CME Course #110Mycosis Fungoides: A Review

Introduction Skin & Aging is proud to bring you this latest installment in its CME series. The series, brought to you by HMP Communications, consists of regular CME activities that qualify you for two Category One Physician Credit Hours. As a reader of Skin & Aging, you aren? required to pay a processing fee for this course. If Mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma, is caught early there are many options for successfully treating the disease. But when left unfound, can be fatal. This month, Seth Stevens, M.D., examines the latest options available to you to treat your patients with MF. Dr. Stevens discusses diagnostic pearls so you can make sure patients are treated in early stages. Cordially, Steven R. Feldman, M.D., Ph.D. CME Editor, Skin & Aging How to obtain two Category One Physician Credits by reading this article Instructions: Physicians may receive two Category One Physician Credits by reading the article on p.41-50 (with references on p.51) and successfully answering the questions found on p. 50. Use the postage-paid card provided to submit your answers, or log on to www.skinandaging.com and respond electronically. Accreditation: HMP Communications, LLC is accredited by the Accreditation Council for Continuing Medical Education to sponsor continuing medical education for physicians. Designation: HMP Communications, LLC designates that this continuing education offering meets the criteria for two hours in Category one of the Physicians Recognition Award of the American Medical Association. Disclosure Policy: All faculty participating in Continuing Medical Education programs sponsored by HMP Communications, LLC are expected to disclose to the audience any real or apparent conflicts of interest related to the content of their presentation. Grading: Answers to the CME exam will be graded by HMP Communications,LLC. Within 60 days, you will be advised that you have passed or failed the exam. A score of 70 percent or above will comprise a passing grade. A certificate will be awarded to participants who successfully complete the exam. Learning objectives: At the conclusion of this article, participants should be able to: •discuss the fundamental features of diagnosing mycosis fungoides. • state the treatment regimens for this as disease. •understand the expectations regarding risks and benefits of these treatment options. This CME activity was planned and produced in accordance with ACCME essentials. Sponsored by HMP Communications, LLC. Although mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma, it? still not a common disease. The Surveillance, Epidemiology, and End Results cancer registry program and the National Center for Health Statistics collected data from 1973 to 1992, which demonstrates an incidence in the United States of 0.36/100,000 persons per year. There is a racial predilection with the incidence among African-Americans being 1.6 times that in European-Americans; and among Asian-Americans the incidence is 0.6 times that in European-Americans.1 Pathogenesis The lymphoid system is comprised of organ-specific subsets. The skin associated lymphoid tissue (SALT) is comprised of the lymphocytes and antigen-presenting cells that traffic between the skin and its draining lymph nodes via lymphatics and blood vessels. The bronchial (BALT) and gut (GALT) organ systems also have recognized specific lymphoid systems. MF is a malignancy of the SALT, and as such, the malignant T cells express cell-surface molecules that direct them to skin, such as cutaneous lymphocyte antigen (CLA).2,3 The trafficking pattern of the normal SALT is recapitulated in the expression of disease in MF, which involves skin, then lymph nodes. It only goes outside of the normal SALT circuit to involve viscerae during advanced disease. This concept of SALT trafficking helps us understand how cells of a single clone (see next paragraph) can be present in sites that are distributed to distant body sites. The appearance of a second (and subsequent) lesion implies lymphatic and hematogenous spread. You can detect such spread in the blood, bone marrow and lymph nodes of patients with early stage MF.4 Additionally, malignant cells can be attracted to distant sites by reactive inflammation, such as is induced by contact dermatitis.5 In addition to expression of cell-surface molecules associated with skin trafficking, the malignant cells of MF typically express the memory T cell marker CD45RO. While CD8 variants exist, the cells in the majority of MF cases are CD4+. The so-called pan T cell markers are present on the cell surface of most normal T cells. Examples are CD2, CD3, CD5, and CD7. While MF cells normally express the first three, CD7 is frequently not expressed.6 This CD7 deficiency is not unique to MF or cutaneous lymphomas ?it? often seen in the circulation of patients with inflammatory dermatoses as well as in normal subjects.7 The phenotype of MF is typically CD2+CD3+CD4+CD5+CD7-CLA+CD45RO+ ?a memory cutaneous CD4 T cell with a CD7 deficiency. Using Molecular Biology Techniques to Identify MF Clonality is another well-established feature of the malignant cell in MF.8 During normal T cell development and differentiation, individual T cells undergo somatic mutation of the DNA encoding the T cell antigen receptor. This unique sequence is passed on only to progeny cells of the clone. During clonal expansion, which occurs during an infection, many daughter cells derive from the progenitor cell, all bearing the same T cell receptor gene rearrangement. After danger passes, the size of the expanded clone is reduced by such mechanisms as apoptosis. In MF, as with other malignancies, the process of regression fails and leads to the persistence and continued growth of clonal expansion. Because of the unique nucleotide sequence of the rearranged T cell receptor, you can use the molecular fingerprint to identify the expanded clone, whichis the malignancy in MF. This property of clonality allows for molecular biology techniques to be utilized diagnostically. The fundamental pathophysiology of MF is ill-characterized. While great strides have been made in the past few years in understanding how specific alterations in tumor suppressor genes and other cell cycle progression control genes give rise to