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| Malignant Melanoma and Nonmelanoma Skin Cancer Lauren S. Levine • David Y. Chen • Lynn A. Cornelius • Gerald P. Linette |
I. MALIGNANT MELANOMA
A. Background
1. Epidemiology. The Surveillance, Epidemiology, and End Results Program (SEER) data demonstrate a steady rise in the incidence of cutaneous melanoma since 1975 and a continued average of 1.8% year-over-year increase between 2002 and 2011. The American Cancer Society estimates that in 2014, approximately 76,100 cases of melanoma will be diagnosed, and 9,710 individuals will die of melanoma. The lifetime risk of being diagnosed with melanoma in the United States is approximately 1 in 50 for whites, 1 in 1,000 for blacks, and 1 in 200 for Hispanics. Overall, more men account for new cases of melanoma than women (27.7 vs. 16.7 new cases per 100,000).
2. Risk factors. There are clear genetic and environmental determinants of melanoma risk. One study found that mutations in the CDKN2A tumor suppressor gene are present in 39% of families with multiple occurrences of melanoma, while another population-based study found that though CDKN2A mutations were associated with greater risk of first degree relatives with melanoma, only one out of 18 families with three or more affected first-degree relatives carried CDKN2A mutations, suggesting other heritable factors. Low penetrance gene variants associated with increased melanoma risk include melanocortin 1 receptor (MC1R), tyrosinase (TYR), cyclin-dependent kinase 4 (CDK4), micropthalmia transcription factor (MITF), BAP1, and others. New genetic risk factors are being described with the proliferation of next-generation sequencing, including a recent study that identified a nongenic polymorphisms affecting the regulatory region in telomerase (TERT) in a family with multiple family members with melanoma. Despite identification of genetic risk factors, the utility of their detection is not established and genetic testing is not a routine practice in the clinical setting.
The most significant environmental exposure that drives melanoma, and nonmelanoma skin cancer, risk is ultraviolet (UV) exposure. The WHO has classified UV radiation between 100 and 400 nm as a known carcinogen. UV exposure interacts with genetic risk factors, including fair skin, red hair (MC1R variants), and UV sensitivity syndromes like xeroderma pigmentosum. Fair-skin people are at higher risk of melanoma from UV exposure. Additionally, SEER registry data demonstrate that prior history of melanoma confers 10-fold risk of subsequent melanoma compared to the general population, likely reflecting a confluence of genetic and environmental causes. Other risk factors include increased number of nevi (>50), history of greater than five clinically atypical nevi, large congenital nevi, and history of immune suppression with solid organ transplantation.
B. Primary cutaneous melanoma
1. Diagnosis. Cutaneous melanomas commonly arise in the absence of a clinically apparent precursor, although in some instances benign nevi are associated with melanoma on histologic examination. Patients may report the appearance of a new skin lesion or change in an existing lesion and will occasionally note associated symptoms such as itching and bleeding. Nonpigmented, or amelanotic, primary lesions comprise approximately 5% of cutaneous melanomas.
a. Physical examination. While evaluating a pigmented skin lesion, the ABCD morphologic criteria are helpful, but not absolute.
• Asymmetry. One half of the lesion does not match the other.
• Border irregularity. The lesion has ragged or notched edges.
• Color variegation. Pigmentation is a heterogeneous mixture of tan, brown, or black. Red, white, or blue discolorations are particularly of concern.
• Diameter. Larger than 6 mm in diameter.
• Evolution. Any change in clinical characteristics of a lesion noted by the patient or physician.
Particular attention should be given to lesions that are evolving by clinical documentation (i.e., written or photographic records) or by patient report. Together, these sets of criteria are sometimes known as the ABCDE’s of melanoma. Lesions with one or more of these attributes should be brought to the attention of a physician, preferably a dermatologist, and evaluated for the possibility of melanoma. Other characteristics such as itching, bleeding, and the presence of ulceration should also prompt a careful evaluation for melanoma. In addition to examination of the lesion in question, a comprehensive skin examination by a dermatologist is critical in evaluating and monitoring patients with multiple or atypical nevi, a history of excessive sun exposure, or a history of melanoma or nonmelanoma skin cancer. Full body examination is essential, including scalp, hands and feet, genitalia, and oral cavity.
b. Biopsy. The differential diagnosis of a pigmented skin lesion includes an atypical nevus, a benign growth such as melanocytic nevus, solar lentigo, seborrheic keratosis, angioma, and other malignant growths such as basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). When melanoma or other malignant lesion is a consideration, a biopsy without delay is required to establish a diagnosis.
• Excisional biopsy. Full thickness removal of the entire clinical lesion with 1 to 3 mm margins is optimal for diagnosis and accurate staging by Breslow’s depth. Avoiding wider margins facilitates accurate sentinel lymph node mapping if later required.
• Incisional biopsy. For large lesions or lesions on special sites like the palms and soles, face, ears, or digits, full thickness incision or punch biopsy of the thickest clinical portion may be appropriate.
