What are the updated guidelines of care for the management of primary cutaneous melanoma?

By Kathryn Schwarzenberger, MD, December 3, 2018

In this month’s Acta Eruditorum column, Physician Editor Kathryn Schwarzenberger, MD, talks with Susan M. Swetter, MD, and Hensin Tsao, MD, PhD, about their recent Journal of the American Academy of Dermatology article, “Guidelines of care for the management of primary cutaneous melanoma.”

Dr. Schwarzenberger: I would like to thank you, your colleagues, and the involved AAD staff members for the enormous amount of time and effort it must have taken to update the AAD guidelines of care for the management of primary cutaneous melanoma. I enjoyed reading your manuscript — all 111 pages of it! There have been some significant changes in the management of primary cutaneous melanoma since the last set of guidelines was published in 2011. Can you briefly list the key topics that were updated since the last guideline?

Drs. Swetter and Tsao: Beyond the topics of appropriate melanoma biopsy techniques, pathology reporting, surgery, sentinel lymph node biopsy for pathological staging, and work-up/follow-up for patients with cutaneous disease, several new topics were addressed in the 2018 melanoma guideline. These included ancillary molecular techniques that may aid in diagnosis and prognosis; the use of Mohs and other types of staged excision for melanoma in situ, lentigo maligna type; alternative therapies for this subtype; the impact of American Joint Committee (AJCC) on Cancer 8th edition for melanoma staging on SLNB recommendations; and key issues related to melanoma and pregnancy, genetic testing for hereditary risk, and the management of dermatologic toxicities from newer, more effective melanoma drugs. The field is evolving rapidly along technological and therapeutic lines, and these guidelines reflect the rapid changes.

Dr. Schwarzenberger: The AJCC published their 8th edition this year. What changes were made regarding cutaneous melanoma, and how will these impact us?

Drs. Swetter and Tsao: Primary tumor thickness — as measured by the Breslow depth, histologic ulceration, and dermal mitotic rate remains the key histologic prognostic factors for cutaneous melanoma, although mitotic rate — has been removed from staging of melanoma less than or equal to 1 mm depth. It is worth noting that removal of mitotic rate from the 8th edition does not imply that mitotic rate itself is no longer predictive; it merely reflects the challenges of creating a threshold for an otherwise continuous variable. The main change for cutaneous melanoma is that the Breslow thickness measurement is now recorded to the nearest 0.1 mm, rather than the nearest 0.01 mm. This means that a melanoma measured as 0.75-0.84 mm thickness would be rounded to 0.8 mm, and one measuring 0.95-1.04 mm would be rounded to 1 mm. Pathologic staging with sentinel lymph node biopsy is generally not indicated for the new T1a designation of less than 0.8 mm without ulceration but may be considered for T1b melanoma (<0.8 mm with ulceration or 0.8-1.0 mm with or without ulceration), although sentinel lymph node positivity in this subgroup is still relatively low. The presence of microsatellites or those that are palpable (i.e., macrosatellites) connotes intralymphatic metastasis and is a key clinicopathologic factor, upstaging a melanoma to stage III at the outset.

Dr. Schwarzenberger: Is there anything new in the guidelines regarding how to biopsy, and subsequently excise, cutaneous melanoma? What do the guidelines recommend when I excise a thin melanoma with an appropriate surgical margin, but the dermatopathologist notes that the histologic margin is only a few millimeters? Do I need to re-excise it?

Drs. Swetter and Tsao: The guideline addresses the most appropriate types of excisional, or complete, biopsy and recommends that biopsy be intended to completely remove the visible tumor with a narrow 1-3 mm margin of surrounding tissue, whenever possible. It is important that dermatologists and other practitioners understand that excisional/complete biopsy can be done with the elliptical/fusiform, saucerization (deep shave), or punch techniques and that partial biopsy can impede histologic microstaging of the melanoma by the pathologist. Further aspects of appropriate biopsy include avoidance of a wide surgical margin at the outset, which could affect the ability to perform lymphatic mapping and sentinel lymph node identification in appropriate patients, as well as the need for correct orientation of elliptical/fusiform biopsies axially, along underlying lymphatics, to optimize pathological staging with SLNB. When a patient’s melanoma meets criteria for SLNB on a partial biopsy, further excisional biopsy is generally not indicated and may add to patient morbidity and cost of procedures.