other malignancies, the understanding of such mechanisms in MF is far from complete. Little chromosomal analysis has been performed in MF because it? difficult to obtain appropriate metaphase spreads from skin lesions. Analysis of peripheral blood from patients with Sezary syndrome patients has yielded inconsistent results. One line of enquiry suggests that mutations of the tumor suppressor gene p53 may have a role in the advancement of MF from plaque to tumor stage disease, though support for a role in initial malignant transformation is lacking.9,10 Another intriguing association with the development of MF is the role of biologic agents, specifically viral and bacterial agents. The role for the human T cell lymphotropic virus type I (HTLV-I) in the development of MF has been particularly controversial. A group at New York University11 has generated a fair bit of cell culture appearance, PCR and antibody data, with others finding corroborating evidence of high frequency of anti-HTLV antibodies.12 However, a variety of other groups have been unable to find such corroborating data.13-15 The matter is further confused by findings that some, but not all, genes of the virus can be found in some MF specimens, suggesting that HTLV-I genes that are present outside of the context of actual HTLV-I virus may participate in the pathogenesis of MF.16 Differences in laboratory techniques and differences in clinical nosology of cutaneous T cell lymphomas are possible causes of the diversity of results. A possible role for bacteria has been proposed in the pathogenesis of MF. Toxic shock syndrome toxin-secreting Staphylococcus aureus have been linked to erythrodermic or rapidly expanding plaque or tumor MF.17 Thus, appropriate anti-staphylococcal antibiotics may help this type of patient. Chlamydia pneumoniae bacterium has also been associated with MF.18 A product of this bacterium, Sezary T Cell-Activating Factor, can induce malignant cell activation and proliferation in, at least, Sezary cells.19 I speculate that there may be some, as yet unclear, relationship between possible roles of C. pneumoniae and HTLV-I-related products in the development of MF. Abnormalities Contributing to MF Regardless of the mechanisms that give rise to malignant cells in MF, it is clear that two fundamental abnormalities contribute to clinical expression of disease. One is the failure of immune surveillance to mount an adequate response against the malignancy and the other is failure of the malignant cells to undergo apoptosis. An interesting recent observation is that MF cells and MF-derived cell lines express fas ligand.20 Within the lesions, adjacent CD8+ cells, presumably cytotoxic lymphocytes that could mount an immune response against the malignant cells, were reduced in number adjacent to the fas ligand-bearing CD4+CD45RO+ (presumed malignant cells), and the remaining CD8+ cells were more frequently undergoing apoptosis than CD8+ cells further away. These findings show that the malignant cells in MF may be actively killing the lymphocytes that otherwise would be responsible for killing the malignant cells.20 This observation dovetails with previous work demonstrating the expression of cell proteins by MF cells that inhibit the cytotoxic activity of tumor infiltrating lymphocytes.21 Perhaps these inhibitory molecules are related to the tumor cell production of transforming growth factor ?-22, a cytokine with known immune down regulatory effects. Also, the same group has shown that in at least a subset of MF patients, cytotoxic lymphocytes that are successful in killing tumor cells use granzyme/perforin or TRAIL-dependent killing of malignant cells and not the more typical fas-dependent killing of malignant cells. Therefore, it appears that MF cells are simultaneously capable of killing normal host immune cells that might otherwise restrain the tumor cells while forcing the remaining tumor infiltrating cells to utilize less common apoptotic pathways.22 While defective apoptotic pathways can be inferred in MF,23 few data actually demonstrate this defect directly. Clinical Presentation of MF Initially, MF typically arises as variably pruritic erythematous scaling macules and patches, which can be non-descript and not diagnosable. In fact, in 1991 the average time from onset of symptoms to diagnosis averaged 6 to 7 years.24 Patients may have had a rash for decades that was variously diagnosed as eczema, contact dermatitis, psoriasis, etc. While improvements in diagnosis may have shortened this time in the last decade, it remains common for the undiagnosed, symptomatic stage to last many years. During this phase, patients may be treated with topical steroids, which will frequently be effective, though for variable amounts of time. Non-specific histology usually accompanies this stage. In more evolved stages, the macules and patches may exhibit fine wrinkling and develop well-defined borders. They tend to be distributed in sun-protected areas, where extremities meet the trunk; such as the proximal medial arms, axillary folds, groins, buttocks and proximal medial thighs. The color may run the gamut of erythema from slightly orange to dusky purple. Poikiloderma atrophicans vasculare may manifest and it presents as hypo- and hyper-pigmented macules with telangiectasia. Either over time or de novo plaques of various thickness may develop. The plaques may merge to form larger plaques and they may continue to thicken. In these early stages there is usually scale, a reflection of the predilection of these SALT lymphocytes to enter into the skin and particularly the epidermis, known as epidermotropism. Variations on this theme of tropism for skin epithelia exist and may manifest as papules in follicular MF (tropism for follicular epithelium) or eccrine MF (tropism for eccrine epithelium). Erythodermic MF can arise from previous early stage disease or may be the presenting sign of MF. Distinction from Sezary syndrome, which also has significant blood involvement leading to the designation leukemic phase, must be made. You may have difficulty distinguishing erythrodermic MF from other causes of erythroderma including atopic dermatitis, psoriasis, drug eruption and pityriasis rubra pilaris. Clinical features such as island sparing and lichenification may mislead your clinical