Here we report the case of a patient presenting a bilateralrecurrence of pemphigus vulgaris following adjuvant radiotherapy treatment for a bilateral breast cancer. To date, after a careful review of the literature, we report 17 cases of radio-induced pemphigus in a context of breast cancer, including ours (9-24). These cases are described in Table 1. Five presented with pemphigus foliaceus (PF) and 12 with pemphigus vulgaris (PV). Four patients had an immunological history of which 3 presented a recurrence of pemphigus vulgaris during their treatment with radiotherapy. Patients ranged in age from 44 years to 92 years old with a median of 65 years old. In 7 cases (41%), the disease appeared very early within 1 month after the end of radiotherapy. In the majority of cases (12 cases; 71%), it occurred within 3 months and in 5 cases (29%) beyond 3 months with one very distant case at 22 months. Ten cases (59%) were initially limited to the irradiation area with secondary progression, 4 cases (23%) presented pemphigus limited to the irradiated area and 3 cases (18%) presented lesions in a non-irradiated area (mouth and esophagus). The diagnosis was made by direct immunofluorescence (DIF) in 13 cases (76%) supplemented in 6 cases by indirect immunofluorescence. Two cases were diagnosed by indirect immunofluorescence. The prescribed dose of breast radiotherapy treatment varied between 40 and 68 Gray. All but two of the patients were treated orally or intravenously with corticosteroids (prednisone or prednisolone) at medium to high doses. However, these treatments were not sufficient for the majority of patients (9 cases; 56%), as these patients required additional treatments such as methotrexate, dapsone, azathioprine, mycophenolate mofetil, and immunoglobulins (fSCIG). Finally, only four cases appeared (including our own) with acute toxicity documented on radiotherapy prior to the appearance of pemphigus lesions (grade 1 or 2 radiodermatitis).
In the light of these cases, we highlight a tendency towards the severity of these lesions with resistance to oral and general corticosteroids treatments in more than half of the cases (56%) as well as a tendency for the lesions progression in non-irradiated areas. Schauer et al. had indeed shown that for one third of documented cases of radio-induced pemphigus, it is necessary to add an immunosuppressant to control the disease (24). In three cases, rituximab, an anti-CD20 monoclonal antibody, had been used for rapid and complete lesions remission. In breast cancer, no corticosteroids resistant patients have been treated with rituximab. A clinical trial and two recent meta-analyses revealed high efficacy and safety of this systemic immunotherapy for the treatment of pemphigus (26-28). Thus, rituximab could be an interesting treatment choice in patients resistant to corticosteroids with radio-induced pemphigus associated with breast cancer. Otherwise, Hung et al. had shown a strong association between the development of autoimmune bullous disease (including pemphigus) and radiotherapy in breast cancer patients (29). Indeed, while breast cancer appears to be a risk factor for the development of these bullous diseases (OR: 1.5), the addition of radiotherapy leads to a substantial increase in the risk of appearance (OR: 2.9) (29).
Several studies attempted to explain the physiopathology of pemphigus. Among these, Ruocco et al. hypothesized a modification of keratinocyte antigens by the triggler factor, these keratinocyte antigens being the target of intercellular pemphigus antibodies (30;31). A more recent study showed that an alteration of the skin condition was often found, preceding the appearance of pemphigus (32). In our case, we could identify this skin alteration by the acute dermatitis found during radiotherapy treatment. This could lead to the exposure of new antigens and the formation of pemphigus autoantibodies. It should be noted that in the era of immunotherapy, pemphigus is likely to be a disease that will be more and more encountered by oncologists and therefore should not be disregarded (33).
In our case, diagnosis of paraneoplastic pemphigus, which is caused by a solid tumor in 10% of cases, was ruled out for several reasons. First, the patient had no typical mucosal lesions of paraneoplastic pemphigus phenotype. Then, immunological findings were not in favor of paraneoplastic pemphigus (anti-intercellular substance antibodies but no anti-basement membrane and anti-plakin antibodies). Finally, paraneoplastic pemphigus is associated with poor prognosis, deep organs involvement and most of the time a fatal outcome whereas in our case imaging at 3 and 6 months showed complete remission. Concerning the herpes zoster presented 2 months later, we think that it was favored by immunosuppression induced by the general steroid therapy. However, we cannot eliminate with certainty that it was not induced by radiotherapy as suggested in several articles (34,34).
In conclusion, radiotherapy appears to be a rare cause for the development of pemphigus in breast cancer with 17 cases (including ours) documented to date. Despite the rarity of this condition, the radiotherapist must be vigilant with regard to the occurrence of radio-induced pemphigus in a context of breast cancer in order to have the earliest treatment to limit the impact of this disease on the quality of life and prognosis of patients.