# Lecture 10: Skin Cancer ## Unit 2.10: Musculoskeletal System/Dermatology --- ## Learning Objectives By the end of this lecture, students will be able to: 1. Describe the epidemiology and risk factors for skin cancer 2. Explain the clinical features and management of basal cell carcinoma 3. Describe squamous cell carcinoma and its variants 4. Explain the types, staging, and treatment of melanoma 5. Describe precursor lesions and prevention strategies 6. Explain emerging therapies for advanced skin cancer --- ## Lecture Outline ### I. Skin Cancer Overview Skin cancer is the most common malignancy in humans, and understanding the relative frequency of its subtypes is essential for clinical prioritization and patient counseling. Basal cell carcinoma (BCC) is the most common skin cancer, accounting for approximately 80% of all cases, followed by squamous cell carcinoma (SCC) at approximately 16%, with melanoma comprising only about 4% of skin cancers yet being responsible for the majority of skin cancer deaths due to its propensity for early metastasis. Other rare skin cancers include Merkel cell carcinoma (a neuroendocrine tumor associated with Merkel cell polyomavirus), dermatofibrosarcoma protuberans, and cutaneous lymphomas, each with distinct clinical behavior and management approaches. Risk factors for skin cancer are well characterized and center on the interaction between ultraviolet radiation exposure and host susceptibility. Ultraviolet (UV) exposure is the single most important modifiable risk factor, with both cumulative lifetime exposure (more relevant for BCC and SCC) and intermittent intense exposure with blistering sunburns (more relevant for melanoma) contributing to cancer risk. Fair skin, classified as Fitzpatrick types I and II (characterized by easy burning and poor tanning), confers significantly increased risk compared to darker skin types due to lower melanin-mediated photoprotection. A history of sunburns, especially blistering sunburns during childhood and adolescence, is a particularly strong risk factor for melanoma. Immunosuppression, particularly in organ transplant recipients on chronic immunosuppressive medications and in HIV-infected individuals, dramatically increases the risk of skin cancer, with transplant recipients having a 65-fold increased risk of SCC. Genetic conditions including xeroderma pigmentosum (a DNA repair deficiency causing extreme UV sensitivity) and oculocutaneous albinism (absent melanin production) predispose to early-onset, multiple skin cancers. A personal history of any type of skin cancer significantly increases the risk of developing additional skin cancers over one's lifetime. Ultraviolet radiation damages skin through distinct mechanisms depending on the wavelength. UVA radiation (320-400 nm) penetrates deeper into the dermis, causes photoaging, and is the predominant wavelength emitted by tanning beds, contributing to cancer risk through generation of reactive oxygen species. UVB radiation (290-320 nm) is more energetic, directly damages DNA by causing pyrimidine dimer formation between adjacent thymine or cytosine bases, and is the primary cause of sunburn. The DNA damage induced by UV radiation leads to photocarcinogenesis through accumulation of mutations in key tumor suppressor genes and oncogenes, with p53 mutations being particularly common in BCC and SCC and PTCH (Patched) gene mutations driving the hedgehog signaling pathway that is central to BCC pathogenesis. Prevention of skin cancer relies on a multifaceted approach combining sun protection, surveillance, and education. Sun protection should include broad-spectrum sunscreen with SPF 30 or higher applied generously and reapplied every two hours during sun exposure, along with protective clothing, wide-brimmed hats, and seeking shade during peak UV hours. Tanning bed use should be strongly discouraged, as indoor tanning is associated with a significantly increased risk of melanoma, particularly when exposure begins before age 35. Regular skin examinations, including patient self-examination of the entire skin surface and professional screening examinations for high-risk individuals, facilitate early detection when treatment is most effective. Patient education targeting high-risk populations, including fair-skinned individuals, those with a personal or family history of skin cancer, and immunosuppressed patients, should emphasize both prevention and early recognition of suspicious lesions. Panel A: Skin cancer types showing relative frequency with basal cell carcinoma (80%), squamous cell carcinoma (16%), melanoma (4%), and other rare types, emphasizing melanoma's disproportionate mortality. Panel B: Risk factors diagram including UV exposure (cumulative and intermittent), fair skin (Fitzpatrick I-II), immunosuppression, genetics, and prior skin cancer history. Panel C: UV radiation spectrum showing UVA (320-400 nm, deeper penetration, aging) versus UVB (290-320 nm, causes sunburn, direct DNA damage with pyrimidine dimer formation). Panel D: Photocarcinogenesis pathway from UV exposure through DNA damage, p53 mutations, and clonal expansion to skin cancer development. --- ### II. Basal Cell Carcinoma Basal cell carcinoma originates from the basal keratinocytes of the epidermis and is the most common malignancy in humans, with over 3 million cases diagnosed annually in the United States alone. Despite its extraordinary frequency, BCC is characterized by locally invasive behavior with a very low metastatic potential, metastasizing in fewer than 0.1% of cases, meaning that mortality from BCC is exceedingly rare. BCC occurs predominantly on sun-exposed areas, with the head and neck accounting for approximately 80% of cases, reflecting the importance of cumulative UV exposure in its