๐ ็ธฝ็ฎ้ ๏ฝ ๐ ่ฑๆๅๆ๏ผๆฌ็ฏ๏ผ ๏ฝ ๐ ๅฎๆด็ฟป่ญฏ ๏ฝ โญ ็ฒพ่ฏ็ญ่จ
MELANOMA
MELANOMA
Clinical features
Over the last several decades, the conspicuous increasing incidence of this malignant neoplasm has made this disease more prominent, linked to some rise in morbidity and mortality.1โ7 While roughly half of the major cancers in the United States showed decreasing incidence trends from 2009 to 2013, melanoma incidence continued to significantly increase over this period just as it had done previously in both men and women.8,9 At present it accounts for approximately 4% and 6% of all new malignancies in females and males, respectively.5 This has made melanoma the fifth and sixth most common cancers in the United States in terms of estimated new cases in 2017.10 However, the number of deaths from this disease places it well outside the top 10 causes of cancer-related deaths for both sexes at 9730 annually.10 Mortality for this disease is still increasing in males, but has leveled off and appears to be decreasing in females, according to present data.6 Currently, the average rate of increasing incidence is of the order of 4โ6% per year.7,11โ13 The estimated number of new cases of melanoma per year is in excess of 87,000 in the United States.6,10,14 Current projections for non-Hispanic white individuals in the United States estimate that 1 person in 28 males and 1 in 44 females will ultimately develop melanoma.10,15 Men are 1.6 times more likely to suffer from melanoma, but 2.4 times more likely to die of the disease.10
adults, especially in patients less than 10 years of age; however, metastasis rates of 36โ39% and overall mortality of 10โ29% after 5 years or more follow-up have been documented.20,27,28 Transplacental spread with resultant congenital melanoma has been documented exceptionally rarely.29
Melanoma may:
โข develop within a pre-existent benign (congenital or acquired) melanocytic nevus,30โ36
โข complicate a dysplastic nevus,
โข arise de novo,
โข very rarely, evolve within a cellular blue nevus or other dermal dendrocytosis (see malignant blue nevus). Precise figures are not available, but considering that the average adult has approximately 15โ40 acquired melanocytic nevi and that the incidence of melanoma in the United States is roughly 30 per 100,000 of the population per annum, then the likelihood of any one benign acquired melanocytic nevus undergoing malignant transformation is markedly remote.2,37 On the other hand, at least 35% of nodular and superficial spreading melanomas arise within a background of melanocytic nevi (congenital, acquired or dysplastic).3,30,36,38โ42 Only very rarely do the more typical (small) congenital nevi develop melanomatous features. Giant โbathing-trunkโ variants, however, are a greater cause for concern, with approximately 3โ18% undergoing malignant transformation.22,43โ45 Lentigo maligna melanoma is not associated with pre-existent benign or dysplastic nevi.
Although melanoma is seen predominantly in adults, it occasionally presents in children.10,16โ23 The latter often have an associated risk factor, such as xeroderma pigmentosum, congenital bathing-trunk nevus, familial dysplastic nevus syndrome or familial melanoma, and possibly immunosuppression. Pediatric melanoma accounts for 1โ3% of all childhood malignancies, amounting to less than 500 cases per year in the United States.24โ26 Its biological behavior is more variable and difficult to predict than melanoma in
While the etiology is multifactorial, including genetic and racial factors, by far the most important known predisposing environmental agent in the majority of tumors (with the exception of acral lentiginous and mucosal variants) is excessive exposure to ultraviolet (UV) light.46โ49 Surprisingly, the contribution of the UV is modest, with an estimated 1.7-fold increase in risk.50 Although traditionally UVB has been regarded as the causative agent,
more recent evidence implicates UVA, at least in some patients.51โ55 This association is complex and recent compelling work also stresses the importance of moderate, non-burning sun exposure for overall human health including vitamin D production and other benefitsโincluding prevention of skin cancer.56โ58 Melanin pigment protects against the effects of solar irradiation and therefore cutaneous melanoma is rare in dark-skinned races, except for albinos and at those sites where pigment is absent (e.g., nail beds, palms, soles, and mucous membranes). UV irradiation, possibly by inducing free-radical formation, results in the development of dimers between adjacent pyrimidine molecules. Patients who lack the necessary endonucleases for repairing such damage, such as those with xeroderma pigmentosum, have a greatly increased risk of developing cutaneous neoplasms, including melanoma.59
1311 Clinical features
โข a size of 6.0โฏmm diameter or greater,
โข irregularity of the border of the lesion, usually with scalloping,
โข irregular and variable pigmentation,
โข asymmetry,
โข recent and rapid change in a pre-existing lesion. Irritation and bleeding are also a source of concern. The development of ulceration, which often relates to a rapidly evolving tumor, is important and is regarded as an indication of a potentially poor prognosis. Clinical evidence of nodule formation by definition implies that the tumor has entered the vertical growth phase. In contrast to benign melanocytic nevi, the skin lines are usually absent over the surface of a melanoma.