impression to one of these benign dermatoses. Histologically, such features as psoriasiform hyperplasia or the lack of epidermotropism may also make diagnosis difficult. Infiltration of the face to yield leonine facies may be seen. Additionally, features may include fissuring of the hands and feet (which may be very painful), ectropion, alopecia, peripheral edema, and systemic signs and symptoms such as fever, malaise, fatigue, and night sweats. With further progression, tumors may develop. They may arise from a previously existing plaque or de novo in previously uninvolved skin. Tumor d?mblee MF describes rapidly arising tumors in the absence of antecedent patches and plaques. The use of this term has diminished because many of these tumors can be better described as variants of CTCL other than MF. In addition to the distribution seen with patch-plaques stage MF, tumors have a predilection for the face. Progression to tumor stage MF is associated with more aggressive behavior, and may be analogous to the switch from radial to vertical growth phase seen with melanomas. Tumors may ulcerate, and infection can be a significant problem. Clinical Variants As mentioned previously, classic MF is a malignancy of epidermotropic CD4+ T cutaneous T cells, which presents as patches, plaques, erythroderma and tumors. Variants have been described in cell type, tropism to epithelia of adnexal structures, or distinct clinical presentations. Several of these variant will now be introduced. •CD8+ MF: Some of these CD8+ MF cases are very similar to classic MF, but differ in that the malignant cells are CD4-CD8+. It? only through the use of Immunohistochemistry that this difference is brought to light. There are, however, some patients who have a distinct clinical presentation in the setting of their CD8+ malignancy. Of particular note is that subset with papulonodular lesions, which may ulcerate. Such patients tend to have a more aggressive course and you may distinguished them by a lack of expression of the pan T cell surface marker CD2 and intense expression of CD7.25 This is the opposite immunophenotype of classic MF. I?e seen patients with CD8+ CD7- MF who had patches that displayed slight superficial erosions, perhaps related to the cytotoxic function of the malignant CD8+ T cells. •Follicular and Eccrine MF: Characterized clinically by follicular-based erythematous papules that coalesce into plaques and in distinction to alopecia mucinosa, follicular MF is without mucin deposition. There may be comedone-like features. Additionally, consideration as a distinct entity may be worthwhile because several case reports suggest that follicular MF tends to be more aggressive than classic MF.26-28 Eccrine MF similarly may present as papules that coalesce to plaques.29 It seems reasonable that these variants represent alterations in the homing mechanisms of the involved T cells that go beyond expression of CLA. The functional and biologic significance are likewise unclear, though we do have the hint that follicular MF may be more aggressive than Eccrine MF. What distinguishes the folliculotropic and syringotropic variants is the lack of involvement of interfollicular epidermis. Clues to understanding the relevance of these observations to normal SALT function and to MF may come from the recognition that there is a spectrum of involvement of epithelia in MF.30 • Alopecia mucinosa: This may or may not be associated with MF in a given patient, though those patients who have the benign variant are at increased risk of evolving to overt MF. This pattern is analogous to the classic MF in which benign appearing patches may resolve or may evolve to diagnosable MF. Clinically the lesions are erythematous follicular-based papules within alopecic patches. The distinction between benign and malignant alopecia mucinosa are also analogous to classic MF in that the integration of histologic, immunophenotypic and immunogenotypic findings is sometimes required to derive a diagnosis. •Hypopigmented MF: This variant is typically seen as hypopigmented patches in younger, darker-skinned patients. There frequently is no erythema and only mild scale. For some time it was thought that this variant didn? occur in lighter-skinned patients, however, a few more recent case reports demonstrate that is not true.31 Such cases raise the question as to whether hypopigmented MF in fair-skinned individuals is more common than we recognize because the lack of contrast between effected and adjacent normal skin is minimal. Typically, hypopigmented MF is readily treatable, though subject to relapse and in most has a non-aggressive course.32 •Woringer-Kolopp Disease: Also termed pagetoid reticulosis, Woringer-Kolopp disease is characterized by a single plaque on acral skin. Whether or not unilesional MF at other sites are distinct is not resolved.33 This variant typically responds readily to treatment and runs a particularly non-aggressive course. • Granulomatous Slack Skin: Granulomatous slack skin, as the name suggests, presents as areas of loose skin in association with granuloma formation. Fibrotic bands are associated with these lax areas of skin. Involvement of deeper structures of the skin and subcutis must be considered when therapeutic options are considered, as phototherapy and topical agents can? adequately penetrate to all involved structures. ¥ Others: From time to time, distinct variants of MF are reported. One relatively common variant is pigmented purpuric MF.34 Another variant is bullous MF.35 For those of you frequently treating MF patients, it becomes apparent that MF can present with similar clinical findings to most lymphocyte mediated dermatoses. This raises interesting questions regarding cause and effect in MF: •Does chronic antigenic stimulation give rise to malignant lymphocytes-implying that the condition began as a benign lymphocytic dermatosis that eventually became malignant? •Alternatively, does malignant T cell infiltration into skin present as distinct eruptions because different clones of T cells are producing their own set of products, such as cytokines etc. and each unique set of products cause its own response in the skin, mimicking a benign dermatosis? •Do the malignant cells provoke distinct responses from the host immune system, which in turn give rise to