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Could wart immunotherapy open a therapeutic window for congenital nevi at risk for melanoma?

DII small banner By Warren R. Heymann, MD
June 13, 2017

congenital melanocytic nevi
Dermatoscopic image of congenital melanocytic nevus. Arrows point to reticular network (left), perifollicular hypopigmentation (center), and globules contained within empty spaces in the network (“target globules,” right), features that are reportedly suggestive of congenital melanocytic nevi.
Credit: JAAD
Two of the most vexing problems pediatric dermatologists face is treating recalcitrant warts and managing large congenital nevi.

We are all familiar with the innumerable therapeutic options for warts, with none being optimal. Increasingly, intralesional immunotherapy, most typically with Candida antigen, has been utilized with reasonable success. Khozeimeh et al, evaluated sixty patients with verruca vulgaris and plantar warts that were randomly divided into two groups. One group received intralesional injection of Candida antigen repeated every 3 weeks until complete improvement of all warts or for a maximum of three sessions. The second group was treated by cryotherapy with liquid nitrogen for a maximum of ten sessions or until clearance of all lesions. Patients showed a significant therapeutic response to immunotherapy compared to cryotherapy (P = 0.023); 76.7% of patients were completely cured with immunotherapy, while only 56.7% responded to cryotherapy. Immunotherapy was well-tolerated except for the pain during injection that was the most common side effect. The authors concluded that intralesional immunotherapy is a more effective treatment of warts than cryotherapy with the added benefit of capably treating distant warts (1). (Personally, I have had some success with Candida injections for verrucae, but I don’t think my response rate is as high.)
Kollmann et al reported the case of a 7-year-old girl with no significant medical history with a single large wart on her left medial malleolus. At the initial visit, she was noted to have a congenital nevus of the right upper arm, measuring 3.5 x 1.5 cm. She was treated with 4 injections of Candida antigen. After her second injection the congenital nevus developed a surrounding area of depigmentation. Following the third visit, other nevi became halo nevi, with two lesions completely regressing. The authors hypothesize that the Candida injections activate both the innate and adaptive immune systems with a primarily Th1-mediated response, which would be anti-human papilloma virus and active against distant nevus cell and melanocytes. The authors conclude that “physicians should inform patients, especially those with a history of autoimmune diseases, that halo nevi and vitiligo are possible side effects of Candida immunotherapy.” (2)
Although I have no argument with that conclusion (other than the fact that it is based on a solitary case report), if you allow yourself to fantasize, can you imagine inducing regression of congenital nevi (or melanoma) by Candida immunotherapy?

Before getting carried away, spontaneous involution of congenital nevi has been reported, often in association with the halo phenomenon or vitiligo. The presumption is that this is due to cytotoxic T cells (3). Perhaps this was the case for the patient described by Kollmann et al, and the injection of Candida was just a coincidence — or not.

I highly recommend the article by Kinsler et al reviewing the latest data on the risk of melanoma in congenital melanocytic nevi. They note that the overall absolute risk of developing melanoma for all types of congenital nevi is low, although should melanoma occur in these lesions, it may be highly aggressive. When melanoma arises in children with multiple congenital melanocytic nevi, the primary in the CNS is at least as common as in the skin. CNS melanoma currently has a 100% mortality, but oral mitogen-activated kinase inhibition (trametinib) in NRAS-mutation mosaic patients may improve symptom control (3).

Admittedly, I have never seen (or was unaware of) regressed nevi in patients that I have treated with Candidal immunotherapy. Other than some local swelling and inflammation (which may be unpleasant, possibly causing a compartment syndrome) it is a benign treatment. Given the limited options for preventing melanoma in patients with giant congenital melanocytic nevi, perhaps it’s worth setting up a trial with Candidal antigen immunotherapy to determine if this has any value.

1. Khozeimeh F, et al. Intralesional immunotherapy compared to cryotherapy in the treatment of warts. Int J Dermatol 2017; 56: 474-8.
2. Kollmann E, et al. Regression of nevi after Candida injection for the treatment of verruca vulgaris. Pediatr Dermatol 2017; 34: 199-200.
3. Lee NR, et al. Spontaneous involution of congenital melanocytic nevus with halo phenomenon. Am J Dermatopathol 2015; 37: e137-9.
4. Kinsler VA, et al. Melanoma in congenital melanocytic nevi. Br J Dermatol 2017; Jan 12 [Epub ahead of print]

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