Part 2 book “Manual of clinical oncology” has contents: Skin cancers, miscellaneous neoplasms, chronic leukemias, chronic leukemias, acute leukemia and myelodysplastic syndromes, metabolic complications, thoracic complications, cutaneous complications, abdominal complications, renal complications, neuromuscular complications,… and other contents.
17 Skin Cancers Bartosz Chmielowski, Richard Wagner Jr, and Antoni Ribas F Malignant Melanoma I EPIDEMIOLOGY AND ETIOLOGY A Incidence Malignant melanoma accounts for about 2% of all skin cancers, but it is responsible for 80% of deaths The incidence of melanoma in the United States has been rising for the last 40 years Before the age of 45, women have a higher risk than men, but after the age of 60, the risk for men is twice as high as for women The estimated number of new cases in the United States in 2016 is 76,380, and 10,130 patients would die of melanoma The incidence of melanoma rose rapidly in the 1970s at about 6% per year; it continues to rise but at a lower rate of 2.7% per year from 2006 to 2010 White people have a 2.4% lifetime risk for the development of melanoma and African Americans 0.1%, but melanoma is diagnosed among all races B Risk factors The strongest risk factors for melanoma are a family history of melanoma, multiple benign or atypical nevi, and a previous melanoma The list of additional risk factors includes immunosuppression, sun sensitivity, and exposure to ultraviolet (UV) radiation Familial factors Approximately 10% of melanomas are familial The higher risk of melanoma in these families may be attributed to both shared susceptibility genes and shared environment a High-penetrance susceptibility genes Two genes, CDKN2A and CDK4, are associated with high-penetrance susceptibility Mutated CDKN2A is the most prevalent gene in families with 641 melanoma It is located on chromosome 9p21, and it encodes cyclin-dependent kinase inhibitor 2A (p16INK4a) CDK4 encodes cyclin-dependent kinase 4, which is one of the binding partners of p16INK4a Mutations in CDK4 are found much less frequently than in CDKN2A Other less common high-penetrance genes are BAP1, TERT, XP (various genes mutated in individuals with xeroderma pigmentosum) The higher the number of family members with melanoma, the higher the probability of carrying a high-penetrance gene Mutated CDKN2A was found in 14% families with cases of melanoma, in 67% families with to cases, and 100% families with to 10 cases Overall, between 20% (in Australia) and 57% (in Europe) of the cases of familial melanoma are associated with CDKN2A b Low-penetrance susceptibility genes Epidemiologic studies suggest that low-penetrance susceptibility genes are found frequently among families with melanoma The list includes BRCA2, MC1R, MITF E318K, shelterin complex genes (POT1, ACD, TERF2IP) c Familial atypical multiple mole melanoma (FAMMM) syndrome, also known as the familial dysplastic nevus syndrome, was described in 1978 in families whose members suffered from melanoma and had multiple (usually >100) large moles of variable size and color (reddish brown to bright red) with pigmentary leakage The median age of the development of melanoma in persons with this syndrome is 33 years, and 9% of affected people develop it before the age of 20 The syndrome is transmitted in autosomal dominant fashion, but there are sex differences in penetrance Males develop melanoma less frequently and at an older age than women Nevi Typical nevi are frequently precursors of melanoma, but more importantly, they are markers of increased risk High common nevus counts (50 or more common nevi) account for 27% of melanoma cases, whereas individuals with few common nevi (0 to 10) account for only 4% of melanoma cases Congenital nevi are benign neoplasms that are present at birth and composed of nevomelanocytes The malignant potential of giant congenital nevi varies between different types Pigmented giant nevi have especially high risk for malignant transformation Nevus 642 sebaceous is associated with the development of basal cell carcinoma Verrucous epidermal nevi and woolly hair nevi not have malignant potential Previous melanoma The rate of a second primary cutaneous melanoma is 6% to 7%; the risk is higher among patients who initially presented with melanoma in situ than in those with invasive melanoma The greatest risk is within the first years, but it remains