Does he or doesn’t he? Only his oncologist knows for sure!

By Warren R. Heymann, MD
July 17, 2017

I’m racking my brain wondering if I have ever seen a case of idiopathic facial aseptic granuloma (IFAG) — I know that I never made the diagnosis because I had never heard the term until I read the first reference. I surmise that I have seen and misdiagnosed it as an inflamed epidermoid cyst or acne. I am delighted to be able to place a name on such a lesion that may present so dramatically.
 
Satta et al reported the case of a 1 year-old boy who developed multiple asymptomatic firm reddish nodules of the frontal, zygomatic, palpebral area, and chin. There was some drainage, but all cultures were negative. A biopsy demonstrated a granulomatous infiltrate with giant cells. The lesions were present for 4 months and were unresponsive to topical and systemic antibiotics. Over the following year “the lesions gradually and spontaneously healed without sequelae.” (1)
Years ago, when my hair was rapidly going gray, my children suggested that I dye it. I wasn’t opposed to having a more youthful appearance; my primary reason for not embarking on this path was simple — laziness. I did not want to start a process that required meticulous maintenance. I have enough to do already. I surmised that perhaps in my lifetime the mysteries of reversing deteriorating follicular melanogenesis would be unraveled and there would be a better way for me to return to my native brunet state. Intriguing developments suggest that we are on the cusp of understanding this process, based on observations from oncologic patients undergoing treatments with PD-1 inhibitors. (Of course we want the drug’s benefit without associated malignancies!)
 
Rivera et al assessed 14 patients (13 men and 1 woman; mean age, 64.9 years) receiving anti–PD-1 or anti–PD-L1 therapy (11 nivolumab, 1 pembrolizumab, 2 atezolizumab) for non-small-cell lung cancer (10 with adenocarcinoma and 4 with squamous cell carcinoma) presenting with hair repigmentation during follow-up. Hair repigmentation appeared as a diffuse darkening of the hair, to the patients’ original color, in 13 of 14 patients, or in black patches between white hairs in one patient. Thirteen of 14 patients presented a good clinical response to the treatment, with at least stable disease, and only 1 had to stop the therapy after only 4 cycles of treatment owing to a life-threatening progression of the disease. The authors concluded that hair repigmentation could be a good response marker in patients receiving anti-PD1/anti–PD-L1 therapy for lung cancer. (1)
 
The pathogenesis of graying hair is due to a marked reduction in melanogenically active melanocytes in the hair bulb of gray anagen hair follicles. Defective melanosomal transfer to the cortical keratinocytes or melanin incontinence due to melanocyte degeneration is also believed to contribute to graying. Ultrastructurally, remaining melanocytes contain fewer and smaller melanosomes. Additionally, there is autophagolysosomal degradation of melanosomes within the melanocyte itself and is usually followed by the degeneration of the melanocyte. (2) Canities is a frequent accompaniment of vitiligo, and repigmentation characteristically occurs in the perifollicular region. In their excellent review of repigmentation in vitiligo, Birlea et al note that in the epidermal basal layer of vitiligo skin, mature melanocytes have been killed by cytotoxic T cells specific for melanocyte antigens. Repigmentation consists of mobilization of melanocyte precursors in the hair follicle bulge and infundibulum to proliferate, migrate, and differentiate into mature melanocytes, moving from the hair follicle bulge to the interfollicular epidermis. The most potent stimulus for repigmentation is the UV light, although steroids, calcineurin inhibitors, vitamin D analogues, statins, afamelanotide, and JAK inhibitors may result in repigmentation. JAK inhibitors have an anti-interferon gamma effect and may also activate follicular melanocyte stem cells (3).

JAK inhibitors are the current darlings of the dermatologic therapeutic forefront — aside from their use in alopecia areata and psoriasis, they have been reported to be effective topically (1.5% ruxolitinib cream bid) or orally (tofacitinib 5 mg bid) for vitiligo, although their effect may be enhanced by ultraviolet light. (4)

In a previous post (Hair Repigmentation in Frontal Fibrosing Alopecia, April 25, 2016) I described my patient, an 81 year-old woman with FFA whose hair color was returning to baseline. She was the second reported case of this phenomenon. I stated: “Somehow, somewhere, someone will figure out the immunologic dynamics of cases like these that will make hair dye obsolete.”

Pembrolizumab has been associated with a variety of dermatologic adverse events, including morbilliform eruptions, lichenoid reactions, eczema, keratoacanthomas, bullous pemphigoid, and vitiligo. (5,6). The relationship between JAK inhibition and PD-1 requires further study as JAK mutations may contribute to acquired resistance of PD-1/PDL-1 blockade. (7)

Hair pigmentation could theoretically occur by either: 1) activation of pluripotential follicular stem cells becoming melanocytes; 2) reactivation or stimulation of dormant melanocytes; or 3) decreasing or eliminating inhibitory factors (cytokines) that block melanocyte function or migration. Based on current literature, the following hypothesis is proposed:

Whether by drugs such as a PD-1 inhibitors (or others), or diseases that cause lichenoid inflammation (such as FFA), an anti-interferon-gamma process (in concert with other cytokines) is allowing one, or a combination, of the previously mentioned mechanisms to repigment hair. Perhaps it will not be long before a compounded product (maybe with minoxidil thrown in for senescent alopecia!) will enable our manes to return to their color of youth. As of now, though, there is a major advantage to having gray hair. When I tell my patients that I do not know what their problem is, they accept that. When I was just as unknowledgeable when my hair was brown, they assumed my ignorance was a reflection of inexperience.

1. Rivera N, et al. Hair repigmentation during immunotherapy treatment with an anti-programmed cell death 1 and anti-programmed cell death ligand 1 agent for lung cancer. JAMA Dermatol 2017; Jul 12 [Epub ahead of print].
2. Pandhi D, Khanna D. Premature graying of hair. Indian J Dermatol Venereol Leprol 2013; 79: 641-53.
3. Birlea SA, et al. Repigmentation through melanocyte regeneration in vitiligo. Dermatol Clin 2017; 35: 205-18.
4. Joshipura D, et al. Importance of light in the treatment of vitiligo with JAK inhibitors. J Dermatolog Treat 2017; Jun 29 [Epub ahead of print].
5. Freitas-Martinez A, et al. Eruptive keratoacanthomas associated with pembrolizumab therapy. JAMA Dermatol 2017; 153: 694-7.
6. Jour G, et al. Autoimmune dermatologic toxicities from immune checkpoint blockade with anti-PD-1 antibody therapy: A report on bullous skin eruptions. J Cutan Pathol 2016; 43: 688-96.
7. Wang Q, Wu X. Primary and acquired resistance to PD-1/PD-L1 blockade in cancer treatment. Int Immunopharmacol 2017; 46: 201-9.

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