• Deep shave (Saucerization). Wide sampling is preferred in superficial lesions such as lentigo maligna, where atypical melanocytes may extend beyond the clinically observed lesion. Superficial shave biopsy is not recommended for any lesion suspected to be melanoma.
c. Histologic reporting and classification. Breslow’s thickness in millimeters, presence or absence of histologic ulceration, dermal mitotic rate per square millimeter, and presence or absence at the lateral or deep margins comprise the bare minimal elements that should be reported with the histologic evaluation of melanoma. Reports may include additional elements encouraged by the American Academy of Dermatology such as the presence or absence of regression, microsatellitosis, tumor infiltrating lymphocytes, lymphovascular invasion, neurotropism, or whether there is vertical growth phase. The pathologist may also report the histologic subtype, which includes superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, and acral lentiginous melanoma. Superficial spreading melanoma is the most common subtype comprising 75% of all melanomas, while lentigo maligna comprises 10% to 15% and is thought to have an extended radial growth phase. Nodular melanomas are by definition in vertical growth phase. Acral lentiginous melanoma is the least common type and characteristically arises on specialized sites including palmar, plantar, and subungual locations. Aside from the four dominant subtypes, there are rare variants including nevoid melanoma and desmoplastic melanoma. Although histologically distinct, the subtype does not affect staging as it does not influence management or prognosis with the exception of pure desmoplastic melanoma, with which sentinel node biopsy may not be indicated.
d. Diagnostic dilemmas. Distinguishing melanoma from benign growths can be challenging, despite thorough clinical exam and adequate sampling of the lesion. Immunohistochemistry may be utilized to highlight cells of melanocytic origin, including S100, MART-1, and HMB-45. These antigens are not specific to melanoma but can highlight the architecture of the lesion as well as aid in the identification of nodal metastases. In certain cases, further testing for chromosomal aberrations and copy number variability with fluorescence in situ hybridization (FISH) or comparative genomic hybridization (CGH) can help distinguish benign from malignant lesions.
Staging. The most commonly used staging system is found in the AJCC Cancer Staging Manual, 7th edition. The T stage is defined by the tumor thickness (T1—≤1 mm, T2—1.01 to 2 mm, T3—2.01 to 4 mm and T4—>4 mm). The presence of ulceration defines the b substaging. The N stage is defined by the number of lymph nodes involved (N1—1 lymph node, N2—2 to 3 lymph nodes and N3—4 or more lymph nodes, matted lymph nodes or in-transit metastases). The M stage may be further subdivided into M1 (involvement of skin, subcutaneous tissue, or distant lymph nodes with normal LDH), M2 (lung metastases with normal LDH), and M3 (metastases to other organs or any metastasis with elevated LDH). The melanoma stages are as follows: IA (T1a), IB (T1b or T2a), IIA (T2b or T3a), IIB (T3b or T4a), IIC (T4b), III (N1, N2, or N3), IV (M1). Although many of the staging criteria remained the same, the new staging system reflects the rise in utilization of sentinel lymph node biopsy technique and the attendant increase in detection of micrometastases. Importantly, microstaging now distinguishes mitotic rate less than 1/mm2 or 1/mm2 or greater as a separate staging criterion in determining T1a from T1b lesions, respectively, in addition to the existing criterion regarding the presence or absence of ulceration. The most important prognostic factors in the staging of melanoma are the thickness of the primary lesion measured in millimeters, the presence of histologic ulceration, the mitotic rate, and regional lymph node involvement. The thickness of the primary melanoma is known as the Breslow thickness and is measured in millimeters from the top of the granular layer in the epidermis to the base of the deepest tumor nest in the dermis. The Breslow thickness cutoffs for primary tumor classification are 1.0, 2.0, and 4.0 mm, while mitotic activity and ulceration modify tumor staging. Tumor staging, in combination with clinical findings, guide the next steps of the staging workup.
a. Sentinel lymph node biopsy. Stage 0, I, and II melanoma is localized to the skin, while stage III melanoma denotes regional metastasis, which is detected by clinical exam or by sentinel lymph node biopsy. Lymphoscintigraphy and sentinel lymph node biopsy is performed at the time of wide-local excision and offers prognostic value to patients with primary melanoma thicker than 1.0 mm. This is supported by multiple studies and recently reaffirmed in the final analysis of the Multicenter Selective Lymphadenectomy Trial-1 (MSLT-1). Generally, sentinel lymph node biopsy is not recommended for primary melanomas less than 0.75 mm, and there is no general consensus for melanomas between 0.76 and 1.0 mm.
b. Imaging. Routine imaging is not recommended in stage I or II disease unless used to evaluate specific signs and symptoms. The exception is ultrasonography of a nodal basin for an indeterminate lymph node clinical exam, which can help guide decisions for fine-needle aspiration (FNA) or sentinel biopsy. For stage III disease as determined by sentinel biopsy, clinically positive nodes, or in-transit metastases, baseline contrast-enhanced CT exam is recommended, with or without positron emission tomography with computed tomography (PET-CT) or MRI, based on clinical context. For suspected stage IV disease, in addition to CT of the chest, abdomen, and pelvis, gadolinium-enhanced brain MRI is recommended in the initial staging because of its increased sensitivity for detecting small posterior fossa lesions (<1 cm) compared to head CT. PET-CT is also appropriate for initial staging.