Surgery remains the cornerstone of cutaneous melanoma treatment. Regarding pathologist assessment of surgical margins, the general recommendation is to report whether the melanoma is present or absent at the peripheral and deep margins and NOT measure the distance of the tumor from these margins. All prospective randomized trials for surgical margins of invasive melanoma were conducted using clinical margins measured by the surgeon, and not histologic margins measured by the pathologist. Evidence is lacking that histologic margin assessment is necessary, or that its histologic margins should equal clinical/surgical margins. The only exception may be when the invasive or in situ melanoma is very close to the margin, as this may provide guidance as to whether further surgery or adjuvant topical therapy is indicated. In general, though, further excision is not needed when the histologic margins are clear and standard surgical margins are performed at the outset.

Dr. Schwarzenberger: What do the guidelines say about the use of diagnostic molecular techniques, such as gene expression profiling, in the diagnosis and management of primary cutaneous melanoma?

Drs. Swetter and Tsao: The guidelines recognize the potential value of both diagnostic and prognostic molecular techniques in cutaneous melanoma. However, there is insufficient evidence at present to recommend routine molecular profiling assessment for baseline prognostication or that molecular classification should be used to alter patient management (including SLNB eligibility, surveillance intensity, and/or therapeutic choice) outside of current guidelines issued by the National Comprehensive Cancer Network (NCCN) and the AAD. It remains unclear whether gene expression profiling is simply a surrogate for a combination of known pathologic risk factors, and thus further study is needed. There remains great interest in the use of these techniques, which may one day enhance pathology diagnosis of challenging melanocytic lesions and help to target the most appropriate treatment for patients with low- versus high-risk of metastasis.

Dr. Schwarzenberger: Is there anything new regarding Mohs surgery or other forms of staged excision and alternatives to surgery for certain melanoma subtypes?

Drs. Swetter and Tsao: Mohs micrographic surgery and other staged excision techniques (employing routine histologic assessment of paraffin-embedded tissue) can provide exhaustive peripheral margin histologic assessment for melanoma in situ, lentigo maligna type, as well as tissue sparing in anatomically constrained sites, such as the face, ears, and scalp. The value of Mohs surgery for melanoma in situ, superficial spreading type (which is generally well-defined clinically and tends to lack subclinical extension), and for melanomas on head/neck and acral sites remains uncertain.

Although most randomized trials for surgical margins excluded cases on the head and neck, removal of less than 1 cm margins (either by wide excision or Mohs surgery for primary invasive melanomas) at these anatomically constrained sites is generally not recommended until further studies are available. It is important to remember that the propensity for microsatellites, macrosatellites, and in-transit metastasis in thicker invasive tumors suggests that melanoma itself is prone to local lymphatic spread, which is much less common in BCCs and SCCs, and can thus thwart tight margin control with Mohs. Nonsurgical approaches (imiquimod and traditional forms of radiation therapy) should only be considered if surgery is impractical or contraindicated, and only for melanoma in situ, lentigo maligna type, as cure rates are lower.

Dr. Schwarzenberger: Anything new on sentinel lymph node biopsy?

Drs. Swetter and Tsao: Pathological staging with sentinel lymph node biopsy remains the standard means to determine whether regional lymph nodes are microscopically involved, and a positive SLNB now allows a cutaneous melanoma patient to pursue potentially lifesaving systemic adjuvant therapy. Only in the last year have effective adjuvant therapies been FDA-approved, including anti-PD-1 monotherapy and BRAF/MEK inhibitor regimens, which have been associated with improved disease-free and overall survival. Given the proven benefit of these drugs in the adjuvant setting (i.e., after surgery is performed for cutaneous and regional nodal melanoma), it is imperative that accurate pathological staging of cutaneous melanoma be pursued, when appropriate. The other key development is the lack of improved survival demonstrated in two randomized controlled trials with performance of completion lymph node dissection (CLND). This emphasizes the need for increased use (and adoption by U.S. radiologists) of regional lymph node ultrasound surveillance when CLND is not performed.

Dr. Schwarzenberger: Unfortunately, as we diagnose more melanomas in young women, we will all potentially have to address the issue of melanoma in pregnancy. How can the guidelines help us in this situation?

