Amer N. Kalaaji, MD

A number of adverse cutaneous effects may result from radiation therapy, including radiodermatitis, alopecia, and radiation-induced neoplasms. Radiation therapy rarely induces pemphigus or pemphigoid disease, but awareness of this disorder is of clinical importance because these cutaneous lesions may resemble other skin diseases, including recurrent underlying cancer. We report 3 cases of pemphigus or pemphigoid disease that occurred after radiation therapy for in situ ductal carcinoma of the breast, cervical squamous cell carcinoma, and metastatic squamous cell carcinoma of unknown origin, respectively.

Case Reports

To identify all the patients with radiation-induced pemphigus, pemphigoid diseases, or both diagnosed and treated at Mayo Clinic (Rochester, Minnesota) from 1988 to 2009, we performed a computerized search of dermatology, laboratory medicine, and pathology medical records using the following keywords: radiation, pemphigoid, pemphigus vulgaris, pemphigus foliaceus, pemphigus erythematosus, and blistering disease. Inclusion criteria were a history of radiation therapy and subsequent development of pemphigus or pemphigoid disease within the irradiated fields. Patients with a history of immunobullous disease preceding radiation therapy and patients with a diagnosis of paraneoplastic pemphigus or paraneoplastic autoimmune multiorgan syndrome were excluded. The diagnoses were confirmed by routine pathology as well as direct and indirect immunofluorescence examinations.

We identified 3 patients with severe extensive radiation-associated pemphigus/pemphigoid disease that had developed within 14 months after they received radiation therapy for their underlying cancer. The identified patients’ medical records were reviewed for underlying malignancy, symptoms at the time of diagnosis, treatment course, and follow-up. The protocol was reviewed and approved by the Mayo Clinic institutional review board.

Patient 1—A 58-year-old woman was diagnosed with in situ ductal carcinoma of the right breast and underwent a lumpectomy with subsequent radiation therapy at an outside institution. Fourteen months after the final radiation treatment, she developed localized flaccid blisters and a superficial erosion on the right areola (Figure 1). Routine pathologic and direct immunofluorescence studies performed on shave biopsies in conjunction with serum analysis by indirect immunofluorescence confirmed the diagnosis of pemphigus vulgaris (Figure 2). Additionally, a deeper 4-mm punch biopsy ruled out metastatic breast carcinoma. The patient initially was treated with prednisone 60 mg and azathioprine 50 mg daily. The prednisone was tapered over 4 to 5 months to a dose of 5 mg every other day for another 4 to 5 months. Azathioprine was discontinued after a few months because of increased liver enzyme levels and a rapid clinical response of the pemphigus to this regimen.

Subsequently, she developed oral and ocular erosions that were compatible with pemphigus and were believed to be precipitated by trauma secondary to dental work and to the use of contact lenses. These flares were treated and stabilized with short courses of prednisone at higher doses that were successfully tapered to a maintenance dose of 5 mg every other day to control the pemphigus. With that prednisone dosage, her disease has remained clinically stable.

Patient 2—A 40-year-old woman was diagnosed with stage IIIB cervical squamous carcinoma with para-aortic adenopathy. She was initially treated with primary radiation therapy directed at the pelvis and para-aortic regions using a 4-field approach at our institution, and she received weekly cisplatin chemotherapy at another institution. Nine months later, the patient was admitted to our institution with persistent metastatic cervical carcinoma of the retroperitoneum. She was scheduled for intraoperative radiation therapy as well as aggressive surgical cytoreduction. The day before her surgery she presented to our dermatology clinic with a generalized pruritic rash of 1 month’s duration and occasional blistering without mucosal involvement. Biopsy specimens from the lower back and abdomen were sent for routine histologic studies and direct immunofluorescence. Serum was sent for analysis by indirect immunofluorescence. Pathology results were consistent with a diagnosis of bullous pemphigoid with an infiltrate of eosinophils in the papillary dermis; direct immunofluorescence revealed continuous strong linear deposition of C3, which also was consistent with pemphigoid.

