Dear Editor, Scleroderma associated with
neoplasia is rare, with only a small number of cases reported. We describe 4 patients with paraneoplastic scleroderma who were treated at the I. Department of Dermatovenereology, St. Anna Hospital, during the period between 2004 and 2014. The patients were diagnosed with cholangiogenic
carcinoma, endometrial carcinoma, prostatic
adenocarcinoma, and
adenoma of the suprarenal gland. In the case of concurrent scleroderma and
tumor, four situations may occur: they can develop independently of each other; scleroderma may be induced by the
tumor; the
tumor can develop in the scleroderma; or the
tumor can be induced by immunosuppressive therapy. Sclerotization of the skin was described in association with
lung cancer,
carcinoid,
plasma cell dyscrasia,
cancer of the ovary, cervix, breast, esophagus, stomach, nasopharynx,
melanoma, and
sarcoma (1,2,5,7,10). Symptoms may be induced by substances secreted by the
tumor (
hormones,
cytokines, etc.) (9). Tumorous cells further induce cytotoxic and
autoantibody response. Scleroderma is characterized by immunological dysregulation, vasculopathy, and hyperproduction of the extracellular matrix by activated fibroblasts. Endothelial, inflammatory, and mesenchymal cells produce
cytokines,
chemokines, and
growth factors e.g.
Interleukin-1 (IL1),
Interleukin-6 (
IL6),
tumor necrosis factor alpha (TNF α),
collagen alpha 1,
connective tissue growth factor (CTGF) (3), and
basic fibroblast growth factor (bFGF). This factor is also produced by
lung cancer cells (4). The clinical picture of scleroderma and paraneoplastic scleroderma is similar. Diffuse thickening of the skin and/or sclerodermatous plaques can be seen. The histological picture is consistent with scleroderma. Capillaroscopy changes,
antinuclear antibodies (ANA), sclerodactyly, and
Raynaud phenomenon suggest the diagnosis of
systemic scleroderma (SS) (4). Our patients did not fulfill enough of the criteria for SS. Both diffuse and
localized scleroderma was seen in 3 patients and generalized
localized scleroderma in one case. All patients had a histological picture consistent with scleroderma, negative ANA and ENA
antibodies (Table 1, Figure 1). A 66-year-old woman presented with
a 10 months history of sclerodermatous plaques on her neck, trunk, and upper and lower extremities. The skin on her breasts and cheeks was diffusely indurated. Examination showed
thrombocytopenia, elevated
transaminases,
Cancer antigen 19-9 (Ca 19-9),
thyroid stimulating hormone (TSH), and anti-
thyroid peroxidase antibodies, dysmotility of the lower part of esophagus, hepatosplenomegaly,
cholecystolithiasis, and benign
polyps of colon. She was given
prednisone 40 mg/day but did not return for follow up. After 6 months she was diagnosed with cholangiogenic
carcinoma with metastatic disease and died shortly afterwards. A 74-year-old woman had
localized scleroderma on the trunk for three years. She was treated with
procaine penicillin for positive borrelia
Immunoglobulin M (
IgM)
antibodies. Her condition worsened suddenly with confluent scleroderma plaques on her trunk, extremities, and genital region, and vasoneurosis on her lower extremities; she was started on
prednisone 35 mg/day. Examination revealed
endometrial cancer. The patient underwent a
hysterectomy, adnexectomy, and
radiotherapy with curative effect. Scleroderma patches softened with residual
hyperpigmentation, and
prednisone was stopped two years later. A 80-year-old man had a month-long history of diffuse thickening and toughening of the skin on the forearms and lower legs and scleroderma patches on the thighs and shins. Examination revealed prostate
adenocarcinoma, and
therapy with
antiandrogen bicalutamide and
prednisone 15 mg/day was started. Two years after the diagnosis he continues with
bicalutamide treatment,
prednisone 5 mg q.a.d. and has residual toughening of the skin on his lower legs. A 62-year-old woman with seronegative
rheumatoid arthritis presented with diffusely tough skin on her extremities and trunk, present for 2 months. Examination revealed
cervicitis with a benign endometric
polyp,
cholecystolithiasis, borderline
pulmonary hypertension, and a hormonally inactive suprarenal
adenoma. She was given
prednisone 40 mg/day and
penicillamine with effect. In the 3rd year of
therapy she has residual induration of her lower legs and a scleroderma plaque in the lumbar region. She is monitored for her suprarenal
adenoma. Two patients had scleroderma at the same time as a malignant
tumor; in one patient the
localized scleroderma worsened rapidly at the time of the
tumor diagnosis, and in one patient a clinically silent
adenoma was found. Adrenal tissue can secrete molecules such as serotonine or bFGF involved in fibroplasia (3,6). One patient died of a metastatic disease, two patients after the successful treatment of the
tumor, and the patient with suprarenal
adenoma experienced softening of the skin and regression of scleroderma. Although paraneoplastic scleroderma is often classified as a pseudoscleroderma, we regard
neoplasia as a distinct triggering impulse for scleroderma. Recently, an association between
RNA polymerase I/III
antibodies in
systemic scleroderma and
cancer was suggested (8). Such studies may confirm the true link between scleroderma and
malignancy. These patients are characterized by older age, sudden onset, diffuse thickening of the skin, and/or generalized
morphea with a concurrent neoplastic process. In the case of a successful
tumor treatment, skin changes regress.