Scleroderma and malignancy. Mechanisms of interrelationship

ARTICLE

Introduction

Scleroderma (progressive systemic sclerosis) is an autoimmune disease with a usually progressive and frequently fatal course. It is characterised by widespread alterations in connective tissue, vascular lesions and immunological abnormalities. The pathogenesis remains unclear although genetic predisposition, auto-antibodies and auto-aggressive T-lymphocytes seem to be of pathogenetic relevance.

A variety of associations between scleroderma and malignancies have been described in recent years. These include bronchial carcinoma, lymphoma, melanoma, epithelial skin cancer, leukaemia, carcinomas of breast, uterus, liver, stomach, oesophagus, colon, ovary, kidney, urothelium and prostate [1-4]. Furthermore, various scleroderma-like skin lesions have been described in patients suffering from malignancy.

The significance of association between scleroderma and malignancy has been a source of controversy in recent years. However, today an increased coincidence is assumed, confirmed by extensive long-term studies [5-9].

A large number of mechanisms for the interrelationship between scleroderma and malignancy were found and/or suggested in earlier studies and reports.

In general, the cases of coincidental appearance of both may be divided into three groups, depending on the suggested pathogenetic relationship: 1) independent appearance of both scleroderma and neoplasia; 2) malignancy secondary to scleroderma and 3) scleroderma secondary to malignancy.

Independent appearance of both scleroderma and neoplasia

Two factors may cause an increased independent association of both scleroderma and neoplasia: age and disease susceptibility.

Several communications report the increase of malignancy as well as of autoimmune diseases with ageing [10, 11]. The increased appearance of both malignancies and scleroderma may be causative for an increased association-ratio in older patients.

Moreover, disease susceptibility-genes for scleroderma and for neoplasia might be linked to the major histocompatibility complex. Lee et al. found in 1983 an increased incidence of the HLA-DR2 antigen in scleroderma and breast cancer patients. They deduced from this that HLA-DR2-positive patients might be a subset with increased susceptibility to both diseases [12].

Malignancy secondary to scleroderma

Several authors discuss a higher risk of developing cancer for patients suffering from scleroderma. The corresponding hypothesis is that scleroderma leads to changes in biological structures that predispose to subsequent malignant transformation. These mechanisms are mentioned especially in the genesis of bronchial and oesophageal carcinomas. Long-standing pulmonary fibrosis is suspected to predispose to bronchial carcinoma, decreased oesophageal motility and reflux oesophagitis to predispose to oesophageal carcinoma.

A variety of studies support this hypothesis. In an epidemiological follow-up study, Roumm et al. found an increase of lung cancer in patients with systemic sclerosis, which occurred in the setting of long-standing pulmonary fibrosis [5]. Winkelmann et al., Peters-Golden et al. and Abu-Shakra et al. also provided evidence for these findings [9, 13, 14]. Nearly all cases of lung cancer were subsequent lesions, occurring after an average of 9 years after the diagnosis of scleroderma. Pulmonary fibrosis regularly preceded the cancer [5, 9, 13, 14].

In a population-based retrospective cohort study, including 917 patients with systemic sclerosis, Rosenthal et al. found an increased standardised incidence ratio (SIR) of 4.9 to develop lung cancer. Furthermore they found an increased risk of non-melanoma skin cancer in these patients (SIR: 4.2). They concluded that specific tumour sites correspond to the sites commonly affected by fibrosis, such as the lung and skin [6].

In oesophagus-carcinoma a similar interaction is supposed. Sclerosis of the oesophageal mucosa and muscles caused by scleroderma leads to a decreased oesophageal motility and an insufficiency of the lower sphincter. These factors may predispose to cancer. The fact that most oesophageal cancers in scleroderma patients are localised in the sub-oesophageal area and that most of these cancers are adeno-carcinomas supports this theory. Barrett's oesophagus might be an important pathogenetic link [1, 15, 16].

An additional factor of possible relevance for developing neoplasia in scleroderma-patients is immunosuppressive drugs. Many therapeutic agents used in recent years for the treatment of scleroderma are known to have a carcinogenic effect [17]. Unfortunately, comprehensive literature on this subject is not available.

