New Options in Diagnosis and Management of Mycosis Fungoides and Sézary Syndrome

The article entitled “Diagnosis and Management of Mycosis Fungoides” by Shira Galper, Benjamin Smith, and Lynn Wilson is an excellent contemporary summary of the workup and management of mycosis fungoides (MF) and its leukemia variant, Szary syndrome (SS). In their discussion of the diagnosis and staging of MF and SS, the authors include a discussion of proposed revisions by the International Society for Cutaneous Lymphoma and the European Organisation for the Research and Treatment of Cancer (ISCL/EORTC) which seek to identify prognostic subgroups. In addition, there is a complete overview of the various treatment options for management of MF and SS. This treatment overview closely parallels the 2010 National Comprehensive Cancer Network (NCCN) Practice Guidelines for MF and SS.

The overall diagnosis and management of cutaneous T-cell lymphoma (CTCL), including MF and SS, has evolved over the past two decades. Historically patients were diagnosed and managed almost exclusively by dermatologists. While challenges still remain in confirming a diagnosis of MF, particularly in early presentations, there has been a significant decrease in the amount of time it takes to suspect and confirm a diagnosis of CTCL (typically mycosis fungoides). Many patients are managed by multidisciplinary teams or clinics that include dermatologists, hematologic pathologists, medical oncologists, and radiation oncologists. Even staging has evolved to routinely include an analysis of the presence of Szary cells and the addition of diagnostic imaging including PET/CT (positron emission tomography/computed tomography) for patients with more advanced presentations.

The determination of < 10% vs ≥ 10% of skin surface area is important to differentiate between T1 and T2 disease. Different methods have been used to determine the percentage of skin involvement. In the ISCL/EORTC revision to the staging and classification of MF and SS, the two methods described include the palm and fingers of the patient’s hand equaling 1% of body surface area (BSA). The second method divides the body surface into 12 standard regions, each with a set percentage of the BSA. The fraction of involvement in each of the 12 sites is calculated and added together to determine the total percentage of involved skin.[1]

Several new therapeutic options have been added to skin-directed therapy that traditionally included topical chemotherapy, topical steroids, and light therapy consisting of ultraviolet B and ultraviolet A, the latter being frequently combined with oral 8-methoxypsoralen (PUVA). Involved-field radiation therapy for patients with early-stage unilesional therapy and total skin electron beam therapy (TSEBT) remain important. The authors describe the Stanford 6 field technique to deliver TSEBT. We have used a dual field rotational technique for more than 20 years to deliver TSEBT.[2] This approach allows the entire skin surface to be treated in a single fraction. Typically, two or three fractions are delivered per week. Dosimetric studies have shown superiority over other techniques and it is relatively easy to plan and deliver. Like other techniques, boosting of certain anatomic locations is required. With the availability of new skin-directed and systemic therapies, there has been a decrease in the use of TSEBT at the University of Nebraska Medical Center, or at least a shift towards moving it to later in the treatment paradigm.

Newer skin-directed therapies include topical retinoids, such as bexarotene (Targretin) and tazarotene (Avage, Tazorac). Newer systemic therapies that are used routinely include retinoids (bexarotene), histone deacetylase (HDAC)-inhibitors, and denileukin diftitox (Ontak). Several additional systemic therapies that have been studied include gemcitabine (Gemzar) and liposomal doxorubicin (Doxil) followed by chlorambucil; pentostatin (Nipent); temozolomide (Methazolastone, Temodar); bortezomib (Velcade); etoposide (Toposar, VePesid); and cyclophosphamide.

Patients with smaller-volume stage IA disease may have a normal or near-normal life expectancy. Therefore, it is appropriate to consider possible late side effects of various treatment options. For most patients, CTCL is a chronic condition requiring long-term treatment, Long-term topical steroids can result in skin atrophy and striae formation. High-potency steroid creams can result in systemic side effects of corticosteroid use. There is an increase in both melanoma and nonmelanomatous skin cancers associated with phototherapy. These risks appear to be related to the cumulative UV dose. TSEBT can increase the risk of heat intolerance, particularly in patients who receive a second course of TSEBT. There is also a dose-dependent increased risk of secondary skin cancers with TSEBT. One of the goals of management of CTCL is to minimize the long-term side effects of treatment. The authors mention the possible association of topical mechlorethamine (Mustargen) with nonmelanomatous skin cancers.

Another evolving treatment strategy is the combination of skin-directed therapies with a systemic therapy or combinations of systemic therapy. This strategy has been shown to yield much higher initial response rates and more durable responses. Another personal observation is the management of limited disease progression in patients who have had a sustained remission with a particular skin-directed or systemic therapeutic approach. It may be worthwhile to consider involved-field electron beam therapy in these situations. In our experience, we have frequently observed continued long-term disease-free progression without abandoning the primary therapeutic approach.

Overall, significant progress has been made in the diagnosis and management of mycosis fungoides. The accurate diagnosis of MF is improved with the addition of immunophenotyping and T-cell gene receptor rearrangement analysis. Attention to the clinical features is still very important, particularly in the early presentation of CTCL. The authors point out the need for a multidisciplinary approach. Such a strategy appears to have resulted in improvements in outcome. The numerous emerging skin-directed and systemic therapies have given us new tools with which to manage CTCL. The authors should be commended on their thoughtful review of this interesting lymphoma subtype.

Financial Disclosure:The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

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References

1. Duvic M, Olsen E: International Society of Cutaneous Lymphoma (ISCL) and the European Organisation for Research and Treatment of Cancer (EORTC) revisions to the staging and classification of mycosis fungoides and Sézary syndrome. Internet J Dermatol 2009 ISSN 1531-3018. Available at http://www.ispub.com/journal/the_internet_journal_of_dermatology/cme/article
international-society-of-cutaneous-lymphoma-iscl-andthe- european-organization
of-research-and-treatment-of-cancer-eortc-revisions-to-the-staging-and-classification-of-mycosis-fungoides-and-sezary-syn.html. Accessed April 15, 2010.

2. Kumar P, Good R, Jones E, et al: Dual-field rotational (DFR) technique for total skin electron beam therapy (TSEBT). Am J Clin Oncol 10:344-354, 1987.