elevated for at least 20 years Males, elderly patients, and individuals with the first melanoma on the face, the neck, and the trunk are at especially high risk The incidence of a third primary melanoma from the time of second primary melanoma is 16% at year and 31% at years Immunosuppression Among organ allograft recipients, melanoma constituted 5% of skin cancers and was significantly higher than in the general population (2.7%) Sun sensitivity Light-skinned and redheaded people frequently carry a polymorphism in the melanocortin receptor gene (MC1R) that results in a decreased melanin production after exposure to UV radiation and in an increased risk of melanoma Exposure to sun and to UV radiation It is known that UV radiation causes genetic changes in the skin, impairs cutaneous immune function, increases the local production of growth factors, and induces the formation of DNA-damaging reactive oxygen species that affect keratinocytes and melanocytes Epidemiologic studies revealed that intermittent sun exposure and frequent sunburns, especially during childhood, increase the risk of melanoma Chronic low-grade sun exposure may be protective, although data also show that higher total exposure to the sun is associated with a higher risk of melanoma among non-Hispanic White individuals In addition, exposure to UV light from recreational tanning salons is an important risk factor for melanoma Occupational exposure Exposure to coal tar, pitch, creosote, arsenic compounds, or radium increases the risk of melanoma development Other An increased rate of melanoma was seen in patients with Parkinson disease, prostate cancer, and endometriosis and patients treated with voriconazole, sildenafil, and tumor necrosis factor (TNF) inhibitors 643 II PREVENTION Avoidance of exposure to the sun during the midday hours, wearing skinprotecting clothing, sunglasses, use of sunscreens with a sun protective factor (SPF) of 15 or higher, and avoidance of sunburns and tanning beds are recommended as a primary prevention It is unclear if dietary vitamin D has any impact on development of melanoma Patients with a family or personal history of melanoma should undergo at least one annual skin examination performed by a dermatologist as a secondary prevention III PATHOLOGY HISTORY AND NATURAL A Pathology Melanoma originates from melanocytes, the neural crestderived cells that migrate into the epidermis during embryogenesis to reside in the basal layer of the epidermis The overwhelming majority of melanomas originate in the skin, but some melanomas may arise from other primary sites Potential extracutaneous sites include the choroidal layer of the eye and mucosal surfaces in the upper respiratory tract (most frequently, the nose and nasopharynx), gastrointestinal (GI) tract (most frequently, the anus), and genitourinary tract (most frequently, the vagina) Several steps occur in the process of their malignant transformation According to the Clark model, initially normal melanocytes proliferate and form a benign nevus In the next phase, abnormal growth appears in the form of a dysplastic nevus Melanoma may originate from a benign nevus, but it can also start from scattered melanocytes present in the normal skin Next, in the radial growth phase, the cells acquire the ability to grow intraepidermally and have all the features of cancerous cells Then, the lesion invades the dermis (vertical growth phase) and finally spreads to other organs and other areas of the skin (metastasis) Not all melanomas pass through each of these individual phases, however B Molecular events in the pathogenesis of melanoma Several molecular alterations have known pathogenic effects in the transformation of melanocytes and the evolution of melanoma Alterations in signal transduction pathways Mutually exclusive somatic activating point mutations in NRAS (15% to 20% of melanomas) and BRAF (40% to 50% of melanomas), two members 644 of the mitogen-activated protein kinase (MAPK) that provides proliferation signaling from surface receptors to the nucleus, are present in most melanomas of skin primary More than 75 different mutations in the BRAF gene in melanoma have been described: V600E mutation 90% of cases, V600K 5% to 6%, V600R 1%, and V600D 0.1%; other BRAF mutations are less common Mutations in NF1 (neurofibromatosis 1) tumor suppressor gene leading to loss of its function are seen in 