Radiodermatitis consists of a set of cutaneous manifestations secondary to exposure to ionizing radiation and linked to individual risk factors (Table 2), total dose received, and depth of penetration.6

The acute form develops within 90 days of therapy and the chronic form appears later.

Acute radiodermatitis

The acute form generally appears in the irradiated zone an average of 10 to 14 days after radiotherapy.6 Currently, the clinical manifestations are mild to moderate in their intensity, attributable to advances in modern devices such as linear accelerators and megavoltage units that assist in delineating the radiation field (conformal radiotherapy) and in appropriately fractioning the dose.

The severity of acute radiodermatitis is usually classified in 4 levels according to the fourth version of the unified criteria of the National Cancer Institute7 (Table 3). The initial stages are marked by desquamation and limited extension. The rash then becomes progressively more exudative, extends beyond skin folds, and finally causes cutaneous necrosis and ulceration.

Table 3.

Acute Radiodermatitis Severity Scale According to the National Cancer Institute (Version 4).

	Grade 1	Grade 2	Grade 3	Grade 4
Skin lesions	Faint erythema Dry scaling	Moderate–brisk erythema Moist desquamation	Intense erythema Pitting edema Moist desquamation	Ulceration Necrotic plaques
Epidermal necrosis	No	No	Superficial	Full thickness dermis
Location	Initially follicular	Mostly confined to skin folds	Not confined to skin folds	Not confined to skin folds
Other	Depigmentation, hair loss	Moderate edema	Hemorrhagic zones after trauma	Spontaneous bleeding
Examples

The synergy between chemotherapy and radiotherapy in treating malignant tumors sometimes increases toxic skin effects. New targeted therapy drugs, such as anti-epithelial growth factor agents (cetuximab, panitumumab) associated with radiation usually trigger high-grade acute radiodermatitis early because these drugs have radiosensitizing effects.8 A higher rate of late cutaneous fibrosis has also been described in association with their use.9

The immediate appearance of acute radiodermatitis is the result of structural changes that occur when ionizing radiation leads to the release of free radicals that damage DNA and alter the maturation and reproduction of basal stem cells in the epidermis.10 This process alters the barrier function of the epidermis, leading to greater transdermal loss of water and partial or total epidermal necrosis. A proinflammatory environment is also generated through local recruitment of white blood cells and sustained production of interleukin (IL) 1.11 Angiogenesis, fibrogenesis, and the formation of granulation tissue also change during the process.12,13 The loss of Langerhans cells combined with a proinflammatory environment and impairment of the epidermal barrier function can invite superinfections.14

Reduced mitotic activity of the germ cells of sebaceous glands, hair follicles, and the epidermis accounts for the dryness, hair loss and other manifestations associated with radiotherapy.

Histopathology reveals epidermal changes, including vacuolar degeneration of the basement membrane and necrotic keratinocytes as well as the presence of spongiosis that can lead to subepidermal blister formation.15 Perivascular inflammatory infiltrates, dilated blood vessels with thrombi, and dermal edema can also be observed.

Recent systematic reviews of means to prevent and treat acute radiodermatitis describe management strategies in detail and include the following recommendations1,16:

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  Wash the irradiated areas with a mild shampoo or soap to prevent superinfection.

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  Although deodorants containing aluminum salts or pads containing metals were formerly believed to increase radiotherapeutic toxicity and were therefore contraindicated, clinical trials have demonstrated that these products do not exacerbate the severity of radiodermatitis (evidence level IA).16,17

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  The use of topical corticosteroids, for their anti-inflammatory effect, is controversial. Medium to high potency corticosteroids are effective in treating already established radiodermatitis,18 but trials have been unable to demonstrate their efficacy in reducing the severity of radiodermatitis when used prophylactically. However, they do improve quality of life by reducing itching and burning.16

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  If a superinfection is suspected, a bacterial culture should be started, along with topical (silver sulfadiazine cream) or systemic (antibiotic) treatment.

Special precautions should be taken with gynecologic or anal canal tumors because they are associated with grade 3 or 4 severity and greater risk of superinfection.

