Patient 3—A 72-year-old woman presented with a blistering eruption that had developed on the neck, the upper part of the chest, and other body sites, including the oral mucosa, 6 months after radiation therapy for metastatic squamous cell carcinoma of unknown origin on the neck. On admission to the local hospital, she received a diagnosis of pemphigoid, although the outside biopsy specimens and reports were not available.
The patient was initially treated with prednisone, which was rapidly taperedbecause she was diabetic and her blood glucose levels were labile. Consequently, she was switched to azathioprine 50 mg 3 times dailyand mycophenolate mofetil 500 mg 3 times daily. The patient was transferred to our institution with mild fatigue, dysphagia, weight loss, and generalized blistering involving the skin and lips. Otolaryngologic consultation and radiographic evaluation revealed no evidence of recurrent carcinoma. A shave biopsy was obtained for routine histologic evaluation and immunofluorescence and confirmed the diagnosis of bullous pemphigoid. The patient, however, also was found to have pancytopenia, most likely induced by the combination of azathioprine and mycophenolate mofetil. Her therapeutic regimen was switched to triamcinolone ointment 0.1% to be applied to the eroded areas twice daily and mupirocin ointment to be applied to the hemorrhagic scabs. Subsequently, her complete blood cell count returned to normal.
She continued to use topical corticosteroid therapy to control pemphigoid symptoms, but 6 months later the patient was found to have a lung mass and died secondary to respiratory failure.
Figure 2. Pathologic and immunofluorescence studies confirmed the diagnosis of pemphigus vulgaris. Intraepidermal acantholysis forming a suprabasal blister with a tombstone appearance was seen along the basal cell layer (A)(H&E, original magnification ×400). Intercellular IgG deposition involving the epidermis was noted with direct immunofluorescence (B)(original magnification ×600).
Comment
A wide range of cutaneous reactions are known to occur in conjunction with radiation therapy. Early or acute adverse effects on the skin, such as erythema, edema, and desquamation, can be observed during radiation therapy and for several weeks thereafter. They are usually followed by hair loss and postinflammatory hyperpigmentation. Pemphigus or pemphigoid disease is a rare complication of radiation therapy and has been reported in case reports and small case series.1-17 These disorders include bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, bullous lupus erythematosus, and acquired epidermolysis bullosa.10
The mechanism by which radiation therapy induces pemphigus remains open to speculation. Ionizing radiation may alter the antigenicity of the keratinocyte surface by disrupting the sulfhydryl groups,13 thus changing the immunoreactivity of the desmogleins or unmasking certain epidermal antigens. Another possible explanation is immune surveillance interference by damaged T-suppressor cells, which are preferentially sensitive to radiation.8 Robbins et al12 presented a patient with radiation-induced mucocutaneous pemphigus. They performed immunomapping of perilesional skin for the irradiated field, which illustrated altered expression of desmoglein (Dsg) 1, a commonly targeted antigen in pemphigus. Their study also suggested that radiation changed either the distribution or the expression of Dsg1 in the epidermis.12
Approximately half the reported cases we identified were associated with breast carcinoma,1-4,8,14 as in the case of patient 1. The majority of patients initially experienced blistering confined to the irradiated area followed by a variable degree of dissemination to other sites, probably due to the epitope-spreading phenomenon.12 During the months after radiation therapy, Aguado et al1 documented that their patient, who was initially positive for only anti-Dsg3 antibody, developed anti-Dsg1 antibodies. Therefore, the unusual development of mucosal ulcers, other skin lesions, or both after radiation therapy should raise suspicion for this diagnosis.
Bullous pemphigoid primarily affects elderly patients with blister formation along the dermoepidermal junction. Various causes, such as drugs, trauma, UV light, and ionizing radiation, have been associated with this autoimmune blistering disorder. In a systemic literature review, Mul et al10 discovered 27 case reports of bullous pemphigoid that were associated with radiation. It has been suggested that the alteration of the antigenicity and damaged dermoepidermal junction by radiation is a disease-producing mechanism.15,16 Another explanation is that the patients had subclinical pemphigoid and underwent radiation therapy, which damaged the basal layer sufficiently to produce subepidermal blister formation (triggered pemphigoid).17
The patients in this analysis had clinical presentations similar to those previously reported, with a blistering rash that usually began in the irradiated field, raising the possibility of acute radiation dermatitis. However, unlike acute radiation dermatitis, the lesions extended beyond the radiation fields in all 3 cases with mucosal involvement in patients 1 and 3. Although an onset of pemphigoid was previously observed after a minimum dose of 20 Gy,10 there was no definitive correlation observed between the extent and the severity of the cutaneous eruption and the radiation dose in prior studies. Unfortunately, we could not obtain exact radiation doses in our cases because all 3 patients were treated by radiation oncologists at other institutions. We did not, however, observe in our patients that the eruptions were more severe within the irradiated areas. Our analysis demonstrated that radiation-induced pemphigus or pemphigoid disease does not differ greatly from the endogenous form of the disease in its response to therapy or clinical course.
