Radiation to the skin results in direct cellular injury and inflammatory cell influx. After the initial dose of radiation, cellular damage to epidermal basal cells, endothelial cells, Langerhans cells, and vascular components occur, and an inflammatory response in the epidermis and dermis develops following every subsequent fraction of radiation [1].

Initial cellular injury results from short-lived free-radical production and irreversible double-stranded breaks in nuclear and mitochondrial DNA [6]. Clumping of nuclear chromatin, swelling of the nucleus, nuclear disfiguration or loss of the nuclear membrane, mitochondrial distortion, and degeneration of the endoplasmic reticulum, as well as direct cellular necrosis and apoptosis, occur due to cellular damage. Repetitive cellular damage caused from each fraction of treatment does not allow time for cells to repair DNA damage [7–11].

Because of free-radical production, an inflammatory cytokine cascade is induced, and several cytokines and chemokines are produced including interleukins 1 and 6, tumor necrosis factor-α, and transforming growth factor-β [12]. These cytokines act on the endothelial cells of local vessels, which express adhesion molecules constitutively and induce migration of leukocytes and other immune cells from circulation to irradiated skin [13].

Reduction and impairment of functional stem cells induced by radiation lead to an alteration in the normal turnover of skin cells [6].

A prompt skin reaction may appear after exposure that is related to the inflammatory response, release of histamine-like substances, permeability and dilation of capillaries, and subsequent dermal edema. It presents with early transient skin erythema that can be seen within a few hours after radiation and subsides after 24–48 h [14].

After subsidence of initial erythema, the later phase includes additional edema, an increased dilation in capillaries, and erythrocyte extravasation, which resulted in an erythematous reaction. This phase is followed by thinning of the epidermis, damage to epithelial cells, degeneration of glands, reduced secretion of sebum, and sweat and clumps of exfoliated corneocytes (scales), which manifests as dry desquamation.

If damage to the basal cells and glands is more severe, epidermal necrosis, fibrinous exudates, and moist desquamation occur. The manifestation of moist desquamation results from the formation of small blisters in and around the basal layer of the epidermis that may also extend into the more superficial layers. The epidermis sloughs when these blisters rupture and coalesce, denuding the dermis and causing permanent epilation [15–17]. Finally, skin necrosis or ulceration of the full-thickness dermis may develop as the most severe damage of higher radiation doses [15, 16].

As noted above, a transient early erythema can be seen within a few hours of radiation, even after a single fraction of radiation (2 Gy) and subsides after 24–48 h [14]. The main erythematous reaction appears at about the second to third week (within 1–4 weeks) of radiation. Earlier reaction can be seen in patients with particularly sensitive skin. Effects typically continue to progress during treatment [18–20], and subsequently dry desquamation can develop after the third week or after a cumulative dose of 30 Gy, which is clinically characterized by dryness, scaling, and pruritus. Following 4–5 weeks (45–60 Gy) of therapy, moist desquamation may occur, which is characterized by serous oozing and exposure of the dermis [14]. Symptoms persist for the duration of radiation therapy and peak 1–2 weeks after treatment completion. At about 3–5 weeks after radiation, the skin begins to recover with epidermal regeneration and within 1–3 months (depending on the severity of reaction), complete healing occurs [1, 6, 18, 19, 21, 22]. Post-inflammatory hyperpigmentation may persist for 5–7 weeks or even longer after radiation [20, 23]. Patient skin type may also influence timing and severity of radiation reactions, reflected by interindividual variation in skin presentation of radiation damage.

Mild dermatitis (Grade I) presents with erythematous skin accompanied by mild edema, pruritus, or pain. Dry, peeling skin (desquamation) and temporary epilation due to involvement of adnexal structures may occur (Fig. 1.1).

Moderate dermatitis (Grades 2 and 3) consists of tender or edematous reactions and moist desquamation (Fig. 1.2). The integrity of the dermis is impaired, and secondary infection with Staphylococcus aureus may occur (Fig. 1.3).

Severe dermatitis (acute radionecrosis) is rarely seen and may occur in the setting of very extensive superficial tumors treated with massive radiation doses over a very short period. It manifests as a very painful inflammatory or hemorrhagic plaque with deep necrosis, which can expose the muscles, tendons, and bones [19, 21, 22].

The severity of radiation dermatitis is graded using several grading systems such as Common Terminology Criteria for Adverse Event (NCI-CTCAE grading), Radiation Therapy Oncology Group (RTOG) toxicity scoring system, and the Radiation-Induced Skin Reaction Assessment Scale (RISRAS).

Common Terminology Criteria for Adverse Event (NCI-CTCAE grading) is one of the most commonly used, and NCI-CTCAE v4.3 has been shown in Table 1.1 [24]. RTOG scoring is quite similar to NCI-CTCAE grading.

Treatment and patient-related factors may affect incidence and severity of dermatitis.

Acute radiation dermatitis is a clinical diagnosis based on the finding of skin changes that shows a sharp demarcation of the skin changes and their limitation to the irradiated areas and the history of radiation therapy and its duration. A skin biopsy is usually not necessary for the diagnosis of radiation dermatitis [13].

Two important differential diagnoses of acute radiation dermatitis are radiation recall and cellulitis. Radiation recall is an acute inflammatory skin reaction limited to the area that was previously irradiated and occurs following cytotoxic agents or other drug administration. It occurs at least 7 days after radiation therapy and may occur weeks to years after radiation therapy [46–48]. Cytotoxic drugs such as docetaxel, doxorubicin, and paclitaxel have been associated with radiation recall. Radiation recall manifestations include a rash, dry desquamation, erythema, ulceration, hemorrhage, or even necrosis. Radiation recall generally resolves within 1–2 weeks after drug discontinuation. Patient’s history of skin reaction following radiation treatment and medications will help to reach an accurate diagnosis [49].

Cellulitis is a bacterial infection of skin and subcutaneous tissues. It is characterized by localized erythema, warmth, swelling, pain, tenderness, fevers, and even purulent drainage. These clues can differentiate cellulitis from radiation dermatitis. However, radiation dermatitis is a predisposing factor of secondary cellulitis, and it may be possible for both conditions to exist together. In this condition a culture from the wound may confirm the diagnosis of cellulitis. Empiric antibiotic treatment may also be helpful in these patients [49].

Eczema is a chronic, relapsing, inflammatory skin condition that is diagnosed by clinical presentation of symmetrical, pruritic, dry skin that persists for <6 months. Chronic eczema may exacerbate radiation dermatitis as both conditions are inflammatory in nature. Eczema may be distinguished from radiation dermatitis by its symmetrical distribution. In contrast, radiation dermatitis will only appear within radiation fields [49].

Recurrent or secondary tumors should be considered if atypical plaques and nodules develop within the radiation field. Although irradiated skin may present some difficulty in healing, a biopsy is useful in this clinical situation.

Atopic dermatitis [49], lichen planus [50], pemphigus [51, 52], and dermatophyte infection [53] rarely occur in the site of radiation therapy that clinical course, lesion distribution, and laboratory studies are helpful to distinguish from other diagnoses.