14% of melanomas and they also lead to activation of MAPK pathway Paradoxically, BRAF mutation is also frequent in benign nevi, where its transforming effect may be counteracted by the phenomenon of oncogene-induced senescence Somatic alterations in another signaling pathway important in cell growth, the phosphoinositide-3-OH kinase (PI3K) pathway, are also frequently found in melanoma, including loss of PTEN (phosphate and tensin homologue) and overexpression of Akt About 20% to 40% of melanomas originating from mucosal membranes or from chronic sun damage skin and acral melanomas can harbor an activating mutation in KIT kinase This mutation is not found in melanoma originating from the trunk Finally, more than 80% of uveal melanomas have an activating mutation in GNAQ or GNA11, two small GTP-binding proteins that couple cell surface G-coupled receptors, and are involved in their signal transduction BAP1 mutations are seen in 25% of uveal melanomas and its presence correlates with an increased risk for metastatic disease Aberrant cell cycle control As described above, inherited mutations in the CDKN2A and CDK4 genes are associated with high-penetrance susceptibility to melanoma Somatic mutations in these and other cell cycle control genes seem a requisite for the development of melanoma and escape from oncogene-induced senescence Other genetic events in melanoma pathogenesis MITF gene amplifications are noted in a small subset of melanomas, and this gene has a complex relationship with melanoma oncogenesis Several genetic alterations common in melanoma reduce sensitivity to apoptosis, including overexpression of Bcl-2 (B-cell leukemia/lymphoma-2), silencing of APAF-1 (apoptotic peptidase activating factor-1), and activation of NF-κB (nuclear factor kappa B) C Major clinical–histopathologic subtypes Traditionally, melanomas 645 have been divided based on the histologic subtypes Recently, it has become more important to sequence individual somatic mutations in key genes (i.e., NRAS, BRAF, NF1, c-kit, GNAQ, or GNA11) and use these findings to distinguish different melanoma subtypes The progress in understanding the molecular biology of melanoma will soon lead to further subtyping of the disease Superficial spreading melanoma compromises about 70% of all melanomas It is most common in middle age and develops most frequently on the upper back of both sexes and on the legs of women, but it can occur in any anatomic location Only 25% of lesions are associated with a preexisting nevus It spreads laterally (radial growth) for a period of time before it becomes invasive The lesions appear as variably pigmented plaques or macules that have a bizarre shape with irregular borders Progression correlates with the evolution of multiple shades of color from red (inflammation) through gray (regressed areas) to black (neoplastic melanocytes) Nodular melanoma compromises about 15% to 20% of all melanomas It is more common among older adults, and it occurs twice as frequently in male than in female patients The lesion appears as a darkly pigmented dome-shaped or polypoid nodule that can ulcerate and bleed early Occasionally, it can be amelanotic These tumors grow rapidly and vertically from the onset Lentigo maligna melanoma (4% to 15% of melanomas) is most commonly seen in older individuals (in the sixth and seventh decade of life) It arises in sun-damaged areas of the skin, mainly on the face (90% cases) The lesion appears as a tan-brown macule, very often large in size (3 to cm) The lesion grows slowly and the radial growth phase may last between and 50 years before it starts growing vertically Partial regression is not uncommon during evolution Acral lentiginous melanoma is the least common variant of radial growth phase melanomas It compromises only 2% to 8% of melanomas in Whites, but 30% to 75% cases in Blacks, Hispanics, and Asians It appears on the palms, soles, and terminal phalanges as a dark brown to black, unevenly pigmented patch Rare types a Nevoid melanoma resembles benign nevi It has verrucoid or dome-shaped appearance and can metastasize b Desmoplastic melanomas resemble a scar or fibroma and appear 646 mainly on sun-exposed areas Very often, they are amelanotic They tend to recur locally or as isolated metastasis D Mode of spread Melanoma frequently first spreads through the lymphatic system forming satellite lesions and in-transit metastases