pathogenesis. The risk increases with age, fair skin, and chronic sun exposure, though BCC can also develop in younger individuals, particularly those with genetic predispositions such as basal cell nevus syndrome (Gorlin syndrome). Several clinical subtypes of BCC are recognized, each with characteristic morphologic features and clinical behavior. Nodular BCC is the most common subtype, presenting as a pearly or translucent papule or nodule with visible telangiectasias coursing over the surface and a rolled, raised border. Superficial BCC appears as a thin, pink, scaly patch typically found on the trunk, and may be mistaken for eczema or psoriasis if not carefully examined. Morpheaform (sclerosing) BCC is the most aggressive subtype, presenting as a scar-like, indurated, ill-defined plaque with poorly visible borders that make clinical margin assessment difficult and increase the risk of incomplete excision. Pigmented BCC contains melanin that imparts a brown, blue, or black color to the lesion, potentially mimicking melanoma and requiring careful differentiation. The classic clinical features of BCC are distinctive and allow clinical diagnosis in most cases. The pearly or translucent quality of the lesion, described as having a waxy or glassy appearance, results from the characteristic basaloid cell clusters in the dermis. Telangiectasias, or visible dilated blood vessels, course over the surface of the lesion in an arborizing (tree-like) pattern. The rolled border is a raised, elevated edge that often has a more prominent pearly quality than the center of the lesion. Central ulceration is common in larger or neglected tumors, producing the classic "rodent ulcer" appearance with a depressed, eroded center surrounded by a raised, pearly border. BCC is characteristically slow-growing, enlarging over months to years, and patients often describe a lesion that "never quite heals" or bleeds intermittently. Diagnosis of BCC relies on clinical examination, dermoscopy, and tissue biopsy for histologic confirmation. The characteristic clinical appearance often allows experienced clinicians to make a provisional diagnosis, though biopsy is always performed for confirmation before definitive treatment. Dermoscopy reveals characteristic features including arborizing (tree-like) vessels, blue-gray ovoid nests and globules, leaf-like structures, and spoke-wheel areas that help distinguish BCC from other skin lesions. Biopsy, typically performed as a shave or punch biopsy, provides tissue for histologic examination. Histopathologically, BCC demonstrates nests and islands of basaloid cells with characteristic peripheral palisading (picket-fence alignment of cells at the periphery of tumor nests), retraction artifact creating clefts between the tumor and surrounding stroma, and a myxoid (mucin-rich) stroma. Panel A: Nodular BCC showing pearly, translucent papule with telangiectasias, rolled borders, and central depression or ulceration (rodent ulcer). Panel B: BCC subtypes comparing nodular (dome-shaped, pearly), superficial (pink scaly patch on trunk), morpheaform (scar-like, ill-defined), and pigmented (mimics melanoma). Panel C: Dermoscopy features of BCC including arborizing (tree-like) vessels, blue-gray ovoid nests, leaf-like structures, and spoke-wheel areas. Panel D: Histopathology showing basaloid cell nests with peripheral palisading, retraction artifact creating clefts, and myxoid stroma. --- ### III. BCC Treatment The treatment of BCC offers multiple modalities whose selection depends on the tumor characteristics, anatomic location, and patient factors. Standard surgical excision with 4 millimeter clinical margins is the most commonly employed treatment, providing cure rates exceeding 95% for primary, well-defined tumors. Mohs micrographic surgery is preferred for tumors in high-risk locations, particularly the face where tissue conservation is critical, for recurrent tumors, and for aggressive histologic subtypes including morpheaform BCC. Curettage and electrodesiccation (C&E) is appropriate for low-risk, superficial BCCs on the trunk and extremities, where the technique of scraping the friable tumor followed by cauterization of the base achieves acceptable cure rates. Cryotherapy with liquid nitrogen is another option for superficial BCCs, though cure rates are generally lower than with excision. Topical imiquimod, an immune response modifier that stimulates local interferon production, and topical 5-fluorouracil (5-FU), a cytotoxic agent that targets rapidly dividing cells, are both approved for treatment of superficial BCC in patients who are not candidates for or decline surgical intervention. Radiation therapy is reserved for patients who are not surgical candidates due to comorbidities or patient preference. Mohs micrographic surgery represents the gold standard treatment for high-risk BCC, offering the highest cure rates while maximizing tissue preservation. The technique involves sequential excision of thin layers of tissue with immediate examination of 100% of the surgical margin using horizontal frozen sections and detailed margin mapping. This process is repeated until all margins are clear, ensuring complete tumor removal while preserving the maximum amount of uninvolved tissue. The primary indications for Mohs surgery include tumors on the face (particularly the nose, periorbital area, ears, and lips), recurrent tumors, aggressive histologic subtypes (morpheaform, infiltrative), and tumors with poorly defined clinical borders. Mohs surgery achieves cure rates exceeding 99% for primary BCC, the highest of any treatment modality. Risk stratification guides the selection of treatment modality and the intensity of follow-up surveillance. Low-risk BCCs are characterized by small size, location on the