Scleroderma secondary to malignancy

Various case reports describe scleroderma secondary to malignancy. Especially in breast cancer a close temporal relationship between this carcinoma and scleroderma has been described several times [5, 12, 18, 19]. For example, Abu-Shakra presented a case of scleroderma that appeared secondary to breast cancer. In this case skin involvement definitely worsened with recurrence of the carcinoma [9]. In another case scleroderma improved after treatment of the malignancy [18]. Similar observations have been made in prostate carcinoma and lymphoma [7, 20, 21].

Many factors have been supposed to be of pathogenetic relevance for the genesis of scleroderma in patients suffering from neoplasia. These include cytokines, growth factors, hormones, antigen presentation, antibody-genesis and cell-immunological disturbances. Along with these factors, cancer therapy may have an additional effect.

Cytokines

Cytokines and growth factors have been implicated in the pathogenesis of scleroderma. Transforming-growth-factor-beta (TGFbeta) is a ubiquitous growth factor and generally considered to be the most profibrotic cytokine, responsible for the upregulated transcriptional activity of extracellular matrix genes in activated scleroderma fibroblasts [22]. Some malignancies, especially breast, renal and ovarian cancers, produce TGFbeta in excess [23-26]. This added TGFbeta-secretion might accelerate sclerodermatous processes in these malignancies [27].

Cytokines also modulate the expression of cellular adhesion molecules important in cell adhesion and migration. Evidence exists to suggest that both scleroderma and breast cancer show a marked diminution of alpha₁beta₂ integrins. This diminution correlates with extensive collagen production in scleroderma as well as with an increased invasiveness of neoplastic cells in breast cancer [27].

Hormones

Paraneoplastic hormone-expression might play an additional role. MacDonald et al. were able to show that serotonin injected into rats induces dermal fibrosis. Similar effects may be found in human patients with seretonin-producing tumours who exhibit skin-changes resembling scleroderma [28]. In addition, Ratnavel et al. reported scleroderma associated with the carcinoid syndrome and suggested a pathogenetic relevance of tryptophan and serotonin in the genesis of scleroderma [29].

Autoantigens

Various paraneoplastic mechanisms interfering with the immune system may also favour the genesis of scleroderma. An accelerated lysis (either spontaneous or therapeutically induced) of neoplastic tissue sheds enlarged quantities of tumour related antigens. Their stimulatory effect may result in the synthesis of antibodies that cross-react with normal tissue components [30-32].

Some tumours express typical features of autoimmunity. Wang and Chan report an enhanced expression of both SSA/Ro antigens (52 and 60 kD) in the human breast cancer cell line MCF-7 [33]. Antibodies targeting these antigens are frequently found in patients with systemic scleroderma [34].

Autoantibodies

Another suggested factor is autoantibodies, produced by the neoplastic tissue itself. This phenomenon occurs in B-cell lymphoma and in monoclonal gammopathies. Some of the patients suffering from these diseases produce typical autoimmune antibodies such as anti-SSA/Ro, anti-SSB/La and anti-Sm-RNP. However, a small number of them present not only the serological parameters of an autoimmune disease, but also the typical clinical picture [31, 35, 36].

Disturbances of cellular immunity

Disturbances of the cellular immune system may also appear paraneoplastically. Tatal and Bunin reported that an imbalance of the normal immunoregulatory balance augments CD3CD4-cell activity or decreases CD3CD8-cell activity. This perturbation effect may be attributed to both the primary neoplastic disorder or to the cytotoxic immunomodulatory therapy [31]. Some tumours induce immunological disturbances akin to those of chronic graft versus host disease, clinically resembling scleroderma [37, 38].

Cancer therapy

Along with the described paraneoplasic effects, cancer-therapy might play an additional role. Scleroderma-like lesions are a ubiquitous side effect of anti-tumour drugs. An aggravation of pre-existing scleroderma due to therapeutic agents is also known. For example, bleomycin sulphate, a widely used anti-tumour agent, may produce pulmonary fibrosis and sclerotic skin changes [39]. A further example is uracil-tegafur, a second-generation anti-cancer agent, which can induce scleroderma-like reactions [40]. Moreover, Puett et al. reported a rapid exacerbation of scleroderma in a patient treated with interleukin-2 and lymphokine activated killer cells for renal cell carcinoma [41].

