Mycosis fungoides

Abstract

Follicular mycosis fungoides, a subtype of cutaneous T-cell lymphoma, is often difficult to treat. We present a case of a female with follicular mycosis fungoides who showed an excellent response to low-dose (150 mg/[m.sup.2]) oral bexarotene (Targretin). To our knowledge, this is the first reported case of follicular mycosis fungoides demonstrating a response to bexarotene.

**********

Introduction

Follicular mycosis fungoides (MF) is an uncommon subtype of cutaneous T-cell lymphoma. In this condition, atypical lymphocytes show predilection for hair follicles, a phenomenon also known as folliculotropism (1,2). The diagnosis and treatment may be challenging due to the folliculotropism and the depth of the perifollicular infiltrate.

Follicular MF may be refractory to a variety of treatments, such as PUVA, potent topical steroids, nitrogen mustard, and topical carmustine (3,4). PUVA, for example, does not penetrate the skin to the level of follicular units (5). For this reason we selected oral bexarotene as monotherapy for treatment of a patient with follicular MF.

Case Report

The patient is a 54-year-old African-American female with a history of "bumps" on her cheeks, forehead, neck, and back for several years. A few months prior to the presentation they began increasing in size and number and became pruritic. On the initial exam, the patient had multiple erythematous follicular papules on her face and back (Figure 1). It was felt to be folliculitis or an acneiform eruption and was treated with antibiotics. Initial improvement was noted, but the patient relapsed.

[FIGURE 1 OMITTED]

Two months after initial presentation, biopsies were taken of the forehead and cheek. They showed a dense superficial and deep reticular dermal infiltrate with accentuation in and around follicular structures, but no epidermal involvement. There was marked lymphocytic atypia, and labeling of atypical cells with CD-3 and UCHL-1. Colloidal iron stain was positive for follicular mucin. Gene rearrangement studies by PCR analysis were positive for T-cell receptor gamma chain gene rearrangement.

Baseline labs including complete blood count, complete metabolic panel, liver function tests, thyroid function tests, and lipid panel were all within normal limits. She had elevated ANA at 1:640 with a speckled pattern, and she had positive RNP antibodies. She was referred to rheumatologist who concluded that patient had undifferentiated connective tissue disease, and was not a candidate for PUVA.

The patient was placed on bexarotene 150 mg PO once a day for approximately six months, resulting in complete resolution of lesions (Figure 2). Remission lasted for twelve months prior to lowering the dose of bexarotene to 75 mg PO qd.

Discussion

The term 'follicular mycosis fungoides' was first used in the literature by Kim in 1985 when he described two cases of patients with mycosis fungoides who had atypical lymphocytes invading follicular structures rather than the epidermis (6). Since then it has been recognized as an unusual subtype of CTCL with less than 100 cases having been reported in the United States. It has characteristic histological presentation (7), consisting of atypical lymphocytes confined to hair follicles and perifollicular dermis (2,6) with or without involvement of the epidermis.

[FIGURE 2 OMITTED]

Deposition of mucin within follicular epithelium is characteristic for follicular MF, but highly variable. In fact, some consider follicular mycosis fungoides and follicular mucinosis associated with MF two entirely different entities (2). In follicular MF the follicular infiltrate is largely made up of atypical lymphocytes, whereas in follicular mucinosis an infiltrate composed of eosinophils, lymphocytes, and other inflammatory cells is present around the hair follicle (2). In contrast, other authors consider follicular MF and MF with follicular mucinosis the same entity (7).

Mycosis fungoides typically presents as puritic patches, plaques, or tumors with predilection for sun-protected areas. Follicular MF, on the other hand, has predilection for skin of the head and neck regions, and can present as follicular papules, acneiform lesions, and alopecia. In addition, patients often complain of severe pruritus (7).

