doi: 10.1111/j.1346-8138.2010.00906.x Journal of Dermatology 2010; 37: 937–938

LETTER TO THE EDITOR

Tegafur-induced hyperpigmentation of the tongue

Figure 1. Diffuse, black-gray hyperpigmentation limited tothe lateral sides of the tongue.

Figure 2. Mild basal pigmentation and increased melano-phages within the papillary dermis (hematoxylin–eosin,original magnification ·200).

Dear Editor,

Tegafur is a fluorinated pyrimidine analog of 5-fluoro-

uracil (5-FU), used in the treatment of advanced gas-

trointestinal neoplasms.1,2 It is usually well tolerated

and has been used as an alternative oral agent to

i.v. 5-FU. S-1 (TS-1; Taiho Pharmaceutical, Tokyo,

Japan) is a three-component combination drug which

includes an oral anticancer agent (tegafur) and two

modulators (5-chloro-2,4-dihydroxypyridine [CDHP]

and potassium oxonate [Oxo]). CDHP enhances the

pharmacological actions of 5-FU by potently inhibit-

ing its degradation and Oxo reduces the incidence of

gastrointestinal (GI) toxicities by suppressing the

action of 5-FU in the GI tract. With the use of S-1,

the total daily doses of tegafur have been reduced

to 1 ⁄10th the initial value (120 mg ⁄day of S-1 vs

1200 mg ⁄day of tegafur alone), making S-1 a patient-

friendly drug.3 Still, we come across people who

experience the cutaneous side-effects of tegafur in

our daily practice. We herein report a patient who suf-

fered tongue discoloration in relation to this drug.

A 44-year-old woman underwent a curative Billroth

II subtotal gastrectomy with D2 lymph node dissection

for gastric cancer (Borrmann IV + III, pT3N0M0). To

lower the risk of cancer recurrence and metastasis,

S-1 (TS-1; tegafur + CDHP + Oxo, 120 mg ⁄day) was

started. Medication was taken from day 1 to day 28 of

each 42-day cycle. The patient did not receive any

other treatment. Four months after the initiation of

therapy, our patient noted the sudden appearance of

dark spots on her tongue (Fig. 1). Physical examina-

tion revealed localized black-gray hyperpigmentation

limited to the lateral sides of the tongue. She denied

any pain or swelling. Few hyperpigmented macules

were also found on the lower lip and palms and there

was a history of mild hand–foot syndrome. A punch

biopsy from the tongue revealed mild basal pigmenta-

tion and increased melanophages within the papillary

dermis (Fig. 2). A diagnosis of tegafur-induced hyper-

Correspondence: Jun Young Lee, M.D., Ph.D., Department of Dermatol

137-701, Korea. Email: jylee@catholic.ac.kr

� 2010 Japanese Dermatological Association

pigmentation was made. We expect all lesions to clear

within months after the discontinuation of tegafur.

Hyperpigmentation of the tongue is rare and in

many cases occur genetically. Certain foods and bev-

erages (e.g. coffee and tea), habits (e.g. smoking or

chewing tobacco) and drugs (e.g. minocycline,

ogy, Seoul St. Mary’s Hospital, 505 Banpo-dong, Seocho-gu, Seoul

937

H.S. Kim et al.

antipsychotics, cytotoxic drugs) are also capable of

inducing tongue discoloration.4 A number of reports

have been made on tegafur-induced mucocutaneous

hyperpigmentation, however, rarely involving the ton-

gue.5 The mechanism of such pigmentation is largely

unknown but post-inflammatory hyperpigmentation

following drug-induced toxicity to keratinocytes has

been suggested as a cause. The abundance of mela-

nophages in our case strongly supports the theory.

Clinicians should be aware of tongue discoloration

associated with tegafur as this drug is being increas-

ingly used in patients with advanced carcinomas.

Like other tegafur-induced cutaneous hyperpigmen-

tation, pigmentation of the tongue is likely to resolve

within months after stopping the drug.5,6

Hei Sung KIM, Young Min PARK,

Hyung Ok KIM, Jun Young LEEDepartment of Dermatology, Seoul St Mary’s Hospital,

The Catholic University of Korea, Seoul, Korea

938

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2 Shirao K, Ohtsu A, Takada H et al. Phase II study of oralS-1 for treatment of metastatic colorectal carcinoma.Cancer 2004; 100: 2355–2361.

3 Shirasaka T. Development history and concept ofan oral anticancer agent S-1 (TS-1� ): its clinical use-fulness and future vistas. Jpn J Clin Oncol 2009; 39:2–15.

4 Scully C. Discolored tongue: a new cause? Br J Dermatol2002; 144: 1293–1294.

5 Rios-Buceta L, Buezo GF, Penas PF, Dauden E, Fernan-dez-Herrera J, Garcia-Diez A. Palmo-plantar erythrodys-aesthesia syndrome and other cutaneous side-effectsafter treatment with tegafur. Acta Derm Venereol 1997;77: 80–81.

6 Llistosella E, Codina A, Alvarez R, Pujol RM, de MorgasJM. Tegafur-induced acral hyperpigmentation. Cutis1991; 48: 205–207.

� 2010 Japanese Dermatological Association