ࡱ> *E@ L bjbj "L  |DuDuDuDu}4 |=~28SFFFFF.%t(\{{{{{{{$oR{%FF{FF}"FF{{012F, /Du(|22H ~0=~2QQ,22Q2{{||-`G-||`G114 Melanoma  Frank O Nestle  Helmut Kerl  Key features Melanoma is a malignant tumor arising from melanocytes Melanoma has been increasing in incidence and mortality in recent decades Many deaths will occur at a younger age than for other solid tumors Early detection is an important factor in melanoma management Appropriate surgical treatment of low-risk melanoma (<1 mm Breslow depth) with 1 cm margins will cure patients in nine cut of ten cases   INCLUDEPICTURE "http://www.dermtext.com/images/pixel.gif" \* MERGEFORMATINET  INTRODUCTION  Melanoma is a tumor arising from melanocytes. Its incidence and patient mortality rates has been rising in recent decades. Melanoma is among the most common types of cancer in young adults HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114001" \o "Go here now" \t "body" 1. It therefore represents a substantial public health problem. Up to one-fifth of patients develop metastatic disease, which usually is associated with death. However, early detection and appropriate excision of the tumor leads to a cure rate of over 90% in low-risk (<1 mm Breslow depth) melanoma patients. Innovative early detection programs in combination with improved diagnostic tools and new immunological treatments in advanced stages of the disease will likely have an impact on the outcome of the disease in the future.   HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#"  INCLUDEPICTURE "http://www.dermtext.com/content/0323024092/graphics/thumbnails/M24092-114-f001.jpg" \* MERGEFORMATINET  HYPERLINK "http://www.dermtext.com/content/lightbox.cfm?action=add&ImgID=F114001&ImgBody=graphics/M24092-114-f001.jpg&ID=iBox" Add to lightbox  Figure 114.1 Molecular pathogenesis of melanoma development. CDKN2A (INK4a/ARF) encodes two separate gene products p16 and p14ARF, which are both negative regulators of cell cycle progression. The p16 protein executes its effects by competitive inhibition of cyclin-dependent kinase 4 (CDK4). CDK4 interacts with cyclin D and phosphorylates the master gatekeeper retinoblastoma protein (Rb). Phosphorylation of Rb will lead to S phase progression and ultimately cellular division and proliferation. An intact p16 protein is essential for cell cycle arrest. The net effect of CDKN2A mutation with loss of p16 function will increase the likelihood that mutagenic DNA escapes repair before cell division. The second gene product p14ARF binds to MDM2 and regulates melanocyte growth through effects on the p53 'guardian of the genome' pathway. MDM2 accelerates the destruction of p53. The net effect of CDKN2A mutation with loss of p14ARF function is p53 loss with enhanced growth/survival of altered cells. MOLECULAR PATHOGENESIS  page 1789 INCLUDEPICTURE "http://www.dermtext.com/images/pixel.gif" \* MERGEFORMATINET page 1790 Epidemiologic studies have demonstrated a role for genetic predisposition and sun exposure in melanoma development. Substantial information has been added to the body of evidence suggesting that inherited and somatic genetic events contribute to the pathogenesis of melanoma. In particular, aberration of cell cycle control and transcriptional control mechanisms are implicated in the disease pathogenesis HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114002" \o "Go here now" \t "body" 2. The major gene involved in melanoma development resides on chromosome 9p21. This gene (also known as CDKN2A or INK4a/ARF) encodes two separate gene products p16 and p14ARF (alternative reading frame) that are both negative regulators of cell cycle progression ( HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View now" Fig. 114.1). The p16 protein itself executes its effects by competitive inhibition of cyclin-dependent kinase 4 (CDK4). CDK4 interacts with cyclin D and phosphorylates the master gatekeeper retinoblastoma protein (Rb). Phosphorylation of Rb will lead to S phase progression and ultimately cellular division and proliferation. An intact p16 protein is essential for cell cycle arrest. The net effect of CDKN2A mutation with loss of p16 function will increase the likelihood that mutagenic DNA escapes repair before cell division. The second gene product p14ARF (p19ARF in mice) binds MDM2 and regulates melanocyte growth through independent effects on the p53 pathway HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114003" \o "Go here now" \t "body" 3, HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114004" \o "Go here now" \t "body" 4. The net effect of CDKN2A mutation with loss of p14ARF function is increased p53 destruction with enhanced growth/survival of altered cells. p16 is abnormal in about 30-50% of familial melanoma cases and 25-40% of sporadic melanoma. Less frequent genetic alterations may also involve the CDK4 gene, the protooncogene Ras, the phosphatase and tensin homologue/mutated in multiple advanced cancers PTEN/MMAC1 gene (which is also mutated in Cowden's disease) as well as the tumor suppressor gene p53 (also responsible for the Li Fraumeni cancer syndrome) HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114005" \o "Go here now" \t "body" 5. The recently described inactivation of the apoptosis effector Apaf-1 also contributes to inhibition of p53-mediated apoptosis and melanoma development HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114006" \o "Go here now" \t "body" 6.  The impact of these genetic alterations are best studied using in vivo models. These include (1) human skin grafted to immunodeficient mice to provide an orthotopic environment for both melanoma growth and for induction by irradiation with UV light; (2) nongenetic animal model for UV-induced melanoma genesis such as the xiphophorus hybrid fish; and (3) genetically modified mice, e.g. mice with deletions in the INK4A locus crossed with animals expressing the Ras oncogene under a tyrosinase promoter HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114007" \o "Go here now" \t "body" 7, HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114008" \o "Go here now" \t "body" 8. The value of such models has been recently shown by demonstrating that neonatal sunburn induces melanoma in hepatocyte growth factor/scatter factor transgenic mice HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114009" \o "Go here now" \t "body" 9. Although germline mutations in CDKN2A are present in many large multi-case melanoma families, they are much rarer in the smaller melanoma families that make up most individuals reporting a family history of this disease. In addition, only three families worldwide have been reported with germline mutations in a gene other than CDKN2A (i.e. CDK4). Accordingly, current genome-wide scans using high density microarrays are underway with the hope of revealing linkage to one or more chromosomal regions, and ultimately leading to the identification of novel genes involved in melanoma predisposition.  A combination of cytogenetic, molecular, and functional studies suggests that additional genes involved in melanoma development are located to chromosomal regions 1p, 6q, 7p, 11q, and possibly also 9p and 10q. With the completion of the human genome sequencing effort, combined with the advent of high throughput mutation analyses and new techniques including cDNA and tissue microarrays, the identification and characterization of additional genes involved in melanoma pathogenesis and subsequent molecular classification of melanoma seem likely in the near future HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114010" \o "Go here now" \t "body" 10. The first report of the discovery of gene clusters in a subset of melanomas identified by such techniques supports this notion HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114011" \o "Go here now" \t "body" 11.  HOST IMMUNE RESPONSE TO MELANOMA  Clinical observations such as incomplete or complete regression of melanoma, occurrence of vitiligo-like depigmentation and halo nevi as well as a higher rate of melanoma in immunosuppressed patients point to the fact that melanoma is an immunogenic tumor HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114012" \o "Go here now" \t "body" 12. Studies of melanoma have played a central role in understanding recognition and rejection of tumors by the host immune system. The molecular characterization of melanoma antigens recognized by autologous T cells or antibodies was a scientific breakthrough HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114013" \o "Go here now" \t "body" 13, HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114014" \o "Go here now" \t "body" 14.  Major melanoma antigens recognized include (1) mutated antigens (e.g. mutated p16 (CDKN2A); (2) shared tumor-specific antigens of the cancer/testis family (e.g. Mage-1,-3, NY-ESO-1); and (3) differentiation antigens (e.g. tyrosinase, gp100, MelanA/MART-1). The expression pattern of the majority of these antigens may be followed in situ at the protein level using monoclonal antibodies. In an extensive immunohistochemical study, 44% of primary melanomas expressed MAGE-3, while 88% and 94% expressed MelanA/MART-1 and tyrosinase, respectively HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114015" \o "Go here now" \t "body" 15. These proteins are processed inside the cell and presented on the melanoma cell surface as MHC/peptide complexes. CD8+ cytotoxic T cells recognize these antigenic structures and, if appropriately activated, are able to kill such tumor cells in an MHC-dependent manner through release of cytotoxic granules (e.g. perforin and granzyme B) or activation of FAS/TNF pathways. CD8 cells are believed to be the major effector cells for an anti-melanoma-specific immune response, but CD4 helper T cells as well as antibodies also play a critical role. Activation of melanoma-specific CD8 T cells is dependent on the migration of tumor antigen-loaded professional antigen presenting cells (dendritic cells) from the tumor site to a draining lymph node ( HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View now" Fig. 114.2). Here, melanoma antigens are presented to CD8 T cells in the presence of co-stimulatory molecules, which is the decisive step of CD8 T cell activation. This alert system often fails in melanoma patients, but may be activated or substituted by specific immunotherapies (see below).  Since melanoma is an immunogenic tumor a variety of immune escape mechanisms may be found in advanced tumors. These include loss of tumor-specific antigens, loss of MHC class I molecules as well as secretion of immuno-inhibitory cytokines such as IL-10 and transforming growth factor (TGF)-beta HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114016" \o "Go here now" \t "body" 16. New insights into mechanisms of host immune response against melanoma antigens has set the stage for innovative approaches to melanoma immunotherapy (see below).  EPIDEMIOLOGY  The incidence and mortality rate of melanoma has been increasing in recent decades in all parts of the world from which reliable cancer registration data can be obtained, and represents a substantial public health problem. The annual incidence rates have increased in the order of 3-7% in fair-skinned populations in recent decades. The mortality rates have increased at a lower rate. This has been attributed to educational programs designed to improve the early detection of melanoma, as the treatment of melanoma has not changed substantially in recent decades. There has been a decrease in the thickness of melanoma with an increasing proportion of thin melanomas at diagnosis.  The incidence rates in Australia continues to be the highest worldwide approaching 35 per 100 000 individuals in 2000. Yet, cohort analysis of both the incidence and mortality rates for melanoma in Australia reveal that the overall rise is not reflected in all age groups. In the younger cohorts which might have been influenced by public health campaigns in the last 20 years, both incidence and mortality are falling HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114017" \o "Go here now" \t "body" 17. In Europe the rate of increase began in the 1950s in the more affluent European countries and has been in part attributed to greater opportunity for travel to southern European countries for sunbathing. Hope for the end to the melanoma epidemic is seen in the UK where melanoma mortality is falling in young women in spite of a general increase in mortality HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114018" \o "Go here now" \t "body" 18. It has been suggested that the epidemic of lethal melanoma has been arrested by earlier recognition and surgery of thin tumors HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114019" \o "Go here now" \t "body" 19.  In the US more than 40 000 new cases of melanoma were diagnosed in 1997, and it was estimated that in the year 2000, 7700 Americans will die from malignant melanoma HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114020" \o "Go here now" \t "body" 20 indicating that nearly every hour an American will die from melanoma. The incidence has increased from 1 per 100 000 to 15 per 1 000 000 in the last 40 years ( HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View now" Fig. 114.3). This 15-fold increase is more rapid than in any other malignancy. In contrast to women, mortality is still increasing in men ( HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View now" Fig. 114.4). Importantly, deaths from melanoma occur at a younger age than most other cancers, and melanoma is among the most common types of cancer in young adults HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114021" \o "Go here now" \t "body" 21. Moreover, US cancer statistics demonstrate that melanoma had the second highest mortality rate increase among Americans 65 years of age and older (from 1973-1997) especially for men HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114022" \o "Go here now" \t "body" 22.  page 1790 INCLUDEPICTURE "http://www.dermtext.com/images/pixel.gif" \* MERGEFORMATINET page 1791  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#"  INCLUDEPICTURE "http://www.dermtext.com/content/0323024092/graphics/thumbnails/M24092-114-f002.jpg" \* MERGEFORMATINET  HYPERLINK "http://www.dermtext.com/content/lightbox.cfm?action=add&ImgID=F114002&ImgBody=graphics/M24092-114-f002.jpg&ID=iBox" Add to lightbox  Figure 114.2 Anti-melanoma immune response involves migration of dendritic cells into secondary lymphoid organs. Activation of melanoma-specific CD8 T cells is dependent on the migration of tumor antigen loaded professional antigen presenting cells (dendritic cells) from the tumor site to a draining lymph node. Here, melanoma antigens are presented to CD8 T cells in the presence of co-stimulatory molecules as well as CD4 helper T cells which is the decisive step of CD8 T cell activation. Activated T cells upregulate chemokine receptors and adhesion molecules that enables them to enter tissue sites where metastases are located.  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#"  INCLUDEPICTURE "http://www.dermtext.com/content/0323024092/graphics/thumbnails/M24092-114-f003.jpg" \* MERGEFORMATINET  HYPERLINK "http://www.dermtext.com/content/lightbox.cfm?action=add&ImgID=F114003&ImgBody=graphics/M24092-114-f003.jpg&ID=iBox" Add to lightbox  Figure 114.3 Age-adjusted incidence of melanoma in the US from 1969-1998. The incidence has increased for both the male and female population, while an early indication of a plateau or regression may be observed in recent years. This might be related to the effects of public health campaigns. Data from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute, 2001. In conclusion, it seems that public health campaigns in the last 20 years might have had an impact on melanoma incidence and mortality. Future assessments should also include other outcomes such as behavior modification and the stage and thickness at which melanoma are being removed HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114023" \o "Go here now" \t "body" 23. The future will likely emphasize molecular epidemiology which will allow the understanding of the molecular background of phenotypic variations of melanoma including congenital melanoma and correlation of epidemiological data with molecular alterations in melanoma.   HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#"  INCLUDEPICTURE "http://www.dermtext.com/content/0323024092/graphics/thumbnails/M24092-114-f004.jpg" \* MERGEFORMATINET  HYPERLINK "http://www.dermtext.com/content/lightbox.cfm?action=add&ImgID=F114004&ImgBody=graphics/M24092-114-f004.jpg&ID=iBox" Add to lightbox  Figure 114.4 Age-adjusted mortality of melanoma in the US from 1969-1998. Mortality has increased especially for male population in contrast to the female population. Data from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute, 2001. RISK FACTORS  Definition of major risk factors for development of melanoma are essential to optimize primary and secondary (early recognition) prevention strategies. Risk factors may be subdivided into genetic and environmental categories ( HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=T114001" \o "Go here now" \t "body" Table 114.1).  page 1791 INCLUDEPICTURE "http://www.dermtext.com/images/pixel.gif" \* MERGEFORMATINET page 1792  Table 114-1. Risk factors for the development of melanoma. RISK FACTORS FOR THE DEVELOPMENT OF MELANOMAGenetic markers (e.g. CDKN2A mutations) Family history of dysplastic nevi or melanoma Ultraviolet irradiation Sunburns during childhood Intermittent burning exposure in unacclimatized fair skin Number (>50) and size (>5 mm) of melanocytic nevi Congenital nevi Number of atypical nevi (>5) Atypical/dysplastic nevus syndrome Personal history of melanoma High socioeconomic status Skin type I, II Equatorial latitudes DNA repair defects (e.g. xeroderma pigmentosum) Immunosuppression   Genetic markers of individuals at increased risk for melanoma are the subject of intensive research. Three major genes have been identified which influence melanoma risk (see previous section): (1) the CDKN2A gene on chromosome 9; (2) the CDK4 gene on chromosome 12; and (3) a gene on chromosome 1 HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114003" \o "Go here now" \t "body" 3. There is correlation between CDKN2A mutations in family members with the atypical/dysplastic nevus syndromes. Germline mutations of CDKN2A have been described in about 20% of melanoma prone families and CDK4 mutations have been described in three families.  The main environmental risk factor is excessive exposure of fair-skinned individuals to UV irradiation, mainly in the form of natural sunlight. However the exact wavelengths and pattern of exposure are not yet well established. It has been suggested that intermittent high intensity exposure of unacclimatized fair skin is a greater risk factor for melanoma than chronic lifetime sun exposure HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114024" \o "Go here now" \t "body" 24.  Overwhelming evidence indicates that patients with increased numbers of benign melanocytic nevi have increased risk for the development of melanoma. A suggested number of nevi over which patients are at an increased risk for the development of melanoma is 50 HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114025" \o "Go here now" \t "body" 25. Atypical (dysplastic) nevi that are larger than 5 mm in diameter, darkly and/or irregularly pigmented with irregular, ill-defined borders are also risk factors for melanoma, especially if they occur in families as manifestation of the so-called atypical/dysplastic nevus syndrome (see  HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=C11324092" \o "Go here now" \t "body" Chapter 113). The risk for developing melanoma in such families has been estimated to be 10% (close to 100% if a history of previous melanoma is present) HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114026" \o "Go here now" \t "body" 26. Large congenital nevi (>20 cm) have an estimated life time risk between 5 and 20% for malignant transformation ( HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=C11324092" \o "Go here now" \t "body" Chapter 113). Patients with a history of previous melanoma in the absence of atypical nevi are at a 3-5% risk of developing a second melanoma.  Studies have established that melanoma is found more frequently in more affluent persons, but this most likely serves as a surrogate for recreational sporadic sun exposure. Further risk factors include skin type I/II (pale skin, poor tanning ability, light hair and eyes, presence of freckles, burns easily), latitude (inverse relationship of melanoma incidence noted with latitude), immunosuppression (threefold risk, e.g. after solid organ transplantation or inherited immunodeficiencies), and the presence of defective DNA repair mechanisms (e.g. xeroderma pigmentosum). There are conflicting data regarding the impact of sunscreen use on melanoma development. The same is true for commercial sun bed use, where several case/control studies found an association with increase of melanoma risk. There is no clear evidence that pregnancy or estrogen use increases the risk of melanoma. There is also no evidence that pregnancy occurring after the diagnosis of melanoma worsens prognosis.  