Radiation-Induced Skin Ulcer

Etiology

A constant state of skin renewal that occurs approximately every 26 days makes the skin more vulnerable than any other organ to ionizing radiation injury. Ionizing radiation creates free radicals and reactive oxygen intermediates that lead to DNA and protein damage, as well as damage to cellular membranes of rapidly proliferating tissue. 

Epidemiology

Skin injuries ranging from erythema to full chronic wounds occur in about 95% of patients who undergo radiation therapy. Occupational and accidental radiation exposure are also risk factors for radiation injury. The areas of the body that are more susceptible to radiation injury are the skin of the face, neck, trunk, and extremities.

Pathophysiology

There are 4 grades of radiation dermatitis and injury, ranging from erythema to necrotic ulcers.[6][7][8]

• Faint erythema or dry desquamation characterize grade 1.
• Grade 2 exhibits moderate to brisk erythema, patchy moist desquamation, and it is mostly confined to the skinfold creases. There may be moderate edema at the injured site.
• Grade 3 consists of moist desquamation at sites other than skinfold creases; there may be bleeding the site of injury induced by minor trauma.
• Grade 4 consists of skin necrosis or full thickness wounds. There may be spontaneous bleeding at the involved injured site.

As the effects of radiation to the skin are cumulative, there are more severe skin injuries toward the end of the radiation. The degree of injury depends mainly on the radiation intensity and the patient's tissue sensitivity to the radiation.

The concept of radiation recall involves the skin recalling a previous radiation exposure to a particular area when chemotherapeutic agents such as doxorubicin or docetaxel are administered within 2 months of the radiation treatment.

The primary pathophysiology of the injury is hypoxia due to the progressive obliteration of the microvasculature (progressive endarteritis) and fibrosis. Impaired wound healing in a previously irradiated area occurs due to disruption of the natural progression of the overlapping wound healing phases (hemostasis, inflammatory phase, proliferative phase, and remodeling phase). These disruptive can be grouped into several categories: cellular depletion, extracellular matrix (ECM) alteration, microvascular changes, cytokine and growth factor dysregulation.

1. Cellular depletion: ionizing radiation affects cells in the G2 and M phases of the cell cycle, causing cellular apoptosis and impaired cellular proliferation and migration, causing an overall decrease in cells number.
2. Alteration in cellular proliferation: Ionizing radiation effects collagen content and collagen strength, both decreased in irradiated wounds; an increase in matrix metalloproteinases (MMPs) unopposed by tissue inhibitors of MMPs (TIMP) will cause an abnormal degradation of ECM.
3. Microvascular changes: This is caused by overall decreased in angiogenesis as well as physical changes of blood vessels caused by an increase in transforming growth factor-beta (TGF-beta) causing an increase in endothelial fibrosis with subsequent obliteration of the vessel lumen resulting in tissue hypoxia.
4. Cytokines and growth factors dysregulation:

• VEGF, bFGF: Angiogenic growth factors; decreased following radiation
• Nitric oxide: Potent vasodilator and induces collagen deposition; decreased following radiation
• TNF-alfa, IFN-gamma, IL-1, IL-6: Pro-inflammatory cytokines, prevent collagen deposition, induce TGF-beta1 through activation of macrophages/stromal cells; it is increased following radiation
• TGF-beta1: Key mediator of fibrosis, promotes chemotaxis, signals fibroblasts proliferation, prevents collagen breakdown, promotes microvascular changes. It is decreased following radiation.

Histopathology

Pandya et al. examined specimens from 27 patients with OSCC (oral squamous cell carcinoma) who received radiation therapy involving the jaw and neck. He found significant tissue atrophy and severity of dysplasia, an increased presence of fibrinous exudative necrosis, vessel wall thickening, with oropharyngeal ectasia of the salivary gland. In addition, dense fibrosis with thick fibers was a common finding of post-radiation tissue in the same patients. Similar findings at other sites may be inferred regarding increased tissue fibrosis and hypoxia due to damaged microvasculature; glands within the dermal layer will also be affected similarly. These findings again confirmed the microvasculature thrombosis and tissue fibrosis characteristic of post-radiation skin changes that lead to eventual ulcers.[9]

History and Physical

At the time of the patient's evaluation, a thorough history should reveal the initial diagnosis for which radiation therapy was used, as well as the site of the radiation exposure, and finally the total amount of radiation that the patient has received. It is important to note the radiation dose as well as the timing of the onset of the observed skin changes.  Any associated chemotherapy will also need to be documented, in particular, the types of chemotherapeutic agents used.  Again, certain therapeutic agents were present as risk factors for radiation recall, as discussed above; some of the chemotherapeutic agents that will predispose to radiation recall are doxorubicin, docetaxel, paclitaxel, tamoxifen, methotrexate, to name a few. Chemotherapeutic agents such as doxorubicin, bleomycin, disulfiram, cisplatin, and mafenide acetate are also relative contraindications to hyperbaric oxygen treatment, a treatment modality that is often used as an adjuvant treatment for late effects of radiation skin changes such as ulcerations.

