protected area on the buttocks in 150 patients with AMS (cases) and 150 control subjects without AMS. Patients and control subjects were matched for age and sex and were classified into risk groups for the development of malignant melanoma according to the Rigel classification. RESULTS: MN on the buttocks were found in 23% of patients with AMS and 9% of control subjects (p < 0.003). In patients versus control subjects the mean number (1.3 vs 1.2, respectively) and mean diameter (5.7 vs 5.9 mm, respectively) of MN on the buttocks did not differ significantly. The MN in both patients and control subjects were not atypical clinically. The odds ratio for having AMS if MN were present on the buttocks was calculated to be 1.56 (95% confidence interval, 1.25 to 1.95). CONCLUSION: Although the patients were 2.6 times more likely to have MN on their buttocks than the control subjects, clinically the MN did not differ significantly in number or appearance from those found on the buttocks of control subjects. It is hypothesized that the formation of some atypical MN requires direct solar radiation for their phenotypic expression.

An estimate of the incidence of malignant melanoma in the United States. Based on a survey of members of the American Academy of Dermatology.

BACKGROUND: The incidence of malignant melanoma (MM) in the United States (US) must be known to accurately evaluate the costs that MM imposes on the health care system and society in general. Furthermore, knowledge of the incidence is needed to determine the benefit of MM prevention programs. OBJECTIVE: To obtain an estimate of the incidence of MM in the US. METHODS: The data for this study were collected by means of a questionnaire that was sent to all members of the American Academy of Dermatology practicing in the US (N = 7412). RESULTS: Based on the mean number of MMs seen annually per dermatologist in each state and the number of dermatologists per state, the number of new in situ and invasive MMs in the US in 1992 was calculated to be 80,000. This translates to an incidence of 32 MMs per 100,000 persons. CONCLUSIONS: Our estimate of 80,000 new MMs diagnosed in 1992 in the US suggests that MM places much greater burdens on the US health care system and society than that based on current published estimates.

Atypical mole syndrome: risk factor for cutaneous malignant melanoma and implications for management.

The incidence of malignant melanoma is increasing faster than that of any other cancer. It is important to identify subsets of the population at high risk of its development so that they can be observed more closely to identify early melanomas when they are curable. It has been reported worldwide that persons with the atypical mole (dysplastic nevus) syndrome are such a subset at increased risk. A risk gradient for the development of melanoma exists and varies from persons with one or two atypical moles and no family history of melanoma at one end of the spectrum to persons with the familial atypical multiple-mole melanoma syndrome at the other. Guidelines for the management of atypical mole syndrome are presented.

Techniques of cutaneous examination for the detection of skin cancer.

Skin cancers are the most common cancers in humans. The American Cancer Society estimates that in the United States more than 700,000 new skin cancers are diagnosed annually. Although the majority of nonmelanoma skin cancers occur on visibly exposed anatomic areas, most malignant melanomas occur on body sites obscured by clothing. The high mortality associated with advanced melanomas emphasizes the importance of performing regular total cutaneous examinations in all patients to detect early, easily curable lesions. A number of techniques aid in these examinations: (1) physical and psychologic preparation of the patient; (2) appropriate lighting and a suitable examination table; (3) when indicated, use of Wood's light, dermoscopy, and photography. In addition, any suspicious lesion should be biopsied promptly either in parte or in toto. Lastly, the patient should be educated about the signs and symptoms of skin cancer, the role of sunlight in causing skin cancer, and the need for sun avoidance and/or protection. By heightening public awareness of the high incidence of cancers of the skin and by emphasizing the need for routine examination of the entire cutaneous surface, most cutaneous malignancies can be diagnosed early when they can be cured by simple surgical procedures.