and then it involves regional lymph nodes Satellite lesions are skin or subcutaneous lesions within cm of the primary tumor and represent intralymphatic extension of the tumor In-transit metastases are defined as lesions that are >2 cm from the primary tumor, but not beyond the regional lymph node basin Melanoma can also spread hematogenously, sometimes after the nodal spread or skipping the draining nodes, forming distant metastases in the skin, subcutaneous soft tissue, lungs, liver, brain, and other organs E Metastatic melanoma from an unknown primary site accounts for approximately 2% to 6% of all melanoma cases It is assumed that in most these cases, the primary cutaneous melanoma regressed spontaneously Metastases most often develop as cutaneous or subcutaneous nodules or as lymph node metastases The survival of patients with unknown primary melanoma is similar to that of patients with known primary tumors when corresponding stages are compared IV DIAGNOSIS A Symptoms The ABCDE rule Warning signs of melanoma are as follows: a Asymmetry b Irregular borders c Changes in color; pigmentation is not uniform d Diameter >6 mm e Enlarging or evolving lesion The changes in preexisting moles and appearance of a new mole with these features are highly suspicious for melanoma More than 50% of the cases arise in apparently normal areas of the skin Ulceration or bleeding usually represents deeper lesions In-transit lesions and skin metastases appear as skin or subcutaneous erythematous nodules between the primary tumor site and the regional nodal basin The nodules not have to be pigmented As they grow, they can coalesce and ulcerate Symptoms of the metastatic disease are related to the involved site 647 B Physical examination A complete skin examination of the whole body should be performed, including scalp, axillae, genital area, interdigital webs, and mouth Skin lesions that follow the “ugly duckling rule” (i.e., look different from other skin lesions, even if they not fully follow the ABCDE rule) should be biopsied Melanoma in men occurs more frequently on the trunk or head and neck, and in women on the back and legs, but it can arise from any site on the skin surface Although most primary lesions are usually pigmented, frequently skin metastases are not pigmented, and they may appear as red or subcutaneous nodules C Differential diagnosis Compound nevi, halo nevi, dermal nevi, basal cell carcinoma, seborrheic keratosis, angiomas, and dermatofibromas may have features that suggest melanoma Biopsy specimens of these lesions should be obtained Precision of the diagnosis can be increased by use of a dermatoscope, an instrument that magnifies pigmented lesions about 10 times The dermatoscope is especially invaluable for examination of flat to slightly raised pigmented lesions D Biopsy Suspicious lesions should be biopsied and analyzed pathologically A full-thickness excision with 1- to 3-mm margins should be performed if the tumor is highly suspected to be melanoma Larger margins may interfere with planned sentinel lymph node biopsy (SNLB) Incisional biopsies (punch biopsy or tangential), where part of the pigmented lesion is sampled for pathologic diagnosis, may be used for very large lesions or lesions on the face, palmar surfaces of the hand, sole of the foot, ear, distal digits, genitalia, or under nails Incisional biopsies may fail, however, to diagnose melanoma or result in a more favorable early staging impression owing to sampling error If melanoma continues to be suspected or is diagnosed, the biopsy should be repeated or the lesion completely excised for pathologic reevaluation and staging Incisional biopsies not increase the chance for melanoma metastases V PROGNOSTIC FACTORS A Prognostic factors Primary lesion Tumor thickness and ulceration are the most powerful predictors of survival a Tumor thickness as a prognostic factor was first described by Alexander Breslow and it is traditionally reported as Breslow 648 thickness in millimeters The AJCC staging system uses 1-, 2-, and 4-mm cutoffs, but tumor thickness is really a continuous prognostic variable b Ulceration (the absence of intact epithelium over the tumor determined by pathologic analysis) indicates aggressive biology of melanoma c Mitotic rate Increased mitotic rate correlates with a decreased survival It is the most important in staging melanomas with tumor thickness