ULTRAVIOLET RADIATION AND PHOTOPROTECTION  Exposure to sunlight is a major factor in the induction of cutaneous malignant melanoma HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114027" \o "Go here now" \t "body" 27. In particular, recreational, intermittent exposure to the ultraviolet (UV) component of sunlight associated with sunburns may play an important role in melanoma formation. The link of sunburn(s) in childhood to melanoma development later in human life is consistent with recent findings in an experimental model with genetically engineered mice, in which a single dose of burning UV radiation to neonates, but not adults, is sufficient to induce tumors with high penetrance that are reminiscent of human melanoma HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114009" \o "Go here now" \t "body" 9. However, in contrast to non-melanoma skin cancers, in which there are distinctive UVB-induced mutations (i.e. C to T and CC to TT transitions) in the p53 gene, the exact mechanisms and wavelengths by which sunlight induces, promotes or contributes to the development of melanoma have not been identified.  Experimental work in the Xiphophorus fish model indicates that wavelengths other than those in the UVB range of the sunlight spectrum are also important in melanoma formation HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114027" \o "Go here now" \t "body" 27. It was reported that in addition to the induction of melanoma in the UVB wavelength range, there was also induction in the UVA and short visible wavelength range, suggesting that wavelengths not directly absorbed by DNA can still induce melanoma. If the action spectra that cause melanomas in humans and fish are similar, the use of common sunscreens that protect better against UVB than UVA radiation would be sub-optimal. The hypothesis that UVA is important in the etiology of melanoma is also supported by epidemiologic studies, in which exposure to UVA-emitting sun beds was related to an increased melanoma risk HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114027" \o "Go here now" \t "body" 27. Moreover, the fact that in Norway a higher melanoma to non-melanoma skin cancer ratio parallels a higher UVA to UVB ratio, implicates UVA radiation in the etiopathogenesis of melanoma. UVB is still a critical factor. Experimental animal work in the South American opossum (Monodelphus domestica) and in different mouse strains has suggested that exposure to UVB is significant in the initiation of melanoma. Atillasoy et al. HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114028" \o "Go here now" \t "body" 28 reported that treatment with 7,12-dimethyl(a)benzanthracene and UVB radiation induced atypical melanocytic lesions and melanoma in human skin grafted onto RAG-1 mice.  page 1792 INCLUDEPICTURE "http://www.dermtext.com/images/pixel.gif" \* MERGEFORMATINET page 1793  Table 114-2. Table 114.2 Different types of malignant melanoma. DIFFERENT TYPES OF MALIGNANT MELANOMAType of melanomaFrequency (%)SiteRadial growthSpecial featuresSuperficial spreading melanoma60-70Any site, preference for lower extremities (female), trunk (male)YesMore pagetoid, less solar elastosisNodular melanoma15-30Any site, preference for trunk, head, neckNoNodule with vertical growthLentigo maligna melanoma5-15Face, especially nose and cheeksYesSlower growth over years on sun-damaged skinAcral lentiginous melanoma5-10Palms, soles, subungualYesMost common melanoma in patients with darker skin types  Several retrospective epidemiologic studies have assessed the risk of melanoma in relation to sunscreen use HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114029" \o "Go here now" \t "body" 29. In some of those studies the use of sunscreens offered no protection against melanoma, but instead was associated with an increased melanoma risk. The interpretation of these studies must be done with great caution, because retrospective data collection is not optimal. For example, persons with a history of sunburn and increased sun exposure are more likely to use sunscreens more frequently, thus sunscreen use may erroneously appear as a risk factor. There is also controversial evidence as to whether chemical sunscreens have the capacity to protect humans against UV-induced formation of melanocytic nevi, which are potential precursors of melanoma HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114030" \o "Go here now" \t "body" 30, HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114031" \o "Go here now" \t "body" 31. One mechanism by which sunscreens may lead to an increased melanoma risk is that their use may allow prolonged intensive sun exposures, which may increase the melanoma risk HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114031" \o "Go here now" \t "body" 31. Also, UV radiation-induced immune suppression may be an important factor in the pathogenesis of melanoma and there is conflicting evidence from animal and human studies as to whether chemical sunscreens offer sufficient immunoprotection HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114032" \o "Go here now" \t "body" 32. A recent study HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114032" \o "Go here now" \t "body" 32 has indicated that UVA sunscreen protection may be particularly important in preventing the suppression of the efferent immune response that may be a crucial factor in the protection against the formation of skin cancer, including malignant melanoma (see  HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=C15424092" \o "Go here now" \t "body" Chapter 154).  TYPES OF PRIMARY MELANOMAS  Four major subtypes (growth patterns) of primary cutaneous melanoma have been historically differentiated. These include (1) superficial spreading melanoma; (2) nodular melanoma; (3) lentigo maligna melanoma; and (4) acral lentiginous melanoma ( HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=T114002" \o "Go here now" \t "body" Table 114.2) HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114033" \o "Go here now" \t "body" 33. It should be noted that these clinical subtypes do not predict prognosis independently of other factors such as the measured depth of the lesion (Breslow's thickness) or ulceration, and the argument has been made that such categorization has limited value.  Superficial Spreading Melanoma   HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#"  INCLUDEPICTURE "http://www.dermtext.com/content/0323024092/graphics/thumbnails/M24092-114-f005.jpg" \* MERGEFORMATINET  HYPERLINK "http://www.dermtext.com/content/lightbox.cfm?action=add&ImgID=F114005&ImgBody=graphics/M24092-114-f005.jpg&ID=iBox" Add to lightbox  Figure 114.5 Melanoma in situ. Note the macular character, indistinct defined borders and variations in color.  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#"  INCLUDEPICTURE "http://www.dermtext.com/content/0323024092/graphics/thumbnails/M24092-114-f006.jpg" \* MERGEFORMATINET  HYPERLINK "http://www.dermtext.com/content/lightbox.cfm?action=add&ImgID=F114006&ImgBody=graphics/M24092-114-f006.jpg&ID=iBox" Add to lightbox  Figure 114.6 Melanoma in situ. Tan to dark-brown macule with irregular outline.  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#"  INCLUDEPICTURE "http://www.dermtext.com/content/0323024092/graphics/thumbnails/M24092-114-f007.jpg" \* MERGEFORMATINET  HYPERLINK "http://www.dermtext.com/content/lightbox.cfm?action=add&ImgID=F114007&ImgBody=graphics/M24092-114-f007.jpg&ID=iBox" Add to lightbox  Figure 114.7 Melanoma. This small lesion is only 5 mm at its greatest diameter. page 1793 INCLUDEPICTURE "http://www.dermtext.com/images/pixel.gif" \* MERGEFORMATINET page 1794  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#"  INCLUDEPICTURE "http://www.dermtext.com/content/0323024092/graphics/thumbnails/M24092-114-f008.jpg" \* MERGEFORMATINET  HYPERLINK "http://www.dermtext.com/content/lightbox.cfm?action=add&ImgID=F114008&ImgBody=graphics/M24092-114-f008.jpg&ID=iBox" Add to lightbox  Figure 114.8 Melanoma - superficial spreading type. This neoplasm is characterized by asymmetry, scalloped borders, a combination of various colors and an ulcerated nodule.  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#"  INCLUDEPICTURE "http://www.dermtext.com/content/0323024092/graphics/thumbnails/M24092-114-f009.jpg" \* MERGEFORMATINET  HYPERLINK "http://www.dermtext.com/content/lightbox.cfm?action=add&ImgID=F114009&ImgBody=graphics/M24092-114-f009.jpg&ID=iBox" Add to lightbox  Figure 114.9 Melanoma with regression. Note asymmetry, variegation in color and uneven surface. The lighter zones are evidence of regression. Superficial spreading melanoma (SSM) is the most common type of cutaneous melanoma in the fair skinned individuals and is diagnosed most frequently between the ages of 30 to 50 years. It accounts for approximately 70% of all melanomas and occurs at any site, but is most frequently seen on the trunk of men and the legs of women. It begins as an asymptomatic brown to black macule with color variations and irregular, notched borders. Melanoma in situ is usually a macule with an irregular outline and variable size ( HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View now" Figs 114.5 &  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View now" 114.6), including diameters d"5 mm ( HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View now" Fig. 114.7). After a typically slow horizontal (radial) growth phase limited to the epidermis or focally in the papillary dermis, a rapid vertically oriented growth phase which presents clinically with development of a papular nodule can be frequently observed ( HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View now" Fig. 114.8). In up to two-thirds of cases regression (visible as hypo- or depigmentation) of part of the lesion is observed ( HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View now" Fig. 114.9), potentially reflecting the interaction of the host immune system with the progressing tumor. About one-third of these melanomas arise in a pre-existing nevus. In this instance, a previously stable melanocytic nevus is generally observed to change, becoming asymmetric with an irregular border, color variation and an enlarging diameter (ABCD mnemonic). Melanomas lacking clinically evident pigment are termed 'amelanotic' ( HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View now" Fig. 114.10).  Nodular Melanoma   HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#"  INCLUDEPICTURE "http://www.dermtext.com/content/0323024092/graphics/thumbnails/M24092-114-f010.jpg" \* MERGEFORMATINET  HYPERLINK "http://www.dermtext.com/content/lightbox.cfm?action=add&ImgID=F114010&ImgBody=graphics/M24092-114-f010.jpg&ID=iBox" Add to lightbox  Figure 114.10 Amelanotic melanoma. Hypopigmented erythematous patch with focally pigmented margin.  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#"  INCLUDEPICTURE "http://www.dermtext.com/content/0323024092/graphics/thumbnails/M24092-114-f011a.jpg" \* MERGEFORMATINET  HYPERLINK "http://www.dermtext.com/content/lightbox.cfm?action=add&ImgID=F114011&ImgBody=graphics/M24092-114-f011a.jpg&ID=iBox" Add to lightbox   HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#"  INCLUDEPICTURE "http://www.dermtext.com/content/0323024092/graphics/thumbnails/M24092-114-f011b.jpg" \* MERGEFORMATINET  HYPERLINK "http://www.dermtext.com/content/lightbox.cfm?action=add&ImgID=F114011&ImgBody=graphics/M24092-114-f011b.jpg&ID=iBox" Add to lightbox  Figure 114.11 Melanoma - nodular type. A Black nodule on the nose. Courtesy Ron Rapini M.D. B This lesion is technically classified as a nodular component of superficial spreading melanoma because of the adjacent flat tanbrown intraepidermal component (radial growth phase) extending beyond the nodule. page 1794 INCLUDEPICTURE "http://www.dermtext.com/images/pixel.gif" \* MERGEFORMATINET page 1795 Nodular melanoma (NM) is the second most common type of cutaneous melanoma in the fair-skinned population and is diagnosed most frequently in patients in their sixth decade of life. It accounts for approximately 15 to 30% of all melanomas and occurs at any body site, but is most frequently seen on the trunk, head and neck. It is observed more frequently in men than in women. It usually presents as a blue to black sometimes red to skin-colored nodule which might be ulcerated or bleeding and has rapidly developed over months ( HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View now" Fig. 114.11). Nodular melanoma lacks significant surrounding macular hyperpigmentation and thus should not be confused with nodules occurring in superficial spreading melanoma.  Lentigo Maligna Melanoma  Lentigo maligna melanoma (LMM) represents a minority of cutaneous melanoma (up to 15%) and is diagnosed most frequently in the seventh decade of life. It occurs on chronically sun-damaged skin, most commonly on the face, with a preference for the nose and cheek. It usually develops as a slowly growing asymmetric brown to black macule with color variations and irregular, indented borders ( HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View now" Fig. 114.12). The term lentigo maligna is used to mean melanoma in situ of sun-damaged skin (radial growth only) and lentigo maligna melanoma is used for those with dermal invasion (vertical growth). Lentigo maligna has a slow evolution over years and may develop a papule or nodule, generally indicating invasion.  Acral Lentiginous Melanoma  Acral lentiginous melanoma (ALM) is a relatively uncommon type of cutaneous melanoma and is diagnosed most frequently in the seventh decade of life. It typically occurs on the palms and soles or in and around the nail apparatus. It accounts for approximately 5 to 10% of all melanomas but represents up to 70% of melanomas in darkly complected individuals and up to 45% in Asians. ALM is cumulatively more common in fair-skinned patients, but is the most common type found in pigmented races.  It presents as an asymmetric brown to black macule with color variation and irregular borders ( HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View now" Fig. 114.13). It is believed that the progression of this type of melanoma tends to be faster than for LMM or SSM. Amelanotic tumors are diagnostically challenging and may be mistaken for warts or squamous cell carcinoma. Subungual melanoma accounts for 1 to 3% of all melanomas and is typically classified as a variant of ALM. They present as longitudinal nail pigmentation or ulcerated nodules ( HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View now" Figs 114.14 &  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View now" 114.15). Persistence of a pigmented band in the nail bed, particularly in an elderly patient, should raise suspicion of melanoma and prompt a biopsy. That said, any persistent pigmentation of the nail apparatus should raise concern for melanoma, realizing that benign causes are common (see  HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=C07124092" \o "Go here now" \t "body" Chapters 71 &  HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=C11324092" \o "Go here now" \t "body" 113). Correct biopsy of the nail matrix is important (see  HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=C14924092" \o "Go here now" \t "body" Chapter 149). Extension of pigment into the proximal or lateral nail fold is known as a Hutchinson sign and generally indicates the presence of ALM.   HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#"  INCLUDEPICTURE "http://www.dermtext.com/content/0323024092/graphics/thumbnails/M24092-114-f012.jpg" \* MERGEFORMATINET  HYPERLINK "http://www.dermtext.com/content/lightbox.cfm?action=add&ImgID=F114012&ImgBody=graphics/M24092-114-f012.jpg&ID=iBox" Add to lightbox  Figure 114.12 Melanoma - lentigo maligna type on sun-damaged skin. The neoplasm is broad and flat, asymmetrical, poorly circumscribed and shows various shades of tan-brown to black. OTHER MELANOMA VARIANTS  Malignant melanoma may present with unusual manifestations. Some of these are defined by clinical features, others by histologic findings.   HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#"  INCLUDEPICTURE "http://www.dermtext.com/content/0323024092/graphics/thumbnails/M24092-114-f013a.jpg" \* MERGEFORMATINET  HYPERLINK "http://www.dermtext.com/content/lightbox.cfm?action=add&ImgID=F114013&ImgBody=graphics/M24092-114-f013a.jpg&ID=iBox" Add to lightbox   HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#"  INCLUDEPICTURE "http://www.dermtext.com/content/0323024092/graphics/thumbnails/M24092-114-f013b.jpg" \* MERGEFORMATINET  HYPERLINK "http://www.dermtext.com/content/lightbox.cfm?action=add&ImgID=F114013&ImgBody=graphics/M24092-114-f013b.jpg&ID=iBox" Add to lightbox  Figure 114.13 Acral lentiginous melanoma. A Extensive centrifugal spread, illustrating the macular character, irregular shape, poor circumscription, variations in color, reticulation, and whitish area of regression. B This lesion on the toe could be mistaken for a traumatically-induced injury. Courtesy Ron Rapini, M.D.  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#"  INCLUDEPICTURE "http://www.dermtext.com/content/0323024092/graphics/thumbnails/M24092-114-f014.jpg" \* MERGEFORMATINET  HYPERLINK "http://www.dermtext.com/content/lightbox.cfm?action=add&ImgID=F114014&ImgBody=graphics/M24092-114-f014.jpg&ID=iBox" Add to lightbox  Figure 114.14 Melanoma in situ of the nail. Darkly pigmented band in the nail bed and matrix. page 1795 INCLUDEPICTURE "http://www.dermtext.com/images/pixel.gif" \* MERGEFORMATINET page 1796  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#"  INCLUDEPICTURE "http://www.dermtext.com/content/0323024092/graphics/thumbnails/M24092-114-f015.jpg" \* MERGEFORMATINET  HYPERLINK "http://www.dermtext.com/content/lightbox.cfm?action=add&ImgID=F114015&ImgBody=graphics/M24092-114-f015.jpg&ID=iBox" Add to lightbox  Figure 114.15 Subungual melanoma. Ulcerated nodule with destruction of the nail.  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#"  INCLUDEPICTURE "http://www.dermtext.com/content/0323024092/graphics/thumbnails/M24092-114-f016.jpg" \* MERGEFORMATINET  HYPERLINK "http://www.dermtext.com/content/lightbox.cfm?action=add&ImgID=F114016&ImgBody=graphics/M24092-114-f016.jpg&ID=iBox" Add to lightbox  Figure 114.16 Nevoid melanoma. The patient developed metastases from this red-brown plaque.  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#"  INCLUDEPICTURE "http://www.dermtext.com/content/0323024092/graphics/thumbnails/M24092-114-f017a.jpg" \* MERGEFORMATINET  HYPERLINK "http://www.dermtext.com/content/lightbox.cfm?action=add&ImgID=F114017&ImgBody=graphics/M24092-114-f017a.jpg&ID=iBox" Add to lightbox   HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#"  INCLUDEPICTURE "http://www.dermtext.com/content/0323024092/graphics/thumbnails/M24092-114-f017b.jpg" \* MERGEFORMATINET  HYPERLINK "http://www.dermtext.com/content/lightbox.cfm?action=add&ImgID=F114017&ImgBody=graphics/M24092-114-f017b.jpg&ID=iBox" Add to lightbox  Figure 114.17 Histopathology of melanoma mimicking Spitz nevus. This neoplasm could be misdiagnosed as a Spitz nevus because the lesion is symmetrical and well-circumscribed. This is a melanoma because: nests of melanocytes have become confluent with formation of sheets; there is no distinct maturation of melanocytes; nuclei of melanocytes are atypical; and melanocytes are in mitosis, also at the base of the neoplasm. Nevoid Melanomas  These melanomas do not display clinically distinct features, creating diagnostic difficulty ( HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View now" Fig. 114.16) because they may resemble a Spitz nevus or an acquired or congenital type of a melanocytic nevus HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114034" \o "Go here now" \t "body" 34. Two histologic types of nevoid melanoma are be recognized and are described below.  Melanoma with features of a Spitz nevus ('spitzoid' melanoma)  This variant shows histologic features suggestive of Spitz nevus ( HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View now" Fig. 114.17) with overall symmetry and a dermal nodule of epithelioid melanocytes that do not mature with progressively deeper dermal extension. Other important histological clues for the diagnosis of a melanoma are sheets of atypical melanocytes in the dermis and mitotic figures at the base of the lesion (see  HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=C11324092" \o "Go here now" \t "body" Chapter 113).  Melanoma with small nevus-like cells (small cell melanoma)  This tumor contains large variably sized nests of small melanocytes with hyperchromatic nuclei and prominent nucleoli. Mitoses are generally found throughout the dermal tumor.  Malignant Blue Nevus: Malignant Melanoma in Association with Blue Nevus  Malignant blue nevus is a rare dermal tumor of melanocytes most commonly located on the head and particularly the scalp ( HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View now" Fig. 114.18). It appears as a blue-black, deeply situated nodule, generally >1 cm in diameter. Histologically, elements of a classic benign blue nevus are associated with nodular areas of atypical spindle-shaped and bipolar dendritic melanocytes, mitotic figures, necrosis, and melanophages HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114035" \o "Go here now" \t "body" 35. The clinical course is characterized by a high rate of recurrence and metastasis.  Desmoplastic/Spindled/Neurotropic melanoma  page 1796 INCLUDEPICTURE "http://www.dermtext.com/images/pixel.gif" \* MERGEFORMATINET page 1797  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#"  INCLUDEPICTURE "http://www.dermtext.com/content/0323024092/graphics/thumbnails/M24092-114-f018.jpg" \* MERGEFORMATINET  HYPERLINK "http://www.dermtext.com/content/lightbox.cfm?action=add&ImgID=F114018&ImgBody=graphics/M24092-114-f018.jpg&ID=iBox" Add to lightbox  Figure 114.18 Melanoma in association with blue nevus (malignant blue nevus). Satellite metastases at the periphery.  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#"  INCLUDEPICTURE "http://www.dermtext.com/content/0323024092/graphics/thumbnails/M24092-114-f019a.jpg" \* MERGEFORMATINET  HYPERLINK "http://www.dermtext.com/content/lightbox.cfm?action=add&ImgID=F114019&ImgBody=graphics/M24092-114-f019a.jpg&ID=iBox" Add to lightbox   HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#"  INCLUDEPICTURE "http://www.dermtext.com/content/0323024092/graphics/thumbnails/M24092-114-f019b.jpg" \* MERGEFORMATINET  HYPERLINK "http://www.dermtext.com/content/lightbox.cfm?action=add&ImgID=F114019&ImgBody=graphics/M24092-114-f019b.jpg&ID=iBox" Add to lightbox  Figure 114.19 Histopathology of desmoplastic malignant melanoma. A Loosely textured spindle cells in focally fibroblastic stroma. In the epidermis there are changes of melanoma in situ with proliferation of atypical melanocytes. Note lymphoid infiltrates. B Positive S-100 spindle cells within the dermis. While this type of melanoma is histologically defined, the typical clinical lesion consists of a skin-colored, red to hyperpigmented nodule or plaque, mostly on sun-exposed skin. It may arise de novo, but is also the most common melanoma arising in lentigo maligna, ALM and mucosal melanoma. Metastasis is uncommon, but the tumor is highly infiltrative and thus, locally aggressive with recurrence after incomplete excision. Deep tissue samples are necessary to establish the diagnosis ( HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View now" Fig. 114.19) as superficial portions of the tumor show subtle or nondiagnostic findings which may be mistaken for fibrosis of a scar or other spindle cell neoplasms.   HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#"  INCLUDEPICTURE "http://www.dermtext.com/content/0323024092/graphics/thumbnails/M24092-114-f020.jpg" \* MERGEFORMATINET  HYPERLINK "http://www.dermtext.com/content/lightbox.cfm?action=add&ImgID=F114020&ImgBody=graphics/M24092-114-f020.jpg&ID=iBox" Add to lightbox  Figure 114.20 Ciliary body melanoma. Clear Cell Sarcoma: Melanoma of Soft Parts  Clear cell sarcoma most often presents on the distal extremities of adolescents and young adults. Several features point to melanocytic derivation (expression of HMB45, S-100 protein and melanosomes on electron microscopy), but clear cell sarcoma and cutaneous melanoma may be two distinct clinicopathological entities HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114036" \o "Go here now" \t "body" 36. The tumors usually arise in association with tendons and aponeuroses. The tumor is composed of nests and fascicles of oval to spindled cells with vesicular nuclei, basophilic nucleoli, and eosinophilic to clear cytoplasm. Multinucleated giant cells and melanin can be frequently demonstrated. Upon incomplete excision, local recurrence and metastasis may ensue.  Animal-type Melanoma  Animal type melanoma is characterized by nodules and fascicles of epithelioid melanocytes with pleomorphic nuclei and striking hyperpigmentation, dendritic cells, numerous melanophages and sometimes an inflammatory infiltrate of lymphocytes HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114037" \o "Go here now" \t "body" 37. Clinically, blue to jet black plaques or nodules have been described. The prognostic features are not well known; metastases have been observed in several patients. It is so named because it resembles melanocytic neoplasms with similar morphological features seen in gray horses and laboratory animals.  Ocular Melanoma  Primary ocular melanomas, which are very rare (5% of all melanomas), can be divided into conjunctival melanomas and uveal melanomas (iris-, choroidal- and ciliary-body melanomas) ( HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View now" Fig. 114.20). Little is known about the pathogenesis of these tumors. Patients with dysplastic nevus syndrome have an increased number of conjunctival and uveal nevi. Although the true association between dysplastic nevus syndrome and ocular melanoma is controversial, it has been suggested that patients with ocular melanoma have an increased risk for cutaneous melanoma. Patients with type I neurofibromatosis and melanosis oculi (nevus of Ota) may also be at higher risk for uveal melanoma. The prognostic features and the treatment of ocular melanoma differ from cutaneous tumors HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114038" \o "Go here now" \t "body" 38.  Mucosal Melanoma  page 1797 INCLUDEPICTURE "http://www.dermtext.com/images/pixel.gif" \* MERGEFORMATINET page 1798  Table 114-3. Melanocytic lesions that simulate melanomas clinically and/or histopathologically39. MELANOCYTIC LESIONS THAT SIMULATE MELANOMAS CLINICALLY AND/OR HISTOPATHOLOGICALLY HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114039" \o "Go here now" \t "body" 39Acral nevi Ancient nevi Black (hypermelanotic) nevi Blue nevi and variants Combined nevi Congenital nevi biopsied shortly after birth Deep penetrating nevus Dysplastic (Clark's) nevi Halo nevi Hyperplasia of melanocytes in sun-damaged skin or in the epidermis Melanocytic proliferation over some benign neoplasms* Longitudinal melanonychia Melanosis of mucosal regions* Nevi exposed to UV radiation Nevi in genital regions (including milk-line nevi and flexural nevi) 'Nevus sur nevus' (Nevus on nevus) Pigmented streaks in melanoma scars* Proliferating nodules in giant congenital nevi in newborns Recurrent (persistent) nevi Reticulated (ink-spot) lentigo* Spitz nevi and variants   *These are not melanocytic diseases strictu sensu. Melanomas may occur in the mouth, nasopharynx, larynx, vagina and anus. These are rare, but tumors tend to be advanced, perhaps because early detection is difficult.  DIFFERENTIAL DIAGNOSIS: MELANOMA SIMULATORS  A variety of conditions may simulate malignant melanoma either clinically, histopathologically or both. Awareness of these simulators is of great practical importance to avoid over-diagnosis of melanoma HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114039" \o "Go here now" \t "body" 39.  HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=T114003" \o "Go here now" \t "body" Tables 114.3 and  HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=T114004" \o "Go here now" \t "body" 114.4 list several melanocytic and non-melanocytic lesions that can mimic malignant melanomas and which should be included in the differential diagnosis.  MELANOMA AND PREGNANCY  During pregnancy levels of melanocyte-stimulating hormones are elevated. Increased pigmentation occurs in some patients. More than 10% of women experience darkening of melanocytic nevi in the first 3 months of pregnancy HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114040" \o "Go here now" \t "body" 40. However, an association between hormonal changes during pregnancy and development of melanoma or worsening of the prognosis of an existing melanoma has not been demonstrated HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114041" \o "Go here now" \t "body" 41. Transplacental metastases may arise in pregnant women with melanoma. Surgery with local anesthesia is the treatment of choice in stage I or II melanoma patients (see  HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=T114008" \o "Go here now" \t "body" Table 114.8). In more advanced stages discussions with the patient of the advantages and disadvantages of possible termination of the pregnancy is recommended. There have been no studies demonstrating an adverse effect of hormonal contraception on melanoma development HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114042" \o "Go here now" \t "body" 42. Due to the presence of estrogen receptors on a certain percentage of melanomas, alternative forms of contraception are recommended in women after excision of thick tumors (>1.5 mm) with increased risk of recurrence HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114041" \o "Go here now" \t "body" 41. In women with a history of high risk melanoma it may be reasonable to wait 2 years after diagnosis before becoming pregnant, because two-thirds of recurrences occur within this time period.  CHILDHOOD MELANOMA   Table 114-4. Non-melanocytic simulators of melanoma39. NON-MELANOCYTIC SIMULATORS OF MELANOMA HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114039" \o "Go here now" \t "body" 39Paget's disease Extramammary Paget's disease Pigmented epidermotropic metastasis of breast carcinoma Epidermotropic neuroendocrine carcinoma Bowen's disease (pagetoid or pigmented) Pagetoid reticulosis 'Clear-cell' artefacts around keratinocytes Complete regression of skin tumors other than malignant melanoma (e.g., lichen planus-like keratosis, basal cell carcinoma) Pigmented basal cell carcinoma Pigmented actinic keratosis Dermatofibroma Seborrheic keratosis Pigmented poroma and pigmented porocarcinoma Pigmented pilomatrixoma Subungual hematoma Black heel (hemorrhage in stratum corneum caused by trauma) ( HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View now" Fig. 114.21) Pyogenic granuloma Tinea nigra Thrombosed hemangioma    HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#"  INCLUDEPICTURE "http://www.dermtext.com/content/0323024092/graphics/thumbnails/M24092-114-f021.jpg" \* MERGEFORMATINET  HYPERLINK "http://www.dermtext.com/content/lightbox.cfm?action=add&ImgID=F114021&ImgBody=graphics/M24092-114-f021.jpg&ID=iBox" Add to lightbox  Figure 114.21 Black heel. Traumatically induced subcorneal hematoma simulating acral melanoma. page 1798 INCLUDEPICTURE "http://www.dermtext.com/images/pixel.gif" \* MERGEFORMATINET page 1799  Table 114-5. Dermatoscopic criteria and their corresponding histopathological features. DERMATOSCOPIC CRITERIA AND THEIR CORRESPONDING HISTOPATHOLOGICAL FEATURESCriterionMorphological definitionAssociated histopathological changesDiagnosisPigment networkNetwork of brownish lines over a diffuse tan backgroundPigmented rete ridgesMelanocytic lesionTypical networkBrown pigmented, regularly meshed and narrowly spaced networkRegular and elongated rete ridgesBenign melanocytic lesionAtypical networkBlack, brown, or gray network with irregular meshes and thick linesIrregular and broadened rete ridgesMelanomaDots/globulesBlack, brown, and/or gray round to oval, variously sized structures regularly or irregularly distributed within the lesionPigment aggregates within stratum corneum, epidermis, dermo-epidermal junction, or papillary dermisIf regular: benign melanocytic lesion; If irregular: melanomaStreaksIrregular, linear structures not clearly combined with pigment network lines at the marginsConfluent junctional nests of melanocytesMelanomaBlue-whitish veilIrregular, confluent, gray-blue to whitish-blue diffuse pigmentationAcanthotic epidermis with focal hypergranulosis above sheets of heavily pigmented melanocytes in the dermisMelanomaBlotchesBlack, brown, and/or gray pigmented areas with regular or irregular shape/distributionHyperpigmentation throughout the epidermis and/or upper dermisIf regular: benign melanocytic lesion; if irregular: melanomaRegression structuresWhite (scar-like) areas, blue (pepper-like) areas, or combinations of bothThickened papillary dermis with fibrosis and/or variable amounts of melanophagesMelanomaMilia-like cystsWhite-yellowish, roundish dotsIntraepidermal horn globules, also called horn pseudocystsSeborrheic keratosisComedo-like openingsBrown-yellowish, round to oval or even irregularly shaped, sharply circumscribed structuresKeratin plugs situated within dilated follicular openingsSeborrheic keratosisLeaf-like areasBrown-gray to gray-black patches revealing a leaflike configurationPigmented, solid aggregations of basaloid cells in the papillary dermisBasal cell carcinomaRed-blue lacunasSharply demarcated, roundish to oval areas with a reddish, red-bluish, or red-black colorationDilated vascular spaces situated in the upper dermisVascular lesionVascular structuresComma-like vessels Arborizing vessels Hairpin vessels Dotted or irregular vesselsBenign melanocytic lesion Basal cell carcinoma Seborrheic keratosis Melanoma  With permission from Argenziano & Soyer HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114046" \o "Go here now" \t "body" 46, Lancet Oncology 2:443-9. 2001 Elsevier. Childhood melanomas are extremely rare. Between 1 and 4% of melanoma cases occur in patients younger than 20 years of age, and 0.3% are younger than 14 years HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114043" \o "Go here now" \t "body" 43. Tumors may arise de novo or in association with congenital melanocytic nevi. Children with xeroderma pigmentosum, inherited or acquired immunodeficiencies or a family history of melanoma have an increased risk of melanoma development. Histologically, these tumors may resemble those of adults, but small cell melanomas and melanomas with features of Spitz tumor are reported HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114044" \o "Go here now" \t "body" 44. The diagnosis is difficult because the clinical and histological distinction is often subtle. Of special importance is the differentiation of melanoma from Spitz nevi with atypical features. Overall survival and prognosis seems to be stage dependent and similar to adults HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114045" \o "Go here now" \t "body" 45. Treatment follows the same rationale as in adults with the aim of early detection and appropriate resection of primary melanoma.  DERMATOSCOPY  Most melanocytic lesions of the skin can be correctly diagnosed based on unaided clinical observation. That said, certain melanocytic and non-melanocytic tumors may prove to be diagnostically challenging.  Dermatoscopy, also known as skin surface microscopy or epiluminescence microscopy (ELM), is a helpful noninvasive tool in this setting HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114046" \o "Go here now" \t "body" 46. For dermatoscopic examination the skin lesion is covered with mineral oil, alcohol or even water, and a hand-held lens, stereomicroscope, camera or digital imaging system is used to inspect it. The magnifications of these instruments range from sixfold to 100-fold. The most widely used dermatoscope provides a tenfold magnification and is sufficient for routine assessment of pigmented skin lesions. The fluid placed on the lesion eliminates surface reflection and renders the cornified layer translucent, so that morphologic structures within the epidermis, the dermo-epidermal junction, and the superficial dermis can be better visualized. The most important practical application for dermatoscopy is differentiation of the early stages of melanoma in situ and melanoma from benign lesions. Differentiation of melanocytic tumors in general from non-melanocytic pigmented skin lesions such as seborrheic keratosis, pigmented basal cell carcinoma and vascular proliferations is also possible.  A crucial aspect of dermatoscopy is the observation of the pigment-network in melanocytic tumors, which histologically corresponds to elongated and pigmented rete ridges with an increased number of melanocytes in the basal layer. Other structures that can be seen are brown globules, black dots, irregular streaks and the blue-whitish veil.  HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=T114005" \o "Go here now" \t "body" Table 114.5 lists the dermatoscopic criteria and their corresponding histopathological features.  The clinical application of dermatoscopy requires training and experience. Various steps can be used. The approach of pattern analysis ( HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=T114005" \o "Go here now" \t "body" Table 114.5) correlates individual criteria with each other and puts them into the context of a pattern that is typical for the specific pathology of a lesion ( HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View now" Fig. 114.22). Other diagnostic approaches, including the ABCD rule HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114047" \o "Go here now" \t "body" 47, Menzies method HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114048" \o "Go here now" \t "body" 48 and the seven-point checklist HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114049" \o "Go here now" \t "body" 49, represent advances in dermatoscopic diagnosis in terms of sensitivity and specificity. Clinical examination allows a correct diagnosis in 65 to 80% of melanomas, based on physician experience, whereas the proportion of correct diagnoses based on dermatoscopic observation ranges from 70 to 95% and depends on training HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114050" \o "Go here now" \t "body" 50.  page 1799 INCLUDEPICTURE "http://www.dermtext.com/images/pixel.gif" \* MERGEFORMATINET page 1800  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#"  INCLUDEPICTURE "http://www.dermtext.com/content/0323024092/graphics/thumbnails/M24092-114-f022a.jpg" \* MERGEFORMATINET  HYPERLINK "http://www.dermtext.com/content/lightbox.cfm?action=add&ImgID=F114022&ImgBody=graphics/M24092-114-f022a.jpg&ID=iBox" Add to lightbox   HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#"  INCLUDEPICTURE "http://www.dermtext.com/content/0323024092/graphics/thumbnails/M24092-114-f022b.jpg" \* MERGEFORMATINET  HYPERLINK "http://www.dermtext.com/content/lightbox.cfm?action=add&ImgID=F114022&ImgBody=graphics/M24092-114-f022b.jpg&ID=iBox" Add to lightbox  Figure 114.22 Dermatoscopy. This pair of images from an invasive malignant melanoma illustrates the clinical pictures (A) and the same lesion viewed with dermatoscopy (B). Note the multicomponent pattern with an atypical pigment network, black dots, irregular streaks, focally a blue-whitish veiland a white regression zone with hairpin vessels. All these dermatoscopic criteria are suggestive of a melanoma. Dermoscopy is also useful in follow-up examinations of pigmented skin tumors to document morphological changes including growth and/or alterations in color. This approach is especially important for monitoring patients, who have many atypical melanocytic nevi or the familial dysplastic nevus syndrome. Teledermatoscopy, the combined use of dermatoscopy and telemedicine technologies, enables general practitioners and specialists to exchange digital image information. It has been shown that excellent diagnostic results can be achieved in this manner.  Computer-assisted diagnosis based on systems analyzing symmetry and color are available. Dermatoscopy has opened a new dimension in determining clinical morphology. The method is a useful addition to the clinical evaluation of pigmented skin tumors by improving the diagnostic accuracy and allowing a more reliable preoperative assessment of malignant melanoma.  PATHOLOGY  Since the basic histologic criteria for melanoma are the same at all anatomic sites, it has been proposed that the classification of malignant melanoma into distinct histopathologic subtypes should be omitted HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114051" \o "Go here now" \t "body" 51. The criteria listed in  HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=T114006" \o "Go here now" \t "body" Table 114.6 overlap variably in individual tumors but generally enable distinction of melanoma from melanocytic nevi.  