Melanoma is particularly common in those individuals who are most susceptible to the effects of excessive sunlight (e.g., Celts with red hair, blue eyes, and fair complexions who tan poorly and tend towards sunburn and excessive freckling, i.e., skin types I and II). It is noteworthy that the incidence of superficial spreading melanoma is more closely related to sporadic intensive exposure to sunlight, particularly isolated episodes of severe sunburn in childhood, rather than to chronic lifelong exposure as with lentigo maligna melanoma.47,53,60โ62 It is more common in those who sporadically sunbathe than in long-term outdoor workers. The relationship between melanoma and sunlight is further highlighted by the increasing incidence towards the equator where UV radiation is most intense.49,63
Lesions on the integument have traditionally been classified into four major clinicopathological subtypes although in the more recent literature the validity of such subdivision has been questioned, and classification into more genetically oriented groups may offer advantages.101โ103 Gene profiling and the results of other high-throughput technologies will also likely aid in revising our traditional classification scheme so that clinically and therapeutically relevant subsets can be identified.104,105 An evolving molecular classification is presented in the final section of this chapter. The currently accepted subdivision is particularly based on perceived differences in prognosis and etiology and the genomic features of these groups largely bear this out. Although any variation in biological behavior relates more to tumor thickness than histogenetic subtype, there are certainly histologic differences that make the distinction possible in the majority of cases. Contrariwise, in some melanomas, it is not possible to effect a precise classification and, in such instances, an unqualified diagnosis of melanoma is quite sufficient. For the moment, however, subtyping melanoma is firmly entrenched in both the literature and pathology dogma.106 Four major subtypes of cutaneous melanoma are currently recognized:29,107โ113
โข lentigo maligna melanoma (melanoma arising within a pre-existent lentigo maligna),
โข superficial spreading melanoma,
โข acral lentiginous melanoma,
โข nodular melanoma. The majority of melanomas have a radial (in situ) growth phase before the development of invasive tumor.114 The radial growth phase is greatest in lentigo maligna, of shorter duration in superficial spreading melanoma and acral lentiginous melanoma, and, by definition, absent in nodular melanoma.
Patients who already have one melanoma have an increased risk of developing a second independent primary tumor. The reported incidence varies from 1% to 8% of cases, with the upper end of this range being seen in the setting of familial melanoma.64โ67 It should be noted, however, that much of the literature referring to multiple melanomas does not take epidermotropic metastatic disease into account and therefore the true incidence is likely to be towards the lower figure. The incidence of other cancers is increased in melanoma survivors as well.68
There is a lack of convincing evidence that pregnancy strongly influences the outcome and prognosis of melanoma.69โ71 Although earlier studies indicated that the mean thickness of pregnancy-associated tumors was significantly greater than that of nonpregnancy-associated melanomas, later studies have not, and the clinical outcome parallels that of nonpregnant female patients of the same age and tumor characteristics, though dissenting meta-analyses remain.72โ84 Similarly, there is no clearly acceptable proof that the use of oral contraceptives by females increases the risk of developing melanoma.69,74,85
Familial melanoma accounts for between 8% and 14% of affected patients.86,87 Genes that have been implicated include CDKN2A (9p21) (the majority), and very occasionally CDK4 (12q14). The former encodes p16, which normally functions to inhibit CDK4 activity.88,89 Approximately 20โ30% of patients with familial melanoma have germline mutations in CDKN2A.86,90,91 Genetic variants in MC1R encoding the melanocortin 1 receptor and associated with red hair appears to increase the penetrance of melanoma in CDKN2A and CDK4 germline families.92,93 BAP1 germline deficits are associated with familial ocular melanoma.94โ96 Researchers are focusing on other predisposition genes as well, such as EBF3, though additional work is needed.97 Familial melanoma patients are often younger than those who develop sporadic melanoma and tumors are frequently multiple. Dysplastic nevi can be present.98
Our understanding of melanoma has been radically transformed through research of the genomics and tumor biology of this disease. These topics are discussed in the final section of this chapter, under the molecular classification of melanoma. A number of efficacious targeted treatments are available for melanoma such as those inhibiting the constitutively activated signaling proteins produced by mutated BRAF and KIT genes. In addition, the current ability to unleash the patientโs own immune system through the application of immune checkpoint inhibitor therapy is providing treatment for many patients for whom there was little to offer in the past. Such therapies are transforming the treatment landscape for patients with metastatic disease and much research is ongoing to test such approaches in lower stage disease with adjuvant approaches. Much research is ongoing to identify which subsets of patients will benefit from immuno-oncological approaches and why some patients respond while others do not. Many factors including tumoral mutational load, tumor-infiltrating lymphocytes, serum lactate dehydrogenase (LDH) levels, oncogenic signaling pathways, gut microbiome, and immune checkpoint protein expression, to name a few, have been correlated with responses. However, a full understanding of exactly how and why these agents work in some patients and not others has yet to emerge and our ability to predict is currently limited. Discoveries are proceeding at an incredible rate in this area and thus are not addressed in greater detail in this chapter.
Melanoma shows a male preponderance (3โ:โ2) and males have a higher mortality.6,10,37 This probably relates at least in part to later presentation. Females generally have thinner tumors than males at first examination. The leg (particularly the calf) is the site of predilection in females, whereas the back is most often affected in males.37 Melanoma arising on the head and neck is also more common in males than in females.37
The prognosis of melanoma is to some extent site dependent. Tumors arising on the BANS sites (upper back, posterior arm, posterior neck, and posterior scalp) behave less favorably than those on the extremities.37,99
The majority of melanomas arise de novo and as such, at least in their radial (in situ) growth phase, they clinically present as flat lesions. The most important signs for newly acquired potentially early melanoma include100: