Simultaneous occurrence of distantly located multiple sebaceous carcinomas with elevated serum TGF-β in Muir-Torre syndrome

ARTICLE

ejd.2012.1705

Auteur(s) : Satoshi Nakamizo, Akiko Arakawa arakawa@kuhp.kyoto-u.ac.jp, Akihiko Kitoh, Satoshi Kore-Eda, Atsushi Utani, Yoshiki Miyachi

Department of Dermatology, Kyoto School of Medicine, 54 Shogoin-Kawara, Sakyo, Kyoto 606-8507, Japan

Muir-Torre syndrome (MTS) is a cancer susceptibility syndrome, defined as the association of sebaceous tumor and internal malignancy [1]. Tumors in MTS are characterized by the accumulation of microsatellite instability (MSI) in a repeated sequence of genomic DNA [2]. Although the TGF-β signal targeted by MSI is known to promote human colorectal MSI carcinogenesis [3], the mechanism of sebaceous tumourigenesis in MTS remains unclear.

A 66-year-old man presented with a 5-month history of skin tumors located on the right temple and lower abdomen. The patient had a past history of colon cancer, which had been excised 14 years before. His family history was significant for cancer susceptibility; colon cancer in his father and brother, lung cancer in his mother, and brain cancer in his sister. On physical examination, the two tumors showed similar phenotypes; one, ulcerative and centroclinal, 8×10 mm, on the temple and one, 10×13 mm, on the abdomen (figures 1A-B). The patient underwent wide excision of the two tumors with negative surgical margins. Histological findings of both tumors confirmed sebaceous carcinoma, showing sebaceous differentiation, frequent mitotic figures, and nuclear polymorphisms (figures 1C-D). A clinical diagnosis of MTS was made, based on the double sebaceous carcinomas associated with a past history of colon cancer. Molecular diagnosis of MTS was established by unequivocal MSI in the tumor genome, compared with genomic stability of the peripheral blood, which suggested accelerated accumulation of mutations throughout the tumor genome. Then, screening examinations for visceral malignancy were examined; colonoscopy revealed hyperplasic polyps and no clinically detectable cancer. Gastroscopy, computerized tomography (CT) scan on the head and thoraco-abdominal region, and urinary cytology did not detect tumors. After 6 months, he was hospitalized to find the cause of increased abdominal girth. On his face and abdomen, a total of 6 skin tumors had developed during this short period, all of which proved to be sebaceous carcinoma by histopathology. At this time, serum TGF-β1 was extremely high (16.1 ng/mL, normal 1.56∼3.24 ng/mL). The sebaceous tumors in this case demonstrated diffuse and cytoplasmic expression of TGFBR2 (figure 1E), compared to membranous expressions limited to the outer layers of nevus sebaceus and sebaceous hyperplasia in non-MTS (figure 1F). Abdominal CT revealed massive ascites, and multiple lymphadenopathies. Colonoscopy revealed superficial colon cancer, which had not been detected previously. Peritoneal metastasis was suspected with unknown origin, since he and his family refused further examinations.

Transforming growth factor-beta (TGF-β) promotes tumor development when mutational defects occur in the TGF-β pathway [4]. Since TGF-β signal components have multiple loci targeted by MSI, aberrant TGF-β signaling plays an important role in progression of colorectal tumor in MTS [5]. Though the precise mechanism remains unclear in this case, we speculated that high levels of serum TGF-β1 might have contributed to the synchronized multiple development of sebaceous carcinomas in the anatomically remote sites, probably via TGFBR2 or the other components in TGF-β pathway.

Disclosure

Financial support: none. Conflict of interest: none.

References

1. Abbas O, Mahalingam M. Cutaneous sebaceous neoplasms as markers of Muir-Torre syndrome: a diagnostic algorithm. J Cutan Pathol 2009; 36(6):613-9.

2. Boland CR, Thibodeau SN, Hamilton SR, et al. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 1998; 58(22):5248-57.

3. Bian Y, Caldes T, Wijnen J, et al. TGFBR1*6A may contribute to hereditary colorectal cancer. J Clin Oncol 2005; 23(13):3074-8.

4. Massague J. TGFbeta in Cancer. Cell 2008; 134(2):215-30.

5. Duval A, Hamelin R. Mutations at coding repeat sequences in mismatch repair-deficient human cancers: toward a new concept of target genes for instability. Cancer Res 2002; 62(9):2447-54.