Drs. Swetter and Tsao: The role of pregnancy in both melanoma incidence and outcome is now better understood; evidence is lacking that pregnancy increases the risk of developing cutaneous melanoma or alters the prognosis. However, work up and treatment for a woman diagnosed during pregnancy must take the safety of the fetus into consideration and should involve a multidisciplinary approach to care. In women with a history of cutaneous melanoma, a prolonged waiting period prior to subsequent pregnancy is not recommended. Factors that impact disease recurrence, including melanoma stage, as well as age and fertility of the mother, should determine whether a woman with a history of CM should delay becoming pregnant and for how long.

As for melanocytic nevi in pregnant women, management should be the same as for non-pregnant patients. Any changing nevus during pregnancy should be evaluated and biopsied if clinically and/or dermoscopically concerning. It is also important to note that oral contraceptives and hormone-containing contraceptive devices/implants, post-menopausal hormone replacement therapy, or hormones associated with assisted reproductive technology may be used in women who have had melanoma.

Dr. Schwarzenberger: The spectrum of cutaneous melanoma tumor syndromes has grown significantly since the last guidelines were published, which may reflect in part the relative ease/lower cost now of doing multi-gene testing. Do the guidelines offer recommendations as to who should be referred for genetic screening?

Drs. Swetter and Tsao: The key with genetic testing for hereditary melanoma risk is to identify patients with risk factors and refer them for cancer risk counseling by a qualified genetic counselor. Risk factors do not include having increased moles alone, including atypical/dysplastic nevi, but rather are based on personal and family history of melanoma and other cancers. For the most common germline mutation, risk is associated with having a family history of invasive cutaneous melanoma or pancreatic cancer (three or more affected members on one side of the family) and/or multiple primary invasive CM (three or more), including one early onset tumor (<45 years). Risk factors for rarer mutations include having at least one melanocytic BAP1-mutated atypical intradermal tumor (MBAIT) and a family history of mesothelioma, meningioma, and/or uveal melanoma or having two or more MBAITs. In the past, familial melanoma largely focused on the number of primary melanomas in the kindred. Now, with the recognition of “melanoma tumor syndromes,” the various patterns of melanoma and internal malignancies have been characterized. In other words, it is probably insufficient these days to ask, “Are there any other family members with melanoma?” We should be asking, “Are there any other unusual cancers in the family, such as pancreatic cancer, eye melanoma, kidney cancer, mesothelioma, and meningioma?” The process of ascertaining a pedigree does require training, and that is why the guidelines recommend referral to a genetic cancer risk counselor.

Dr. Schwarzenberger: Do you anticipate anything in these new guidelines will significantly alter the way dermatologists in the U.S. manage cutaneous melanoma and, if so, in what way?

Drs. Swetter and Tsao: While early detection of thinner tumors remains critical, we are in a new era of melanoma management, in which patients with advanced disease are living longer, and in many cases, being cured with the use of newer immunotherapies and targeted agents. As options to treat metastatic disease have greatly improved, including in the adjuvant setting, accurate staging is critical and currently incorporates sentinel lymph node biopsy for pathological staging of the regional lymph nodes in appropriate patients. As the use of radiation therapy has declined in patients with more advanced melanoma, the hope is that less surgery will be performed in the future and will be replaced by better drugs that cure disease. Further investigation of molecular techniques may allow for improved identification of those patients at highest risk of disease relapse and death, so that appropriate interventions can be made. In the past, dermatologists had largely one task after surgery, which was to provide prognostic information and follow up since curative therapies were nonexistent. While these are still important, the old survival numbers no longer hold since long-term remission with contemporary drugs have dramatically changed the outcomes landscape. It is becoming more relevant for dermatologists today to help guide our high-risk cutaneous melanoma patients to adjuvant treatment when indicated, work with other specialists to explain the variety of available treatments, and to manage the skin toxicities which can result from these powerful agents. 

Drs. Swetter and Tsao are co-chairs of the Academy’s melanoma clinical guidelines workgroup. Dr. Swetter serves as professor of dermatology at Palo Alto Veterans Affairs Health Care System and the Stanford University Medical Center. Dr. Tsao is the clinical director of the Massachusetts General Melanoma & Pigmented Lesion Center, director of the Melanoma Genetics Program, and a member of the Massachusetts General Hospital Cancer Center’s Center for Melanoma. Their article appeared in the Journal of the American Academy of Dermatology, doi: 10.1016/j.jaad.2018.08.055.

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