trunk or extremities, well-defined clinical borders, and nodular or superficial histologic subtype, and may be treated with standard excision, curettage and electrodesiccation, or topical therapy. High-risk BCCs include tumors on the head and neck, lesions greater than 2 centimeters in diameter, aggressive histologic subtypes (morpheaform, infiltrative, micronodular), recurrent tumors after prior treatment, and tumors with poorly defined clinical margins, warranting Mohs surgery or excision with wider margins and careful margin assessment. Treatment selection should be individualized based on this risk stratification framework, balancing cure rates against cosmetic outcomes, patient morbidity, and treatment accessibility. Advanced or metastatic BCC, though rare, requires systemic therapy that targets the hedgehog signaling pathway driving tumor growth. Hedgehog pathway inhibitors, including vismodegib and sonidegib, block the Smoothened (SMO) protein, a key transmembrane receptor in the hedgehog signaling cascade that is constitutively activated in BCC due to loss-of-function mutations in the PTCH (Patched) tumor suppressor gene. These agents are indicated for locally advanced BCC that is not amenable to surgery or radiation and for the extremely rare cases of metastatic BCC. Side effects of hedgehog inhibitors include muscle spasms (the most common and often dose-limiting adverse effect), alopecia (hair loss), dysgeusia (taste disturbance), weight loss, and fatigue, which significantly impact quality of life and may lead to treatment discontinuation. Panel A: Mohs micrographic surgery technique showing sequential excision with horizontal frozen sections, margin mapping, and tissue-sparing approach achieving greater than 99% cure rate. Panel B: Treatment algorithm based on risk stratification from low-risk (excision, curettage) through high-risk (Mohs surgery) to advanced disease (hedgehog inhibitors). Panel C: Hedgehog signaling pathway showing PTCH receptor, SMO protein, and GLI transcription factors with vismodegib/sonidegib blocking SMO activation. Panel D: Advanced BCC treatment with hedgehog inhibitors showing indications (locally advanced, metastatic), response rates, and side effect profile (muscle spasms, dysgeusia, alopecia). --- ### IV. Squamous Cell Carcinoma Squamous cell carcinoma arises from the malignant transformation of squamous keratinocytes in the epidermis and represents the second most common skin cancer with a significantly higher metastatic potential than BCC. SCC is locally invasive and can metastasize to regional lymph nodes and distant sites, with an overall metastatic rate of 2-5% that increases substantially in the presence of high-risk features. The majority of cutaneous SCCs develop from precursor lesions, most notably actinic keratoses, which represent a continuum of UV-induced epidermal dysplasia progressing from mild atypia to invasive carcinoma. Risk factors for SCC largely overlap with those for BCC but include several distinctive elements. Cumulative UV exposure is the primary environmental risk factor, and the correlation between lifetime sun exposure and SCC risk is stronger than for either BCC or melanoma. Immunosuppression, particularly in solid organ transplant recipients, confers a dramatically increased risk of SCC estimated at 65 times the general population risk, and the ratio of SCC to BCC is reversed in transplant recipients (SCC becomes more common than BCC). Chronic wounds, scars, and areas of chronic inflammation can give rise to SCC, a phenomenon historically referred to as a Marjolin ulcer when SCC develops in a chronic burn scar or wound. HPV infection, particularly with high-risk types, is associated with anogenital SCC. Arsenic exposure, both historically from contaminated well water and occupationally, is an established risk factor for multiple SCCs as well as other malignancies. The clinical presentation of SCC is characterized by a scaly, crusted, erythematous lesion that is typically firm and indurated on palpation. The texture is distinctly firm compared to the softer consistency of BCC, reflecting the keratinizing nature of the squamous proliferation. SCC occurs on sun-exposed skin with a particular predilection for the lips (especially the lower lip), ears, and dorsal hands, sites that receive high cumulative UV exposure. Ulceration is common in SCC and may produce a crater-like or exophytic appearance. SCC generally grows faster than BCC, with patients noting progressive enlargement over weeks to months rather than the years-long growth pattern typical of BCC. Several histologic variants of SCC demonstrate distinct clinical behavior and prognosis. Well-differentiated SCC produces abundant keratin with keratin pearl formation visible histologically and carries a better prognosis due to its less aggressive biologic behavior. Poorly differentiated SCC demonstrates minimal keratinization and more anaplastic cellular features, carrying a higher risk of metastasis and local recurrence. Keratoacanthoma is a controversial entity that may represent a well-differentiated variant of SCC; it is characterized by rapid growth over 4 to 8 weeks producing a dome-shaped nodule with a central, keratin-filled crater (volcano-like architecture) and may undergo spontaneous regression, though most clinicians treat it as SCC given the difficulty of distinguishing it from invasive carcinoma clinically and histologically. Verrucous carcinoma is a low-grade, warty variant of SCC that is locally invasive but rarely metastasizes, presenting as a slow-growing, exophytic, cauliflower-like mass. SCC in situ, known as Bowen disease, is confined entirely to the epidermis without invasion through the basement membrane, presenting as a well-demarcated, scaly, erythematous