Diagnostic Dilemma: Osteoradionecrosis

Department Editor Tania J. Phillips, MD, FRCPC Overall Learning Objective: The physician or podiatrist participant will develop a rational approach to the evaluation and treatment of a variety of uncommon wounds and will have an increased awareness of the differential diagnosis of cutaneous wounds and the systemic diseases associated with these wounds. Submissions: To submit a case for consideration in Diagnostic Dilemmas, e-mail or write to Associate Editor, WOUNDS, 83 General Warren Blvd., Suite 100, Malvern, PA 19355, rolszewski@hmpcommunications.com. Completion Time: The estimated time to completion for this activity is 1 hour. Target Audience: This CME/CPME activity is intended for dermatologists, surgeons, podiatrists, internists, and other physicians who treat wounds. At the conclusion of this activity, the participant should be able to: 1. Discuss the radiobiology and pathogenesis of irradiated skin injury and clinical features 2. List the factors that affect the severity of irradiation damage 3. Describe the treatment of osteoradionecrosis. Disclosure: All faculty participating in Continuing Medical Education programs sponsored by The North American Center for Continuing Medical Education (NACCME) are expected to disclose to the meeting audience any real or apparent conflict(s) of interest related to the content of their presentation. Drs. Dasgeb and Phillips disclose that they have no financial conflicts relevant to the content of this activity. Accreditation: This activity is sponsored by NACCME. NACCME is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. NACCME is approved by the Council on Podiatric Medical Education as a sponsor of continuing education in podiatric medicine. Designation: NACCME designates this continuing medical education activity for 1 credit hour in Category 1 of the Physician’s Recognition Award of the American Medical Association. Each physician should claim only those hours he/she spent in the educational activity. NACCME designates this continuing medical activity for .1 CEUs available to participating podiatrists. Method of Participation: Participants must read the article and take, submit, and pass the post-test by September 15, 2005. Participants must completely fill out the answer and evaluation form, answer at least 70 percent of the questions correctly, and mail or fax the answer/evaluation forms to: Trish Levy, CME Director, NACCME, HMP Communications 83 General Warren Blvd., Suite 100, Malvern, PA 19355 Fax (610) 560-0501 This activity has been planned and produced in accordance with the ACCME Essential Areas and Policies. Release date: September 15, 2004 Expiration date: September 15, 2005 Presentation An 85-year-old Black woman was referred for consultation regarding a necrotic ulcer over her left chest. Her past medical history was significant for breast cancer treated by radical mastectomy and radiation therapy 28 years previously. Two years ago, she developed a spontaneous ulcer at the radiation therapy site. A biopsy in 2003 showed no evidence of malignancy. The ulcer continued to increase in size and depth. She reported the appearance of white fibrotic tissue in the center of the ulcer during the past year. Past medical and surgical history were significant for hypertension, urinary incontinence, and syncope. Current medication include hydrochlorothiazide 12.5 mg by mouth every day and donepezil HCl 10 mg by mouth every day. Physical Examination Physical examination revealed a pleasant, underweight Black woman who was alert and oriented. In her left chest area, there was a 5cm x 3cm open wound with mildly inflamed borders (Figure 1). The bed of the ulcer was covered by hard, yellow, fibrinous material. The sternum and its fibrosed cartilage extruded through this full-thickness ulcer. The surrounding skin was very indurated and fibrosed. Investigations Laboratory studies included a biopsy, which was negative for malignancy, and a wound culture, which revealed few Gram-positive cocci and Gram-negative rods. A computed tomography (CT) scan revealed chronic inflammation and fibrosis involving skin and soft tissues underneath and surrounding the 2nd, 3rd, and 4th left anterior ribs. The depth of fibrotic process extended from the left anterior chest wall to the upper lobe of the left lung. Diagnosis Osteoradionecrosis is fibrosis of underlying bony structures in irradiated sites. This was first described in the 1950s as “osteomyelitis secondary to radiation.”