different clinical presentations? Diagnosing MF An MF diagnosis is typically made with histopathology of routine sections. Clinically, you should look for the compatible morphology and distribution described above. A recent study from Europe36 defined histological features that were most helpful in the diagnosis of MF: the presence of lymphocytes with extremely convoluted, medium to large (7 - 9 micron in diameter) nuclei (medium to large cerebriform cells), singly or clustered in the epidermis and in small sheets in the dermis. Additional helpful features were epidermotropism as single cells lined up along the basal keratinocytes of the dermal-epidermal junction, absence of significant papillary dermis fibrosis, and absence of a significant number of dermal, blast-like cells. However, the diagnosis can be difficult, and as mentioned previously, may be elusive for decades, despite numerous skin biopsies with histologic review. In these cases clinicopathologic correlation is essential. There are a few adjunctive tests that can be quite helpful in diagnosing MF. As mentioned above, T cell clonality is a diagnostically exploitable feature of MF. A variety of specific laboratory assays have been employed including, in increasing order of sensitivity: •Southern blotting, •alternatively taking advantage of the polymerase chain reaction (PCR) to amplify DNA, and •use of denaturing gradient gel electropheresis with PCR techniques or PCR/RNase protection assays. For both practical and biologic reasons, the PCR-based tests (without RNase protection assays) for the presence of a dominant clonal T cell receptor gene rearrangement have become standard. From a practical perspective, the PCR-based technologies are less labor intensive and less expensive. From a biologic perspective, the PCR-based technologies balance the relatively low sensitivity of Southern blotting (requires 10% of T cells present to be of the dominant clone) and the very high sensitivity of RNase protection assays, which requires only 1 in 100,000 cells to be of the dominant clone. Sensitivities at the highest level give rise to false positives as reactive infiltrates may have sufficient numbers of an offspring of a single clone to yield a positive result. The PCR-based techniques have a sensitivity of approximately 1%, which nicely balances these two extremes.37 A second approach to gaining adjunctive information to yield the diagnosis of MF is immunostaining. This less costly surrogate uses antibodies against the classes of the variable regions of the ? chain (V?) of the T cell receptor. Each clone will utilize a single V?, however, there will be many other clones and individual cells that will also utilize the same V?. However, there are no ideal tests. Not only are there false negative tests due to limitations of the PCR technique, but false positive results are also possible in such diseases as pityriasis lichenoides and lymphomatoid papulosis. Again, as noted above, MF is typically a CD2+CD3+CD4+CD7-CD8-CD45RO+ infiltrate. Additionally, keratinocyte expression of the major histocompatibility complex antigen HLA-DR can aid the diagnosis of MF. From time to time additional markers may help you diagnose MF, and quantitative differences in the expression of these markers by cells in the dermis and the epidermis can also be helpful. Immunophenotypic data can also identify whether the patient has a CD8+ variant and if so, whether it is in the high risk, CD7+ category or the low risk, CD7- category. Despite these advances, the diagnosis of MF still remains elusive in many patients. To assist in the integration of the above data, our group has proposed a scoring system that assigns relative values to clinical morphology and distribution, immunohistochemistry and T cell receptor gene rearrangement analysis. This study is currently under review. Staging System Several staging systems exist for MF. Of the ones that have been extant for some time, the TNM system proposed in 197938 is the most commonly used. (See Tables 1 and 2) Recently, a University of California, San Francisco group re-examined their cohort of 450 CTCL (MF and Sezary syndrome) patients and asked whether the above staging system was predictive of survival. Interestingly, they found that clinically positive lymph nodes with negative histology had no worse prognostic significance than did extensive patch disease and that patients with extensive plaque stage disease did have a worse prognosis than those with extensive patches. Further, erythroderma and tumor stage patients had similar survivals. They therefore suggest that the current classification be modified to divide T2 into T2a (patches >= 10% body surface area) and T2b (plaques >= 10% body surface area), and that Stage III be divided into Stage IIIa (tumors with negative nodal histology) and Stage IIIb (erythroderma with negative nodal histology).39 These results seem to be consistent with my experience and I await further validation. Prognosis and Survival Rates In general the prognosis for MF is considered to be good. Most patients present in early stages, with only skin involvement, and do not progress to lymph node or visceral disease. Refer to table three for age adjusted survivals at 5, 10 and 15 years, respectively.39 Stage IV patients have a poor prognosis with a median survival reported to be much worse and may be as low as six months. Therapy Options A variety of therapies exist for MF ranging from those with ancient roots, such as psoralen-ultraviolet A (PUVA) to cutting edge fusion proteins derived from molecular biology techniques. While cure is clearly desirable, because the prognosis of early stage disease is excellent, patient needs are adequately met with chronic therapy. We need new therapies for late-stage disease patients because of its heart-breaking prognosis. Fortunately, in the last few years several such newer therapies have come to clinical trial and a few have been approved for general use in the United States. •Skin-directed Therapies Topical steroids are frequently used to treat MF. In fact, I suspect that most MF patients are treated with topical steroids at some point. Remember that most patients have symptomatic skin disease for many years prior to diagnosis. During this time, they usually carry the diagnosis of some eczematous