There is some evidence that follicular mycosis fungoides carries a worse prognosis than classic mycosis fungoides. A recent study comparing survival of patients with follicular MF with groups of patients with both plaque-stage mycosis fungoides and with tumor-stage disease showed decreased survival and increased disease progression in patients with follicular MF. At 10 years 65% of patients with follicular mycosis fungoides progressed versus 18% of patients with plaque-stage MF and 47% of patients with tumor stage MF. The disease-specific survival was 26% for patients with follicular MF vs. 84% for patients with plaque stage and 61% for patients with tumor stage mycosis fungoides (7).

Staging of MF is occasionally a challenge, complicated by follicular location and the depth of the infiltrate. The current TNM classification for CTCL is based on the level of inflammatory infiltrate, and may be designated (for example, plaque versus tumor) by the presence or absence of epidermal involvement (8). Current methods used to stage mycosis fungoides do not fully take into account follicular involvement, and may be the source of error in staging patients with follicular disease. Early "patch stage" follicular mycosis fungoides, for example, may be mistaken for plaque or even tumor stage disease.

Follicular MF is sometimes less responsive to skin-directed modalities such as potent topical steroids, UVB, and PUVA than non-follicular subtypes (3-5,9). Perhaps this is the function of the depth of infiltrate and the follicular involvement by atypical cells. The FDA has recently approved oral bexarotene and bexarotene gel to be used in all stages of CTCL, including disease resistant to other treatments.

We hypothesize that bexarotene would be an effective treatment of follicular MF, based on its low level RAR receptor affinity (10-12) similar to synthetic retinoids used to treat acne vulgaris. Bexarotene is principally an RXR-selective retinoic acid that interferes with TGF-alpha/RGFR autocrine signaling (10). It was approved in December 1999 for treatment of patients with early stage CTCL, and has both apoptotic and antiproliferative effects (11).

Phase II and III clinical trials of bexarotene conducted at M.D. Anderson Cancer Center have proven it to be effective and safe for refractory/persistent early stage and advanced stage CTCL (13,14). A dose of 300 mg/[m.sup.2] produced a response in 54% of the patients (15 of 28) and doses higher than 300 mg/[m.sup.2] produced responses in 67% (10 out of 15 patients) with early stage CTCL. Overall responses in patients with refractory advanced stage CTCL were 45% (25 of 56) in patients taking 300 mg/[m.sup.2] and 55% (21 of 38) in patients taking > 300mg/[m.sup.2] (2 14).

Another recent study conducted at M. D. Anderson Cancer Center supports the safety and efficacy of bexarotene as monotherapy and when used in combination therapy for CTCL (15). We chose monotherapy for our patient because of her history of undifferentiated connective tissue disease and an elevated ANA, rather than risk using PUVA.

The most common side effects reported included hypertriglyceridemia, hypercholesteremia, headaches, nausea, leucopenia, and hypothyroidism (13,14,16). All of these were reversible, and hyperlipidemia is usually easily controllable with statins or fibrates. Our patient is currently maintained on 150 mg/[m.sup.2] and she has not experienced any of the biochemical abnormalities reported in the studies above. Her complaints are limited to occasional nausea and headaches.

Conclusion

Follicular MF is a newly recognized subtype of CTCL. It is sometimes difficult to stage by conventional means, and may be refractory to skin-directed therapy. We report a nearly-complete response of follicular mycosis fungoides to oral bexarotene and a durable remission lasting for over one year. We suggest that the bexarotene pill is safe and effective enough to be used as first line of treatment in patients with follicular MF.

Drs. Glass and Fenske are currently involved in a clinical study with Ligand; however, no funds were provided for the preparation of this manuscript.

References

1. DeBloom J, et al. Follicular mycosis fungoides: a case report and review of literature. J Cutan Pathol 2001; 28(6): 318-24.

2. Goldenhersh MA, Zlotogorski A, Rosenmann E. Follicular Mycosis Fungoides. Am J Dermatopathol 1994; 16(1):52-55.

3. Ramsey OL. Meller JA, Zackheim HS. Topical Treatment of Early Cutaneous T-cell Lymphoma. Hematol Oncol Clin of North Am 1995; 9:1031-56.

