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.

Risk of developing cutaneous malignant melanoma in atypical-mole syndrome: New York University experience and literature review.

The presence of atypical moles (AM) is considered to be a marker for an increased risk of developing cutaneous malignant melanoma (MM). The extent to which individuals with the atypical-mole syndrome (AMS) are at risk for developing MM is unknown. We present a review of the world literature and of our experience at New York University. We conclude that the presence of AMS in Caucasians significantly increases the risk of developing MM, regardless of geographic location. A further increase in MM risk is noted if there is a personal and/or family history of MM.

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.

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.

Dysplastic melanocytic nevus. Immunohistochemical heterogeneity by melanosomal markers and S-100.

This study evaluates the expression of human melanosome specific antigen-1 and -2 (HMSA-1, -2) by dysplastic melanocytic nevus (DMN) and its significance by (a) immunostaining pattern, (b) other immunohistochemical markers (e.g., S-100), and (c) mesenchymal responses (e.g., lymphocytic infiltration). From 31 patients with DMN syndrome, 55 clinically characteristic and histologically (H&E) proven dysplastic nevi were assessed for HMSA expression. Approximately 70% of DMN lesions expressed the HMSA antigens; similar gross staining patterns were seen with both monoclonal antibodies (MoAbs). The expression of HMSA-2 was invariably associated with that of HMSA-1, but the converse did not apply. Two general staining patterns with MoAbs HMSA were appreciated: (a) uniform staining of the epidermal melanocytes in the DMN lesion (type I) and (b) nonuniform staining, with the epidermal melanocytes at the periphery of the DMN lesion reacting most intensely (type II). Although anti-S-100 antibody demonstrated a similar sensitivity (67%), it lacked specificity and did not distinguish different types of DMN, as compared with MoAbs HMSA. There was no correlation between these observed staining patterns and common histological features of DMN. There was a poor correlation between lymphocytic infiltrate (as judged by immunostaining for pan-T, Ti/h, Tc/s, and pan-B markers) and heterogeneity of immunostaining. We conclude that HMSA-1 and -2 are able to delineate two types of DMN and possibly bind different epitopes of the same antigen. Their potential usefulness in predicting malignant transformation of DMN has yet to be established.

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.

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.

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.

Dysplastic melanocytic nevi contain high levels of pheomelanin: quantitative comparison of pheomelanin/eumelanin levels between normal skin, common nevi, and dysplastic nevi.

The degree and type of melanogenesis, i.e., either eumelanin of pheomelanin, has been shown to be a reliable marker for the differentiation of the melanocyte. If exposed to UV light, these two melanins were reported to behave differently; eumelanin was photoprotective whereas pheomelanin was phototoxic to cultured tumor cells. Our previous study indicated that dysplastic melanocytic nevus (DMN) undergoes altered melanogenesis, forming pheomelanosome-like granules. The present study examined chemically the type and degree of melanin synthesized in 31 melanocytic nevi excised from 27 patients as compared with that occurring in the surrounding normal skin. The tissue content of eumelanin and pheomelanin was expressed by the amounts of pyrrole-2,3,5-tricarboxylic acid (PTCA) and aminohydroxyphenylalanine (AHP), respectively. We found that DMN lesions contain significantly higher amounts of pheomelanin than either common melanocytic nevus (CMN) or normal skin. Differences in pheomelanin content between DMN and CMN could not be accounted for by inherently higher levels of pheomelanin within the skin in general from DMN patients. Our present finding substantiates our previous claim that epidermal melanocytes in DMN undergo deranged melanogenesis.

Case report of Darier disease localized to the vulva in a 5-year-old girl.

A 5-year-old girl with Darier disease had numerous verrucous papules coalescing into plaques on both labia majora of approximately one year's duration. She was diagnosed as having genital warts, raising the suspicion of sexual abuse. Subsequently, a biopsy specimen from one of the vulvar lesions revealed histologic characteristics consistent with a diagnosis of Darier disease. The case is unusual for the age of onset and the site of initial involvement, and stresses the importance of including acantholytic disorders such as Darier disease in the differential diagnosis of a child with clinically verrucous lesions.

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.

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.

The epidermal melanin unit in the pathophysiology of malignant melanoma.

The epidermal melanin unit (EMU) denotes the symbiotic relationship between a melanocyte and a pool of associated keratinocytes. We propose to show that alterations in the biology of the EMU are the main determinant of the different patterns of intraepidermal growth of melanocytes in lentigo maligna melanoma (LMM) and superficial spreading melanoma (SSM). They also appear to affect the biosynthesis of melanin and melanosomes during malignant transformation. Findings in histochemical studies with monoclonal antibodies generated against melanosomal proteins to produce different stains of melanocytes of normal skin, dysplastic melanocytic nevi (DMN), common melanocytic nevi (CMN), LMM, and SSM have led to the suggestion that the altered melanosome synthesis is a main phenotype in the pathophysiology in neoplastic transformation of melanocytes. Altered melanin synthesis may also affect the carcinogenesis in malignant melanoma: pheomelanin is increased in malignant melanoma and DMN, but not in normal skin and CMN. Pheomelanin and its precursors could aid the malignant transformation of melanocytes through the generation of mutagenic ultraviolet photoproducts in familial DMN syndrome.

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.

Basal cell and squamous cell carcinomas are important risk factors for cutaneous malignant melanoma. Screening implications.

BACKGROUND: This study was designed to determine the risk of developing malignant melanoma (MM) in patients with a history of basal cell and/or squamous cell skin cancer (BCC/SCC) and to determine whether surveillance efforts can be directed toward these patients for the detection of early MMs. METHODS: The study cohort was followed by annual total cutaneous examination (TCE). Controls consisted of individuals from the United States population matched for age, sex, and length of follow-up. The anatomic locations of the study cohorts' newly diagnosed MMs were plotted on an anatomic chart. The setting was a private dermatology practice. Two hundred, ninety consecutive white patients with a history of BCC/SCC but with no personal or family history of MM were followed by annual TCEs. The main outcome measures were the relative risk of developing MM and their prognosis. RESULTS: Ten of the 290 patients developed an MM within an average of 109 months of follow-up (range, 3-17 years). All MMs were less than 0.70 mm in Breslow thickness and 80% occurred on usually clothed cutaneous sites. The expected number of MMs in the control population was 0.59 (P = 0.006), resulting in a relative risk of 17. CONCLUSION: Patients with BCC/SCC skin cancer are at substantial increased risk for developing MM. Regular and life-long surveillance TCE is an inexpensive and effective method for detecting curable MMs in such patients.

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.