dermatitis and are treated with topical steroids. Many of these patients are adequately treated, the disease goes into remission and the patients don? follow-up. Some of these patients actually have nascent MF. For many patients, however, topical steroids fail to be a good long-term solution. The use of topical steroids for diagnosed MF patients has been systematically studied.40 This study of 79 patients found a 49% complete response rate and a 41% partial response rate. Unfortunately, time to treatment failure was not noted, though this study does highlight that the effects (presumably lympholytic effects) of topical steroids can benefit some patients in the short term. A theoretic disadvantage might be cutaneous immunosuppression and diminished host immunity to the malignancy. Topical mechlorethamine or nitrogen mustard is a mainstay of MF therapy at most centers. It may be formulated as 10 mg dissolved in 50 cc of tap water and painted on the skin or mixed into an ointment base at 10 to 20% concentration. Daily neck-down application is standard. The main adverse effects are contact dermatitis, which can be reduced by lessening the concentration of the nitrogen mustard and then slowly increasing it as tolerated, or phototherapy to attempt to induce immunologic tolerance. The induction of secondary skin cancers is a second complication. For example, there is a relative risk of 8.6 for the development of squamous cell carcinoma in patients using topical mechlorethamine.41 On the positive side, the complete response rate at 2 years is 75.8% with a mean duration of 66 months for stage I patients and a complete response rate at 2 years of 44.6% with a mean duration of 44 months for stage II patients.42 Phototherapy including PUVA therapy is another standard therapy of MF that is familiar to most of us. For patch-plaque disease, complete response rates of 65% and partial response rates of 30% or better can be expected,43 and can frequently be achieved in 3 to 5 months. Nausea can be a problem with oral psoralen that can be addressed with topical psoralen. Secondary skin cancers, including possible risk of melanoma, are possible adverse effects. For patches, but not plaques, broadband UVB can be a more convenient option without some of the inconveniences associated with PUVA, such as oral medication and protective eyewear outside of the phototherapy cabinet. An 83% complete response rate of patch stage patients and a mean duration of remission of 22 months has been reported.44 The differential therapeutic response of patch stage and plaque stage disease adds weight to the argument to distinguish these lesion types in a modified staging scheme. Narrow band UVB is a newer modality that also has efficacy in MF, the exact place of which in the armamentarium is still to be determined, though we have had success in both patch and plaque stage disease. Radiation therapy has been employed for MF. Both electron beam and orthovoltage radiation has been utilized. Total body electron beam leads to complete remission in 84% of a mixed population of MF patients.45 This therapy requires specialized equipment and skill. Because electrons penetrate only to upper dermis there are both advantages (reduced adverse effects involving mucosal surfaces) and disadvantages (mainly in exposing all involved sites). Adverse effects include altered sweat gland function, anonychia, and alopecia. Modifications in fractionation of doses, dosing and shielding may minimize these and other adverse effects. A variety of orthovoltage regimens are utilized, usually to treat individual, problematic lesions. •Systemic Therapies Extracorporeal photochemotherapy, or photopheresis, is used for MF, though its use in disease that lacks significant blood involvement is controversial. Photopheresis is an apheresis-based therapy in which mononuclear leukocytes are isolated outside of the body. In some systems, the patient has previously ingested psoralen. In another, liquid psoralen is delivered extracorporeally to the collected leukocytes. This second approach circumvents absorption issues with oral psoralen, delivering precise drug levels to the cells to be exposed to UVA. Much lower total doses of psoralen are required (400 mcg) than with oral ingestion, the risk of ocular, GI, adverse effects or systemic photosensitization are reduced. Depending on the stage of CTCL treated, efficacy data vary. As a rule, I expect complete responses in approximately one third of patients, partial responses in one third of patients, and minimal to no response in the remaining third of patients.46, 47 Interferon therapy, particularly interferon alpha has been utilized for MF for more than a decade. Initial reports suggested modest efficacy of 10 to 27% with relapses typically within 6 months.48 Doses range from 3 million units three times a week to as much as 20 million units per day. Toxicities generally limit its use. These are flu-like symptoms of fever, anorexia, malaise, myalgia, to which patients harden, to varying degrees. Additionally neurologic, hematologic and rarely cardiac toxicities occur. In my practice, I rarely use interferon alpha as monotherapy, however, I do employ it at low doses of 1.5 to 6 million units three times a week in conjunction with PUVA, as this can induce remission in patients who are incompletely responsive to PUVA alone.49 Interferon gamma may be useful in the treatment of MF50 though the optimal use is unclear.51 Bexarotene is a recently FDA-approved therapy for MF available in both oral and topical formulations. Bexarotene is a selective retinoid X receptor-blocking agent. Typical doses are 300-400 mg/m2 po daily, for the oral agent. Response rates are reported at 45 to 54% with durati

