A 49-year-old woman insidiously developed spotty depigmentation of the chest along with thickened and bound-down skin of the upper torso. In addition, all of her fingers were swollen and her facial skin became so tight that she had difficulty smiling. Facial skin did not contain telangiectatic mats, and no digital tip ulcers were found. Finally, she complained about difficulty swallowing and dyspnea on exertion. Laboratory evaluation disclosed the following abnormalities: albuminuria, positive antinuclear antibodies (ANA) test (titer 1:160, speckled pattern), and positive anti-topoisomerase 1 antibody (Scl-70) test. Mild interstitial pulmonary fibrosis was detected on chest radiograph and decreased esophageal motility on manometry.
C. Progressive systemic sclerosis
Based on well-recognized and reasonably well-validated criteria, this patient clearly has scleroderma. The lack of certain signs and symptoms (such as Raynaud phenomenon, telangiectasia, and calcinosis cutis), exclude the limited variant of scleroderma, CREST syndrome. Conversely, the presence of other signs and symptoms (such as subjective dyspnea, objective interstitial lung disease, and a positive Scl-70 test) point to the more ominous progressive systemic sclerosis.[1,2] Progressive systemic sclerosis (PSS), although rare (approximately 10 cases per 100,000 population in industrialized nations in North America and Europe), remains a therapeutic challenge. Recent data suggest that sclerosis involving major organs (heart, kidneys, lungs) may occur early and rapidly, resulting in significant morbidity and mortality, regardless of any immunosuppressive or other interventions. Overall, PSS carries an increased risk of death compared to age- and sex-matched controls. The standardized mortality ratio of PSS compared to the general population has been estimated to be at least 1.5 and as high as 7.2. At the same time, a better understanding of disease pathogenesis has created a number of new target-based therapeutic options, especially for scleroderma-related cutaneous vasculopathy and pulmonary arterial hypertension.[5-7]
Aside from disease-specific complications, an increased incidence of cancer in PSS patients compared with the general population has been suggested based on case reports, small series, and observational reports. The most important limitation of such reports is that the data were retrospectively retrieved from record linkage between various healthcare databases, such as hospital discharge data sets and national registers, which did not contain detailed clinical information. As a consequence, relevant confounding or modifying factors, such as smoking habits and previous potentially carcinogenic immunotherapies (such as cyclophosphamide or methotrexate), could not be considered. Moreover, the time relationship between clinical onset of scleroderma and diagnosis of malignancy, a crucial issue to understand possible underlying mechanisms, was not always reported. In an effort to clarify this situation, a massive meta-analysis was recently performed and reported. From among the vast literature on scleroderma, 16 original studies, both prospective and retrospective, involving over 7,000 patients from the United States, Europe, Australia, Japan, and Taiwan were selected for inclusion and review. This meta-analysis disclosed a 75% increased risk of developing cancer among the PSS patients compared with their respective general populations. More specifically, the highest increased risk was for lung cancer, with a relative risk ratio of 4.3. There was a predominance of adenocarcinoma (32%) and squamous cell carcinoma (32%), with the remaining cases including similar numbers of small-cell lung cancer, undifferentiated non–small-cell cancer, and oat-cell carcinoma. The second highest increased risk was for the grouped category of hematologic malignancy, with a relative risk of 2.24. Interestingly, three of four studies included in this meta-analysis suggested an increased risk of esophageal cancer in association with PSS, but the fourth (and largest, involving over 2,000 patients) failed to demonstrate this association.
What is the importance of these data? First, active surveillance of scleroderma patients for early detection of cancer is advisable. With regard to the lung, specific guidelines to define modalities and timing of screening need to be developed. Does the benefit of a periodic CT scan of the lung outweigh the risk of exposure to radiation? Secondly, alkylating agents should be used very judiciously in PSS as they may further increase the susceptibility to cancer in patients who already carry an increased risk.