Initially localized bullous pemphigoid at the irradiation site of breast carcinoma

ARTICLE

A 78 year-old women was admitted in April 1998 with a seven month history of erosions on the right thorax. In 1994, she had undergone surgery at this site for an infiltrating duct carcinoma of the right breast (stage pT2N0G3) and afterwards had received radiotherapy at a total energy dose of 50 Gy. She then came to us for clinical investigations as she was suspected of having chronic radiodermatitis. The dermatological examination revealed large erosions on the lateral aspect of the mamma with haemorrhagic crusts surrounded by erythema and a few clear blisters at the margin (Figs. 1 and 2). Histological examination of one lesion (Fig. 3) revealed a subepidermal blister with a moderately dense, upper dermal infiltrate composed of neutrophils, abundant eosinophils, some mononuclear cells and a relatively high number of plasma cells.

Initially localized bullous pemphigoid at the irradiation site of breast carcinoma

Direct immunofluorescence of perilesional skin showed a linear and continuous band of C3 and IgG deposition along the basement membrane zone. Routine laboratory parameters were within normal limits except for an elevated C-reactive protein and erythrocyte sedimention rate as well as an elevated gamma GT. Serological findings for syphilis and borreliosis as well as lesional PCR for Borrelia-antigen were negative. Indirect immunofluorescence analysis of the patient's serum revealed a positivity for anti-basement-membrane-zone (BMZ) antibodies 1:320, and western immunoblotting of serum confirmed autoantibodies against the 180 kDa and the 230 kDa BP antigen. HLA typing revealed HLA-DR 11 and 13 as well as HLA DQ 03 and 06. Tumor markers, i.e. CA 15-3, TPA, NSE, and CEA were within the normal range, and thorough examination including thoracoabdominal scan did not reveal any sign of local breast cancer relapse or distant metastases.

Comment

There is only a limited number of case reports about bullous pemphigoid (BP) in its localized subtype which has been observed to arise e.g. under the adhesive pad at an ostomy site [1], on the irritated stump of an amputee with a tight fitting artificial leg [2] as well as in the area used for the harvesting of mesh grafts [3]. Radiotherapy may cause some well recognized cutaneous side effects such as acute and chronic radiodermatitis, and in rare cases it may induce rheumatoid arthritis, systemic lupus erythematosus, subacute cutaneous lupus erythematosus [4], systemic scleroderma, dermatomyositis/polymyositis and even graft-versus host disease as well as lichen sclerosus et atrophicus. A review of the literature revealed however, only 8 patients in whom radiation-induced bullous pemphigoid occurrred within the boundaries of the radiation treatment field [5-9]. In all cases, the total dose of energy delivered to the patient varied from 20 to 80 Gy, and the median time interval from the last irradiation treatment to the appearance of first lesions was approximately 9 months. Our patient developed BP more than three years after radiotherapy, which was initially confined strictly to the irradiation area. Seven months after this development of a localized BP, a few fresh blisters appeared in a disseminated pattern over the ventral and dorsal trunk and the left upper leg. The inflammatory infiltrate of the erosive-bullous lesions from the irradiation area was rich in plasma cells, so that a concomitant borreliosis had to be excluded. High dose prednisolone was administered, but because of a suspicion of borreliosis this was supplemented with the antibiotic amoxicillin. Prednisolone was subsequently reduced to 10 mg a day, and then combined with mycophenolate mofetil (Cellcept^®) at 2 x 1,000 mg a day, which has recently been proven to be efficacious in the treatment of BP [10]. The new xenobiotic mofetil is a non-competitive, selective, and reversible inhibitor of the enzyme ionisine monophosphate dehydrogenase, which controls the de novo synthesis of guanosin nucleotides. Guanosin nucleotides are an important substrate of cell proliferation in lymphocytes, so that mofetil acts as a fairly specific inhibitor of lymphocyte proliferation. The drug also interferes with T cell-B cell collaboration, and therefore inhibits the production of autoantibodies [11, 12]. In our patient, clinical symptoms cleared after six weeks of therapy. Concerning the localized subtype of bullous pemphigoid, there seem to exist different variants: the localized BP of the lower legs of older men [13], the localized BP of the mouth [14], the dyshidrosiforme manifestation [15] which remains localized in 15-30% of cases, the cicatricial, localized BP (Brunsting-Perry type) and a heterogenous subgroup of the remaining forms of chronic localized BP. In a certain number of patients, as in the case of our patient, the disease remains localized for only a limited time. It was also the case that in our patient it was possibly precipitated by preceeding cancer surgery in conjunction with subsequent high voltage irradiation. Pathogenesis of so-called "initially localized BP" has not yet been elucidated in detail. Increased permeability of blood vessels, leading to an increased deposition of antibodies on the basement membrane zone, and alterations in the basement membrane zone following irradiation with unmasking of the antigen, as well as modification of antigenicity and triggered antigen production have been discussed. Alternatively, a local modification of the immune system induced by radiotherapy must also be considered since radiotherapy has been found to depress circulating T-lymphocyte levels and certain T cell functions for more than one year following treatment [16]. To what extent the unusually large number of dermal plasma cells found at the site of BP lesions in our patient may have contributed to the initiation of the disease remains an open question. Antigen sharing between tumor tissue and the basement membrane zone has also been discussed as a pathogenic mechanism. Although normal human breast epithelium is not stratified, breast epithelium has been demonstrated to express hemidesmosomes and hemidesmosome protein components at the basal lamina in vivo. Invasive breast cancer cells have lost this functional characteristic, on the other hand, primary human malignant breast cells in culture exhibit a mixture of hemidesmosome phenotypes [17]. BP antigens are known to consist of hemidesmosome proteins (BP-Ag 1 = 230 kD; BP-Ag 2 = 180 kD). Concerning these pathogenic factors, it may be hypothesized that BP occurring subsequently to irradiation, especially in conjunction with invasive breast carcinoma, may represent a distinct sub-entity. Future studies may define more clearly the cascade of molecular events enrolled pathogenically in this heterogenous group of diseases called "initially localized BP".

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