¹ When fibrosis replaces the normal structure of the bone after irradiation, it is defined as osteoradionecrosis. Discussion Pathogenesis of irradiated skin. When skin is exposed to high doses of fractionated ionizing radiation inflammation, intercellular and endothelial edema, erythema, moist desquamation, erosion, and epilation are the early phase reactions. Over the next months to years, atrophy, telangiectasia, hypopigmentation and hyperpigmentation, hyperkeratosis, ulceration, and necrosis can occur. This chain of events can ultimately progress to fibrosis, involving underlying bony structures, or osteoradionecrosis. The magnitude of cutaneous response to radiation is altered by a variety of factors (Table 1). Radiation induces a long-term increase in the turnover of type 1 collagen and leads to the accumulation of crosslinked type 1 collagen.² Cutaneous bioradiology can be discussed under three entities: 1) acute radiation dermatitis, 2) chronic radiation dermatitis, and 3) radiation necrosis. Phase 1: Acute radiation dermatitis. Superficial radiation usually is followed by a diphasic reaction. During the first phase, edema and erythema occur at 24–72 hours post exposure. Within 10 days, the second phase occurs, manifested by increased erythema and edema resolving in four weeks. With more deeply penetrating radiation, a third phase of erythema occasionally occurs at six weeks and persists for several weeks. Post-radiation hyperpigmentation occurs after a month and can persist indefinitely. Pain and occasionally pruritus are prominent symptoms of acute radiation dermatitis. Other less encountered signs of this phase consist of blisters, erosions, alopecia, or even nail shedding in severe cases. Severe reactions can be precipitated by concomitant chemotherapy even in sites irradiated month to years previously.^3,4Phase 2: Chronic radiation dermatitis. When ionizing radiation exposure exceeds a certain dose, persistent skin atrophy can result. It can also develop subsequent to repeated small erythemogenic doses (often used in the past for treatment of benign dermatoses or related to occupational exposure). Recently, several case reports of chronic radiation dermatitis have been associated with prolonged or repeated fluoroscopically guided studies or treatment procedures, such as angioplasty. Chronic radiation dermatitis starts months after exposure and further evolves over subsequent years. At the microscopic level, vascular changes include proliferation of subendothelial connective tissue in small arteries, inducing marked narrowing, thrombosis, and obliteration of the lumina, which further compromises tissue oxygenation. This eventually results in ischemia, which is the main pathogenesis underlying chronic radiation dermatitis. The skin is thin, dry, hyperkeratotic, and atrophied. Hypopigmentation is a more prominent indication of this phase than hyperpigmentation. Loss of skin appendages are typically associated with chronic radiation exposure of skin. As this phase progresses, spontaneous and/or post-traumatic ulcers can develop. Phase 3: Radiation necrosis and fibrosis. Skin is a highly proliferative organ and tolerates high doses of radiation very poorly. If a certain dose of radiation is exceeded, radionecrosis will occur. Early ulceration results from epidermal necrosis, while deeper ulcers due to dermal ischemia tend to present years after exposure. They develop spontaneously or are precipitated by factors, such as trauma, chronic friction, pressure, cutaneous infection, and sunlight exposure. The pathogenesis of these nonhealing wounds is deep-vessel occlusion leading to ischemia in the dermis of irradiated sites. These wounds progress horizontally and vertically and sometimes penetrate well beyond subcutaneous fat, involving the underneath mesodermal structures, exposing muscle, cartilage, and bone. As a result, ischemia induced fibrosis becomes the predominant histological feature underlying necrotic and ulcerated skin. Radiation and skin cancer. The occurrence of malignancy in irradiated sites has been well established. Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), which are the typical post-radiation skin cancers, tend to occur during radiation necrosis or phase 3. The most common skin cancer occurring at the irradiation site is BCC (10–20 times more common that SCC) followed by SCC. Rare cases of fibrosarcoma and melanoma have been reported. Metastasis occurs more frequently in skin cancers due to irradiation than solar damage. The presence of malignant cells in nonhealing post-radiation ulcers might herald the recurrence of the primary tumor for which radiation was applied. Finally, like any other scenario, the two pathological conditions of necrosis and malignancy might coexist independently. Any deeply penetrating radiation also puts the adjacent soft tissues, such as thyroid and brain, at greater risk for tumorigentic mutations.