Introduction Skin & Aging is proud to bring you this latest installment in its CME series. The series, brought to you by HMP Communications, consists of regular CME activities that qualify you for two Category One Physician Credit Hours. As a reader of Skin & Aging, you aren? required to pay a processing fee for this course. If Mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma, is caught early there are many options for successfully treating the disease. But when left unfound, can be fatal. This month, Seth Stevens, M.D., examines the latest options available to you to treat your patients with MF. Dr. Stevens discusses diagnostic pearls so you can make sure patients are treated in early stages. Cordially, Steven R. Feldman, M.D., Ph.D. CME Editor, Skin & Aging How to obtain two Category One Physician Credits by reading this article Instructions: Physicians may receive two Category One Physician Credits by reading the article on p.41-50 (with references on p.51) and successfully answering the questions found on p. 50. Use the postage-paid card provided to submit your answers, or log on to www.skinandaging.com and respond electronically. Accreditation: HMP Communications, LLC is accredited by the Accreditation Council for Continuing Medical Education to sponsor continuing medical education for physicians. Designation: HMP Communications, LLC designates that this continuing education offering meets the criteria for two hours in Category one of the Physicians Recognition Award of the American Medical Association. Disclosure Policy: All faculty participating in Continuing Medical Education programs sponsored by HMP Communications, LLC are expected to disclose to the audience any real or apparent conflicts of interest related to the content of their presentation. Grading: Answers to the CME exam will be graded by HMP Communications,LLC. Within 60 days, you will be advised that you have passed or failed the exam. A score of 70 percent or above will comprise a passing grade. A certificate will be awarded to participants who successfully complete the exam. Learning objectives: At the conclusion of this article, participants should be able to: •discuss the fundamental features of diagnosing mycosis fungoides. • state the treatment regimens for this as disease. •understand the expectations regarding risks and benefits of these treatment options. This CME activity was planned and produced in accordance with ACCME essentials. Sponsored by HMP Communications, LLC. Although mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma, it? still not a common disease. The Surveillance, Epidemiology, and End Results cancer registry program and the National Center for Health Statistics collected data from 1973 to 1992, which demonstrates an incidence in the United States of 0.36/100,000 persons per year. There is a racial predilection with the incidence among African-Americans being 1.6 times that in European-Americans; and among Asian-Americans the incidence is 0.6 times that in European-Americans.1 Pathogenesis The lymphoid system is comprised of organ-specific subsets. The skin associated lymphoid tissue (SALT) is comprised of the lymphocytes and antigen-presenting cells that traffic between the skin and its draining lymph nodes via lymphatics and blood vessels. The bronchial (BALT) and gut (GALT) organ systems also have recognized specific lymphoid systems. MF is a malignancy of the SALT, and as such, the malignant T cells express cell-surface molecules that direct them to skin, such as cutaneous lymphocyte antigen (CLA).2,3 The trafficking pattern of the normal SALT is recapitulated in the expression of disease in MF, which involves skin, then lymph nodes. It only goes outside of the normal SALT circuit to involve viscerae during advanced disease. This concept of SALT trafficking helps us understand how cells of a single clone (see next paragraph) can be present in sites that are distributed to distant body sites. The appearance of a second (and subsequent) lesion implies lymphatic and hematogenous spread. You can detect such spread in the blood, bone marrow and lymph nodes of patients with early stage MF.4 Additionally, malignant cells can be attracted to distant sites by reactive inflammation, such as is induced by contact dermatitis.5 In addition to expression of cell-surface molecules associated with skin trafficking, the malignant cells of MF typically express the memory T cell marker CD45RO. While CD8 variants exist, the cells in the majority of MF cases are CD4+. The so-called pan T cell markers are present on the cell surface of most normal T cells. Examples are CD2, CD3, CD5, and CD7. While MF cells normally express the first three, CD7 is frequently not expressed.6 This CD7 deficiency is not unique to MF or cutaneous lymphomas ?it? often seen in the circulation of patients with inflammatory dermatoses as well as in normal subjects.7 The phenotype of MF is typically CD2+CD3+CD4+CD5+CD7-CLA+CD45RO+ ?a memory cutaneous CD4 T cell with a CD7 deficiency. Using Molecular Biology Techniques to Identify MF Clonality is another well-established feature of the malignant cell in MF.8 During normal T cell development and differentiation, individual T cells undergo somatic mutation of the DNA encoding the T cell antigen receptor. This unique sequence is passed on only to progeny cells of the clone. During clonal expansion, which occurs during an infection, many daughter cells derive from the progenitor cell, all bearing the same T cell receptor gene rearrangement. After danger passes, the size of the expanded clone is reduced by such mechanisms as apoptosis. In MF, as with other malignancies, the process of regression fails and leads to the persistence and continued growth of clonal expansion. Because of the unique nucleotide sequence of the rearranged T cell receptor, you can use the molecular fingerprint to identify the expanded clone, whichis the malignancy in MF. This property of clonality allows for molecular biology techniques to be utilized diagnostically. The fundamental pathophysiology of MF is ill-characterized. While great strides have been made in the past few years in understanding how specific alterations in tumor suppressor genes and other cell cycle progression control genes give rise to other malignancies, the understanding of such mechanisms in MF is far from complete. Little chromosomal analysis has been performed in MF because it? difficult to obtain appropriate metaphase spreads from skin lesions. Analysis of peripheral blood from patients with Sezary syndrome patients has yielded inconsistent results. One line of enquiry suggests that mutations of the tumor suppressor gene p53 may have a role in the advancement of MF from plaque to tumor stage disease, though support for a role in initial malignant transformation is lacking.9,10 Another intriguing association with the development of MF is the role of biologic