At that time, we recommended application of topical clobetasol 0.05% twice daily to affected areas before initiating prednisone. Postoperatively, her rash improved dramatically with clobetasol monotherapy. However, 4 months after discharge from our hospital, her local dermatologist called us for a telephone consultation regarding clinical and laboratory evidence of pemphigoid relapse. A direct immunofluorescence study showed both linear IgG and C3 deposition. The patient had healed well from the surgery, and the metastatic cervical carcinoma was quiescent. Prednisone in combination with a second immunosuppressive agent was recommended, pending approval by her local oncologist. No further follow-up information is available at this time.

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 tapered because she was diabetic and her blood glucose levels were labile. Consequently, she was switched to azathioprine 50 mg 3 times daily and 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.

In summary, radiation-induced pemphigus or pemphigoid disease, a rare but serious adverse effect of radiation therapy, should be considered in patients with new-onset blistering or erosive skin disease who have recently undergone irradiation. The accurate diagnosis of pemphigus or pemphigoid disease is important because such diseases often require long-term immunosuppressive therapy. A thorough history and skin examination must be obtained from all patients who receive radiation therapy and subsequently have blisters or eruptions on the skin, mucous membranes, or both. Appropriate diagnostic studies, including routine biopsy for histologic evaluation and direct immunofluorescence, serum for indirect immunofluorescence, and enzyme-linked immunosorbent assay, should be performed to exclude pemphigus or pemphigoid disease.

A number of adverse cutaneous effects may result from radiation therapy, including radiodermatitis, alopecia, and radiation-induced neoplasms. Radiation therapy rarely induces pemphigus or pemphigoid disease, but awareness of this disorder is of clinical importance because these cutaneous lesions may resemble other skin diseases, including recurrent underlying cancer. We report 3 cases of pemphigus or pemphigoid disease that occurred after radiation therapy for in situ ductal carcinoma of the breast, cervical squamous cell carcinoma, and metastatic squamous cell carcinoma of unknown origin, respectively.

Case Reports

To identify all the patients with radiation-induced pemphigus, pemphigoid diseases, or both diagnosed and treated at Mayo Clinic (Rochester, Minnesota) from 1988 to 2009, we performed a computerized search of dermatology, laboratory medicine, and pathology medical records using the following keywords: radiation, pemphigoid, pemphigus vulgaris, pemphigus foliaceus, pemphigus erythematosus, and blistering disease. Inclusion criteria were a history of radiation therapy and subsequent development of pemphigus or pemphigoid disease within the irradiated fields. Patients with a history of immunobullous disease preceding radiation therapy and patients with a diagnosis of paraneoplastic pemphigus or paraneoplastic autoimmune multiorgan syndrome were excluded. The diagnoses were confirmed by routine pathology as well as direct and indirect immunofluorescence examinations.

We identified 3 patients with severe extensive radiation-associated pemphigus/pemphigoid disease that had developed within 14 months after they received radiation therapy for their underlying cancer. The identified patients’ medical records were reviewed for underlying malignancy, symptoms at the time of diagnosis, treatment course, and follow-up. The protocol was reviewed and approved by the Mayo Clinic institutional review board.

Patient 1—A 58-year-old woman was diagnosed with in situ ductal carcinoma of the right breast and underwent a lumpectomy with subsequent radiation therapy at an outside institution. Fourteen months after the final radiation treatment, she developed localized flaccid blisters and a superficial erosion on the right areola (Figure 1). Routine pathologic and direct immunofluorescence studies performed on shave biopsies in conjunction with serum analysis by indirect immunofluorescence confirmed the diagnosis of pemphigus vulgaris (Figure 2). Additionally, a deeper 4-mm punch biopsy ruled out metastatic breast carcinoma. The patient initially was treated with prednisone 60 mg and azathioprine 50 mg daily. The prednisone was tapered over 4 to 5 months to a dose of 5 mg every other day for another 4 to 5 months. Azathioprine was discontinued after a few months because of increased liver enzyme levels and a rapid clinical response of the pemphigus to this regimen.