It has been proposed that tumor progression in melanoma exhibits two patterns, which are correlated with prognosis HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114052" \o "Go here now" \t "body" 52. The first is the horizontal (radial) growth pattern, characterized by intraepidermal centrifugal spread of neoplastic melanocytes and infiltration of the papillary dermis as single cells or small nests. In the vertical growth phase, large dermal nodules with melanocytes that differ cytologically from the intraepidermal cells are found. It has been further postulated, that the horizontal growth phase lacks metastatic potential even in the presence of dermal invasion, whereas the vertical growth phase correlates with the capacity for metastasis.   Table 114-6. Criteria for histopathologic diagnosis of malignant melanoma. CRITERIA FOR HISTOPATHOLOGIC DIAGNOSIS OF MALIGNANT MELANOMAArchitectural pattern Asymmetry Poor circumscription of intraepidermal melanocytic component Silhouette of tumor base uneven (except in nevoid melanoma) No maturation of melanocytes with progressive descent into the dermis Nests of melanocytes within the epidermis not equidistant from one another Nests of melanocytes vary in size and shape Some nests of melanocytes become confluent Scatter of melanocytes above the dermo-epidermal junction Melanocytes arranged as solitary units predominate over nests within the epidermis Melanocytes in some nests are not cohesive Melanocytes extend down adnexal epithelium Sheets of melanocytes within the dermis Nests at base of lesions occasionally large Cytomorphology Atypical melanocytes (with pleomorphic nuclei) Mitotic figures Necrotic melanocytes Other features Signs of regression Actinic elastosis Melanin is not distributed in uniform fashion Plasma cells at base of the lesion   Adapted from Ackerman et al HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114051" \o "Go here now" \t "body" 51. Early diagnosis and accurate identification of malignant melanoma is crucial in order to remove lesions at a stage when complete cure can still be achieved. The majority of melanomas evolve in a similar way. The earliest histological changes ('melanoma in situ') are characterized by increased numbers of individually disposed atypical melanocytes in the basal layer ( HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View now" Fig. 114.23). Some melanocytes, singly or in nests, are scattered higher in the epidermis and often reach the granular layer (pagetoid spread) HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114053" \o "Go here now" \t "body" 53. After a variable period of time, neoplastic melanocytes invade the papillary dermis, either as coalescent nests or as multiple single cells.  page 1800 INCLUDEPICTURE "http://www.dermtext.com/images/pixel.gif" \* MERGEFORMATINET page 1801  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#"  INCLUDEPICTURE "http://www.dermtext.com/content/0323024092/graphics/thumbnails/M24092-114-f023.jpg" \* MERGEFORMATINET  HYPERLINK "http://www.dermtext.com/content/lightbox.cfm?action=add&ImgID=F114023&ImgBody=graphics/M24092-114-f023.jpg&ID=iBox" Add to lightbox  Figure 114.23 Pathology of melanoma in situ. Increased number of melanocytes with atypical nuclei not only in the basal zone, but also at the upper levels of the epidermis.  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#"  INCLUDEPICTURE "http://www.dermtext.com/content/0323024092/graphics/thumbnails/M24092-114-f024.jpg" \* MERGEFORMATINET  HYPERLINK "http://www.dermtext.com/content/lightbox.cfm?action=add&ImgID=F114024&ImgBody=graphics/M24092-114-f024.jpg&ID=iBox" Add to lightbox  Figure 114.24 Pathology of melanoma. Pagetoid melanocytes organized as solitary units and nests varying in size and shape are present throughout the entire epidermis. Neoplastic melanocytes extend into the dermis. Absence of maturation at deeper levels of the dermis. A classic melanoma ( HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View now" Fig. 114.24) HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114051" \o "Go here now" \t "body" 51, HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114054" \o "Go here now" \t "body" 54 is asymmetrical, poorly circumscribed and characterized by nests of melanocytes within the epidermis that are not equidistant from one another, vary in size and shape, and have become confluent in foci. Melanocytes disposed as solitary units within the epidermis predominate over nests. Some solitary melanocytes and nests of melanocytes are present well above the dermo-epidermal junction, at times extending into the upper epidermis, even the cornified layer. One element of this histologic asymmetry is the observation of these intraepidermal changes away from the invasive intradermal component. Similar findings are present in the adnexal epithelium of pilosebaceous units and eccrine ducts. Within the dermis, nests of melanocytes do not become smaller with progressive descent (absence of maturation). In parallel, nuclei of melanocytes do not become smaller.  Nests of melanocytes within the dermis also vary in size and shape and become confluent, sometimes forming sheets of cells. The base of the neoplasm is uneven. Melanin is sometimes more plentiful at the base than at the surface of the neoplasm. Frequently, an infiltrate of lymphocytes can be observed. The neoplastic melanocytes show a wide spectrum of cytomorphological features including spindled, pagetoid, small and large round-shaped, polygonal, multinucleate and dendritic characteristics. Certain cytological features of the melanocytes are more common in particular anatomical sites than in others. For example, the finding of increased numbers of intraepidermal atypical melanocytes with elongated branching dendritic processes are a very helpful diagnostic sign of early melanomas on palms and soles.   HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#"  INCLUDEPICTURE "http://www.dermtext.com/content/0323024092/graphics/thumbnails/M24092-114-f025.jpg" \* MERGEFORMATINET  HYPERLINK "http://www.dermtext.com/content/lightbox.cfm?action=add&ImgID=F114025&ImgBody=graphics/M24092-114-f025.jpg&ID=iBox" Add to lightbox  Figure 114.25 Pathology of melanoma in situ on sun-exposed surfaces. Atypical melanocytes both singly and in small nests within the epidermis and along the follicular epithelium. Identifying atypia of melanocytes may be quite subjective. Generally, atypia is defined by nuclear features including variable nuclear size, shape and basophilia. Even in highly anaplastic tumors, the intranuclear pseudoinclusions typical of benign melanocytic tumors, may be identified. Mitotic figures in the dermal component of benign melanocytic tumors are distinctly uncommon. In melanoma, atypical mitotic forms may be observed in addition to more typical ones with tripolar and other bizarre configurations. The absence of mitotic figures in the dermal component of a melanocytic tumor does not exclude the diagnosis of melanoma.  LMM differs from the stereotypical melanoma by its presence on sun-damaged skin of older patients, and the tendency to have little pagetoid spread within the epidermis. The atypical melanocytes are commonly present along the epithelium of adnexal structures especially along the external root sheath of hair follicles ( HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View now" Fig. 114.25). The invasive component is more often composed of spindle cells. Desmoplastic stromal change and neurotropism of tumor cells are common findings. Epidermal atrophy and signs of solar elastosis can be observed in the upper dermis.  ALM often shows a proliferation of atypical melanocytes within the basal layer of a hyperplastic epidermis. Atypical melanocytes are arranged singly and in irregularly shaped nests, at all levels of the epidermis ('pagetoid scatter') with predominance of single cells. In the cornified layer numerous melanocytes and melanin granules are usually found in a diffusely scattered distribution. Notably, melanomas in volar and subungual sites display strikingly dendritic melanocytes ( HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View now" Fig. 114.26).  Microstaging  page 1801 INCLUDEPICTURE "http://www.dermtext.com/images/pixel.gif" \* MERGEFORMATINET page 1802  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#"  INCLUDEPICTURE "http://www.dermtext.com/content/0323024092/graphics/thumbnails/M24092-114-f026.jpg" \* MERGEFORMATINET  HYPERLINK "http://www.dermtext.com/content/lightbox.cfm?action=add&ImgID=F114026&ImgBody=graphics/M24092-114-f026.jpg&ID=iBox" Add to lightbox  Figure 114.26 Melanoma in situ on the plantar surface of a foot. Atypical melanocytes are scattered throughout the hyperplastic epidermis including the horny layer. Note dendritic melanocytes. The Breslow tumor thickness (depth of invasion) is measured in millimeters from the top of the granular cell layer of the epidermis (or base of an ulcer) to the deepest point of tumor penetration using an ocular micrometer ( HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View now" Fig. 114.27). Clark's levels of invasion utilize a stair-step determination: level 1 is confined to the epidermis (in situ); level 2 invades the papillary dermis; level 3 fills the papillary dermis to the junction of the superficial reticular dermis; level 4 invades the reticular dermis; and level 5 invades the fat. In addition to tumor thickness, a number of other histological features including ulceration, Clark's level of invasion HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114054" \o "Go here now" \t "body" 54, presence of tumor infiltrating lymphocytes, mitoses/mm2, regression, vascular invasion and microscopic satellites may be associated with an unfavorable prognosis. Several studies of interobserver agreement that compared a variety of microstaging criteria, revealed that tumor thickness and ulceration were more reliable than Clark's level of invasion, growth pattern (radial/vertical growth phase) and mitotic index HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114055" \o "Go here now" \t "body" 55.  HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=T114007" \o "Go here now" \t "body" Table 114.7 shows a recommendation of the features that should be included in the histopathological report of a malignant melanoma HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114056" \o "Go here now" \t "body" 56.  Immunohistology  A wide range of monoclonal antibodies reactive with melanoma-associated antigens is available. Special stains are not used in routine cases and are mainly employed to confirm derivation of a tumor from melanocytes when this is unclear with H&E stains. Most frequently used and particularly helpful are antisera to S-100 protein and HMB45, which recognizes a pre-melanosomal glycoprotein. The most useful marker in terms of identifying spindled forms of melanoma is S-100, since HMB45 and MART-1 are often negative in spindled melanocytes. Immunohistological markers are not reliable in the differential diagnosis of melanoma from benign melanocytic tumors.  STAGING   Table 114-7. Histopathological reporting of cutaneous melanoma. HISTOPATHOLOGICAL REPORTING OF CUTANEOUS MELANOMADiagnosis Thickness (Breslow depth) Mitoses/mm2 Level of invasion (Clark) Regression, tumor infiltrating lymphocytes, presence of plasma cells Ulceration Vascular invasion Microscopic satellites Associated nevus Margins   The World Health Organization has recommended notation of radial or vertical growth phase.  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#"  INCLUDEPICTURE "http://www.dermtext.com/content/0323024092/graphics/thumbnails/M24092-114-f027.jpg" \* MERGEFORMATINET  HYPERLINK "http://www.dermtext.com/content/lightbox.cfm?action=add&ImgID=F114027&ImgBody=graphics/M24092-114-f027.jpg&ID=iBox" Add to lightbox  Figure 114.27 Microstaging of malignant melanoma. Breslow's method: measure from the granular layer of the epidermis to the deepest part of the tumor. page 1802 INCLUDEPICTURE "http://www.dermtext.com/images/pixel.gif" \* MERGEFORMATINET page 1803  Table 114-8. Proposed stage groupings for cutaneous melanoma. PROPOSED STAGE GROUPINGS FOR CUTANEOUS MELANOMASurvival (%)*Clinical stagingPathologic stagingTNMTNM0TisN0M0TisN0M0IA95T1aN0M0T1aN0M0IB90T1b T2aN0M0T1b T2aN0M0IIA78T2b T3aN0M0T2b T3aN0M0IIB65T3b T4aN0M0T3b T4aN0M0IIC45T4bN0M0T4bN0M0III#Any TN1 N2 N3M0M0IIIA66T1-4a T1-4aN1a N2aM0IIIB52T1-4b T1-4b T1-4a T1-4a T1-4a/bN1a N2a N1b N2b N2cM0IIIC26T1-4b T1-4b Any TN1b N2b N3M0IV7.5-11Any TAny NAny M1Any TAny NAny M1  *Approximate five-year survival in percent, modified from Balch et al HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114057" \o "Go here now" \t "body" 57. Clinical staging includes microstaging of the primary melanoma and clinical/radiologic evaluation for metastases. By convention, it should be used after complete excision of the primary melanoma with clinical assessment for regional and distant metastases. Pathologic staging includes microstaging of the primary melanoma and pathologic information about the regional lymph nodes after partial or complete lymphadenectomy. Pathologic stage 0 or stage IA patients are the exception. #There are no stage III subgroups for clinical staging. Modified from Balch et al HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114063" \o "Go here now" \t "body" 63.  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#"  INCLUDEPICTURE "http://www.dermtext.com/content/0323024092/graphics/thumbnails/M24092-114-f028.jpg" \* MERGEFORMATINET  HYPERLINK "http://www.dermtext.com/content/lightbox.cfm?action=add&ImgID=F114028&ImgBody=graphics/M24092-114-f028.jpg&ID=iBox" Add to lightbox  Figure 114.28 Fifteen-year survival curves comparing different melanoma stages. Survival of localized melanoma (stage I and II), regional metastases (stage III) and distant metastases (stage IV) are compared. The numbers in parentheses are patients from the AJCC melanoma staging database used to calculate the survival rates. The differences between the curves are significant (p <0.05). Reproduced from Balch et al. Journal of Clinical Oncology 19:3635-3648. The staging of melanoma is categorized into local, regional or distant disease and strongly correlates with survival ( HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=T114008" \o "Go here now" \t "body" Table 114.8 &  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View now" Fig. 114.28). Microstaging of localized disease is performed using the Breslow depth (see above) HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114058" \o "Go here now" \t "body" 58. A distinction between low-risk stage I patients with a Breslow depth of d"1 mm and high-risk stage II patients with a Breslow depth of >1 mm is usually made. Involvement of regional lymph nodes (stage III) or distant metastases (stage IV) is associated with increasingly worse prognosis. This difference in prognosis is reflected in current staging classifications of melanoma. The American Joint Committee on Cancer (AJCC) staging classification distinguishes localized disease (T1-T4), regional lymph nodes metastases (N1-N3) and distant metastases (M1a-M1c) ( HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=T114008" \o "Go here now" \t "body" Tables 114.8 &  HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=T114009" \o "Go here now" \t "body" 114.9). There has been considerable investigation of clinical and pathological features of melanoma that predict the risk of metastases and survival. A major advance in the ability to stage patients more accurately is provided by a minimally invasive microscopic staging technique: the so-called sentinel node biopsy. This technique has changed our understanding of the natural history of melanoma HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114059" \o "Go here now" \t "body" 59, HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114060" \o "Go here now" \t "body" 60. Increased ability to detect micrometastasis has caused a significant upward stage migration that has necessitated a revision of older staging classifications. A new tumor-node-metastases (TNM) staging system was introduced by the AJCC in 2000, critically evaluated by the European Union for Research and Treatment of Melanoma group HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114061" \o "Go here now" \t "body" 61, and revised in 2001 based on a 17 600 melanoma patient database derived from 13 cancer centers and melanoma cooperative groups ( HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=T114008" \o "Go here now" \t "body" Tables 114.8 &  HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=T114009" \o "Go here now" \t "body" 114.9) HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114057" \o "Go here now" \t "body" 57. With the publication of the sixth edition of the AJCC Cancer Staging Manual in 2002 this classification is now in use.  The most important modifications are: (1) the noted gradations for tumor thickness are d"1 mm, 1 to 2 mm, 2 to 4 mm, and >4 mm; (2) the primary determinant of tumor (T) staging is tumor thickness as measured in millimeters. The Clark level of invasion is used only for further defining T1 melanomas; (3) microscopic ulceration has been added as a major prognostic factor of the primary tumor; (4) local recurrence, satellite disease, and in-transit metastases are now all classified together as regional stage III disease because of similar prognosis; (5) size of lymph node as a prognostic factor has been eliminated and replaced with the number of positive nodes; (6) the presence of an elevated serum lactate dehydrogenase (LDH) level is used in the metastasis (M) category; and (7) the site of distant metastases is of importance for prognosis. Furthermore, the intent of the surgical procedure that led to the detection of nodal metastases should be reported, i.e. therapeutic lymphadenectomy, lymphadenectomy for clinically detectable metastatic lymph nodes or either sentinel or elective lymphadenectomy that detected clinically occult metastases. Stage grouping includes clinical and pathologic parameters. Clinical staging requires histological microstaging of the primary melanoma as well as clinical/radiological evaluation for metastases. Pathologic staging includes microstaging of the primary melanoma and pathologic information about regional lymph nodes after selective or complete lymphadenectomy. The revised AJCC staging system includes new prognostic markers and hopefully improves the stratification of patients in future clinical trials. This staging system may not accurately reflect variants of melanoma such as desmoplastic, childhood, mucosal or ocular melanoma.  PROGNOSIS  page 1803 INCLUDEPICTURE "http://www.dermtext.com/images/pixel.gif" \* MERGEFORMATINET page 1804  Table 114-9. Melanoma TNM classification. MELANOMA TNM CLASSIFICATIONT classificationThicknessUlceration statusT1d"1.0 mma: Without ulceration and level II/III b: With ulceration or level IV/VT21.01-2.0 mma: Without ulceration b: With ulcerationT32.01-4.0 mma: Without ulceration b: With ulcerationT4> 4.0 mma: Without ulceration b: With ulcerationN classificationNumber of metastatic nodesNodal metastatic massN11 nodea: Micrometastasis* b: MacrometastasisN22-3 nodesa: Micrometastasis* b: Macrometastasis c: In transit met(s)/satellite(s) without metastatic node(s)N34 or more metastatic nodes, or matted nodes, or in transit met(s)/satellite(s) with metastatic node(s)M classificationSiteSerum lactate dehydrogenaseM1aDistant skin, subcutaneous, or nodal metsNormalM1bLung metastasesNormalM1cAll other visceral metastases Any distant metastasisNormal Elevated  *Micrometastasis are diagnosed after sentinel or elective lymphadenectomy. Macrometastases are defined as clinically detectable nodal metastases confirmed by therapeutic lymphadenectomy or when nodal metastasis exhibits gross extracapsular extension. Adapted from Balch et al HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114057" \o "Go here now" \t "body" 57. The prognosis of a patient with melanoma is dependent on its stage at diagnosis ( HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View now" Fig. 114.28). Prognosis for patients with localized melanoma and no nodal or distant metastases is generally good. An overall 5 year survival rate of over 79% for stage I/II disease has been reported HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114062" \o "Go here now" \t "body" 62. Clinical variables with prognostic significance in stage I/II disease include tumor thickness, ulceration, sex, age and anatomic site HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114063" \o "Go here now" \t "body" 63-65 ( HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=T114010" \o "Go here now" \t "body" Table 114.10). Ulceration is defined as the absence of an intact epidermis overlying a major portion of the primary tumor based on microscopic examination. Women with stage I/II disease tend to have better survival than men. Location of the primary melanoma on the trunk, head or neck portends a poorer prognosis than a location on the extremities. Tumor regression, which can occur in up to 20% of melanomas, has been proposed by some researchers to be of prognostic significance but has not been confirmed by others HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114066" \o "Go here now" \t "body" 66. There is evidence that Clark's level, growth phase, tumor-infiltrating lymphocytes and mitotic rate also have prognostic value. However, the applied accuracy of these measurements and the definition of these attributes among pathologists has been questioned in the recent American Academy of Dermatology melanoma guidelines HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114067" \o "Go here now" \t "body" 67.  