patch with irregular borders. Panel A: Invasive SCC showing scaly, crusted, erythematous nodule or plaque with induration, possible ulceration, and location on sun-exposed skin (face, ears, lips). Panel B: Keratoacanthoma with rapid growth, volcano-like architecture with central keratin-filled crater, and potential for spontaneous regression. Panel C: Bowen disease (SCC in situ) presenting as well-demarcated, scaly, erythematous patch with irregular borders confined to epidermis. Panel D: High-risk features including size greater than 2 cm, depth greater than 4 mm, perineural invasion, poor differentiation, and immunosuppression with corresponding metastatic potential. --- ### V. SCC Management Surgical management of SCC aims to achieve complete excision with clear margins while preserving function and cosmesis. Standard surgical excision with 4 to 6 millimeter clinical margins is appropriate for most primary SCCs and achieves high cure rates when margins are histologically clear. Mohs micrographic surgery is preferred for high-risk SCCs, tumors in cosmetically or functionally sensitive locations where tissue preservation is important, and recurrent tumors, providing the highest cure rates with 100% margin assessment. Radiation therapy may be used as primary treatment for patients who are not surgical candidates or as adjuvant therapy following excision of high-risk tumors with perineural invasion, positive margins, or extensive local disease. Lymph node dissection is indicated when there is clinical or radiographic evidence of regional lymph node involvement, as sentinel lymph node biopsy is not yet established as standard of care for cutaneous SCC as it is for melanoma. Multiple features identify high-risk SCCs with increased potential for recurrence and metastasis. Tumor size greater than 2 centimeters is associated with a doubled recurrence rate and increased metastatic risk compared to smaller tumors. Depth of invasion greater than 4 millimeters or extension beyond the subcutaneous fat significantly increases the risk of metastasis. Perineural invasion, the growth of tumor along nerve sheaths, is associated with both higher recurrence rates and increased metastatic potential and may produce clinical symptoms of pain, paresthesia, or cranial nerve deficits. Poor histologic differentiation indicates more aggressive biologic behavior. Location on the ear or lip carries a higher metastatic rate compared to other anatomic sites. Immunosuppression dramatically increases the risk of metastasis and disease-specific mortality from SCC. Staging of cutaneous SCC follows the American Joint Committee on Cancer (AJCC) system. Stage I disease includes tumors 2 centimeters or smaller without high-risk features, representing the most favorable prognosis. Stage II encompasses tumors greater than 2 centimeters or those with high-risk features such as depth greater than 4 millimeters, perineural invasion, or poor differentiation. Stage III indicates regional lymph node involvement, which significantly worsens the prognosis and necessitates multidisciplinary management. Stage IV represents distant metastatic disease, most commonly involving the lungs, liver, and bone, and carries the poorest prognosis. Advanced SCC that is not amenable to surgery or radiation has benefited from the introduction of immune checkpoint inhibitors. Cemiplimab, an anti-PD-1 monoclonal antibody, was the first immunotherapy agent specifically approved for advanced cutaneous SCC and serves as first-line treatment for locally advanced or metastatic disease. Pembrolizumab, another anti-PD-1 antibody, has also demonstrated efficacy in advanced SCC and provides an additional treatment option. These immunotherapy agents achieve response rates of approximately 40-50% in advanced SCC, with some patients experiencing durable complete responses. Platinum-based chemotherapy regimens serve as second-line options for patients who do not respond to or cannot tolerate immunotherapy, though response rates are generally lower and less durable than with checkpoint inhibitors. Panel A: AJCC staging for cutaneous SCC showing Stage I (small, no high-risk features), Stage II (large or high-risk features), Stage III (lymph node involvement), and Stage IV (distant metastasis). Panel B: Surgical management with standard excision (4-6 mm margins) versus Mohs surgery for high-risk tumors and cosmetically sensitive locations. Panel C: Immunotherapy for advanced SCC with cemiplimab and pembrolizumab (anti-PD-1 antibodies) showing mechanism of T cell activation and 40-50% response rates. Panel D: Transplant-associated SCC showing 65-fold increased risk in immunosuppressed patients, aggressive behavior, and management considerations including immunosuppression reduction. --- ### VI. Actinic Keratosis Actinic keratosis (AK) is the most common pre-malignant skin lesion, representing an intraepidermal proliferation of atypical keratinocytes that exists on a continuum with SCC in situ and invasive SCC. These lesions result from chronic UV damage to the epidermis, predominantly affecting sun-exposed areas of fair-skinned individuals with a lifetime of cumulative sun exposure. The risk of any individual actinic keratosis progressing to invasive SCC is estimated at 1-10%, though the cumulative risk in patients with multiple AKs is considerably higher and cannot be predicted for any specific lesion, justifying treatment of all identified lesions. The clinical features of actinic keratosis are characteristic and often allow diagnosis on clinical examination alone. Lesions appear as rough, scaly, erythematous papules or patches on sun-damaged skin, frequently easier to detect by palpation than by visual inspection alone. The surface has a distinctive sandpaper-like texture that