Radiation port cutaneous metastases: a further example of immunocompromised district.

Sir,

We read with great interest the report recently published in the Indian Journal of Dermatology by Hoyt and Cohen,[1] which describes two patients with internal malignancies who developed cutaneous metastases within their radiation ports following radiotherapy (RT).[1] In both cases, cutaneous metastases, strictly localized on the irradiated zone, appeared some months after the last cycle of RT, suggesting induction by ionizing radiation (IR).[1]

Radiation dermatitis has for a long time been known to be the most fertile ground for the subsequent development of primary skin cancers on the irradiated area.[2] Less commonly, treatment with IR may be associated with the appearance of metastasis from internal malignancy to the irradiated skin.[1] The mutagenic effect of IR can well account for the oncogenic potential of irradiated areas, but other factors can concur in this direction. In fact, as Hoyt and Cohen themselves noticed,[1] an irradiated area is prone to the development not only of tumors, but also of opportunistic infections and immune-mediated skin disorders, depicting a typical example of ‘immunocompromised cutaneous district’ (ICD).[3] Whatever the cause,[23456] the concept of ICD refers to a skin site of locoregional immune dysregulation due to an obstacle to the normal trafficking of immunocompetent cells through lymphatic channels, and/or an interference with the signals that the neuropeptides and neurotransmitters, related to peripheral nerves, send to cell membrane receptors of immunocompetent cells. Depending on which of the neurotransmitters and immune cells are involved, this destabilization could be either defective, thus predisposing to infections and tumors or excessive, thus favoring the occurrence of some immune disorders or dysimmune reactions at the sites ‘marked’ by prior clinical events or injury.[23456]

In radiation dermatitis, the lymph network is profoundly disrupted with abnormal dilation of some vessels [Figure 1] and obstruction of others, which results in an obvious obstacle to the trafficking of immune cells. Moreover, peripheral nerve fibers are throttled by dermal fibrosis. Therefore, the dysregulation of the immune control occurring in irradiated areas may be explained by the impaired lymph flow on the one hand, and the fibrotic throttling or reduction of peptidergic nerve fibers on the other hand. Both changes locally alter the interplay between immune cells conveyed by lymph vessels and neuromediators running along peripheral nerve fibers.[2] Moreover, as demonstrated by Baroni et al.,[7] some components of skin innate immunity (cytokines, neuropeptides, and receptors) are altered in lymphedematous areas.

Figure 1

Radiation dermatitis. Lymphangectasias in the diffusely fibrotic dermis (H and E), ×100

Although Hoyt and Cohen correctly refer to the concept of ICD,[1] they do not fully clarify the pathomechanism involved in the spreading of malignant cells to the previously irradiated skin. A postulated mechanism is the ‘trapping’ effect of fibrin in the vessels of the irradiated sites, which could partly explain the local growth of entrapped neoplastic cells.

Interestingly, cutaneous metastases can also occur on recent surgery scars. While this can obviously be related to local cell diffusion from the primary tumor in locoregional metastases; for distant scars metastases, a role of adhesion molecules, metalloproteinases, or cytokines related to angiogenesis and tissue repair can be considered.[8]

We thank the authors for giving us the opportunity to discuss such a complex and interesting topic. We think that the novel concept of ICD[3] will certainly shed new light on the mechanisms regulating the development of radiation port (or scar) cutaneous metastases.