4. Jorg B, et al. Therapeutic approaches in cutaneous lymphoma. Dermatol Clin 1994; 12:433-41.

5. Klemke CD, et al. Follicular mycosis fungoides. Br J Dermatol 1999; 141:137-40.

6. Kim SY. Follicular mycosis fungoides. Am J Dermatopathol 1985; 7(3):300-04.

7. van Doorn R. Scheffer E. Willemze R. Follicular mycosis fungoides, a distinct disease entity with or without associated follicular mucinosis: a clinicopathologic and follow-up study of 51 patients. Arch Dermatol 2002; 138(2):191-98.

8. Fung MA, et al. Practical Evaluation and Management of Cutaneous Lymphoma. J Am Acad Dermatol 2002; 46:325-57.

9. Ramsay DL, et al. Ultraviolet-B phototherapy for early-stage cutaneous T-cell lymphoma. Arch Dermatol 1992; 128:931-3.

10. Miller VA, et al. Initial Clinical Trials of a selective retinoid X receptor ligand, LGD 1069. J Clin Oncol 1997; 15(2):790-95.

11. Apisarnthanarax N, Duvic M. New Immunomodulators. Dermatol Clin 2001; 19(4):737-48.

12. Duvic M, Cather J. Emerging new therapies for cutaneous T-cell lymphoma. Dermatol Clin 2000; 18(1):148-56.

13. Duvic M, et al. Phase 2 and 3 Clinical Trials of Oral Bexarotene (Targretin Capsules) for the Treatment of Refractory or Persistent Early-Stage Cutaneous T-cell Lymphoma. Arch Dermatol 2001; 137(5):581-93.

14. Duvic M, et al. Bexarotene is Effective and Safe for Treatment of Refractory Advanced-Stage Cutaneous T-cell Lymphoma: Multinational Phase II-III Trial Results. J Clin Oncol 2001; 19(9):2456-2471.

15. Stern DK, Lebwohl M. Treatment of Mycosis Fungoides with Oral Bexarotene Combined with PUVA. J Drugs Dermatol 2002; 1(2):134-35.

16. Sherman S, et al. Central Hypothyroidism Associated with Retinoid X Receptor-Selective Ligands. N Engl J Med 1999; 340:1075-79.

GALINA SHISTIK MD, LEIGH ANN SCALF MD, NEIL FENSKE MD, L FRANK GLASS MD

DIVISION OF DERMATOLOGY, UNIVERSITY OF SOUTH FLORIDA TAMPA, FLORIDA

ADDRESS FOR CORRESPONDENCE:

L Frank Glass MD

Clinical Professor, Division of Dermatology

12901 Bruce B. Downs Blvd.

MDC Box 79

Tampa, FL 33612

Phone: (813) 974-3744

Fax: (813) 974-4272

E-mail: fglass@hsc.usf.edu

THE JOURNAL OF DRUGS IN DERMATOLOGY IS PLEASED TO ANNOUNCE AN ONGOING DERMATOLOGY CASE REPORT CONTEST, OPEN TO RESIDENTS, FELLOWS, AND PRACTICING PHYSICIANS.

IN EACH ISSUE OF THE JOURNAL, SIX WINNING CASE REPORTS--AS JUDGED BY A LEADING PANEL OF DERMATOLOGISTS--WILL BE PUBLISHED IN THIS SECTION, WITH THE WINNERS RECEIVING A COMPLIMENTARY ONE-YEAR SUBSCRIPTION TO THE JOURNAL OF DRUGS IN DERMATOLOGY.

WINNERS WILL BE SELECTED BASED ON NOVELTY, RELEVANCE, AND OVERALL QUALITY OF THEIR SUBMISSIONS, AND MULTIPLE ENTRIES ARE ENCOURAGED. FULL RULES AND AN ENTRY FORM CAN BE FOUND ON THE LAST PAGE OF THE JOURNAL, OR ONLINE AT WWW.DRUGSINDERMATOLOGY.COM.

COPYRIGHT 2004 Journal of Drugs in Dermatology
COPYRIGHT 2004 Gale Group