EXPERT ANALYSIS from PDA 2015

PARK CITY, UTAH (FRONTLINE MEDICAL NEWS) – Dr. Glen M. Bowen has been working to improve the surgical treatment of lentigo maligna ever since he joined the Huntsman Cancer Institute at the University of Utah 16 years ago. A retrospective review from Memorial Sloan-Kettering Cancer Center found that on average, 7.1-mm margins are required to remove lentigo maligna (LM) ( J. Am. Acad. Dermatol. 2008;58[1]:142-8 ).

“If you have an LM with a 10-mm diameter to begin with, 7.1-mm margins give you a final surgical diameter of 24.2 mm,” Dr. Bowen said at the annual meeting of the Pacific Dermatologic Association. “These are very morbid surgeries in cosmetically sensitive areas for a relatively low-risk tumor.”

The risk of LM progressing to an invasive melanoma is not known, but is estimated to range between 5% and 33%. Of 2,016 patients treated for LM at the Huntsman Cancer Institute, 522 have been treated with neo-adjuvant topical imiquimod 5% cream followed by a conservative staged excision with 2-mm margins with a recurrence rate of 2.3% during median follow-up of 5 years. Of their recurrences, about 20% recurred with invasion. All recurrences to date have been less than 1 mm in depth (stage IA), which has an estimated mortality risk of 5% at 5 years. “A 5% mortality rate of the 20% that recur with invasion of the 2.3% that recur after surgery yields a mortality risk of 0.023%,” Dr. Bowen said. “Due to the very low risk of actually dying from a recurrent LM, very large and morbid surgical defects strike me as a punishment that doesn’t fit the crime in terms of the cost-benefit ratio.”

He and his associates at the Huntsman Cancer Institute have observed some deaths in patients who presented with LM melanoma (invasive melanoma) but have not observed a single death in patients who presented with LM in situ that subsequently recurred. For these reasons, Dr. Bowen favors pretreating LM with imiquimod 5% cream followed by a conservative staged excision, a process that substantially decreases the size of the surgical defects.

His current treatment protocol involves a five-step process that begins with removing all of the visible lentigo maligna to rule out invasion, since 16% of LMs referred to him have harbored invasion when removed and are upgraded from stage 0 to IA. “I am not going to use a topical cream on an invasive melanoma,” he said. “After an excisional biopsy with minimal margins, I usually close the defect with a purse-string suture because it avoids removing standing cones and consequently enlarging the treatment area.”

Second, he traces a template of the LM border on transparent plastic and places a tiny tattoo in the center of the biopsy site to enable pinpoint placement of the template at the time of surgery.

Third, he treats the site with imiquimod 5% cream Monday through Friday for 2-3 months and sees the patient monthly for dosage adjustments when needed. The fourth step involves enabling the site to recover for 2-6 months to allow for resolution of the inflammatory infiltrate. The final step involves re-excising around the original template with 2-mm margins for confirmation with the use of a negative control taken from an equally sun-exposed site taken some distance away from the LM. “Caucasians will have atypical junctional melanocytic hyperplasia (AJMH), which must be subtracted out as background,” he said. “Otherwise, if you hold a non–sun-exposed site as your standard for a negative margin, you will never stop cutting.”

Dr. Bowen likes to use frozen radial sections with routine staining with H and E and immunostaining with MART-1 (Melan-A) and SOX-10. Processing takes 2 hours, he continued, “so I put in relaxing sutures, which will stretch out nicely over 2 hours so I can usually close the defects primarily.”

In Dr. Bowen’s opinion, topical imiquimod as monotherapy for LM is not safe, since about 30% of patients treated with imiquimod will still harbor residual LM. “In our dataset, about 70% have no residual LM, 20% have residual LM in the center but negative perimeter margins, and 10% have LM touching a perimeter margin and require a second stage,” he said. “Taken together, 90% of patients pretreated with imiquimod will be cleared in one stage of surgery with 2 mm margins.”

Making the distinction between LM and AJMH common to chronically sun-damaged skin is no easy task. Dr. Bowen cited a concordance study between dermatopathologists interpreting staged excisional margins on permanent sections for LM where the concordance was only moderate at best. In this study, the use of a negative control improved the concordance rate on “difficult” cases from 46% to 76%; P = .001 ( Arch Dermatol. 2003 May;139(5):595-604 ). “What we really need is a molecular marker that will tell us if a melanocyte is malignant or not,” he said. “All we have now are immunostains that tell you if it’s melanocyte but nothing more.” He went on to say that in multivariate analysis in two studies of the histologic features of LM, the only feature that consistently predicted the difference between LM and AJMH was the melanocyte density and its ratio to the negative control ( Dermatol Surg. 2011;37(5):657-63 and J. Plast. Reconstr. Aesthet. Surg. 2014;67(10):1322-32 ). “The MART-1 immunostain is extremely sensitive, but it makes the slide somewhat muddy, so it’s hard to do an accurate cell count,” he said. “For that reason, we also use a SOX-10 immunostain which is very specific but not as sensitive. I believe that the truth lies somewhere in between those two immunostains in light of a positive control from our lab and a negative control from the patient.”

He concluded that the neoadjuvant use of imiquimod followed by a conservative staged excision “allows me to clear 90% of LM with a 2 mm margin with a recurrence rate of 2.3% in patients with a mean follow-up of 5-years or greater.”

Dr. Bowen reported having no financial disclosures.

dbrunk@frontlinemedcom.com

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