Radiotherapy induced keobernisation of vitiligo

I write with reference to the article titled ‘Koebnerization and generalized spread of vitiligo following radiotherapy’.[1] by Sanghavi SA et al published in the Indian Dermatol Online J 2013. I wish to share points about spread of vitiligo following radiotherapy.’

Koebner phenomenon, also known as isomorphic phenomenon (iso=same, morphic = form) was first described by Heinrich Koebner in 1878. It refers to development of isomorphic/new lesions of the disease at sites of local trauma in traumatized but otherwise normal skin(uninvolved skin). The response should be reproducible and not limited to one type of trauma.[2] It is seen in psoriasis, vitiligo, lichen planus etc. Many forms of mechanical/physical/chemical/allergic trauma, incision and laceration, skin tests, burns, freezing, UV light and ionizing radiation have been implicated.[2,3,4] Koebnerization occurs commonly in vitiligo, developing on sites of mild friction, cuts burns and abrasion.[5]

Irradiation is associated with early and late toxicity to the skin and subcutaneous tissues, common being fibrosis and/or necrosis.[6] Tissues with a slow rate of cell division, such as subcutaneous fat, fibrous tissue and small blood vessels, show radiation effects months or years after treatment, which is the late reaction. The irradiated skin may show pallor and a degree of atrophy[7] (differentiating it from vitiligo which is depigmented and does not show atrophy). Patients with collagen vascular diseases have an increased radiation sensitivity of normal tissues to radiation damage, but there is no evidence for increased severity of acute or chronic reactions in patients with vitiligo.[8]

Depigmentation is rarely associated with irradiation, being documented in few vitiligo patients, few patients with breast carcinoma and a single case of metastatic melanoma and nasopharngeal carcinoma respectively.[8,9,10,11] Vitiligo following radiotherapy is reported in patients with a history of vitiligo, being considered as Koebner's phenomenon.[8] Depigmentation develops in the area irradiated by oblique or tangential portals with sparing with a direct incident portal. Tangential portals cause increased electron build-up and consequently increase the dose delivered to the skin.[6]

The suggested mechanism for hypopigmentation is radiation- induced apoptosis of susceptible melanocytes. Loss of melanocytes in the irradiated skin has been demonstrated by Pajonk et al and correlated with dose-dependent decrease in red/green and yellow/blue saturation and overall increase in brightness on colorimetry. Free radical-mediated damage, induced by radiotherapy, may be the initial pathogenic event in melanocyte degeneration in the irradiated skin. Vitiligo is caused by melanocyte depletion, and there is an increased radiosensitivity of melanocyte in vitiligo.[8] The early cell death of melanocytes in vitiligo is related to their increased sensitivity to oxidative stress caused by irradiation, which may arise from complex processes of abnormal synthesis and processing of tyrosinase related protein-1 and its interaction with calnexin. Thus, oxidative stress can occur in irradiated human cells and may play a direct role in radiation induced apoptosis.[6,8]

Keratinocyte apoptosis can cause lower expression of keratinocyte derived factors, including stem cell factors and basic fibroblast growth factor. These factors might be responsible for passive melanocyte death, leading to their detachment and transepidermal elimination, and may explain the Koebner's phenomenon in the vitiligo patients. Auto cytotoxic mechanism may occur through inhibition of thioredoxin reductase by high extracellular calcium levels observed in keratinocytes of vitiligo patients. High levels of thioredoxin and thioredoxin reductases have been shown to protect from ionizing radiation induced cell death. Thus, inhibition of thioredoxin reductase in vitiligo might account for the increased radiosensitivity of melanocytes in this disorder.[8]

In patients with preexisting vitiligo, the risks and benefits of radiation therapy should be carefully weighed in order to prevent undesired cosmetic results. Preserving the skin by using megavoltage beams and low dose per fraction might improve the cosmetic results of radiation therapy in patients with a history of vitiligo.[8]

Thus, prior to therapy, the possibility of development of vitiligo should be taken into account for patients who are candidates for radiotherapy, even if they have no history of vitiligo.[11]