Subsequently, she developed oral and ocular erosions that were compatible with pemphigus and were believed to be precipitated by trauma secondary to dental work and to the use of contact lenses. These flares were treated and stabilized with short courses of prednisone at higher doses that were successfully tapered to a maintenance dose of 5 mg every other day to control the pemphigus. With that prednisone dosage, her disease has remained clinically stable.

Patient 2—A 40-year-old woman was diagnosed with stage IIIB cervical squamous carcinoma with para-aortic adenopathy. She was initially treated with primary radiation therapy directed at the pelvis and para-aortic regions using a 4-field approach at our institution, and she received weekly cisplatin chemotherapy at another institution. Nine months later, the patient was admitted to our institution with persistent metastatic cervical carcinoma of the retroperitoneum. She was scheduled for intraoperative radiation therapy as well as aggressive surgical cytoreduction. The day before her surgery she presented to our dermatology clinic with a generalized pruritic rash of 1 month’s duration and occasional blistering without mucosal involvement. Biopsy specimens from the lower back and abdomen were sent for routine histologic studies and direct immunofluorescence. Serum was sent for analysis by indirect immunofluorescence. Pathology results were consistent with a diagnosis of bullous pemphigoid with an infiltrate of eosinophils in the papillary dermis; direct immunofluorescence revealed continuous strong linear deposition of C3, which also was consistent with pemphigoid.

At that time, we recommended application of topical clobetasol 0.05% twice daily to affected areas before initiating prednisone. Postoperatively, her rash improved dramatically with clobetasol monotherapy. However, 4 months after discharge from our hospital, her local dermatologist called us for a telephone consultation regarding clinical and laboratory evidence of pemphigoid relapse. A direct immunofluorescence study showed both linear IgG and C3 deposition. The patient had healed well from the surgery, and the metastatic cervical carcinoma was quiescent. Prednisone in combination with a second immunosuppressive agent was recommended, pending approval by her local oncologist. No further follow-up information is available at this time.

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 tapered because she was diabetic and her blood glucose levels were labile. Consequently, she was switched to azathioprine 50 mg 3 times daily and 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.

In summary, radiation-induced pemphigus or pemphigoid disease, a rare but serious adverse effect of radiation therapy, should be considered in patients with new-onset blistering or erosive skin disease who have recently undergone irradiation. The accurate diagnosis of pemphigus or pemphigoid disease is important because such diseases often require long-term immunosuppressive therapy. A thorough history and skin examination must be obtained from all patients who receive radiation therapy and subsequently have blisters or eruptions on the skin, mucous membranes, or both. Appropriate diagnostic studies, including routine biopsy for histologic evaluation and direct immunofluorescence, serum for indirect immunofluorescence, and enzyme-linked immunosorbent assay, should be performed to exclude pemphigus or pemphigoid disease.

A number of adverse cutaneous effects may result from radiation therapy, including radiodermatitis, alopecia, and radiation-induced neoplasms. Radiation therapy rarely induces pemphigus or pemphigoid disease, but awareness of this disorder is of clinical importance because these cutaneous lesions may resemble other skin diseases, including recurrent underlying cancer. We report 3 cases of pemphigus or pemphigoid disease that occurred after radiation therapy for in situ ductal carcinoma of the breast, cervical squamous cell carcinoma, and metastatic squamous cell carcinoma of unknown origin, respectively.

Case Reports

To identify all the patients with radiation-induced pemphigus, pemphigoid diseases, or both diagnosed and treated at Mayo Clinic (Rochester, Minnesota) from 1988 to 2009, we performed a computerized search of dermatology, laboratory medicine, and pathology medical records using the following keywords: radiation, pemphigoid, pemphigus vulgaris, pemphigus foliaceus, pemphigus erythematosus, and blistering disease. Inclusion criteria were a history of radiation therapy and subsequent development of pemphigus or pemphigoid disease within the irradiated fields. Patients with a history of immunobullous disease preceding radiation therapy and patients with a diagnosis of paraneoplastic pemphigus or paraneoplastic autoimmune multiorgan syndrome were excluded. The diagnoses were confirmed by routine pathology as well as direct and indirect immunofluorescence examinations.