UPDATEDate Added: 25 October 2004Dr John A. FisherMetallothionein-overexpression as a prognostic factor in melanoma Although metallothioneins (MTs) are ubiquitous and are known to play a role in the metabolism of heavy metal ions such as copper, cadmium, and zinc, their precise function is yet to be defined. They are small, intracellular proteins that are rich in cysteine, which protect cells against ionizing and ultraviolet radiation, as well as (controversially) conferring resistance to anticancer drugs. Their synthesis is induced by glucorticosteroids, interleukins, interferon-, tumor necrosis factor- and vitamin D3. MT overexpression has been reported to be a useful prognostic sign in certain malignancies, including melanoma and nonmelanoma skin cancers.  The authors of this prospective study investigated the role of MT overexpression in melanoma patients in comparison to other factors, as a prognostic factor for progression and survival.  Five hundred twenty patients from an original cohort of 760 were evaluated. Measurement end points were the time of detection of lymph node and/or distant metastases, and death due to widespread disease. The 240 patients who dropped out were either lost to follow up or died from other diseases. Of the 520 who were evaluated, men and women were evenly balanced and the median age was 57.5 years (mean 56.3). The median observation time was 25 months. Breslow thickness (which varied from in situ to1.9 mm), Clark level, ulceration, site of primary tumor, age and gender were all noted for statistical analysis.  The primary monoclonal MT mouse IgG1 antibody E9 was used on routinely fixed and paraffin-embedded tissues. The immunoreactive MT expression in tumor specimens was analyzed visually by two independent observers. The immunohistochemical overexpression of MT was defined as MT reactivity in more than10% of tumor cells.  During the 5 years of the study, 45 patients (8.7%) showed disease progression with a median time of 24.0 months (mean 28.7). Thirty of these patients (5.8% of the total group) died due to metastatic disease. None of the patients with a tumor thickness less than 0.75 mm developed metastasis.  MT overexpression in the primary melanoma (P<0.001) was demonstrated by 73% of patients with progression, and by 80% of those who died due to metastasis. Even in patients with thin melanomas (<1.5 mm), the majority of those who died, i.e. five of six, or showed progression, i.e. six of nine, had statistically significant MT overexpression in their primary melanoma (P<0.005 and P<0.01, respectively).  Over a period of 72 months, 21.2% of the MT-positive group developed metastasis compared with only 3.3% of the MT-negative group (P< 0.0001), MT overexpression proved to be a highly significant and independent factor for prognosis in a univariate analysis with Breslow thickness, and in multivariate analysis with other prognostic markers.  The authors conclude that MT overexpression is a potent and significant factor in determining the risk for melanoma progression, independent of Breslow thickness. It is easy to assess in most laboratories and helps to distinguish thin melanomas which are at increased risk of progression.   HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#"  INCLUDEPICTURE "http://www.dermtext.com/content/0323024092/graphics/thumbnails/20041021ACUP.jpg" \* MERGEFORMATINET   Weinlich G, Bitterlich W, Mayr V, Fritsch PO, Zelger B. Metallothionein-overexpression as a prognostic factor for progression and survival in melanoma. A prospective study on 520 patients. British Journal of Dermatology 2003;149:535-41.   Table 114-10. Major independent prognostic factors of survival in multivariate analyses63. MAJOR INDEPENDENT PROGNOSTIC FACTORS OF SURVIVAL IN MULTIVARIATE ANALYSES HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114063" \o "Go here now" \t "body" 63Prognostic factorCommentaryTumor thicknessd" mm low risk, >1 mm higher risk melanomaUlcerationWorse prognosis with ulcerationAgeHigher age with worse prognosisSexOnly for localized disease, males with poorer prognosisAnatomic SiteTrunk, head and neck with poorer prognosis than extremitiesNumber of involved lymph nodesCut off points: 1, 2-3, 4 or more lymph nodesRegional lymph node tumor burdenMacroscopic (palpable) nodal metastases with poorer prognosis than microscopic (non-palpable) nodal metastasesSite of distant metastasesVisceral metastases with poorer prognosis than non-visceral (skin, subcutaneous, distant lymph nodes)  Stage III melanoma patients are a heterogeneous group with respect to their risk for distant metastases and melanoma specific mortality. The 5-year survival rates range from 69% for patients with non-ulcerated melanomas who had a single clinically occult nodal metastasis to a low of 13% for patients with ulcerated primary melanomas and four or more clinically apparent metastases HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114063" \o "Go here now" \t "body" 63. Major prognostic factors in this group are the number of metastatic lymph nodes and the tumor burden. Tumor burden is reflected by whether the nodal metastases are clinically occult (as detected by sentinel or elective lymph node dissection) or clinically palpable.  In stage IV patients the major prognostic factor is the site of distant metastases with a poorer prognosis for visceral than non-visceral (e.g. skin, subcutaneous, and distant lymph nodes) metastases. The median survival time of stage IV patients in a recent study was 7.5 months; the estimated 5-year survival rate was 6% HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114068" \o "Go here now" \t "body" 68. The main variables that predicted survival were initial site of metastases, disease-free interval before distant metastases and stage of disease preceding distant metastases. Patients with cutaneous, nodal or gastrointestinal metastases had a median survival of 12.5 months (estimated 5-year survival rate 14%); with pulmonary metastases the median survival is 8.3 months (estimated 5-year survival rate 4%); and patients with metastases to the liver, brain or bone had a median survival of 4.4 months (estimated 5-year survival rate 3%). Up to 9% of metastatic melanoma patients present with an unidentified primary tumor. This finding is not in itself a negative prognostic indicator.  There has been a long-standing search for melanoma-specific tumor markers that determine the prognosis. Reverse transcription (RT) of tyrosinase mRNA and specific cDNA amplification to facilitate the early detection of circulating tumor cells in melanoma patients has been reported as a promising tool. However, recent results indicate that a low amount of tyrosinase-specific transcripts is detected only in a small subset of stage IV patients and suggest that the analysis of tyrosinase mRNA in peripheral blood samples is therefore not helpful as a prognostic marker or monitoring tool in these melanoma patients HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114069" \o "Go here now" \t "body" 69.  Serum levels of S-100-beta and melanoma-inhibiting activity (MIA), 5-S-cysteinyldopa as well as conventional variables, such as LDH levels have been proposed as monitors in advanced melanoma patients HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114070" \o "Go here now" \t "body" 70. In a recent study the highest sensitivities for determining metastasis were found for S-100-beta and MIA (91% and 88%, respectively). LDH had the highest specificity (92%). However, LDH was identified to be the only statistically significant marker for progressive disease HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114071" \o "Go here now" \t "body" 71.  page 1804 INCLUDEPICTURE "http://www.dermtext.com/images/pixel.gif" \* MERGEFORMATINET page 1805 EVALUATION OF A PATIENT WITH SUSPECTED MELANOMA  Medical History  A thorough medical history should be taken, focusing especially on risk factors for the development of melanoma (see above), such as a personal or family history of melanoma, skin type I/II (see  HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=C13424092" \o "Go here now" \t "body" Chapter 134), extensive sun bed use, childhood history of sunburns, large number of melanocytic nevi, presence of atypical melanocytic nevi, presence of large congenital melanocytic nevi, genetic syndromes with skin cancer predisposition (e.g. xeroderma pigmentosum), iatrogenic (immunosuppressive drugs used in transplant medicine or extended PUVA therapy) or acquired (e.g. HIV) immunosuppression. A detailed history of the specific lesion in question should be obtained. Was the lesion present at birth? Did the lesion develop in a preexisting mole? Did it change in size or shape? Did it change in color or ulcerate? Was there itching or bleeding? What is the time course of change? Are there systemic symptoms such as weight loss, fatigue, night sweats, headache or cough HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114072" \o "Go here now" \t "body" 72. Other family members should be screened if either melanoma or atypical melanocytic nevi are present. This patient should be educated about the clinical features of melanoma and about sun protection measures (see  HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=C15424092" \o "Go here now" \t "body" Chapter 154). Suggested follow-up intervals are considered in  HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=C11324092" \o "Go here now" \t "body" Chapter 113.  Skin Investigation and Clinical Diagnosis  The patient should undergo a complete physical examination including a whole body skin investigation. The entire skin surface, including the scalp and mucous membranes, should be examined. Bright room illumination is important, and a hand lens is helpful. Clinical criteria for melanoma include a history of increase in size, an asymmetrical appearance, ill-defined and irregular borders, variation in colors with shades of brown, black, gray, red, white and blue HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114073" \o "Go here now" \t "body" 73. There may be focal areas of regression (loss of pigmentation) or newly developing black spots. The American Cancer Society uses the ABCD mnemonic (see above) to describe these changes. A specificity of 0.88 and sensitivity of 0.73 has been reported if two out of three of the following characteristics are noted: irregular outline; diameter greater than 6 mm and color variegation HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114074" \o "Go here now" \t "body" 74. Addition of an 'E' criterion for enlargement was proposed to optimize sensitivity and specificity of diagnosis HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114075" \o "Go here now" \t "body" 75. A melanotic lesion that is atypical beyond the context of surrounding nevi should arouse suspicion of melanoma regardless of specific findings. This has been called the 'ugly duckling' sign HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114076" \o "Go here now" \t "body" 76. Even expert clinicians misdiagnose melanoma in up to one-third of cases and only histologic examination will provide the diagnosis HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114077" \o "Go here now" \t "body" 77. Dermatoscopy is a popular diagnostic tool and increases diagnostic sensitivity when used by dermatologists formally trained in the use of this technique, but may decrease diagnostic accuracy in dermatologists not formally trained in its application HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114050" \o "Go here now" \t "body" 50 (see above). Any lesion suspicious for the diagnosis of melanoma, but lacking the full manifestation of all clinical criteria should be recorded by diagram or photography for follow-up. Alternatively, excisional biopsy is warranted. Examination of lymph node basins and palpation of the abdomen for hepatosplenomegaly should be routinely performed. Length of scars after primary or re-excision should be documented and scars palpated at follow up visits for possible local recurrence.  UPDATEDate Added: 04 August 2003John A. Fisher M.D. Dermoscopy in melanoma screening The authors describe a study designed to evaluate the impact of dermoscopy (epiluminescence microscopy, dermatoscopy) on the false-positive rate in routine melanoma screening activity at a pigmented lesion clinic.  The positive predictive value of melanoma diagnosis by a dermatologist during melanoma screening is less than 20%1 Koh HK, et al. Evaluation of the American Academy of Dermatology's national skin cancer early detection and screening program. J Am Acad Dermatol 1996;34:971-8. i.e. only 2 out of 10 cases of suspected melanoma are confirmed histologically. Surgical excision has its own attendant morbidity and includes the likelihood of scarring.  In a series of 133 patients consecutively referred to the clinic, 2542 pigmented lesions were observed through visual examination. Of those, 43 were defined as suspicious or equivocal and subsequently examined by dermoscopy. Only lesions again defined as suspicious by dermoscopy (13) were excised. Histopathologic examination revealed three malignant melanomas. Other lesions were observed through followed up examination.  Compared with visual examination alone, the addition of dermoscopy resulted in an increase in specificity from 98.4% to 99.6% and in positive predictive value from 6.9% to 23%. The specificity of a "refer for surgical excision" outcome increased from 69.2% to 92.3%. No false-negative melanoma diagnoses from dermoscopy were encountered during a follow-up period of 4 years.  The addition of dermoscopy as a second level diagnostic tool in routine examinations led to a reduction in the number of false-positive diagnoses, with an increase in the specificity and positive predictive value of melanoma diagnosis.  The authors conclude that confirmatory studies are necessary on larger series of patients, to provide data about the theoretical risk of false-negative outcomes from dermoscopy.  Carli P, Mannone F, de Giorgi V, Nardini P, Chiarugi A, Giannotti B. The problem of false-positive diagnosis in melanoma screening: the impact of dermoscopy. Melanoma Research 2003;13:179-182.  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12690302&dopt=Abstract" \o "View this article on Medline in a new window" \t "_new" Medline INCLUDEPICTURE "http://www.dermtext.com/images/linkout.gif" \* MERGEFORMATINET   HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Display&dopt=pubmed_pubmed&from_uid=12690302" \o "View similar articles on Medline in a new window" \t "_new" Similar articles INCLUDEPICTURE "http://www.dermtext.com/images/linkout.gif" \* MERGEFORMATINET   Laboratory Investigations and Imaging  Evaluation of a patient with melanoma might include chest radiography, ultrasound investigation of the abdomen as well as serum markers such as LDH, S100beta or MIA. There is wide variation in the use of these tests in clinical practice. Evidence is accumulating that routine imaging studies including chest radiography and blood work have limited, if any value in the initial work-up of asymptomatic patients with primary cutaneous melanoma 4 mm or less in thickness HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114067" \o "Go here now" \t "body" 67. An American Academy of Dermatology task force recommended that these initial imaging studies and blood work are optional and most appropriately directed based on findings of a thorough medical history and physical examination HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114067" \o "Go here now" \t "body" 67. In a study involving more than 800 asymptomatic patients with localized melanomas initially examined with chest radiography, unsuspected metastasis was demonstrated in only 1 patient HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114078" \o "Go here now" \t "body" 78. Unnecessary investigations are costly, may lead to patient anxiety and are unlikely to impact outcome. Exceptions for obtaining imaging and blood chemistry studies on asymptomatic patients with primary melanoma include thickness >4 mm and in the setting of multidisciplinary referral centers conducting prospective studies.  Investigation of stage III/IV melanoma patients includes radiologic investigations such as magnetic resonance imaging (MRI) of the brain and computed tomography (CT) of the chest, abdomen and pelvis. The most significant advance in imaging technology for early detection of metastases is whole body positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG) HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114079" \o "Go here now" \t "body" 79. It is based on the assumption that melanoma metastases have a higher metabolic rate than normal tissue and utilize more  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View drug information" glucose INCLUDEPICTURE "http://www.dermtext.com/images/linkdrug.gif" \* MERGEFORMATINET . The accuracy of nodal staging can be significantly improved by adding PET to the pre-therapeutic diagnostic procedures HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114080" \o "Go here now" \t "body" 80. A meta-analysis of the existing PET literature determined an overall sensitivity of 92% and an overall specificity of 90% HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114081" \o "Go here now" \t "body" 81. However, in a selected patient population, FDG-PET was found to be inferior to CT for diagnosing lung and liver metastases HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114082" \o "Go here now" \t "body" 82.  The combination of FDG-PET with CT or ultrasound guided fine-needle aspiration (FNA) can increase the sensitivity of both methods HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114083" \o "Go here now" \t "body" 83. FNA is used in the cytologic diagnosis of melanoma metastases often in combination with immunohistochemistry with melanoma-specific antibodies, but should not be used for the diagnosis of the primary melanoma. In a study in 330 melanoma patients with metastasis, 739 FNAs were performed with a sensitivity of 97.9% and a specificity of 100% HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114084" \o "Go here now" \t "body" 84. FNA is especially useful in combination with ultrasound or CT in melanoma follow-up of lymph node, lung and liver metastases and has the potential to identify lesions smaller than 1 cm.  MANAGEMENT  Management of melanoma includes prevention, screening, history, physical examination, histology, laboratory testing, imaging, staging, prognosis, treatment and follow-up.  Management of the Primary Melanoma (Stage I and II)  page 1805 INCLUDEPICTURE "http://www.dermtext.com/images/pixel.gif" \* MERGEFORMATINET page 1806 Early diagnosis and treatment is essential in the management of primary melanoma, since tumor thickness remains the most important prognostic indicator in this setting. Secondary prevention measures such as identification, education and screening of high risk patients complement management of primary melanoma. A lesion that is clinically suspicious for melanoma should ideally undergo an excisional biopsy with narrow margins (such as 2 mm). Although there is evidence that an incisional biopsy does not adversely affect survival HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114085" \o "Go here now" \t "body" 85, this approach should be an exception and reserved for cases in which the tumor is too large to be excised, or when it is impractical to perform an excision (e.g. of the nail unit). The biopsy should be interpreted by a physician experienced in the microscopic diagnosis of melanotic lesions. Fine-needle aspiration cytology should not be used to assess the primary tumor HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114067" \o "Go here now" \t "body" 67. After excisional biopsy and histologic diagnosis melanoma should be re-excised with an appropriate margin determined by the Breslow depth ( HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=T114011" \o "Go here now" \t "body" Table 114.11).  