c. FNA. Suspected regional metastatic disease by clinical exam or imaging should be evaluated histologically by FNA. In the appropriate context, this can be done for suspected stage IV disease except when archival tissue is not available for genetic testing. In this instance, biopsy is preferred over FNA.
d. Lactate dehydrogenase. Elevated serum level of LDH is an independent predictor of poor outcome in stage IV disease and defines the designation of M1c disease. The two-year survival for normal versus elevated LDH at time of staging is 40% versus 18%, respectively, for stage IV (J Clin Oncol 2009;27:6199). For this reason, LDH levels should be evaluated in the initial staging workup of patients with stage IV disease. Monitoring LDH levels in patients with loco-regional disease is not recommended.
C. Treatment of localized disease
1. Wide local excision. In stage 0, I, and II disease, wide local excision of the primary lesion with appropriate clinical margins provides the greatest chance of local control. Margins of 0.5 to 1.0 cm are recommended for melanoma in situ. A margin of 1.0 cm is adequate for primary melanomas with a Breslow thickness of 1 mm or less, while melanomas between 1.01 and 2.0 mm thickness require a 1 to 2 cm margin. Any melanoma with a Breslow thickness of greater than 2 mm requires a 2.0 cm clinical margin. More aggressive margins than those recommended have not been demonstrated to improve survival. In the case of stage III disease with clinically evident lymph nodes, the same margins apply for optimal local control, while stage III in-transit disease should be completely excised with clear margins if possible.
2. Nonsurgical therapy. Although surgical excision is standard of care for in situ melanoma, topical imiquimod may be considered particularly for melanoma in situ or in cases of lentigo maligna when surgical cure is not achievable.
D. Treatment of advanced melanoma
1. Adjuvant therapy. There is no proven benefit for any adjuvant therapy given to patients with low-risk (stage IA) or intermediate-risk (stage IB, IIA) melanoma. Interferon α 2b (Intron) was granted U.S. Food and Drug Administration (FDA) approval in 1995 for administration to patients with surgically resected stage IIB, IIC, and III (high-risk) melanoma. The approved schedule is 1 year of adjuvant treatment given intravenously for the initial 4 weeks at 20 MU/m2 each day (Monday to Friday), followed by subcutaneous administration at 10 MU/m2 for 48 weeks given three days per week. We routinely hydrate patients with 500 mL saline before each i.v. dose of interferon during weeks 1 to 4. Patients are premedicated with acetaminophen 650 mg orally. Three randomized controlled clinical trials have been performed using the FDA-approved schedule and the results of Eastern Cooperative Oncology Group (ECOG) 1684, ECOG 1690, and ECOG 1694 have been published. A recent update of the three trials (Clin Cancer Res 2004;10:1670) confirms the durable benefit with improved relapse-free survival (RFS) at a median follow-up of 12.6 months for patients given interferon when compared to the control group.
Pegylated-interferon α 2b (Sylatron) can be administered as adjuvant therapy to patients with microscopic or macroscopic lymph node involvement with melanoma that has been surgically resected. The greatest risk reductions were observed in patients with ulceration and stage IIb/III-N1. The efficacy of IFN/PEG-IFN is lower in stage III-N2 patients with ulceration and uniformly absent in patients without ulceration. The recommended dose is 6 µg/kg/week subcutaneously for 8 doses, followed by 3 µg/kg/week for up to 5 years (J Clin Oncol 2012;30:3810). There is no role for adjuvant cytotoxic chemotherapy or adjuvant high-dose interleukin 2 (IL-2) for treatment of surgically resected melanoma.
Ipilimumab as adjuvant therapy for high-risk resected stage III patients has been evaluated in two large randomized controlled clinical trials (ECOG 1609 and EORTC 18071). Final RFS data released at ASCO 2014 for EORTC 18071 demonstrated improved median RFS with adjuvant ipilumumab (17.1 months for placebo to 26.1 for ipilimumab (HR 0.75 [CI 0.64 to 0.90], p = 0.0013)). Moreover, the 3-year RFS rate of 46.5% in the ipilimumab arm is significantly improved compared with 34.8% in the placebo arm. Data on overall survival (OS) are still not available.
Targeted agents such as serine/threonine-protein kinase B-Raf (BRAF) inhibitors as single agents or in combination with MEK inhibitors are also currently being evaluated as adjuvant therapy in high-risk surgically resected stage III cutaneous BRAF V600E/K-mutated melanoma. The randomized, placebo-controlled phase III studies are ongoing and no data are currently available.
a. Interferon side effects and toxicities. The side effects and toxicities of interferon are significant and all patients should be counseled before the initiation of therapy (Oncologist 2005;10:739). Virtually all patients experience fatigue and many experience fevers, chills, and diaphoresis (70% patients, grade 3 to 4). Myelosuppression, hepatotoxicity, and neurologic symptoms are frequent. Depression can be severe and precautions should be taken with appropriate referral to mental health professionals. The use of selective serotonin reuptake inhibitors (SSRI) is recommended in suitable patients (N Engl J Med
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