CD4/CD8 double-negative T-cell lymphoma successfully treated with a combination of bexarotene and total skin electron beam therapy

概要

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CD4/CD8 double-negative T-cell lymphoma
successfully treated with a combination of
bexarotene and total skin electron beam therapy

Tanigawa, Ayano ; Fukumoto, Takeshi ; Imamura, Shinya ; Nakamura,
Korefumi ; Tanaka, Tomonori ; Itoh, Tomoo ; Nakano, Eiji ; Nishigori,…
Chikako ; Kubo, Akiharu
(Citation)
The Journal of Dermatology,50(7):e210-e212

(Issue Date)
2023-07

(Resource Type)
journal article

(Version)
Accepted Manuscript

(Rights)
This is the peer reviewed version of the following article: [Tanigawa, A., Fukumoto,
T., Imamura, S., Nakamura, K., Tanaka, T., Itoh, T., Nakano, E., Nishigori, C. and
Kubo, A. (2023), CD4/CD8 double-negative T-cell lymphoma successfully treated with a
combination of bexarotene and total skin electron beam therapy. J Dermatol, 50: e210…
e212.],
which has been published in final form at [https://doi.org/10.1111/1346(URL)
8138.16739]. This article may be used for non-commercial purposes in accordance with
https://hdl.handle.net/20.500.14094/0100482872
Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be
enhanced, enriched or otherwise transformed into a derivative work, without express
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platforms, services and websites other than Wiley Online Library must be prohibited.

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CD4/CD8 double-negative T-cell lymphoma successfully treated with the

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combination of bexarotene and total skin electron beam therapy

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RUNNING HEAD: CD4/CD8 double-negative T-cell lymphoma treated with

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bexarotene and TSEBT

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Ayano Tanigawa1, Takeshi Fukumoto1 ＊ , Shinya Imamura1, Korefumi Nakanura1,

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Tomonori Tanaka2, Tomoo Ito2, Eiji Nakano1, Chikako Nishigori1, and Akiharu Kubo1

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1

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School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 6500017, Japan

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2

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School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 6500017, Japan

Division of Dermatology, Department of Internal Related, Kobe University Graduate

Division of Pathology, Department of Internal Related, Kobe University Graduate

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CORRESPONDING AUTHOR: Takeshi Fukumoto, M.D., Ph.D.

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Division of Dermatology, Department of Internal Related, Kobe University Graduate

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School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan

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Tel.: +81-78-382-6134

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Fax: +81-78-382-6149

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E-mail: fuku@med.kobe-u.ac.jp

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FUNDING STATEMENT: None.

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CONFLICTS OF INTEREST: None.

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INFORMED CONSENT: We obtained the written informed consent of the patient.

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KEYWORDS: CD4/CD8 double-negative, T-cell lymphoma, bexarotene, total skin

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electron beam therapy

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AUTHORS’ CONTRIBUTIONS： A.T., T.F., K.N., and C.N. designed the study. A.T.,

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T.F., S.I., E.N., T.T., T.I., C.N., and A.K. drafted the manuscript. A.T., T.F., S.I., K.N.,

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E.N., T.T., T.I., C.N., and A.K. contributed to data collection and interpretation of the

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results. All authors have read and approved the final manuscript.

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WORD COUNT: 496/500 words

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REFERENCES: 5

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FIGURE: 1

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SUPPLEMENTARY FIGURE: 2

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Dear Editor

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CD4/CD8 double-negative T-cell lymphoma (CD4/8-DN TCL) is rare, which is

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not included in the revised fourth edition of the World Health Organization (WHO)

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classification of Tumors of Hematopoietic and Lymphoid Tissues.1,2 CD4/8-DN TCL

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would be categorized in the “primary cutaneous peripheral T-cell lymphoma, NOS (not

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otherwise specified)” in the WHO classification. The treatment of CD4/8-DN TCL has

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not been established.1,2 Here, we present a case of CD4/8-DN TCL that responded to

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combination therapy of bexarotene and total skin electron beam therapy (TSEBT).

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A 41-year-old man represented skin lesions that had spread throughout his body

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within a few months. Numerous patches, plaques, and nodules, measuring up to 10 cm,

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were observed (Figure 1a–c). Positron emission tomography-computed tomography did

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not show other extracutaneous lesions (Figure 1d). A skin biopsy from the left arm

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showed dense infiltration of atypical lymphocytes into the dermis (Figure 1e–f). Biopsy

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of axillary lymph node, bone marrow, and tonsil showed no infiltration. On

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immunohistochemical examination, the atypical lymphocytes in the dermis were positive

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for CD3, CD5, CD7, granzyme B, and TIA1, but negative for CD4, CD8, CD20, CD25,

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CD30, EBER, and CD56 (Figure 1g–r). T-cell receptor-β (TCRβ)-chain gene

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rearrangement was positive by Southern blotting. The atypical lymphocytes were positive

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for TCRβ-chain and negative for TCRδ-chain by immunohistochemical examination

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(Supplementary Figure 1). Flow cytometry of the skin biopsy specimen showed the

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expression of CD3, CD5, and CD7 with minimal expression of CD4 and CD8

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(Supplementary Figure 2). The diagnosis of mycosis fungoides is not likely because of

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the lack of epidermotropism and the positive stain of CD7. The patient was diagnosed

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with CD4/8-DN TCL.