is often the most prominent finding, particularly when lesions are subtle and minimally erythematous. Lesions may be tender or mildly symptomatic, particularly when irritated by friction or trauma. The concept of field cancerization recognizes that actinic keratoses typically occur in the context of widespread UV damage affecting large areas of sun-exposed skin, with visible AKs representing the clinically apparent "tip of the iceberg" of diffuse subclinical dysplasia, a finding that has important implications for treatment strategy. Treatment of actinic keratoses may target individual lesions (lesion-directed therapy) or broad areas of sun-damaged skin (field-directed therapy). Cryotherapy with liquid nitrogen is the most commonly used lesion-directed treatment, producing rapid destruction of individual AKs through freezing, with healing occurring over 2 to 4 weeks. Topical 5-fluorouracil (5-FU) is a field-directed therapy applied to the entire affected area, producing inflammation and erosion of both visible and subclinical AKs over a treatment course of 2 to 4 weeks. Topical imiquimod is an immune response modifier used for field therapy that stimulates the innate immune system to recognize and destroy dysplastic keratinocytes. Photodynamic therapy (PDT) involves application of a photosensitizing agent (aminolevulinic acid) to the skin followed by activation with a specific wavelength of light, producing selective destruction of dysplastic cells and is effective for both visible and subclinical lesions. Curettage is useful for thicker, more hyperkeratotic lesions that may not respond adequately to topical or cryotherapy approaches. Ingenol mebutate was previously available for field therapy but has been removed from the market due to safety concerns. Follow-up of patients with actinic keratoses is an ongoing process reflecting the chronic nature of sun damage and the continued risk of new lesion development. Sun protection must be emphasized as an ongoing, daily practice including broad-spectrum sunscreen, protective clothing, and sun avoidance during peak UV hours, which reduces both the development of new AKs and progression of existing ones. Regular surveillance with periodic skin examinations by a dermatologist is recommended, with frequency determined by the burden of actinic damage and history of prior skin cancers. New lesions should be treated as they arise to prevent progression to invasive SCC. Any actinic keratosis that demonstrates thickening, rapid growth, or symptoms such as pain or bleeding should raise concern for progression to SCC and warrants biopsy for histologic assessment. Panel A: Actinic keratosis clinical appearance showing rough, scaly, erythematous papules on sun-damaged skin with characteristic sandpaper texture on palpation. Panel B: Field cancerization concept with multiple actinic keratoses in sun-exposed area representing diffuse UV damage requiring field-directed therapy approach. Panel C: Lesion-directed treatments including cryotherapy with liquid nitrogen, curettage for thicker lesions, and expected healing process. Panel D: Field-directed therapies showing topical 5-fluorouracil, imiquimod, and photodynamic therapy with mechanisms and treatment protocols for widespread actinic damage. --- ### VII. Melanoma - Overview Melanoma is a malignant neoplasm arising from melanocytes that, despite accounting for only approximately 4% of skin cancers, is responsible for the majority of skin cancer deaths due to its aggressive behavior and propensity for early metastasis. The incidence of melanoma has been rising steadily over recent decades, with over 100,000 new cases diagnosed annually in the United States alone, making it one of the most rapidly increasing cancers in the developed world. Risk factors include UV exposure, fair skin, family history, and the presence of numerous or dysplastic nevi. Melanoma can occur at any age, including in young adults and even adolescents, distinguishing it from BCC and SCC, which are primarily diseases of older individuals with cumulative sun damage. Risk factors for melanoma encompass genetic, phenotypic, and environmental elements that interact to determine individual susceptibility. A family history of melanoma approximately doubles the risk, with the risk increasing further when multiple first-degree relatives are affected, suggesting a hereditary component. Dysplastic (atypical) nevi serve both as markers of increased melanoma risk and as potential precursor lesions from which melanoma may arise, though the majority of melanomas develop de novo rather than from pre-existing nevi. Having a large number of common nevi, particularly more than 100, is an independent risk factor for melanoma. Fair skin (Fitzpatrick type I-II), characterized by easy sunburning and poor tanning ability, confers increased risk due to reduced melanin-mediated photoprotection. A personal history of prior melanoma significantly increases the risk of developing a second primary melanoma. Immunosuppression from any cause, including organ transplantation and HIV infection, increases melanoma risk and may worsen prognosis. Genetic syndromes associated with familial melanoma have provided important insights into melanoma biology. Familial melanoma is most commonly associated with germline mutations in CDKN2A (encoding the p16/INK4a and p14/ARF tumor suppressors), which account for approximately 20-40% of melanoma-prone families and confer a lifetime melanoma risk of 60-90%. Xeroderma pigmentosum, caused by defects in nucleotide excision repair genes, produces extreme sensitivity to UV radiation and dramatically increased risk of all skin cancers including melanoma at a young age. BAP1 tumor predisposition syndrome, caused by germline mutations in the BAP1 gene, is