The rationale of excision margin is based on the capacity of melanoma cells to migrate away from the tumor origin. Melanoma may extend wider or deeper than is visibly apparent. The major goal is to prevent local recurrence or persistent disease. A WHO randomized trial indicates that 1 cm excision margins are safe and effective for melanoma with Breslow depth <1 mm HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114086" \o "Go here now" \t "body" 86. A controversy persists about the effectiveness of 1 cm excision margins for melanomas 1 to 2 mm deep, since there was a trend to local recurrence in this group in the WHO trial HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114087" \o "Go here now" \t "body" 87. Several recent reports, including the American Academy of Dermatology Guidelines of Care for Primary Melanoma, have recommended 1 cm margins for melanoma <2 mm depth HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114067" \o "Go here now" \t "body" 67, HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114088" \o "Go here now" \t "body" 88, HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114089" \o "Go here now" \t "body" 89. A randomized trial for intermediate thickness melanoma (1 to 4 mm deep) demonstrated that 2 cm margins are as effective as 4 cm margins in preventing local recurrences HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114090" \o "Go here now" \t "body" 90. For this group of melanoma patients, local recurrence was associated with a high mortality rate. Ulceration of the primary melanoma is the most significant prognostic factor heralding an increased risk for a local recurrence. There are no informative randomized trials that determine the optimal margins of excision for melanoma >4 mm thickness or in situ melanoma. Current recommendation are excision margins of 0.5 cm for in situ melanoma and 2 to 3 cm for melanoma >4 mm depth HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114067" \o "Go here now" \t "body" 67, HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114091" \o "Go here now" \t "body" 91.  Further investigative efforts will likely alter the standards of care over time. Margins of excision are also dictated by surgically difficult anatomic areas such as the distal extremities, the mucous membranes or the face and in many instances an individualized surgical approach must to be taken HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114092" \o "Go here now" \t "body" 92. Some recommendations, such as excision to the underlying fascia, are based on questionable anatomic concepts HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114025" \o "Go here now" \t "body" 25. No randomized trials have compared this approach to excision to the deep subcutaneous fat HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114025" \o "Go here now" \t "body" 25.  Data exist to indicate that definitive surgical treatment may be safely delayed for 3 weeks after an excisional biopsy without adversely influencing the 5-year survival rate HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114094" \o "Go here now" \t "body" 94. Longer time periods may still be permissible, although the upper limit is unknown.  Follow-up is indicated because of the risk of developing a second melanoma (estimated at 3.4-4.3% HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114095" \o "Go here now" \t "body" 95-97) as well as local relapse and/or metastasis from the original tumor HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114098" \o "Go here now" \t "body" 98. There is little evidence to support specific follow-up intervals, but the American Academy of Dermatology melanoma task force recommends follow-up one to four times per year, depending on the thickness of the lesion and other risk factors such as a melanoma family history for 2 years after diagnosis and one to two times per year thereafter HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114067" \o "Go here now" \t "body" 67. Follow-up interventions usually include medical history, clinical examination, laboratory/radiologic tests as indicated and may include patient education.  Local Recurrences   Table 114-11. Surgical treatment of primary melanoma. SURGICAL TREATMENT OF PRIMARY MELANOMAThicknessExcision margins (cm)CommentsIn situ0.5No randomized studies, lentigo maligna of the face might be treated with radiotherapy in specialized centers HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114093" \o "Go here now" \t "body" 93<1 mm1.0AAD task force suggests 1 cm margin for melanoma <2 mm HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114067" \o "Go here now" \t "body" 671-4 mm2.0AAD task force suggests 2 cm margin for melanoma e"2 mm HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114067" \o "Go here now" \t "body" 67>4 mm2.0-3.0No randomized studies   HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#"  INCLUDEPICTURE "http://www.dermtext.com/content/0323024092/graphics/thumbnails/M24092-114-f029.jpg" \* MERGEFORMATINET  HYPERLINK "http://www.dermtext.com/content/lightbox.cfm?action=add&ImgID=F114029&ImgBody=graphics/M24092-114-f029.jpg&ID=iBox" Add to lightbox  Figure 114.29 Recurrent melanoma with metastases. Local recurrence is defined as any recurrence within 2 cm of the surgical scar of a definitive excision for primary melanoma HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114057" \o "Go here now" \t "body" 57. Recurrence results from extension of the primary tumor or intra-lymphatic spread. Every effort should be made to identify hematogenous metastases. The overall risk of recurrence is approximately 3.8%, and is more frequent in thicker or ulcerated tumors as well as head and neck and distal leg locations ( HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View now" Fig 114.29) HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114099" \o "Go here now" \t "body" 99. Ultra late recurrence (>15 years) may occur in melanoma without identifiable risk factors HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114100" \o "Go here now" \t "body" 100. Local recurrence is strongly associated with the appearance of in transit and regional as well as distant metastases but is not an independent prognostic indicator of survival in multivariate analysis HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114099" \o "Go here now" \t "body" 99. There is evidence that patients with local recurrence, satellites and in transit metastases have a similar pathogenesis and outcome HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114101" \o "Go here now" \t "body" 101. There is no evidence that patient survival is adversely affected if local recurrence results from inadequate excision of the primary melanoma (i.e. persistent disease) provided that the residual in situ or radial growth-based tumor is promptly re-excised and provided there is no distant disease at the time HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114025" \o "Go here now" \t "body" 25. In a population-based study, local recurrence had no major detrimental effect on survival HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114102" \o "Go here now" \t "body" 102. However in a recent contradictory study local recurrence was associated with a high mortality rate HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114090" \o "Go here now" \t "body" 90. Development of local recurrence in melanomas <4 mm thick is often due to inadequate surgical treatment HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114103" \o "Go here now" \t "body" 103. Patterns of failure after local recurrence suggest that patients may benefit from aggressive loco-regional therapy HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114104" \o "Go here now" \t "body" 104. Surgical resection with a wide margin (up to 3 cm) depending on the anatomic site is the most common and effective therapy. In selected patients isolated limb perfusion which has high regional response rates for the treatment of in-transit metastases may be considered HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114105" \o "Go here now" \t "body" 105.  Management of Regional Metastatic Melanoma (Stage III)  page 1806 INCLUDEPICTURE "http://www.dermtext.com/images/pixel.gif" \* MERGEFORMATINET page 1807  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#"  INCLUDEPICTURE "http://www.dermtext.com/content/0323024092/graphics/thumbnails/M24092-114-f030a.jpg" \* MERGEFORMATINET  HYPERLINK "http://www.dermtext.com/content/lightbox.cfm?action=add&ImgID=F114030&ImgBody=graphics/M24092-114-f030a.jpg&ID=iBox" Add to lightbox   HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#"  INCLUDEPICTURE "http://www.dermtext.com/content/0323024092/graphics/thumbnails/M24092-114-f030b.jpg" \* MERGEFORMATINET  HYPERLINK "http://www.dermtext.com/content/lightbox.cfm?action=add&ImgID=F114030&ImgBody=graphics/M24092-114-f030b.jpg&ID=iBox" Add to lightbox  Figure 114.30 Sentinel lymph node biopsy. Localization of sentinel lymph node by lymphoscintigraphy: A small incisional biopsy identifies blue sentinel node; B confirmation with handheld gamma counter. Courtesy of M. Hess and W. Knzi, University Hospital Zrich. Metastatic spread of melanoma is often regional and confined to the site of the primary melanoma and its draining lymph nodes. Metastasis may manifest as clinically occult lymph node (micrometastasis), as a rapidly growing clinically evident macrometastasis, or as in-transit metastasis.  Elective lymph node dissection  Approximately 20% of patients with intermediate (1 to 4 mm) and high risk (>4 mm) cutaneous melanoma and no evidence of clinically or radiologically detectable nodal disease at presentation show microscopic involvement HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114106" \o "Go here now" \t "body" 106. On the basis of the primary migration of melanoma cells in an orderly fashion towards the draining lymph node, surgical resection of regional lymph nodes in all patients with intermediate and high risk tumors was proposed as 'elective lymph node dissection (ELND)'. ELND was postulated to be especially beneficial for patients with microscopic disease of the lymph nodes by preventing spread of tumor cells to internal organs. An opposing view was that excision of lymph node metastasis might impair the body's immune response to melanoma HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114107" \o "Go here now" \t "body" 107, HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114108" \o "Go here now" \t "body" 108. There is significant morbidity associated with ELND, such as postoperative lymphedema, wound infection, hematoma and lymph fistulas. While on retrospective trial suggested benefit for ELND in intermediate risk melanoma patients HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114109" \o "Go here now" \t "body" 109, four other multicenter randomized prospective trials in patients with primary melanoma did not show a survival benefit of patients treated with ELND plus wide re-excision compared to wide re-excision alone HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114110" \o "Go here now" \t "body" 110-113. A further randomized trial did not show a benefit of immediate dissection of regional nodes in melanoma patients >1.5 mm depth HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114114" \o "Go here now" \t "body" 114. Current evidence does not suggest that ELND should be performed in patients with primary melanoma.  Sentinel lymph node biopsy  Since in 80% of patients with ELND there is significant morbidity in the absence of microscopic disease. A less traumatic procedure to identify regional metastatic disease was devised based on similar concepts, namely progression of metastatic disease through the lymphatic system before widespread dissemination HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114115" \o "Go here now" \t "body" 115. This so-called sentinel lymph node biopsy (SLNB) is based on the concept that the skin involved with melanoma drains to one or more lymph node basins and particularly to one (rarely more) lymph node, the sentinel node, which is the first site of deposition of metastatic cells. The concept and its utility are also based on the ability to accurately identify this node. The sentinel node is identified by intraoperative lymphatic mapping using lymphoscintigraphy and dye injection. Lymphoscintigraphy is performed by injection of 99 mTechnetium sulfur colloids around the tumor site or scar of primary excision. The isotope is transported through the draining lymphatics and phagocytosed by macrophages and concentrated within the sentinel lymph node before draining to other regional lymph nodes. The position of the sentinel node is marked on the skin by a hand-held gamma counter. Additionally, a blue dye is injected around the primary tumor or scar which is also transported through the lymphatics to the sentinel node. The blue dye is helpful in giving visual conformation intraoperatively ( HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View now" Fig 114.30). The 'hot, blue' sentinel node(s) is selectively biopsied through a small incision and examined by serial sectioning using H&E stains combined with immunohistochemistry (S-100, HMB45). If metastatic melanoma is identified, then complete regional lymph node dissection is undertaken. Draining patterns are sometimes difficult to predict, especially on the head, neck and trunk. For example, two sentinel lymph nodes may be identified or the skin may drain into the contralateral site of the original tumor. It is recommended to remove all radioactive nodes HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114116" \o "Go here now" \t "body" 116. Since the application of lymphoscintigraphy for SLNB it has been realized that ELND based on classic draining patterns might have led to resection of inappropriate lymphatic basins HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114117" \o "Go here now" \t "body" 117. A recent trial comparing SLNB followed by node dissection to ELND showed no difference in survival.  page 1807 INCLUDEPICTURE "http://www.dermtext.com/images/pixel.gif" \* MERGEFORMATINET page 1808 Training and experience are important in SLNB. SLNB performed with blue dye plus a radiocolloid is more accurate (99.1%) than SLNB performed with blue dye alone (95.2%). Evidence exists that at least 30 SLNBs are required to gain the appropriate skill level HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114118" \o "Go here now" \t "body" 118. Numerous studies have documented the accuracy of this procedure for identifying nodal metastases. A randomized trial provided further evidence that lymphatic mapping and SLND biopsy accurately reflect the status of the regional nodal basin HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114119" \o "Go here now" \t "body" 119. This study also reported a low rate of tumor recurrence (11%) in sentinel node negative patients. In 80% of these cases occult micrometastases were later identified by serial sectioning and appropriate immunohistochemistry using S-100 and HMB45 monoclonal antibodies. The use of RT-PCR to examine sentinel nodes for mRNA of melanoma associated proteins such as tyrosinase or MelanA might increase sensitivity of detection. In one study tyrosinase transcripts were detected in 36-52% of stage I and II melanoma patients with negative sentinel nodes by histopathology alone. Importantly, the recurrence rate was significantly higher in patients with histologically negative sentinel nodes who were found to be positive by RT-PCR than in patients with negative results by both techniques HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114120" \o "Go here now" \t "body" 120. Unanswered questions such as the clinical importance of RT-PCR positive sentinel nodes as well as the effect of adjuvant therapy in patients with negative sentinel nodes will hopefully be answered on-going prospective trials HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114121" \o "Go here now" \t "body" 121.  Based on current data, there are four major reasons to perform SLNB. First, SLNB provides information on subclinical lymph node status with minimal morbidity. As such it is not only a staging tool but provides valuable prognostic information for patients and physicians to guide subsequent treatment decisions. Second, SLNB identifies patients with metastatic lymph nodes for early therapeutic lymph node dissection (see below). Third, SLNB identifies patients who might be candidates for adjuvant therapy with interferon alpha. Fourth, results of SLNB are a stratification criterion to enter more homogeneous patients into adjuvant clinical trials HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114122" \o "Go here now" \t "body" 122.  From the perspective of staging, SLNB has caused stage migration. This means that detection of microscopic metastases in patients leads to an upgrading to stage III disease. This is recognized in the recent revision of the AJCC TNM classification system ( HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=T114008" \o "Go here now" \t "body" Tables 114.8 &  HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=T114009" \o "Go here now" \t "body" 114.9). The marked diversity in the natural history of stage III melanoma is demonstrated by fivefold differences in 5-year survival rates for defined substages that range from 69% for patients with non-ulcerated melanoma who had a single clinically occult metastases to 13% for patients with an ulcerated melanoma with four or more clinically apparent nodal metastases as detected by therapeutic lymphadenectomy HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114063" \o "Go here now" \t "body" 63. These differences are so great that the AJCC recommends that all patients with a primary melanoma >1.0 mm in tumor thickness have nodal staging with sentinel lymphadenectomy before entry into melanoma clinical trials HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114063" \o "Go here now" \t "body" 63.  The above mentioned reasons have led some investigators to propose SLNB as standard of care HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114121" \o "Go here now" \t "body" 121 which is disputed by others HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114067" \o "Go here now" \t "body" 67, HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114123" \o "Go here now" \t "body" 123, HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114124" \o "Go here now" \t "body" 124. Certainly, the use of SLNB in specialized centers in the context of controlled studies may answer important issues relating to melanoma treatment. Whether SLNB represents a clinical standard of care is debatable HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114067" \o "Go here now" \t "body" 67, HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114121" \o "Go here now" \t "body" 121, HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114123" \o "Go here now" \t "body" 123, HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114124" \o "Go here now" \t "body" 124.  From a therapeutic perspective there is little evidence that early dissection in sentinel node positive patients affords improved survival compared to dissection performed when clinically detectable nodes develop. However, a recent study suggested that further node dissection in patients with positive lymph nodes might be beneficial HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114114" \o "Go here now" \t "body" 114.  In conclusion, intraoperative lymphatic mapping and SLNB followed by selective complete lymphadenectomy has revolutionized the management of the regional lymph node basin in patients with melanoma. The sentinel node hypothesis has been validated by a multicenter clinical trial showing that SLNB in melanoma can be accurately performed in a uniform manner by multidisciplinary teams. Although the diagnostic and prognostic accuracy of SLNB has been established, demonstration of the therapeutic use of this procedure awaits analysis of survival data from multicenter randomized trials of wide excision alone versus wide excision plus SLNB/complete lymphadenectomy HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114115" \o "Go here now" \t "body" 115, as well as trials linking SLNB to adjuvant therapies.  Adjuvant therapy  The goal of adjuvant therapy is the active suppression of growth of clinically inapparent micrometastases. A major emphasis in adjuvant therapy are patients with resected high risk stage II and III melanoma. Trials have also targeted resected stage IV patients. A number of postsurgical adjuvant approaches have been tested including systemic chemotherapy, immunotherapy using microbial agents such as Bacillus Calmette-Guerin (BCG) or Corynebacterium parvum HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114125" \o "Go here now" \t "body" 125-127. None of these approaches were successful in randomized controlled trials HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114117" \o "Go here now" \t "body" 117.  