^5,6 Treatment In the final stage of radiation necrosis, topical wound care is of little benefit. It is prudent to take preventive measures to stop progression and further damage. Preventive therapy in this case includes meticulous cleansing, aggressive treatment of infection, and appropriate dressings. Some therapeutic modalities have shown to be beneficial in radiation-induced wound management. Hyperbaric oxygen. Hyperbaric oxygen (HBO) provides a favorable environment for healing of ischemic tissues and revascularization and an unfavorable condition for growth of some microorganisms. Osteoradionecrosis is one of the most common conditions treated at hyperbaric units.⁷Antifibrotics. In an uncontrolled study, a combination of pentoxifylline (PTX), tocopherol (Vitamin E), and clodronate have been shown to be of clinical benefit with more than 50 percent regression of progressive osteoradionecrosis at six months in 12 patients. In one patient with extensive osteoradionecrosis of the chest wall due to breast cancer radiotherapy, this combination for three years resulted in total regression of clinical fibrosis.⁸Pedicled omentoplasty and split-thickness skin graft (POSSG). This procedure has been successfully tried for infected osteoradionecrotic ulcers that failed to respond to antibiotics⁹ and as a palliative measure for local symptom control, such as pain and bleeding.¹⁰ Reduced morbidity and minimal hospital stay make this approach very appealing for more elderly and debilitated patients.¹¹Myocutaneous flaps. Osteoradionecrosis following radiation for breast cancer occurs often concomitant with brachial plexus neuropathy. Application of flaps that have adequate vasculature structures and blood supply can reconstruct these wounds faster and more effectively.¹² Management To exclude malignancy in the authors’ patient, a punch biopsy was taken from the friable edge of the open wound. Tissue was sent for microbiological culture. The risks versus benefits of reconstructive surgery should be weighed in each individual case. In this 85-year-old patient, who is healthy, cancer free, self sufficient, and the sole caregiver of her husband, it was important to create a management plan that did not compromise the quality of her life. The risk of reconstructive surgery versus conservative management was discussed, and she decided to continue with conservative wound care. Based on her CT scan, radiotherapy has been delivered in anterior-posterior direction rather than more parallel to the chest wall, resulting in deeper radiation penetration. In her case, a trial of pentoxifylline, Vitamin E, and clodronate was recommended. Questions 1) What is osteoradionecrosis? A. Necrosis of the irradiated skin B. Hardening of the soft tissue in the irradiated area C. Fibrosis of the bony structure underlying irradiated skin D. Exposure of the bone and cartilage through a full-thickness damage of irradiated skin 2) With which phase of the post-radiation skin reaction is the loss of skin appendages typically associated? A. Acute radiation dermatitis B. Chronic radiation dermatitis C. Radiation necrosis D. None of the above 3) Which cancer is most common at the irradiation site? A. Basal cell carcinoma B. Squamous cell carcinoma C. Melanoma D. Metastasis 4) Which of the following drugs has antifibrinolytic action? A. Pentoxyphylline B. Vitamin E C. Clodronate D. All of the above 5) Which of the following is not seen predominantly in chronic radiation dermatitis? A. Proliferation of the endothelial connective tissue B. Pain C. Hypopigmentation D. Loss of hair follicle 6) Which of the following is associated with acute radiation dermatitis? A. Edema B. Hyperpigmentation C. Alopecia D. All of the above Osteoradionecrosis Answer Form Please print clearly: Name Degree Position/Title Organization/Institute Department Mailing Address for Certificate (H or W): City, State Zip Code Email Address Social Security Number Phone (area code) Fax (area code) Answers (Refer to questions on other side of page) Circle one letter for each answer: 1. A B C D 2. A B C D 3. A B C D 4. A B C D 5. A B C D 6. A B C D Evaluation (circle one) Excellent (4) Good (3) Satisfactory (2) Poor (1) Accuracy and timeliness of content: 4 3 2 1 Relevance to your daily practice: 4 3 2 1 Impact on your professional effectiveness: 4 3 2 1 Relevance of the content to the learning 4 3 2 1 objectives: Effectiveness of the teaching/learning 4 3 2 1 methods: This activity avoided commercial bias or influence YES NO Now that you have read this article, can you: 1. Discuss the radiobiology and pathogenesis of irradiated skin injury and clinical features? YES NO 2. List the factors that affect the severity of irradiation damage? YES NO 3. Describe the treatment of osteoradionecrosis? YES NO What questions do you still have?_______________________________________________________________________________ How will you use what you have learned from this activity?___________________________________________________ All tests must be received by 9/15/05.