agents, specifically viral and bacterial agents. The role for the human T cell lymphotropic virus type I (HTLV-I) in the development of MF has been particularly controversial. A group at New York University11 has generated a fair bit of cell culture appearance, PCR and antibody data, with others finding corroborating evidence of high frequency of anti-HTLV antibodies.12 However, a variety of other groups have been unable to find such corroborating data.13-15 The matter is further confused by findings that some, but not all, genes of the virus can be found in some MF specimens, suggesting that HTLV-I genes that are present outside of the context of actual HTLV-I virus may participate in the pathogenesis of MF.16 Differences in laboratory techniques and differences in clinical nosology of cutaneous T cell lymphomas are possible causes of the diversity of results. A possible role for bacteria has been proposed in the pathogenesis of MF. Toxic shock syndrome toxin-secreting Staphylococcus aureus have been linked to erythrodermic or rapidly expanding plaque or tumor MF.17 Thus, appropriate anti-staphylococcal antibiotics may help this type of patient. Chlamydia pneumoniae bacterium has also been associated with MF.18 A product of this bacterium, Sezary T Cell-Activating Factor, can induce malignant cell activation and proliferation in, at least, Sezary cells.19 I speculate that there may be some, as yet unclear, relationship between possible roles of C. pneumoniae and HTLV-I-related products in the development of MF. Abnormalities Contributing to MF Regardless of the mechanisms that give rise to malignant cells in MF, it is clear that two fundamental abnormalities contribute to clinical expression of disease. One is the failure of immune surveillance to mount an adequate response against the malignancy and the other is failure of the malignant cells to undergo apoptosis. An interesting recent observation is that MF cells and MF-derived cell lines express fas ligand.20 Within the lesions, adjacent CD8+ cells, presumably cytotoxic lymphocytes that could mount an immune response against the malignant cells, were reduced in number adjacent to the fas ligand-bearing CD4+CD45RO+ (presumed malignant cells), and the remaining CD8+ cells were more frequently undergoing apoptosis than CD8+ cells further away. These findings show that the malignant cells in MF may be actively killing the lymphocytes that otherwise would be responsible for killing the malignant cells.20 This observation dovetails with previous work demonstrating the expression of cell proteins by MF cells that inhibit the cytotoxic activity of tumor infiltrating lymphocytes.21 Perhaps these inhibitory molecules are related to the tumor cell production of transforming growth factor ?-22, a cytokine with known immune down regulatory effects. Also, the same group has shown that in at least a subset of MF patients, cytotoxic lymphocytes that are successful in killing tumor cells use granzyme/perforin or TRAIL-dependent killing of malignant cells and not the more typical fas-dependent killing of malignant cells. Therefore, it appears that MF cells are simultaneously capable of killing normal host immune cells that might otherwise restrain the tumor cells while forcing the remaining tumor infiltrating cells to utilize less common apoptotic pathways.22 While defective apoptotic pathways can be inferred in MF,23 few data actually demonstrate this defect directly. Clinical Presentation of MF Initially, MF typically arises as variably pruritic erythematous scaling macules and patches, which can be non-descript and not diagnosable. In fact, in 1991 the average time from onset of symptoms to diagnosis averaged 6 to 7 years.24 Patients may have had a rash for decades that was variously diagnosed as eczema, contact dermatitis, psoriasis, etc. While improvements in diagnosis may have shortened this time in the last decade, it remains common for the undiagnosed, symptomatic stage to last many years. During this phase, patients may be treated with topical steroids, which will frequently be effective, though for variable amounts of time. Non-specific histology usually accompanies this stage. In more evolved stages, the macules and patches may exhibit fine wrinkling and develop well-defined borders. They tend to be distributed in sun-protected areas, where extremities meet the trunk; such as the proximal medial arms, axillary folds, groins, buttocks and proximal medial thighs. The color may run the gamut of erythema from slightly orange to dusky purple. Poikiloderma atrophicans vasculare may manifest and it presents as hypo- and hyper-pigmented macules with telangiectasia. Either over time or de novo plaques of various thickness may develop. The plaques may merge to form larger plaques and they may continue to thicken. In these early stages there is usually scale, a reflection of the predilection of these SALT lymphocytes to enter into the skin and particularly the epidermis, known as epidermotropism. Variations on this theme of tropism for skin epithelia exist and may manifest as papules in follicular MF (tropism for follicular epithelium) or eccrine MF (tropism for eccrine epithelium). Erythodermic MF can arise from previous early stage disease or may be the presenting sign of MF. Distinction from Sezary syndrome, which also has significant blood involvement leading to the designation leukemic phase, must be made. You may have difficulty distinguishing erythrodermic MF from other causes of erythroderma including atopic dermatitis, psoriasis, drug eruption and pityriasis rubra pilaris. Clinical features such as island sparing and lichenification may mislead your clinical impression to one of these benign dermatoses. Histologically, such features as psoriasiform hyperplasia or the lack of epidermotropism may also make diagnosis difficult. Infiltration of the face to yield leonine facies may be seen. Additionally, features may include fissuring of the hands and feet (which may be very painful), ectropion, alopecia, peripheral edema, and systemic signs and symptoms such as fever, malaise, fatigue, and night sweats. With further progression, tumors may develop. They may arise from a previously existing plaque or de novo in previously uninvolved skin. Tumor d?mblee MF describes rapidly arising tumors