Overall, a thorough history will be important in providing documentation that will aid in choosing a specific treatment algorithm, especially if it involves hyperbaric oxygen treatment.

In addition to the physical exam that is customary for every patient evaluated for any disease process, there should be a particular focus on the presentation of the skin injury itself, as this will decide the treatment modality to be used, depending on the classification of radiation injury. Clinical manifestation of chronic radiation skin injury includes xerosis, hyperkeratosis, decreased or absent sweating, skin atrophy and dyspigmentation, as well as necrosis with full-thickness wounds, and others.

There should be a particular focus in identifying any contraindication to possible hyperbaric oxygen treatment, a treatment modality that is often used with late effects of radiation on the skin. A neck and head and exam is important, with a special focus on the eye for cataracts. The tympanic membranes should be evaluated for any scarring or other abnormalities that may make it hard for the pressure to equalize within the inner year. A chest radiograph to confirm the absence of any acute disease processes and for bullous diseases should be obtained given the high incidence of pneumothorax under more than one atmospheric pressure that is typical of a hyperbaric treatment protocol.

Evaluation

Evaluation of the patient with skin injury due to radiation treatment should include all relevant tests necessary for initiation of a specific treatment modality such as hyperbaric oxygen treatment; these tests would include a chest x-ray, a hemoglobin A1C, a sedimentation rate, and a complete blood count (CBC) if infection might be present.

Other tests may be ordered as applicable depending on the presentation of the patient at the time of the initial visit or if any complications were to arise during treatment.

Treatment / Management

In general, the treatment of radiation injury to the skin, acute, subacute or delayed, should reflect the extent of the injury itself,  keeping  in mind that necrotic tissue should be debrided, infection and inflammation should be managed properly, moisture management should not be ignored and continuous evaluation of the progression of the wound given the therapy employed should be done regularly with a treatment modality change depending on the status of the reepithelialization progress. In other words, standard wound management concepts should still be applied, with strict modifications given the etiology of the of the injury itself, ether just acute erythema at the skin or full thickness chronic wound.[10][11][12](A1)

Management of Injury to the irradiated skin should begin with patient education in regards to skin care during the pre-radiation phase, post radiation phase and during the radiation treatment period. Education to the patient should include promotion of personal hygiene and wound hygiene, promotion of comfort, prevention of trauma to the affected skin, and management of radiation dermatitis.

Choices of cleanser and moisturizers and topical creams in radiation-induced skin injuries should reflect the extent of the injury itself. Products such as Natural Care Gel, Eucerin cream, Lubriderm, and corticosteroid cream can be used for erythema and dry desquamation.  If an infection is present topical antibiotic ointment such as Neosporin or silver sulfadiazine 1% can be used, although the need for systemic antibiotic should be assessed as well'

Additional management manifesting irradiation injuries to the skin can be broken down by the presenting clinical pathology:

1. Radiation-induced fibrosis: Delanian showed that the use of pentoxifylline, a methylxanthine derivative, and alpha-tocopherol may cause partial reversibility of the fibrosis. In severe cases of fibrosis, surgical resection of the affected tissue may be indicated, with the reconstruction of the defect by a free flap or split thickness skin graft, with hyperbaric oxygen treatment as a possible adjuvant therapeutic agent as well.
2. Nonhealing call service/soft tissue necrosis: initial treatment includes hyperbaric oxygen treatment and Pentoxyfilline and later surgical resection of the tissue followed by surgical reconstruction of the defect (
3. Osteoradionecrosis/chondronecrosis: it usually affects irradiated facial bone (the mandible). Dental extraction and infection predispose osteoradionecrosis; management varies, from dental extraction before radiation therapy to pentoxifylline and vitamin E before dental extraction in post-irradiated tissue. Hyperbaric oxygen treatment has been used successfully for this type of chronic manifestation of radiation-induced injury

Hyperbaric oxygen treatment has one of the most frequent applications and delays radiation injuries, with up to one-third of patients treated with HBO2 for radiation injury in the United States. Even the mechanism of injury of ionizing radiation to be mainly hypoxia and increased district fibrosis, better oxygen treatment has been shown to increase angiogenesis and therefore improving oxygenation as well as reduce fibrosis, although this effect has not been fully investigated and explain.

Another mechanism of action of delayed radiation injury has been the negative impact of ionizing radiation on stem cells (Feldmeier J, Hyperbaric oxygen therapy and delayed radiation injury (soft tissue and bone necrosis. All serious investigations are now being pursued based upon luminary evidence that hyperbaric oxygen treatment increases the number of stem cells radiation injury site.

Differential Diagnosis

• Buruli ulcer

• Chronic herpes ulcers

• Cutaneous tuberculosis

• Deep fungal infection

• Drepanocytosis

• Ecthyma

• Leishmaniasis

• Leprosy

• Phagedenic ulcers

• Skin cancers

• Tropical ulcer

• Vascular or diabetic ulcers

• Yaws

Prognosis

In general, the patient's prognosis will depend on several factors, mainly the extent of the radiation injury in terms of grades 1, 2, 3, or 4, as well as associated comorbidities.