associated with atypical melanocytic tumors, uveal melanoma, mesothelioma, and renal cell carcinoma. The ABCDE criteria represent the most widely used clinical framework for identifying suspicious pigmented lesions that warrant biopsy to exclude melanoma. Asymmetry (A) refers to the lesion being unequal in shape when divided through its center, with one half not matching the other. Border irregularity (B) describes notched, scalloped, or poorly defined edges rather than the smooth, round borders typical of benign nevi. Color variation (C) identifies the presence of multiple shades within a single lesion, including combinations of brown, black, red, white, and blue, in contrast to the uniform pigmentation of benign nevi. Diameter (D) greater than 6 millimeters (the size of a pencil eraser) is concerning, though melanomas may be smaller at initial presentation. Evolving (E) is perhaps the most important criterion, referring to any change in size, shape, color, or symptoms (such as new itching, bleeding, or crusting) in a previously stable lesion. Panel A: ABCDE criteria with clinical examples showing Asymmetry (unequal halves), Border irregularity (notched, scalloped edges), Color variation (multiple shades of brown, black, red, white), Diameter greater than 6 mm, and Evolving (changing) features. Panel B: Benign nevus versus melanoma comparison highlighting symmetric versus asymmetric shape, regular versus irregular borders, and uniform versus variegated color. Panel C: Dermoscopy of melanoma showing atypical pigment network, irregular dots and globules, blue-white veil, and regression structures. Panel D: Ugly duckling sign concept identifying the one lesion that looks different from patient's other nevi as warranting closer evaluation. --- ### VIII. Melanoma - Types and Diagnosis Four major histologic subtypes of melanoma are recognized, each with characteristic clinical presentations and growth patterns that influence prognosis. Superficial spreading melanoma is the most common subtype, accounting for approximately 70% of all melanomas, and is characterized by a prolonged radial growth phase during which the tumor expands laterally within the epidermis before developing the capacity for vertical invasion and metastasis. Nodular melanoma is the second most common subtype and is the most aggressive, lacking a significant radial growth phase and instead demonstrating rapid vertical growth from the outset, which explains its worse prognosis at presentation. Lentigo maligna melanoma arises on chronically sun-damaged skin of elderly individuals, typically on the face, and evolves from lentigo maligna (melanoma in situ) through a prolonged intraepidermal phase before developing invasive capability. Acral lentiginous melanoma occurs on the palms, soles, and subungual areas (beneath the nails) and is the most common subtype in individuals with dark skin, including African American, Asian, and Hispanic populations. The clinical features of each melanoma subtype provide important diagnostic clues for recognition. Superficial spreading melanoma presents as a flat or slightly raised lesion with irregular borders, color variegation including shades of brown, black, red, white, and blue, and asymmetric shape, typically occurring on the trunk of men and legs of women. Nodular melanoma appears as a rapidly growing, raised, dome-shaped nodule that may be amelanotic (pink or red rather than pigmented) and may ulcerate, making it particularly challenging to diagnose clinically as it may lack the classic ABCDE features of melanoma. Lentigo maligna melanoma begins as a large, slowly expanding, tan-to-brown macule on sun-damaged facial skin with irregular borders and subtle color variation, with the development of a palpable nodule or darker area within the macule signaling progression to invasive melanoma. Acral lentiginous melanoma presents as an irregular pigmented macule or patch on the palm, sole, or nail bed, and the Hutchinson sign (extension of periungual pigment onto the nail fold) is an important clinical clue to subungual melanoma. Dermoscopic examination improves diagnostic accuracy for pigmented lesions and has become an essential tool in melanoma detection. Atypical pigment network, characterized by irregular, broad pigmented lines with variable spacing, replaces the regular, symmetric network seen in benign nevi. Blue-white veil is a structureless area of blue-white coloring that correlates histologically with either regression (fibrosis) or deep invasion with overlying orthokeratosis. Irregular dots and globules distributed asymmetrically within the lesion suggest uncontrolled melanocytic proliferation. Pseudopods are bulbous or finger-like projections at the periphery of the lesion indicating radial growth. Negative network refers to a pattern of hypopigmented serpiginous lines surrounding pigmented areas and is highly specific for melanoma. The diagnostic approach to suspected melanoma follows a systematic pathway from clinical assessment through tissue diagnosis. Clinical evaluation using the ABCDE criteria and the "ugly duckling" sign (identifying the one lesion that looks different from a patient's other nevi) identifies suspicious lesions warranting further assessment. Dermoscopy, performed by trained clinicians, improves the sensitivity and specificity of melanoma detection and helps determine which lesions require biopsy. Excisional biopsy with narrow (1-3 mm) margins is the preferred biopsy technique for suspected melanoma, as it provides the full tumor thickness necessary for accurate Breslow depth measurement and staging, with shave biopsies avoided to prevent transection of the deep margin. Sentinel lymph node biopsy is recommended for staging in melanomas greater than 0.8 to 1.0 millimeters in