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Psoralen plus ultraviolet radiation A photochemotherapy (300–400 mJ/cm2/time,

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once per week, four times in total) and steroid ointment had been performed during one

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month for TSEBT preparation, which was ineffective. Next, the patient was treated with

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bexarotene (675 mg/day) and TSEBT (1 Gy/time, a total of 30 Gy during eight weeks) in

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combination. After the combined therapy, the nodules distributed throughout the body

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regressed. However, after the combined therapy, the treatment of bexarotene was

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switched to etretinate due to the patient's financial constraints. The regression continued

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for 19 months by keeping etretinate (Figure 1s-u).

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CD4/8-DN TCL remains challenging to diagnose because it is not classified in

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the current TCL classification.1,2 CD4/8-DN TCL has been reported in various forms,

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including variants of mycosis fungoides or primary cutaneous CD8+ aggressive

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epidermotropic cytotoxic TCL.1,2 Future accumulation and evaluation of patients are

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necessary to evaluate the independence of the CD4/8-DN TCL.

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Bexarotene is an agonist of the retinoid X receptor and is used for refractory-

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advanced cutaneous TCL (CTCL).3,4 The response rate and progression-free survival of

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patients with CTCL improved with the combination of bexarotene and TSEBT compared

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to TSEBT monotherapy.5 However, this is the first case that showed the effectiveness of

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the combined use of bexarotene and TSEBT to treat CD4/8-DN TCL. Other case series

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are needed to evaluate the efficacy of the bexarotene and TSEBT combination therapy

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for CD4/8-DN TCL.

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REFERENCES

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1

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CD4/CD8 double-negative epidermotropic cutaneous T-cell lymphoma: an

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immunohistochemical variant of mycosis fungoides. J Am Acad Dermatol 2006;

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55:276–84.

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2

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lymphoma: a variant of primary cutaneous CD8+ aggressive epidermotropic cytotoxic

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T-cell lymphoma? Acta Derm Venereol 2015; 95:1024–5.

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3

Lowe MN, Plosker GL. Bexarotene. Am J Clin Dermatol 2000; 1:245–50.

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4

Duvic M, Hymes K, Heald P et al. Bexarotene is effective and safe for

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treatment of refractory advanced-stage cutaneous T-cell lymphoma: multinational phase

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II-III trial results. J Clin Oncol 2001; 19:2456–71.

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5

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therapy plus oral bexarotene maintenance therapy for cutaneous T-cell lymphoma. J

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Dtsch Dermatol Ges 2022; 20:279–85.

Hodak E, David M, Maron L, Aviram A, Kaganovsky E, Feinmesser M.

Miyauchi T, Abe R, Morita Y et al. CD4/CD8 double-negative T-cell

Elsayad K, Rolf D, Sunderkötter C et al. Low-dose total skin electron beam

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FIGURE LEGEND

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Figure 1. Clinical manifestations before and after treatment with the

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histopathological findings. (a–c) Asymptomatic patches, plaques, and nodules,

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measuring up to 10 cm, throughout the patient’s body. (d) Positron emission tomography-

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computed tomography imaging showing multiple areas of fluorodeoxyglucose

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accumulation on the skin. (e, f) Hematoxylin-eosin staining of the skin biopsy specimen

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from the left arm revealed diffuse infiltration of atypical lymphocyte-like cells within the

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dermis. (e: ×20, bar=500 µm, f: ×400, bar=20 μm). Immunohistochemical staining

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showing the atypical lymphocytes positive for (g) CD3, (h) CD5, (i) CD7, (j) granzyme

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B, and (k) TIA-1 and negative for (l) CD4, (m) CD8, (n) CD20, (o) CD25, (p) CD30, (q)

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EBER, and (r) CD56 (g–r: ×400, bar=20 μm). (s–u) Improvement of the nodules

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throughout the patient’s body after treatment with bexarotene and TSEBT.

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Supplementary Figure 1. The results of T-cell receptor-β (TCRβ)-chain and TCRδ-

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chain by immunohistochemical examination. (a) The atypical lymphocytes were

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positive for TCRβ-chain. (b) The atypical lymphocytes were negative for TCRδ-chain. (a,

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b ×400, bar=20 μm).

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Supplementary Figure 2. The results of flow cytometry analysis by using skin biopsy

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specimen. ...

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