We identified 3 patients with severe extensive radiation-associated pemphigus/pemphigoid disease that had developed within 14 months after they received radiation therapy for their underlying cancer. The identified patients’ medical records were reviewed for underlying malignancy, symptoms at the time of diagnosis, treatment course, and follow-up. The protocol was reviewed and approved by the Mayo Clinic institutional review board.

Patient 1—A 58-year-old woman was diagnosed with in situ ductal carcinoma of the right breast and underwent a lumpectomy with subsequent radiation therapy at an outside institution. Fourteen months after the final radiation treatment, she developed localized flaccid blisters and a superficial erosion on the right areola (Figure 1). Routine pathologic and direct immunofluorescence studies performed on shave biopsies in conjunction with serum analysis by indirect immunofluorescence confirmed the diagnosis of pemphigus vulgaris (Figure 2). Additionally, a deeper 4-mm punch biopsy ruled out metastatic breast carcinoma. The patient initially was treated with prednisone 60 mg and azathioprine 50 mg daily. The prednisone was tapered over 4 to 5 months to a dose of 5 mg every other day for another 4 to 5 months. Azathioprine was discontinued after a few months because of increased liver enzyme levels and a rapid clinical response of the pemphigus to this regimen.

Subsequently, she developed oral and ocular erosions that were compatible with pemphigus and were believed to be precipitated by trauma secondary to dental work and to the use of contact lenses. These flares were treated and stabilized with short courses of prednisone at higher doses that were successfully tapered to a maintenance dose of 5 mg every other day to control the pemphigus. With that prednisone dosage, her disease has remained clinically stable.

Patient 2—A 40-year-old woman was diagnosed with stage IIIB cervical squamous carcinoma with para-aortic adenopathy. She was initially treated with primary radiation therapy directed at the pelvis and para-aortic regions using a 4-field approach at our institution, and she received weekly cisplatin chemotherapy at another institution. Nine months later, the patient was admitted to our institution with persistent metastatic cervical carcinoma of the retroperitoneum. She was scheduled for intraoperative radiation therapy as well as aggressive surgical cytoreduction. The day before her surgery she presented to our dermatology clinic with a generalized pruritic rash of 1 month’s duration and occasional blistering without mucosal involvement. Biopsy specimens from the lower back and abdomen were sent for routine histologic studies and direct immunofluorescence. Serum was sent for analysis by indirect immunofluorescence. Pathology results were consistent with a diagnosis of bullous pemphigoid with an infiltrate of eosinophils in the papillary dermis; direct immunofluorescence revealed continuous strong linear deposition of C3, which also was consistent with pemphigoid.

At that time, we recommended application of topical clobetasol 0.05% twice daily to affected areas before initiating prednisone. Postoperatively, her rash improved dramatically with clobetasol monotherapy. However, 4 months after discharge from our hospital, her local dermatologist called us for a telephone consultation regarding clinical and laboratory evidence of pemphigoid relapse. A direct immunofluorescence study showed both linear IgG and C3 deposition. The patient had healed well from the surgery, and the metastatic cervical carcinoma was quiescent. Prednisone in combination with a second immunosuppressive agent was recommended, pending approval by her local oncologist. No further follow-up information is available at this time.

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 tapered because she was diabetic and her blood glucose levels were labile. Consequently, she was switched to azathioprine 50 mg 3 times daily and 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.

In summary, radiation-induced pemphigus or pemphigoid disease, a rare but serious adverse effect of radiation therapy, should be considered in patients with new-onset blistering or erosive skin disease who have recently undergone irradiation. The accurate diagnosis of pemphigus or pemphigoid disease is important because such diseases often require long-term immunosuppressive therapy. A thorough history and skin examination must be obtained from all patients who receive radiation therapy and subsequently have blisters or eruptions on the skin, mucous membranes, or both. Appropriate diagnostic studies, including routine biopsy for histologic evaluation and direct immunofluorescence, serum for indirect immunofluorescence, and enzyme-linked immunosorbent assay, should be performed to exclude pemphigus or pemphigoid disease.