Department of Rheumatology, University Hospital of Wales, Cardiff, UK
SIR, Systemic sclerosis (or scleroderma) (SSc) is a disorder characterized by pathological fibrosis of the skin and/or internal organs [1]. Patients with this condition are known to suffer an increased mortality rate, with a 10-yr survival rate of approximately 50% [2, 3]. Factors contributing to early death include scleroderma-related causes, such as pulmonary fibrosis, renal crisis and pulmonary hypertension. Large population studies have also shown that there is a higher incidence of cancer, particularly lung carcinoma, in patients with SSc [47]. Defining the pathological basis for this relationship, however, has proved difficult as patient numbers are few and presentations are widely variable, with reported cases of various types of tumour affecting numerous sites. In most instances malignancy follows the diagnosis of SSc by a period of years [47], although, less commonly, it can precede the development of SSc. We describe a patient who developed rapidly progressive SSc 10 months after the diagnosis of nasopharyngeal carcinoma. To our knowledge, this association has not been reported previously. We also consider the factors that may influence the relationship between SSc and cancer, with emphasis on the emergence of skin fibrosis in patients with preceding malignancy and chemotherapy.
A 52-yr-old male patient with a diagnosis of nasopharyngeal carcinoma received surgical resection and post-operative chemotherapy with cisplatin and 5-fluorouracil. Subsequently he was given consolidation radiotherapy to the head and neck area. He presented to the rheumatology out-patient clinic some 7 months later with a 3-month history of progressive skin tightness and tethering affecting the face and neck, upper thorax and both arms and legs distal to the elbows and knees. Over the same period he also developed severe Raynaud's phenomenon involving the hands and feet. The courses of chemotherapy and radiotherapy had been completed 4 months and 1 month respectively, before the onset of his skin thickening. There was no other significant personal or family history. On systems review, he complained of hoarseness and dysphagia for solids dating from the time of surgery/radiotherapy. There was no history of lower gastrointestinal symptoms or symptoms suggestive of malabsorption. He was dyspnoeic on moderate exertion.
Physical examination revealed that he was markedly cachectic but had normal vital signs. There was diffuse scleroderma affecting the head and neck, upper trunk and the distal aspects of all four limbs. The hands and feet were poorly perfused and cold but there was no ulceration, finger pulp loss or infarction. Chest examination revealed a few bibasal crepitations only. The remainder of his examination was within normal limits and there was no evidence of active malignancy.
Investigations showed normal full blood count, renal profile, erythrocyte sedimentation rate and C-reactive protein. Serum albumin was reduced (20 mg/dl) with otherwise normal liver function tests. Autoantibody screen was negative for antinuclear factor, rheumatoid factor and antibodies to extractable nuclear antigen, Scl-70 and Jo-1. Immunoglobulins were normal, as were complement levels.
Chest X-ray showed a left basal consolidation with no parenchymal disease elsewhere, and a high-resolution computed tomography scan of the thorax 2 weeks later was normal. A pattern consistent with a minimal restrictive defect was noted on pulmonary function tests. Barium swallow confirmed the presence of aspiration and 24-h urine studies for protein estimation and creatinine clearance were normal. A skin biopsy taken from the edge of an area of involved skin showed changes consistent with a sclerodermatous process, i.e. thickening of the collagen fibres in the lower dermis and subcutaneous fibrous septae with obliteration of the normal fat surrounding sweat glands.
Initial treatment with maximal doses of nifedipine and Iloprost (prostacyclin) infusions for his Raynaud's symptoms proved ineffective. Thereafter he was given a trial of oral methotrexate (10 mg weekly) on the basis of his rapidly progressing skin disease and the early lung involvement that was possibly associated with it. There was no response after 4 months of treatment, and similarly a 2-month trial of penicillamine also proved unsuccessful. His skin disease has advanced such that he currently has extensive truncal involvement and scleroderma proximal to the elbows and knees bilaterally. A percutaneous endoscopic gastrostomy has been inserted in view of his severe dysphagia and deteriorating nutritional status, and he has recently been commenced on minocycline which, in an uncontrolled study, has proven beneficial in a small number of patients with progressive skin disease [8].
A recent review of the demographics and survival of patients with SSc found an increased cancer mortality rate, and this is supported by three large population-based studies from Sweden and Canada, all of which showed elevated standardized incidence ratios (the ratio of observed to expected incidence) for lung cancer in SSc (Table 1). The only variable of predictive importance in these patients was the presence of prior interstitial pulmonary fibrosis, often long-standing. A retrospective study of 344 Danish patients with systemic sclerosis found an overall increased mortality, with a standardized mortality ratio of 2.9 [7]. Patients with diffuse skin disease and those under 35 yr were significantly more likely to suffer early mortality. In these patients, excess mortality was secondary to both SSc-related and SSc-unrelated causes. All groups of patients had a higher mortality rate from SSc-unrelated causes, however, and this included a higher incidence of malignancy, 20% of all deaths arising due to cancer, especially lung neoplasms.
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Exaggerated fibrosis, i.e. severe localized skin thickening, has been described previously in two patients with known SSc who subsequently required radiotherapy for cancer [9]. In addition, localized SSc has been reported in the radiation ports of six patients being treated for breast cancer [10]. The fasciitis panniculitis syndrome (characterized histologically by thickening and inflammation of the septae in subcutaneous fat and obliteration of adipose lobules) is a well-known paraneoplastic condition resulting in typical hidebound skin affecting the extremities in the absence of vascular or organ dysfunction. The de novo development of diffuse sclerodermatous changes after radiotherapy has not been described, however.
A number of chemotherapeutic agents may contribute to the development of SSc, especially bleomycin and more recently docetaxel, but in general these skin changes are limited in their distribution and affect only the extremities. The skin thickening also tends to occur within a short time after receiving chemotherapy and improves after its cessation.
In our patient, the skin changes progressed extremely rapidly and were diffuse in distribution rather than limited to the port of radiation. It is also unlikely that the chemotherapy he had received some months previously contributed to the skin changes, as 5-fluorouracil and cisplatin have not been implicated in this process.
In the majority of cases describing the concurrence of SSc and cancer, malignancy occurs some years after the diagnosis of SSc. Rarely, however, the reverse is true and it is likely that the factors contributing to the association are different in these two settings. A close temporal relationship between the onset of SSc and breast carcinoma has been noted by previous investigators [5, 6, 11] and a number of factors make this association particularly interesting. Firstly, in the majority of these patients, malignancy either predated or coincided with the onset of SSc (not all developed systemic features). Furthermore, the possibility that chemotherapeutic or radiotherapeutic regimens used in the treatment of breast cancer may have contributed to the evolution of SSc is remote, given the short interval between the onsets of the two conditions and the development of organ fibrosis at remote sites which were not targeted by such treatment.
In this case, SSc developed 67 months after the diagnosis of nasopharyngeal carcinoma; this association has not been described previously and, although the mechanisms responsible for the increased risk of malignancy in patients with SSc remain undefined, physicians should be aware of this association.
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