thickness or with other high-risk features such as ulceration, as it identifies occult microscopic nodal metastases that significantly impact staging and treatment decisions. Panel A: Superficial spreading melanoma (70% of cases) showing irregular flat lesion with color variegation, radial growth phase, and typical location on trunk or extremities. Panel B: Nodular melanoma demonstrating rapidly growing, raised, often symmetric nodule that may be amelanotic (pink/red), representing vertical growth phase from onset. Panel C: Acral lentiginous melanoma on palm or sole showing irregular pigmented macule, and Hutchinson sign with periungual pigment extending onto nail fold indicating subungual melanoma. Panel D: Lentigo maligna on sun-damaged facial skin of elderly patient showing large, tan-brown macule with irregular borders and slow radial growth. --- ### IX. Melanoma - Staging and Treatment The Breslow depth, measured in millimeters from the granular layer of the epidermis to the deepest point of tumor invasion, is the single most important prognostic factor for cutaneous melanoma and forms the basis of the T-staging system. T1 melanomas are 1.0 millimeter or less in thickness and carry the most favorable prognosis. T2 melanomas measure 1.01 to 2.0 millimeters, representing an intermediate-thickness category with increasing metastatic potential. T3 melanomas are 2.01 to 4.0 millimeters thick and have a significantly higher risk of nodal and distant metastasis. T4 melanomas exceed 4.0 millimeters in thickness and carry the highest risk of metastatic disease. The presence of ulceration within a melanoma increases the substage from "a" to "b" at each T level (for example, T2a without ulceration versus T2b with ulceration), reflecting its independent adverse prognostic significance equivalent to increasing the effective tumor thickness. Multiple prognostic factors beyond Breslow depth contribute to melanoma risk assessment and guide treatment decisions. Breslow depth remains the most important single prognostic factor, with 10-year survival rates decreasing progressively from over 90% for tumors less than 1 millimeter to approximately 50% for tumors greater than 4 millimeters. Ulceration of the primary tumor is an independent adverse prognostic factor that worsens survival at every T stage. Mitotic rate (the number of dermal mitoses per square millimeter) reflects tumor proliferative activity, with higher rates associated with worse outcomes. Sentinel lymph node status is the most important staging factor after primary tumor characteristics, with positive sentinel nodes significantly downgrading prognosis and upstaging the disease. Anatomic site influences prognosis, with tumors on the head, neck, and trunk carrying a worse prognosis than those on the extremities. Surgical treatment of melanoma is guided by Breslow depth, with wider excision margins recommended for thicker tumors. Melanoma in situ is treated with excision margins of 0.5 to 1.0 centimeter. Melanomas up to 1.0 millimeter in thickness require 1 centimeter margins. Tumors between 1.01 and 2.0 millimeters warrant 1 to 2 centimeter margins. Melanomas greater than 2.0 millimeters require 2 centimeter margins. Sentinel lymph node biopsy is recommended for tumors greater than 0.8 to 1.0 millimeters in thickness, or for thinner melanomas with high-risk features such as ulceration, high mitotic rate, or lymphovascular invasion, as the sentinel node status provides essential staging information that guides adjuvant therapy decisions. Adjuvant therapy following surgical resection has significantly improved outcomes for patients with high-risk and stage III melanoma. Stage IIB-IIC melanomas (thick primary tumors with high-risk features) may be considered for adjuvant therapy given their substantial recurrence risk despite negative sentinel nodes. Stage III melanoma, defined by regional lymph node involvement, has the strongest indication for adjuvant systemic therapy, which has been shown to significantly improve recurrence-free survival. Treatment options include pembrolizumab and nivolumab (anti-PD-1 checkpoint inhibitors) and the combination of dabrafenib plus trametinib (BRAF/MEK inhibitors for BRAF-mutant melanomas). These adjuvant therapies have demonstrated significant improvements in recurrence-free survival, transforming the management of high-risk resected melanoma from an era of observation to one of active risk reduction. Panel A: Breslow depth measurement showing tumor thickness in millimeters from granular layer to deepest invasive cell, with T-staging categories (T1 less than 1 mm, T2 1.01-2 mm, T3 2.01-4 mm, T4 greater than 4 mm). Panel B: Surgical margins based on tumor thickness showing 0.5-1 cm for in situ, 1 cm for tumors up to 1 mm, 1-2 cm for 1-2 mm, and 2 cm for greater than 2 mm thickness. Panel C: Sentinel lymph node biopsy technique with radiotracer and blue dye injection, lymphatic mapping, and node identification for tumors greater than 0.8-1 mm or high-risk features. Panel D: Prognostic factors showing Breslow depth (most important), ulceration, mitotic rate, and sentinel node status with corresponding 5-year survival rates. --- ### X. Advanced Melanoma Treatment Immunotherapy has fundamentally transformed the treatment of advanced melanoma, converting what was previously a rapidly fatal disease into one with meaningful long-term survival for a substantial proportion of patients. Pembrolizumab and nivolumab are anti-PD-1 monoclonal antibodies that block the interaction between PD-1 on T cells and PD-L1 on tumor cells, thereby releasing the brakes on anti-tumor immune responses and enabling cytotoxic T cells to recognize and destroy melanoma cells. Ipilimumab is an anti-CTLA-4 antibody that targets an earlier checkpoint in