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  Skin folds should be exposed to air because they are more often affected by radiodermatitis,6 Restrictive clothing, exposure to sunlight, and injury are to be avoided.

Aloe vera, trolamine salicylate creams, hyaluronic acid, and silver or sucralfate dressings have not proven useful for preventing or treating radiodermatitis.16

A lower grade of erythema was reportedly achieved in a single open-label trial of amifostine, used because of its cytoprotective role in radiotherapy and cisplatin chemotherapy.19 The trial enrolled 30 patients.

Chronic radiodermatitis

The chronic form of radiodermatitis appears months or years after irradiation. This condition must be distinguished from so-called late effects of radiotherapy, which are the result of a failure to previously cure high-grade acute radiodermatitis.

There are various stages of chronic radiodermatitis according to the classification of the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer,20 whose system is based on the extension and severity of cutaneous changes (Table 4).

Table 4.

Chronic Radiodermatitis Severity Scalea

	Grade 1	Grade 2	Grade 3	Grade 4
Skin	Slight atrophy Some hair loss Hyper- or Hypopigmentation	Patch atrophy Total hair loss Telangiectasia	Marked atrophy Gross telangiectasia	Ulceration
Subcutaneous cellular tissue	Slight induration (fibrosis) and partial loss of tissue	Moderate fibrosis (asymptomatic) Field contracture <10% linear reduction	Severe induration and loss of subcutaneous tissue Field contracture >10% linear reduction	Necrosis
Mucous membrane	Slight atrophy Slight dryness	Moderate atrophy Telangiectasia	Marked atrophy with associated intense dryness Thick telangiectasia	Ulceration

a

Source: Adapted from Toxicity Criteria of the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer, 1995.20

The condition presents with poikiloderma, hyper- or hypopigmented areas, atrophy, and telangiectasia (Fig. 1). Probably related to microvascular damage, telangiectasia is more common in grade 3 or higher, especially after a booster dose of radiation.21 Desquamation, hyperkeratosis, and xerosis are also common. Loss of nails, hair and skin adnexa may occur and sweating may be impaired in some parts of the body.

Figure 1.

Chronic radiodermatitis with marked skin atrophy and numerous telangiectases.

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Localized or generalized cutaneous fibrosis is another form of presentation. Retraction and associated impedence of movement may develop. Fibrosis is triggered by various factors, but the role of transforming growth factor (TGF) ß stands out. This factor activates fibroblasts, which synthesize and secrete procollagen and other components of the extracellular matrix.22

On histology, epidermal atrophy, endothelial hyperplasia, and sclerotic or thrombosed vessels can be observed. If cutaneous fibrosis develops, the dermis and subcutaneous tissue will be replaced by fibrous tissue and atypical fibroblasts.23

Pulsed laser therapy has been reported to be useful in treating persistent telangiectasia.24 Fibrosis is the most difficult cutaneous complication to treat. Pentoxifylline has been tried at a dose of 800mg/d on its own or in combination with vitaminE.25 This peripheral vasodilator also has antifibrotic properties related to a reduction in TGF-ß expression and the phenotypic normalization of altered fibroblasts. Studies in humans that clearly demonstrate the efficacy of this approach are scarce, however.16 There are anecdotal reports of attempts to use other therapeutic modalities, such as intramuscular injections of liposomal copper/zinc superoxide dismutase 3 weeks after onset of fibrosis26 and low-dose interferon-γ based on its inhibition of dermal fibroblasts.27

A rash confined to previously irradiated skin, recall phenomenon is triggered by certain drugs, mainly chemotherapy agents. A variable amount of time (from days to years) during which the skin appears healthy, without associated radiodermatitis, may pass before signs appear.28 A minimum of 7 days between radiotherapy and drug intake is required for a diagnosis of recall phenomenon, since certain clinical pictures that emerge before that time might be triggered by radiosensitizing substances. Cases of recall phenomenon have been described up to 7 years after radiotherapy.29 The median interval, however, is 39.5 days.28

The skin is affected in 2 out of every 3 patients, but recall has also presented as pneumonitis, mucositis, and esophagitis; the central nervous system and small intestine have also been affected.28

Drugs that trigger the recall phenomenon are usually chemotherapy agents, most often taxanes (paclitaxel, docetaxel) and anthracyclines (adriamycin, doxorubicin), which together account for half the described cases. Other implicated chemotherapeutic agents are bleomycin, actinomycin D, gemcitabine, 5-fluorouracil, methotrexate, and vinblastine. Medications that are not cytotoxic, such as antituberculosis drugs,30 tamoxifen,31 antibiotics,32 and simvastatin33 have also been blamed.