The current recommendation is to include appropriate patients in well controlled clinical studies to obtain valid data leading to recommendations about future adjuvant therapy. One of the most promising candidates for adjuvant therapy of patients with malignant melanoma are recombinant biological response modifiers, in particular the intensively studied interferon alpha (IFN-). IFN- is a type I member of the interferon family of proteins and has pleiotropic functions. These include complex immunoregulatory functions such as induction of MHC class I expression as well as impact on immune effector cells such as the activation of natural killer (NK) cells and the maturation of dendritic cells. Some of its activities may have direct or indirect anti-tumor effects HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114128" \o "Go here now" \t "body" 128. Little anti-tumor activity has been demonstrated in metastatic stage IV melanoma, with overall response rates of 10-15%. However, IFN- has been most widely studied in the adjuvant setting for stage II and III disease. It is important to distinguish high-dose IFN therapy with the aim to reach maximally tolerated dosage (20 MU/m2 intravenously during the induction phase followed by 10 MU/m2 subcutaneously three times per week) from low-dose IFN therapy which is much better tolerated in terms of side effects (typically 3 MU three times per week) ( HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=T114012" \o "Go here now" \t "body" Table 114.12).  High-dose IFN has demonstrated an improvement in relapse-free and overall survival compared to controls in two studies (ECOG 1684 as well as ECOG 1694) ( HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=T114012" \o "Go here now" \t "body" Table 114.12). However, a beneficial effect on overall survival was not seen in another high-dose IFN study (ECOG 1690). Toxicity in high-dose IFN include constitutional (flu-like) symptoms, neuropsychiatric (depression, suicidal intention), hematologic, and hepatic effects as well as cases of fatal rhabdomyolysis HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114129" \o "Go here now" \t "body" 129, HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114130" \o "Go here now" \t "body" 130. These toxicities have a major impact on the patient's quality of life, and on the physician's ability to optimally treat the patient and led to dose modifications in two-thirds of the patients in the first month of high-dose IFN. The application of high-dose IFN was questioned especially in Europe due to the inconsistent impact on overall survival and the considerable dose-dependent toxicity HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114131" \o "Go here now" \t "body" 131, HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114132" \o "Go here now" \t "body" 132. It is possible that recurrence of metastases might have a worse effect on patient's quality of life than high-dose IFN therapy HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114133" \o "Go here now" \t "body" 133. The relative importance of the induction component of this treatment regimen is being addressed in an ongoing Intergroup trial for intermediate-risk melanoma HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114134" \o "Go here now" \t "body" 134. For low-dose IFN, randomized studies have consistently reported a benefit with regard to relapse free but not overall survival for patients treated with IFN- compared to untreated controls HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114135" \o "Go here now" \t "body" 135, HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114136" \o "Go here now" \t "body" 136. The impact on extension of overall survival remains unclear. Currently, the most important question is the efficacy of very toxic high dose therapy compared to lower dose long-term treatment. This will hopefully be answered by the data from the large US-Intergroup high-dose and EORTC intermediate-dose and long-term maintenance therapy trials.  Recently, a meta-analysis has been performed of all available IFN- trial results, largely based on published reports. The endpoints evaluated were disease-free survival and overall survival in approximately 3700 patients included in ten trials HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114137" \o "Go here now" \t "body" 137. For disease-free survival, there was clear benefit for IFN-, but the advantage was less clear for overall survival. There was no statistically significant evidence that the benefit of IFN- is greater in higher than in lower dose trials. The authors conclude that 'decisions on the use of IFN- for melanoma will need to be based on considerations such as the relative importance of benefits on disease-free survival compared to overall survival, patient quality of life and financial costs'.  Management of Distant Metastases (Stage IV)  page 1808 INCLUDEPICTURE "http://www.dermtext.com/images/pixel.gif" \* MERGEFORMATINET page 1809  Table 114-12. Completed trials for adjuvant interferon- 2 therapy in melanoma. COMPLETED TRIALS FOR ADJUVANT INTERFERON-2 THERAPY IN MELANOMATrialTNMnAgentTreatmentRFSOSLow-doseEORTC 18871T3-4, N1800IFN-2b IFN-IFN-2b 1MU sc, qod, 52wk versus IFN- 0.2 mg sc, qod, 52wk versus Iscador versus Observation--WHO 16 HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114138" \o "Go here now" \t "body" 138N1-2444IFN-2a3MU sc, t.i.w, 36mo versus Observation--Austrian trial HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114135" \o "Go here now" \t "body" 135T3-4, N0311IFN-2a3MU sc, daily, 3 wk, followed by 3MU, t.i.w., 48wk versus Observation+-French trial HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114136" \o "Go here now" \t "body" 136T3, N0499IFN-2a3MU sc, t.i.w., 18mo versus Observation+-High-doseNCCTG 837052 HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114139" \o "Go here now" \t "body" 139T3-4, N1262IFN-2a20MU/m2 IM, t.i.w. 12wk--ECOG 1684 HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114140" \o "Go here now" \t "body" 140T4, N1287IFN-2b20MU/m2 IV daily5/7d/wk, 4weeks followed by 10MU/m2 sc t.i.w., 48wk++High-dose versus low-doseECOG 1690 HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114141" \o "Go here now" \t "body" 141T4, N1642IFN-2b20MU/m2 IV daily5/7d/wk,4weeks followed by 10MU/m2 sc t.i.w., 48wk (HDI) versus 3MU sc t.i.w, 24mo (LDI)+-High-dose versus gangliosideECOG 1694 HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114142" \o "Go here now" \t "body" 142T4; N1880IFN-2b versus GMK20MU/m2 IV daily5/7d/wk, 4weeks followed by 10MU/m2 sc t.i.w., 48wk (HDI) versus GMK sc 1/wk, 3mo++  RFS, relapse-free survival; +, statistically significant; -, statistically insignificant; wk, weeks; t.i.w., three times per week; MU, million units; IM, intramuscular; IV, intravenous; SC, subcutaneous; ECOG, Eastern Cooperative Oncology Group; NCCTG, North Central Cancer Treatment Group; mo, months; HDI, high-dose interferon; LDI, low-dose interferon; GMK, GM2 ganglioside, keyhole limpet hemocyanin plus OS21 adjuvant; OS, overall survival. Despite new treatment options, the prognosis of patients with metastatic melanoma has not changed significantly over the last 22 years; with survival rates of 6% and median survival of 7.5 months HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114068" \o "Go here now" \t "body" 68. The initial site of metastasis determines prognosis. Nodal or gastrointestinal metastases (median survival of 12.5 months; estimated 5-year survival rate 14%) have a better prognosis than pulmonary metastases (median survival of 8.3 months; estimated 5-year survival rate 4%). The worst prognosis is associated with metastases to the liver, brain or bone (median survival of 4.4 months; estimated 5-year survival rate 3%) HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114068" \o "Go here now" \t "body" 68. Thus the focus is on palliative therapy with special emphasis on the quality of life of the patient. To enable progress towards new therapeutic approaches in stage IV patients inclusion in controlled clinical trials should be considered and discussed with every patient. There is evidence that patients included in clinical trials have better outcome HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114143" \o "Go here now" \t "body" 143. Recent developments with a favorable benefit/side effect profile include oral chemotherapeutic agents and innovative approaches to therapeutic cancer vaccination. It should be also noted that surgery has its place in management of stage IV patients since randomized trials have demonstrated that the value of surgery for local metastatic disease is probably underestimated while the value of extensive surgery and prophylactic surgical procedures is overestimated HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114132" \o "Go here now" \t "body" 132.  Evaluation of the patient with suspected metastatic disease  Evaluation of the patient with suspected metastatic disease is a demanding task both at the level of interaction with the patient and family as well as the extensive work up which is often necessary. It is essential to get an accurate picture of the metastatic burden before considering therapy. Evaluation and necessary diagnostic tests should be guided by an in depth medical history and a thorough physical examination including a whole-body skin examination as well as palpation of the abdomen and the lymph nodes (see above). Possible symptoms related to metastatic disease are listed in  HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=T114013" \o "Go here now" \t "body" Table 114.13. Further staging investigations include a CT scan of the thorax and abdomen including the pelvis, as well as an MRI of the brain. Ultrasound investigation of the abdomen and lymph nodes are optional. At specialized referral centers FDG PET provides an additional method with high sensitivity for detection of metastases (see above). Measuring soluble melanoma serum markers such as S-100 and MIA gives an early indication of progressive disease as well as treatment response in stage IV patients HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114144" \o "Go here now" \t "body" 144, HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114145" \o "Go here now" \t "body" 145. Further specialized diagnostic tests are performed according to individual symptoms of the patient ( HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=T114013" \o "Go here now" \t "body" Table 114.13).  Surgery  page 1809 INCLUDEPICTURE "http://www.dermtext.com/images/pixel.gif" \* MERGEFORMATINET page 1810  Table 114-13. Symptoms and diagnostic tests for metastatic melanoma. SYMPTOMS AND DIAGNOSTIC TESTS FOR METASTATIC MELANOMAMetastatic site (TNM)SymptomsDiagnostic tests*Skin, soft tissue metastasis (TxNxM1), in-transit metastasis (TxN2cM0)Skin-colored to blue/brownish patches/nodules, ulceration, bleedingBiopsy + histologyBrain metastasis (TxNxM3)Headache, nausea, seizures, depression, visual disturbance, numbness, paralysisMRI scanLung metastasis (TxNxM2)Chest pain, dyspnea, cough, hemoptysisChest radiograph, CT scanGastrointestinal metastasis (TxNxM3)Abdominal pain, anemia vomiting, constipation, melena, jaundiceLiver function tests, fecal occult blood test, ultrasonography, CT scan, radiography, endoscopyBone metastasis (TxNxM3)Pain, spontaneous fracturesBone scan  *Always include thorough medical history and physical investigation as well as complete blood count and blood chemistry including LDH. Special procedures such as FDG-PET investigation as well as detection of soluble melanoma markers (e.g. S-100, MIA) are performed at selected melanoma referral centers for increased sensitivity of metastasis detection as part of controlled studies.  Table 114-14. Treatment options for metastatic melanoma. TREATMENT OPTIONS FOR METASTATIC MELANOMAMetastatic site (TNM)Treatment choiceIn-transit metastasis (TxN2cM0)1st: <5 surgery, >5: extremity perfusion* 2nd: radiotherapy, CO2 laser ablation, intralesional IL-2 3rd: systemic therapyBrain metastasis (TxNxM3) Single Multiple 1st: surgery 2nd: stereotactic radiosurgery 1st: radiotherapy 2nd: systemic therapyLung metastasis (TxNxM2) Single Multiple 1st: surgery 1st: systemic therapyGastrointestinal metastasis (TxNxM3) Single Multiple 1st: surgery 1st: systemic therapySkin, soft tissue metastasis (TxNxM1) Single Multiple 1st: surgery 1st: systemic therapyPainful bone metastasis (TxNxM3)1st: radiotherapyDisseminated metastasis (TxNxM3)1st: systemic therapy +/- surgery, radiotherapy of symptomatic metastasis  *Should be performed as part of controlled studies. Despite the well-known behavior of melanoma to disseminate to various organs, resection of metastases can often provide excellent palliation and in selected patients long-term survival ( HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=T114014" \o "Go here now" \t "body" Table 114.14). Factors that positively influence prognosis are isolated non-visceral metastasis and complete resection with free surgical margins. In certain cases median 5-year survival can even approach up to 35% after surgical treatment. Complete resection of lung metastases can lead to a median survival of 19 months and a 5-year survival of 25%. Patients rarely survive long-term after brain or gastrointestinal metastases, but surgical resection extends median survival to about 10 months in this group with a significant improvement in quality of life HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114146" \o "Go here now" \t "body" 146. The combination of cytoreductive surgery, with the goal of resecting clinically evident disease, and immunotherapy is a valuable future approach to management of stage IV patients HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114147" \o "Go here now" \t "body" 147.  Radiation therapy  Radiotherapy for melanoma never gained acceptance due to unfavorable clinical results observed in early studies. Recent evidence indicates that melanoma is not only highly variable in its radiosensitivity but that radioresistance of melanoma might be overcome using large individual dose fractions HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114148" \o "Go here now" \t "body" 148. Radiation therapy has been useful in some extensive lentigo malignas (see  HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=C13924092" \o "Go here now" \t "body" Chapter 139). Radiotherapy provides effective palliation in symptomatic advanced melanoma ( HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=T114014" \o "Go here now" \t "body" Table 114.14) HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114149" \o "Go here now" \t "body" 149. Special indications include pain associated with bone metastases, spinal cord compression, brain metastases and local control of cutaneous disease. Studies do not support the recommendation of adjuvant radiotherapy following resection of regional lymph node metastases in patients with malignant melanoma HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114150" \o "Go here now" \t "body" 150.  Whole brain radiotherapy combined with surgical resection have been the mainstay of the treatment of cerebral metastases. This approach results in a median survival of about 10 months HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114151" \o "Go here now" \t "body" 151. A new development producing at least similar results is stereotactic radiosurgery using either the so-called 'Gamma Knife' or linear accelerator radiosurgical techniques. Radiosurgery has been shown to be effective in metastatic tumors in surgically inaccessible sites such as the brainstem. A benefit of radiosurgery is the virtual absence of perioperative complications and the reduced adverse impact on quality of life compared either to surgery or to whole brain radiotherapy. Long-term complications of radiosurgery are infrequent and primarily relate to failure of local tumor control (10%) and radiation-induced edema or necrosis HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114151" \o "Go here now" \t "body" 151.  Chemotherapy  Over the past four decades cytotoxic chemotherapy, has had a low but reproducible level of activity against metastatic melanoma ( HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=T114014" \o "Go here now" \t "body" Table 114.14). Drugs employed include DTIC/temozolomide,  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View drug information" cisplatin INCLUDEPICTURE "http://www.dermtext.com/images/linkdrug.gif" \* MERGEFORMATINET , vindesine/vinblastine, BCNU/fotemustine and taxol/taxotere HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114152" \o "Go here now" \t "body" 152. Chemotherapeutic treatment of stage IV melanoma has been disappointing and has not had a positive impact on melanoma survival during the last 20 years even though several chemotherapeutic agents have shown activity against melanoma cells in-vitro and in phase I/II clinical trials HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114068" \o "Go here now" \t "body" 68. A promising new development is the selection of melanoma chemotherapy according to in vitro chemosensitivity assays HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114153" \o "Go here now" \t "body" 153. Recent new developments include oral delivery of the prodrug of a  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View drug information" dacarbazine INCLUDEPICTURE "http://www.dermtext.com/images/linkdrug.gif" \* MERGEFORMATINET  metabolite:  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View drug information" temozolomide INCLUDEPICTURE "http://www.dermtext.com/images/linkdrug.gif" \* MERGEFORMATINET , combination chemotherapy as well as combinations of chemotherapy and immunotherapy HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114154" \o "Go here now" \t "body" 154. The most widely used single chemotherapeutic agent is  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View drug information" dacarbazine INCLUDEPICTURE "http://www.dermtext.com/images/linkdrug.gif" \* MERGEFORMATINET  (DTIC). It has shown the greatest effectiveness as a single agent in most trials and was equally effective when combined with IFN- or tamoxifen HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114155" \o "Go here now" \t "body" 155. With DTIC as single agent, an approximately 20% response rate can be achieved with median response duration of 5 to 6 months and complete response rates of 5% HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114156" \o "Go here now" \t "body" 156. A novel oral alkylating agent is  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View drug information" temozolomide INCLUDEPICTURE "http://www.dermtext.com/images/linkdrug.gif" \* MERGEFORMATINET  (a pro-drug of MTIC, the active metabolite of DTIC) with some efficacy in CNS metastasis and equal efficacy to DTIC HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114157" \o "Go here now" \t "body" 157, HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114158" \o "Go here now" \t "body" 158. Fotemustine is a member of the nitrosourea family and has some efficacy in melanoma including brain metastases HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114159" \o "Go here now" \t "body" 159.  page 1810 INCLUDEPICTURE "http://www.dermtext.com/images/pixel.gif" \* MERGEFORMATINET page 1811 Combination chemotherapy regimens like CVD ( HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View drug information" cisplatin INCLUDEPICTURE "http://www.dermtext.com/images/linkdrug.gif" \* MERGEFORMATINET , vinblastine, DTIC) and BOLD (bleomycin, vincristine,  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View drug information" lomustine INCLUDEPICTURE "http://www.dermtext.com/images/linkdrug.gif" \* MERGEFORMATINET , DTIC) have induced responses in metastatic lesions typically unresponsive to DTIC alone, including the liver, bone and brain, but have failed to improve overall patient survival. The CBDT ( HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View drug information" cisplatin INCLUDEPICTURE "http://www.dermtext.com/images/linkdrug.gif" \* MERGEFORMATINET ,  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View drug information" carmustine INCLUDEPICTURE "http://www.dermtext.com/images/linkdrug.gif" \* MERGEFORMATINET , DTIC and tamoxifen) or 'Dartmouth regimen' has achieved high response rates in earlier trials (up to 55%) but a recent phase III trial did not show a statistical survival benefit compared to DTIC alone HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114160" \o "Go here now" \t "body" 160. Therefore DTIC remains the reference standard of chemotherapy in stage IV melanoma.  Combination chemo-immunotherapy involves the addition of the biological response modifiers interleukin-2 (IL-2) and IFN-. These substances have shown modest activity as single agents with response rates between 15-20% but durable responses have been observed especially after IL-2 therapy HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114161" \o "Go here now" \t "body" 161. Combination chemotherapy with IFN- or IL-2 has generally resulted in improved survival but may cause unacceptable levels of myelosuppression HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114162" \o "Go here now" \t "body" 162.  