Radiation treatment can induce dermal sclerosis as well. Abu-Shakra et al. reported two patients with exaggerated fibrosis with systemic sclerosis following radiation therapy. In addition, localised scleroderma has been reported in patients with breast cancer treated with radiation [42-44]. Moreover, some authors suggest an influence of silicone-implants on the pathogenesis of scleroderma. It is suggested that the disease might be induced by the conversion of silicone in the prosthesis to silica, a chemical which can affect the immune system [45, 46].

Questions (answers to be given in the next issue)

Case study 1:

A 61-year-old man with a cutaneous sclerosis of both legs. One year before the lesions started on the lower legs then spread to the thighs.

He smokes up to 30 cigarettes per day and regularly drinks beer and spirits. Weight loss or night sweat had not been observed

1. Which clinical and imaging investigations are required?
a) Clinical whole-body examination
b) Digital rectal examination
c) Chest X-ray and possibly computed tomography or bronchoscopy
d) Gastroscopy
e) Phlebologic consultation with Doppler ultrasonography or phlebography
f) All of them

2. Which laboratory investigations are useful?
a) Routine laboratory investigation including differential blood cell count, creatine kinase and lactate dehydrogenase
b) Detection of autoantibodies, including anti-Scl 70, -Ro/SSA, -La/SSB, -Sm, -RNP
c) Detection of a well-selected spectrum of tumor markers for example NSE, CEA and PSA
d) All of them

3. What kind of procedure is correct if the above investigations were without pathologic result?
a) Immunosuppressive therapy
b) Chemotherapy
c) Phototherapy
d) Radiation
e) Re-evaluation of the above investigations after a period of about three months.
f) A follow up examination of the patient is not necessary

Case study 2:

A 48-year-old woman with a long-standing pulmonary fibrosis caused by progressive systemic scleroderma presents because of persistent cough. Over the previous four months she had lost eight kilograms body weight without dieting.

4. Which of the following investigations has the highest priority:
a) Clinical whole-body examination
b) Detection of the serum autoantibody-profile
c) Imaging of the lung (X-ray, bronchoscopy, CT)
d) Pulmonary function test
e) Mammography

5. Which of the following statements is correct?
a) All patients with scleroderma sooner or later develop a malignancy
b) Scleroderma patients have a higher incidence of all cancer types.
c) Scleroderma patients with a long standing pulmonary fibrosis have an increased risk of developing lung cancer
d) Scleroderma patients have a lower incidence of cancer

6. Which of the following statements is correct?
a) Malignancy may appear secondary to scleroderma
b) Scleroderma may appear secondary to malignancy
c) Both scleroderma and malignancy may appear independently
d) All of them

CONCLUSION

The epidemiological studies carried out in recent years suggest an increased association of scleroderma and malignancies. Especially, the risk of scleroderma-patients developing neoplasia seems to be increased. Sclerotic skin changes, pulmonary fibrosis and decreased oesophageal motility due to scleroderma seem to predispose to non-melanoma skin cancer, lung cancer and oesophagus carcinoma, respectively (see above).

Equally, some tumour-entities may precede scleroderma. In this context breast carcinoma should be mentioned especially. Several case reports show a near concurrence of this cancer and scleroderma suggesting some aetiological relationship [5, 12, 18, 19]. Similar observations were made in prostate carcinoma and lymphoma [7, 20, 21].

However, despite the various clinical observations of the paraneoplastic appearance of scleroderma, a pathogenetic link could not be identified.

Unfortunately, most investigations done in the last few years focus on the risk of scleroderma-patients developing neoplasia. Less attention was paid to the sclerotic skin-changes appearing secondary in tumour-patients.

However, these paraneoplastic situations may be of particular importance for learning more about the pathogenesis of scleroderma.

Acknowledgements

The author would like to acknowledge the assistance of Alice von Canstein in preparation of this manuscript.

Article accepted on 5/2/02

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