Clinical manifestations, which overlap those of acute radiodermatitis, involve an erythematous plaque that is more or less exudative and has well defined edges coinciding with the irradiated field (Fig. 2). Recall can be distinguished, however, by the fact that radiodermatitis or other lesions need not have developed previously in the irradiated field (Table 5). Depending on severity of the eruption, blisters, ulcers, hemorrhagic zones, or necrosis might develop. Signs and symptoms are more intense when the interval between the use of radiotherapy and the chemical trigger is shorter.28

Figure 2.

A, Recall Phenomenon in a patient irradiated for soft-tissue sarcoma. B, Map of the irradiated field.

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Table 5.

Differential Diagnosis of Eruptions in Patients Exposed to Radiation.

	Radiodermatitis	Recall Phenomenon	Erythema Multiforme	SJS/TEN/SJS–TEN
Extension	Irradiated field	Irradiated field	Irradiated field+dissemination	Irradiated field+dissemination
Rash type	Erythema/desquamation/ulceration	Erythema/desquamation/edema	Maculopapular	Maculopapular+mucositis
Latency period, after radiotherapy	2 wk	1 wk to months	10–20 d	10–20 d
Fever	Yes/no	No	Yes/no	Yes/no
Mechanism	Cytotoxicity	Possible hypersensitivity	Hypersensitivity	Hypersensitivity

Abbreviations: SJS, Stevens–Johnson syndrome; TEN, toxic epidermal necrolysis.

There seems to be a radiation dose threshold that must be reached for recall dermatitis to develop. Patients who received radiation on several fields at different doses have been reported to develop a recall phenomenon only on more intensely treated fields.34

Likewise, the time elapsing between therapy and the appearance of a recall phenomenon also seems to be dose dependent, as higher doses lead to more rapid reactions.28 In addition, intravenous administration of the trigger drug produces a more rapid recall phenomenon than oral administration.

Histologic findings overlap those of both acute and chronic forms of radiodermatitis. The fairly nonspecific findings described include vacuolar degeneration of the basement membrane, necrotic keratinocytes, and superficial vascular ectasia.35 A mixed inflammatory infiltrate, dermal sclerosis, and a psoriasiform pattern of dermatitis are also common.36

Pathophysiologic observations described in the context of recall phenomenon have included vascular injury in the irradiated zone31 and cellular reduction or changes in the basement membrane of the epidermis.37

Currently the most widely accepted theory holds that recall phenomenon is a hypersensitivity drug reaction35 similar to a fixed drug eruption. According to this view, it would be a nonimmunologically mediated inflammatory reaction. Supporting the theory is the high frequency of onset after first exposure to a trigger drug in HIV-infected patients with CD4 counts under 30.38 Also pertinent is the proinflammatory role of increased secretion of cytokines such as IL-1, IL-6, and tumor necrosis factor in the irradiated field. Thus, these patients develop the inflammatory response at a lower radiation threshold as soon as the trigger drug responsible for the recall phenomenon is introduced.

