To the Editor:

We read with interest the review article by Varga (1), in which modulation of transforming growth factor β (TGFβ)–mediated profibrotic action by the Smad protein family was discussed. In systemic sclerosis (SSc), inflammatory cells infiltrating lesional tissues secrete TGFβ, which also stimulates connective tissue growth factor (CTGF) secretion in lesional fibroblasts (1). TGFβ, however, is also secreted from other cells, such as tumor cells. In particular, expression of TGFβ1 is detected in 22.8–35.9% of patients with gastric carcinoma (2, 3). Here we discuss a patient in whom severe proximal scleroderma, esophageal dysmotility, and bibasilar pulmonary fibrosis developed along with development of TGFβ1–producing gastric carcinoma.

In December 2000, an 83-year-old Japanese man noticed sclerotic skin changes in his neck and upper/lower extremities and visited the dermatology clinic of Keio University Hospital. A skin biopsy specimen obtained from his right thigh showed hyperproliferation of swollen, homogeneous collagen fibers. The histologic skin changes were identical to those of SSc but not of scleredema. He did not present with Raynaud's phenomenon, sclerodactyly, digital pitting scar, or telangiectasia. Because the sclerotic skin changes subsequently spread to his upper chest, abdomen, back, and buttocks, he was admitted to the rheumatology section in our hospital. His total skin thickness score (TSS) (4) was 66 (based on a possible total score of 104). A blood test revealed no evidence of diabetes mellitus. Serum antinuclear antibodies and rheumatoid factor were not detected, but a slight increase in the white blood cell count (10,000/mm3), the erythrocyte sedimentation rate (18 mm/hour), the C-reactive protein level (0.5 mg/dl), and the IgG level (2,290 mg/dl) was observed. Serum levels of interleukin-6 (IL-6) (5.41 pg/ml; normal <4.62) and plasma TGFβ1 (2.15 ng/ml; normal <1.80) as determined by enzyme-linked immunosorbent assay were also elevated. Gastrointestinal examination detected severe esophageal dysmotility and gastric carcinoma. An endoscopic biopsy of the gastric carcinomatous lesion showed poorly differentiated adenocarcinoma. A full-body computed tomography scan indicated bibasilar pulmonary fibrosis but no evidence of lung or abdominal metastasis. Two months after total gastrectomy, the patient's esophageal dysmotility and pulmonary fibrosis had not changed, but his TSS improved to 29. The serum level of IL-6 was normalized (1.30 pg/ml), and plasma TGFβ1 in post-tumor resection was decreased (1.88 ng/ml).

Reverse transcriptase–polymerase chain reaction (RT-PCR) analysis of samples from the resected stomach was performed (5). Total RNA from specimens obtained from both carcinomatous and normal sites (Figure 1A) was isolated by guadidinium thiocyanate–phenol–chlorform extraction. Complementary DNA (cDNA) amplification for β-actin (541 bp) was performed for 30 cycles, with an annealing temperature of 58°C. Amplification of cDNA for TGFβ1 (247 bp) was performed for 35 cycles, with an annealing temperature of 65°C. Primer sequences for β-actin and TGFβ1, respectively, were as follows: forward 5′-GTG-GGG-CGC-CCC-AGG-CAC-CA-3′, reverse 5′-CTC-CTT-AAT-GTC-ACG-CAC-GAT-TTC-3′; forward 5′-AAG-TGG-ATC-CAC-GAG-CCC-AA-3′, reverse 5′-GCT-GCA-CTT-GCA-GGA-GCG-CA-3′. Aliquots of the PCR products (7.5 μl) were separated and visualized with ethidium bromide staining after electrophoresis on a 1.5% agarose gel in Tris–acetate–EDTA buffer at 100V for 20 minutes (Figure 1B). TGFβ1 messenger RNA (mRNA) was detected in the carcinomatous site but not in the normal gastric site.

thumbnail image

Figure 1. A. Normal (1) and carcinomatous (2) sites in the resected stomach. B, Reverse transcription–polymerase chain reaction analysis. Transforming growth factor β1 (TGFβ1) was detected (247 bp) in the sample obtained from the carcinomatous site but not in that obtained from the normal site. β-actin (541 bp) was amplified in both samples.

Download figure to PowerPoint

Sclerotic skin diseases resembling SSc and occurring in patients with malignant tumors or other diseases are sometimes referred to as pseudoscleroderma or pseudosclerosis (6, 7). Because the distribution of skin sclerosis in our patient was different from that of SSc, he was diagnosed as having pseudoscleroderma associated with an advanced gastric carcinoma. Querfeld et al described a patient with pseudoscleroderma associated with lung cancer, in whom expression of collagen α1 and CTGF mRNA were markedly increased in fibroblasts scattered throughout the dermis (7). Although acrosclerosis and nailfold changes were observed in that patient, TGFβ1 expression in the lesional skin was not detected, and which tissue secreted collagen α1– or CTGF-stimulating factors such as TGFβ was not determined. The patient described by Querfeld et al had high titers of antinuclear antibodies and IgM anticardiolipin antibodies but not scleroderma-specific autoantibodies. Our experience together with that of Querfeld et al suggests that certain tumor cells secrete soluble factors that induce SSc-mimicking skin changes and organ involvement.

In our patient, removal of TGFβ1-producing tumor cells resulted in the amelioration of sclerotic skin changes. This is the first report of pseudoscleroderma associated with TGFβ1-secreting gastric carcinoma. Further study of the abnormal up-regulation of TGFβ1 (including the latent form of TGFβ1) in malignant tumors is needed to clarify this association.

Takao Fujii MD, PhD*, Tsuneyo Mimori MD, PhD*, Noriko Kimura MD†, Shinji Satoh MD†, Michito Hirakata MD, PhD†, * Kyoto University Graduate School of Medicine, Kyoto, Japan, † Keio University School of Medicine, Tokyo, Japan.