Biochemotherapy uses combination chemotherapy plus IL-2 and IFN-. A widely employed combination is  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View drug information" cisplatin INCLUDEPICTURE "http://www.dermtext.com/images/linkdrug.gif" \* MERGEFORMATINET , vinblastine and DTIC (CVD) IFN- and IL-2. In phase II trials durable complete remissions have been observed in 10-15% of patients with metastatic melanoma HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114152" \o "Go here now" \t "body" 152. In other trials, the combination of IFN- and IL-2 with  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View drug information" cisplatin INCLUDEPICTURE "http://www.dermtext.com/images/linkdrug.gif" \* MERGEFORMATINET  HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114163" \o "Go here now" \t "body" 163 or cisplatin/DTIC/tamoxifen HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114164" \o "Go here now" \t "body" 164 did not show significant improvement compared to biochemotherapy.  Another approach is chemohormonal therapy using tamoxifen in addition to chemotherapy. Addition of tamoxifen has not been shown to improve survival compared to single agent/combination chemotherapy alone HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114160" \o "Go here now" \t "body" 160, HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114165" \o "Go here now" \t "body" 165.  In conclusion, a survival benefit from chemotherapy in combination with immunotherapy or hormonal therapy has not been shown in metastatic melanoma patients. Patients should therefore be included in randomized controlled trials to hopefully discover new, more effective protocols. Some long term survivors have been reported with high dose IL-2-based regimens, but prospective randomized phase III trials are necessary to establish efficacy HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114156" \o "Go here now" \t "body" 156.  Immunotherapy  Immunotherapy builds on the concept that the immune system is able to fight cancer HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114166" \o "Go here now" \t "body" 166. Melanoma is one of the prototypic immunogenic cancers HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114012" \o "Go here now" \t "body" 12. Therapeutic effect might be achieved passively by infusing effectors of the immune system such as cytokines, killer cells or antibodies. On the other hand active immunization tries to stimulate the patients own immune effector cells in response to an injected vaccine (antigen plus adjuvant).  Treatment of advanced melanoma with single cytokines such as IFN- or IL-2 has been disappointing, even though high-dose IL-2 might lead to long-term remissions HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114167" \o "Go here now" \t "body" 167. Antibody (ab)-based therapies, including the use of anti-ganglioside ab or anti-high molecular weight ab, which might be coupled to a toxin (e.g. ricin) or radioactive isotope (e.g. 131I) has not shown marked effect in melanoma similar to the activity of anti-CD20 ab in lymphoma HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114168" \o "Go here now" \t "body" 168. Adoptive immunotherapy using in vitro expansion of tumor infiltrating killer cells targeting melanoma epitopes is an interesting concept but failed to translate into practical use due to low response rates and technical difficulties. However, it led to the identification of new melanoma antigens HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114169" \o "Go here now" \t "body" 169.  Recently, there has been a marked resurgence of interest in the use of vaccination for the treatment of advanced melanoma. In the past most vaccines under study were whole cell preparations or lysates of melanoma in combination with a variety of adjuvants. Examples are (1) polyvalent allogeneic melanoma cell lines +/- BCG (CancerVax) HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114170" \o "Go here now" \t "body" 170; (2) allogeneic melanoma lysates plus 'detox' (a 'detoxified' bacterial endotoxin) (Melacine) HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114171" \o "Go here now" \t "body" 171; (3) autologous melanoma cells modified with the hapten dinitrophenol (M-VAX) HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114172" \o "Go here now" \t "body" 172; and (4) shed antigen vaccine HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114173" \o "Go here now" \t "body" 173. These have shown effects in phase II trials in advanced melanoma patients but were for the most part disappointing in randomized controlled trials HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114174" \o "Go here now" \t "body" 174. Cellular vaccines are currently tested in four randomized phase III trials in resected stage II/III/IV melanoma patients HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114174" \o "Go here now" \t "body" 174. A study performed by the South West Oncology Group in stage IIA melanoma with a vaccine prepared from two mechanically disrupted allogeneic melanoma patients admixed with 'detox' adjuvant led to a significant prolongation of disease free survival but not overall survival HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114175" \o "Go here now" \t "body" 175. A prospective randomized study in resected stage III patients with a shed polyvalent vaccine achieved significant improvement of time to disease progression but not overall survival compared to placebo HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114173" \o "Go here now" \t "body" 173. Gene modified whole cell vaccines are at an early stage of development but have failed to demonstrate a significant clinical effect HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114176" \o "Go here now" \t "body" 176. An antigen based ganglioside vaccine (GM2-KLH/QS21)-induced antibody responses was less effective than high-dose IFN- in a randomized trial HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114142" \o "Go here now" \t "body" 142.  Progress in the field of melanoma immunology has allowed the identification of new melanoma antigens. Based on this knowledge the new field of antigen specific peptide vaccination is rapidly expanding. These peptides are defined stretches of  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View drug information" amino acids INCLUDEPICTURE "http://www.dermtext.com/images/linkdrug.gif" \* MERGEFORMATINET  corresponding to a known melanoma epitope. Peptide epitopes differ depending on HLA class I molecules. An advantage of the peptide approach is the ability to exactly follow the melanoma specific immune response during vaccination. Rosenberg et al. HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114177" \o "Go here now" \t "body" 177 have demonstrated clinical responses in patients injected with melanoma peptides, incomplete Freund's adjuvant and IL-2. In other trials tumor regression as well as immunological responses were observed HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114178" \o "Go here now" \t "body" 178, HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114179" \o "Go here now" \t "body" 179. An innovative approach is the use of dendritic cells to boost a melanoma-specific immune response. Early promising clinical trials using dendritic cells pulsed with melanoma peptides have demonstrated immune responses as well as clinical responses in selected patients HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114180" \o "Go here now" \t "body" 180, HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114181" \o "Go here now" \t "body" 181.  The field of melanoma immunotherapy is rapidly expanding and will hopefully provide potent anti-cancer treatments, especially in the adjuvant/minimal residual disease setting HYPERLINK "http://www.dermtext.com/passthru/linktopage.cfm?showtab=toc&xrefID=R114182" \o "Go here now" \t "body" 182.  References  1. Weinstock MA. Early detection of melanoma. J Am Med Assoc. 2000;284:886-9.  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1439445&dopt=Abstract" \o "View this article on Medline in a new window" \t "_new" Medline INCLUDEPICTURE "http://www.dermtext.com/images/linkout.gif" \* MERGEFORMATINET   HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Display&dopt=pubmed_pubmed&from_uid=1439445" \o "View similar articles on Medline in a new window" \t "_new" Similar articles INCLUDEPICTURE "http://www.dermtext.com/images/linkout.gif" \* MERGEFORMATINET   2. Halachmi S, Gilchrest BA. 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HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11167684&dopt=Abstract" \o "View this article on Medline in a new window" \t "_new" Medline INCLUDEPICTURE "http://www.dermtext.com/images/linkout.gif" \* MERGEFORMATINET   HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Display&dopt=pubmed_pubmed&from_uid=11167684" \o "View similar articles on Medline in a new window" \t "_new" Similar articles INCLUDEPICTURE "http://www.dermtext.com/images/linkout.gif" \* MERGEFORMATINET   154. Dummer R, Nestle FO, Hofbauer G, Burg G. [Systemic therapy of metastatic melanoma]. Ther Umsch. 1999;56:330-3.  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Phase III trial of  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View drug information" dacarbazine INCLUDEPICTURE "http://www.dermtext.com/images/linkdrug.gif" \* MERGEFORMATINET  versus  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View drug information" dacarbazine INCLUDEPICTURE "http://www.dermtext.com/images/linkdrug.gif" \* MERGEFORMATINET  with interferon alpha-2b versus  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View drug information" dacarbazine INCLUDEPICTURE "http://www.dermtext.com/images/linkdrug.gif" \* MERGEFORMATINET  with tamoxifen versus  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View drug information" dacarbazine INCLUDEPICTURE "http://www.dermtext.com/images/linkdrug.gif" \* MERGEFORMATINET  with interferon alpha-2b and tamoxifen in patients with metastatic malignant melanoma: an Eastern Cooperative Oncology Group study. J Clin Oncol. 1998;16:1743-51.  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11167684&dopt=Abstract" \o "View this article on Medline in a new window" \t "_new" Medline INCLUDEPICTURE "http://www.dermtext.com/images/linkout.gif" \* MERGEFORMATINET   HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Display&dopt=pubmed_pubmed&from_uid=11167684" \o "View similar articles on Medline in a new window" \t "_new" Similar articles INCLUDEPICTURE "http://www.dermtext.com/images/linkout.gif" \* MERGEFORMATINET   156. Serrone L, Zeuli M, Sega FM, Cognetti F. Dacarbazine-based chemotherapy for metastatic melanoma: thirty-year experience overview. J Exp Clin Cancer Res. 2000;19:21-34.  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11167684&dopt=Abstract" \o "View this article on Medline in a new window" \t "_new" Medline INCLUDEPICTURE "http://www.dermtext.com/images/linkout.gif" \* MERGEFORMATINET   HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Display&dopt=pubmed_pubmed&from_uid=11167684" \o "View similar articles on Medline in a new window" \t "_new" Similar articles INCLUDEPICTURE "http://www.dermtext.com/images/linkout.gif" \* MERGEFORMATINET   157. Middleton MR, Grob JJ, Aaronson N, et al. Randomized phase III study of  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View drug information" temozolomide INCLUDEPICTURE "http://www.dermtext.com/images/linkdrug.gif" \* MERGEFORMATINET  versus  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View drug information" dacarbazine INCLUDEPICTURE "http://www.dermtext.com/images/linkdrug.gif" \* MERGEFORMATINET  in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol. 2000;18:158-66.  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11167684&dopt=Abstract" \o "View this article on Medline in a new window" \t "_new" Medline INCLUDEPICTURE "http://www.dermtext.com/images/linkout.gif" \* MERGEFORMATINET   HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Display&dopt=pubmed_pubmed&from_uid=11167684" \o "View similar articles on Medline in a new window" \t "_new" Similar articles INCLUDEPICTURE "http://www.dermtext.com/images/linkout.gif" \* MERGEFORMATINET   158. Agarwala SS, Kirkwood JM.  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View drug information" Temozolomide INCLUDEPICTURE "http://www.dermtext.com/images/linkdrug.gif" \* MERGEFORMATINET , a novel alkylating agent with activity in the central nervous system, may improve the treatment of advanced metastatic melanoma. Oncologist. 2000;5:144-51.  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11167684&dopt=Abstract" \o "View this article on Medline in a new window" \t "_new" Medline INCLUDEPICTURE "http://www.dermtext.com/images/linkout.gif" \* MERGEFORMATINET   HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Display&dopt=pubmed_pubmed&from_uid=11167684" \o "View similar articles on Medline in a new window" \t "_new" Similar articles INCLUDEPICTURE "http://www.dermtext.com/images/linkout.gif" \* MERGEFORMATINET   159. Ulrich J, Gademann G, Gollnick H. Management of cerebral metastases from malignant melanoma: results of a combined, simultaneous treatment with fotemustine and irradiation. J Neurooncol. 1999;43:173-8.  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11167684&dopt=Abstract" \o "View this article on Medline in a new window" \t "_new" Medline INCLUDEPICTURE "http://www.dermtext.com/images/linkout.gif" \* MERGEFORMATINET   HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Display&dopt=pubmed_pubmed&from_uid=11167684" \o "View similar articles on Medline in a new window" \t "_new" Similar articles INCLUDEPICTURE "http://www.dermtext.com/images/linkout.gif" \* MERGEFORMATINET   160. Chapman PB, Einhorn LH, Meyers ML, et al. Phase III multicenter randomized trial of the Dartmouth regimen versus  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View drug information" dacarbazine INCLUDEPICTURE "http://www.dermtext.com/images/linkdrug.gif" \* MERGEFORMATINET  in patients with metastatic melanoma. J Clin Oncol. 1999;17:2745-51.  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HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11167684&dopt=Abstract" \o "View this article on Medline in a new window" \t "_new" Medline INCLUDEPICTURE "http://www.dermtext.com/images/linkout.gif" \* MERGEFORMATINET   HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Display&dopt=pubmed_pubmed&from_uid=11167684" \o "View similar articles on Medline in a new window" \t "_new" Similar articles INCLUDEPICTURE "http://www.dermtext.com/images/linkout.gif" \* MERGEFORMATINET   162. Ross PJ, Gore ME. Scientific evidence and expert clinical opinion for the investigation and management of stage IV malignant melanoma. In: MacKie RM, Murray D, Rosin RD, et al (eds), The Effective Management of Malignant Melanoma. London: Aesculapius Medical Press, 2001, 83-104.  163. Keilholz U, Goey SH, Punt CJ, et al. Interferon alfa-2a and interleukin-2 with or without  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View drug information" cisplatin INCLUDEPICTURE "http://www.dermtext.com/images/linkdrug.gif" \* MERGEFORMATINET  in metastatic melanoma: a randomized trial of the European Organization for Research and Treatment of Cancer Melanoma Cooperative Group. J Clin Oncol. 1997;15:2579-88.  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11167684&dopt=Abstract" \o "View this article on Medline in a new window" \t "_new" Medline INCLUDEPICTURE "http://www.dermtext.com/images/linkout.gif" \* MERGEFORMATINET   HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Display&dopt=pubmed_pubmed&from_uid=11167684" \o "View similar articles on Medline in a new window" \t "_new" Similar articles INCLUDEPICTURE "http://www.dermtext.com/images/linkout.gif" \* MERGEFORMATINET   164. Rosenberg SA, Yang JC, Schwartzentruber DJ, et al. Prospective randomized trial of the treatment of patients with metastatic melanoma using chemotherapy with  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View drug information" cisplatin INCLUDEPICTURE "http://www.dermtext.com/images/linkdrug.gif" \* MERGEFORMATINET ,  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View drug information" dacarbazine INCLUDEPICTURE "http://www.dermtext.com/images/linkdrug.gif" \* MERGEFORMATINET , and tamoxifen alone or in combination with interleukin-2 and interferon alfa-2b. J Clin Oncol. 1999;17:968-75.  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11167684&dopt=Abstract" \o "View this article on Medline in a new window" \t "_new" Medline INCLUDEPICTURE "http://www.dermtext.com/images/linkout.gif" \* MERGEFORMATINET   HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Display&dopt=pubmed_pubmed&from_uid=11167684" \o "View similar articles on Medline in a new window" \t "_new" Similar articles INCLUDEPICTURE "http://www.dermtext.com/images/linkout.gif" \* MERGEFORMATINET   165. Agarwala SS, Ferri W, Gooding W, Kirkwood JM. A phase III randomized trial of  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View drug information" dacarbazine INCLUDEPICTURE "http://www.dermtext.com/images/linkdrug.gif" \* MERGEFORMATINET  and  HYPERLINK "http://www.dermtext.com/content/bookcontent.cfm?ID=C11424092&searchterms=lentigo%20maligna&framesource=search&RestrictTo=P114035" \l "#" \o "View drug information" carboplatin INCLUDEPICTURE "http://www.dermtext.com/images/linkdrug.gif" \* MERGEFORMATINET  with and without tamoxifen in the treatment of patients with metastatic melanoma. Cancer. 1999;85:1979-84.  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Bystryn JC, Zeleniuch-Jacquotte A, Oratz R, et al. Double-blind trial of a polyvalent, shed-antigen, melanoma vaccine. Clin Cancer Res. 2001;7:1882-7.  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11167684&dopt=Abstract" \o "View this article on Medline in a new window" \t "_new" Medline INCLUDEPICTURE "http://www.dermtext.com/images/linkout.gif" \* MERGEFORMATINET   HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Display&dopt=pubmed_pubmed&from_uid=11167684" \o "View similar articles on Medline in a new window" \t "_new" Similar articles INCLUDEPICTURE "http://www.dermtext.com/images/linkout.gif" \* MERGEFORMATINET   174. Livingston P. The unfulfilled promise of melanoma vaccines. Clin Cancer Res. 2001;7:1837-8.  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11167684&dopt=Abstract" \o "View this article on Medline in a new window" \t "_new" Medline INCLUDEPICTURE "http://www.dermtext.com/images/linkout.gif" \* MERGEFORMATINET   HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Display&dopt=pubmed_pubmed&from_uid=11167684" \o "View similar articles on Medline in a new window" \t "_new" Similar articles INCLUDEPICTURE "http://www.dermtext.com/images/linkout.gif" \* MERGEFORMATINET   175. Hershey P. Current status of vaccines in the treatment of melanoma. Melanoma Res. 2001;11 (Suppl 1):14.  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11167684&dopt=Abstract" \o "View this article on Medline in a new window" \t "_new" Medline INCLUDEPICTURE "http://www.dermtext.com/images/linkout.gif" \* MERGEFORMATINET   HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Display&dopt=pubmed_pubmed&from_uid=11167684" \o "View similar articles on Medline in a new window" \t "_new" Similar articles INCLUDEPICTURE "http://www.dermtext.com/images/linkout.gif" \* MERGEFORMATINET   176. Sun Y, Paschen A, Schadendorf D. Cell-based vaccination against melanoma-background, preliminary results, and perspective. J Mol Med. 1999;77:593-608.  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11167684&dopt=Abstract" \o "View this article on Medline in a new window" \t "_new" Medline INCLUDEPICTURE "http://www.dermtext.com/images/linkout.gif" \* MERGEFORMATINET   HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Display&dopt=pubmed_pubmed&from_uid=11167684" \o "View similar articles on Medline in a new window" \t "_new" Similar articles INCLUDEPICTURE "http://www.dermtext.com/images/linkout.gif" \* MERGEFORMATINET   177. Rosenberg SA, Yang JC, Schwartzentruber DJ, et al. Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nat Med. 1998;4:321-7.  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HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11167684&dopt=Abstract" \o "View this article on Medline in a new window" \t "_new" Medline INCLUDEPICTURE "http://www.dermtext.com/images/linkout.gif" \* MERGEFORMATINET   HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Display&dopt=pubmed_pubmed&from_uid=11167684" \o "View similar articles on Medline in a new window" \t "_new" Similar articles INCLUDEPICTURE "http://www.dermtext.com/images/linkout.gif" \* MERGEFORMATINET   180. Nestle FO, Alijagic S, Gilliet M, et al. Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. Nat Med. 1998;4:328-32.  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