The cornerstone of treatment is to withdraw the trigger drug, after which the eruption should improve quickly. Systemic or topical corticosteroids and antihistamines have not been associated with rapid improvement in established symptoms.39 Reexposure to the trigger reproduces the recall phenomenon in about 75% of the cases, although the eruption is usually less intense.39 If the drug is used again, a lower dose can be given or it can be accompanied by oral corticosteroids in an attempt to prevent an inflammatory response.28

The term eosinophilic, polymorphous, pruritic eruption associated with radiotherapy (EPPER syndrome) was first used in 1999 by Ruedaetal.40 in a study of 83 cancer patients, 17% of whom developed an extensive pruritic rash after radiotherapy. Histology of the lesions showed an abundant eosinophilic inflammatory infiltrate similar to that seen in other eosinophilic skin conditions. This clinical picture typically appears during a radiotherapy cycle or immediately afterwards, although there have been reports of cases in which the rash appeared 9 months later.41

EPPER syndrome was initially described as a polymorphous condition characterized by erythematous papules and abrasions, although wheals, vesicles, firm blisters, or nodules sometimes also appear (Fig. 3). The eruption extends beyond the irradiated field and has a predilection for the extremities. Mucous membranes or palms and soles remain unaffected. Intense generalized pruritus is typical, and symptoms may last weeks or even months.40 Pustular lesions have also been described.42

Figure 3.

A, Multiple vesicles and blisters in the area irradiated to treat an epithelioid peripheral nerve sheath tumor. B, Dense, highly eosinophilic inflammatory infiltrate (hematoxylin-eosin, original magnification ×100).

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The majority of patients who develop EPPER syndrome have squamous cell tumors, mainly cervical carcinoma, but this complication has also been described in patients treated for solid tumors.

The pathophysiologic mechanism is poorly understood. It has been suggested that EPPER syndrome may be a type I (immunoglobulin [Ig] E-mediated) hypersensitivity reaction involving the release of several cytokines. A typeIV hypersensitivity reaction, related to the clonal expansion of type-2 helper T cells—similar to events in systemic hypereosinophilic syndromes—has also been suggested.

A necessary finding for a pathophysiological diagnosis of EPPER syndrome is the presence of a dense, superficial and deep perivascular inflammatory infiltrate (Fig. 3) with over 10000 eosinophils/mm3. Intraepidermal vesicles with eosinophils and subepidermal blisters that are histologically indistinguishable from bullous pemphigoid may also be observed although direct immunofluorescence at the dermal-epidermal junction is negative. Necrotic keratinocytes or other signs of erythema multiforme are not found. Direct immunofluorescence only shows occasional superficial perivascular IgM and C3 deposits, but this finding is common in many inflammatory skin disorders.

A blood work-up occasionally reveals high levels of circulating eosinophils, but this finding is not characteristic. In fact, high concentrations of eosinophils in association with tumors is a well known observation43 and may be merely a casual finding in the context of EPPER syndrome.

This condition usually resolves spontaneously.

Another name for sclerodermiform-like panniculitis after radiation is sclerosing postirradiation panniculitis. This uncommon form of panniculitis presents as a progressive induration of subcutaneous tissue confined to the irradiated zone. Associated epidermal effects are not seen. This condition has been described in women with breast cancer treated with radiotherapy.44,45 The interval between irradiation and cutaneous sclerosis is usually 4 to 8 months, but cases have been said to develop even 7 years after radiotherapy. However, even though onset may be late, the typical signs of chronic radiodermatitis are not present. Suspicion often initially points to local recurrence of a tumor or subcutaneous metastasis.

Histology shows the characteristic features of a predominantly lobular panniculitis without vasculitis.46 Lobules contain necrotic adipocytes and a dense inflammatory infiltrate of foamy histiocytes (Fig. 4). Lipophagic granulomas in the form of histiocytes surrounding necrotic fat cells may be present. Also found are thickened, sclerotic-appearing septa without an associated inflammatory infiltrate.

Figure 4.

A, Predominantly lobular panniculitis (hematoxylin-eosin, original magnification ×100). B, Foamy histiocytes surrounding fat cells (hematoxylin-eosin, original magnification ×400). C, Sclerosis and thickening of hypodermal septa (hematoxylin-eosin, original magnification ×100).

Images provided by Dr. Luis Requena Caballero.

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No specific treatment is available for this condition, which gradually improves spontaneously.

The authors have obtained the informed consent of the patients and/or subjects referred to in this article. The signed forms are in the possession of the corresponding author.