T cell activation, augmenting the initial priming of anti-tumor T cells in the lymph nodes. The combination of nivolumab plus ipilimumab achieves the highest response rates, approximately 50-60% with long-term survival in a significant proportion of responders, but at the cost of increased immune-related toxicity compared to either agent alone. Single-agent anti-PD-1 therapy achieves response rates of 40-45% with a more favorable side effect profile, making it the preferred first-line option for most patients. Targeted therapy with BRAF and MEK inhibitors represents a second major therapeutic axis for advanced melanoma, applicable to the approximately 50% of melanomas harboring activating BRAF mutations. Dabrafenib is a selective BRAF inhibitor that blocks the constitutively active BRAF V600E kinase, the most common oncogenic BRAF mutation in melanoma. Trametinib is a MEK inhibitor that blocks signaling downstream of BRAF in the MAPK pathway. The combination of dabrafenib plus trametinib is the standard targeted therapy regimen, providing higher response rates and longer progression-free survival compared to either agent alone while reducing the paradoxical cutaneous toxicities (keratoacanthomas and SCCs) seen with BRAF inhibitor monotherapy. The BRAF V600E mutation is present in approximately 50% of cutaneous melanomas, making molecular testing of all advanced melanomas for BRAF mutations essential for treatment planning. Targeted therapy produces rapid responses but may eventually be overcome by acquired resistance, contrasting with the slower but potentially more durable responses achieved with immunotherapy. Treatment selection for advanced melanoma depends on the BRAF mutation status, tumor burden, pace of disease, and patient characteristics. BRAF wild-type melanomas are treated with immunotherapy, as targeted therapy is not applicable in the absence of a BRAF mutation. BRAF-mutant melanomas may be treated with either immunotherapy or targeted therapy, with the choice influenced by clinical factors. Patients with high tumor burden or symptomatic disease may benefit from the rapid response characteristic of targeted therapy, while immunotherapy is generally preferred for most patients given its potential for more durable responses. Brain metastases, which occur in up to 50% of patients with advanced melanoma, can be treated with the combination of nivolumab plus ipilimumab, which has demonstrated intracranial activity, or with combined systemic and local therapy (surgery, stereotactic radiosurgery). Several additional considerations are important in the management of advanced melanoma. Brain metastases require a multidisciplinary approach integrating surgery for large or symptomatic lesions, stereotactic radiosurgery (SRS) for limited brain metastases, and systemic therapy that can cross the blood-brain barrier. Immune-related adverse events are a significant concern with checkpoint inhibitor therapy, including colitis, hepatitis, pneumonitis, endocrinopathies (thyroiditis, adrenal insufficiency, hypophysitis), and dermatologic toxicities, requiring vigilant monitoring and prompt management with corticosteroids when indicated. Follow-up after treatment for melanoma includes regular skin examinations and imaging surveillance, as melanoma can recur years after the initial diagnosis, with a median time to recurrence of 2 to 3 years though late recurrences beyond 10 years are well documented. The possibility of late recurrence necessitates long-term surveillance extending well beyond the conventional follow-up periods used for most other malignancies. Panel A: Immune checkpoint inhibitor targets showing PD-1/PD-L1 interaction blocking T cell activation, and anti-PD-1 antibodies (pembrolizumab, nivolumab) restoring anti-tumor immunity with 40-60% response rates. Panel B: CTLA-4 checkpoint and ipilimumab mechanism, with combination nivolumab plus ipilimumab achieving higher response rates but increased toxicity. Panel C: BRAF/MEK pathway in melanoma showing BRAF V600E mutation in 50% of cases, targeted inhibition with dabrafenib (BRAF inhibitor) plus trametinib (MEK inhibitor), and rapid but potentially less durable responses. Panel D: Treatment algorithm for advanced melanoma based on BRAF mutation status, tumor burden, and patient factors, with immunotherapy preferred for most patients and targeted therapy for rapid response needs. --- ## Summary - BCC: most common; locally invasive; pearly, telangiectasias; rarely metastasizes - SCC: second most common; can metastasize; immunosuppression major risk - Actinic keratosis: precursor to SCC; treat with cryotherapy or field therapy - Melanoma: ABCDE criteria; Breslow depth most important prognostic factor - Melanoma subtypes: superficial spreading, nodular, lentigo maligna, acral - Melanoma surgery: margins based on depth; sentinel node for >0.8-1 mm - Advanced melanoma: immunotherapy (PD-1, CTLA-4) or targeted (BRAF/MEK) - BCC advanced: hedgehog inhibitors (vismodegib) - SCC advanced: PD-1 inhibitors (cemiplimab, pembrolizumab) - Prevention: sun protection, skin exams, patient education --- ## Key Terms | Term | Definition | |------|------------| | Basal cell carcinoma | Most common skin cancer; locally invasive | | Squamous cell carcinoma | Second most common; can metastasize | | Melanoma | Malignant tumor of melanocytes | | Actinic keratosis | Pre-malignant lesion; SCC precursor | | Breslow depth | Tumor thickness in mm; key prognostic factor | | Mohs surgery | Micrographic surgery with margin examination | | ABCDE | Asymmetry, Border, Color, Diameter, Evolving | | Sentinel node biopsy | First draining lymph node assessment | --- *This content is subject to the [MIT License](https://opensource.org/licenses/MIT). © 2024–2026 Hibbert School of Medicine.*