in the absence of antecedent patches and plaques. The use of this term has diminished because many of these tumors can be better described as variants of CTCL other than MF. In addition to the distribution seen with patch-plaques stage MF, tumors have a predilection for the face. Progression to tumor stage MF is associated with more aggressive behavior, and may be analogous to the switch from radial to vertical growth phase seen with melanomas. Tumors may ulcerate, and infection can be a significant problem. Clinical Variants As mentioned previously, classic MF is a malignancy of epidermotropic CD4+ T cutaneous T cells, which presents as patches, plaques, erythroderma and tumors. Variants have been described in cell type, tropism to epithelia of adnexal structures, or distinct clinical presentations. Several of these variant will now be introduced. •CD8+ MF: Some of these CD8+ MF cases are very similar to classic MF, but differ in that the malignant cells are CD4-CD8+. It? only through the use of Immunohistochemistry that this difference is brought to light. There are, however, some patients who have a distinct clinical presentation in the setting of their CD8+ malignancy. Of particular note is that subset with papulonodular lesions, which may ulcerate. Such patients tend to have a more aggressive course and you may distinguished them by a lack of expression of the pan T cell surface marker CD2 and intense expression of CD7.25 This is the opposite immunophenotype of classic MF. I?e seen patients with CD8+ CD7- MF who had patches that displayed slight superficial erosions, perhaps related to the cytotoxic function of the malignant CD8+ T cells. •Follicular and Eccrine MF: Characterized clinically by follicular-based erythematous papules that coalesce into plaques and in distinction to alopecia mucinosa, follicular MF is without mucin deposition. There may be comedone-like features. Additionally, consideration as a distinct entity may be worthwhile because several case reports suggest that follicular MF tends to be more aggressive than classic MF.26-28 Eccrine MF similarly may present as papules that coalesce to plaques.29 It seems reasonable that these variants represent alterations in the homing mechanisms of the involved T cells that go beyond expression of CLA. The functional and biologic significance are likewise unclear, though we do have the hint that follicular MF may be more aggressive than Eccrine MF. What distinguishes the folliculotropic and syringotropic variants is the lack of involvement of interfollicular epidermis. Clues to understanding the relevance of these observations to normal SALT function and to MF may come from the recognition that there is a spectrum of involvement of epithelia in MF.30 • Alopecia mucinosa: This may or may not be associated with MF in a given patient, though those patients who have the benign variant are at increased risk of evolving to overt MF. This pattern is analogous to the classic MF in which benign appearing patches may resolve or may evolve to diagnosable MF. Clinically the lesions are erythematous follicular-based papules within alopecic patches. The distinction between benign and malignant alopecia mucinosa are also analogous to classic MF in that the integration of histologic, immunophenotypic and immunogenotypic findings is sometimes required to derive a diagnosis. •Hypopigmented MF: This variant is typically seen as hypopigmented patches in younger, darker-skinned patients. There frequently is no erythema and only mild scale. For some time it was thought that this variant didn? occur in lighter-skinned patients, however, a few more recent case reports demonstrate that is not true.31 Such cases raise the question as to whether hypopigmented MF in fair-skinned individuals is more common than we recognize because the lack of contrast between effected and adjacent normal skin is minimal. Typically, hypopigmented MF is readily treatable, though subject to relapse and in most has a non-aggressive course.32 •Woringer-Kolopp Disease: Also termed pagetoid reticulosis, Woringer-Kolopp disease is characterized by a single plaque on acral skin. Whether or not unilesional MF at other sites are distinct is not resolved.33 This variant typically responds readily to treatment and runs a particularly non-aggressive course. • Granulomatous Slack Skin: Granulomatous slack skin, as the name suggests, presents as areas of loose skin in association with granuloma formation. Fibrotic bands are associated with these lax areas of skin. Involvement of deeper structures of the skin and subcutis must be considered when therapeutic options are considered, as phototherapy and topical agents can? adequately penetrate to all involved structures. ¥ Others: From time to time, distinct variants of MF are reported. One relatively common variant is pigmented purpuric MF.34 Another variant is bullous MF.35 For those of you frequently treating MF patients, it becomes apparent that MF can present with similar clinical findings to most lymphocyte mediated dermatoses. This raises interesting questions regarding cause and effect in MF: •Does chronic antigenic stimulation give rise to malignant lymphocytes-implying that the condition began as a benign lymphocytic dermatosis that eventually became malignant? •Alternatively, does malignant T cell infiltration into skin present as distinct eruptions because different clones of T cells are producing their own set of products, such as cytokines etc. and each unique set of products cause its own response in the skin, mimicking a benign dermatosis? •Do the malignant cells provoke distinct responses from the host immune system, which in turn give rise to different clinical presentations? Diagnosing MF An MF diagnosis is typically made with histopathology of routine sections. Clinically, you should look for the compatible morphology and distribution described above. A recent study from Europe36 defined histological features that were most helpful in the diagnosis of MF: the presence of lymphocytes with extremely convoluted, medium to large (7 - 9 micron in diameter) nuclei (medium to large cerebriform cells), singly or clustered in the epidermis and in small sheets in the dermis. Additional helpful features were epidermotropism as single cells lined up along the basal keratinocytes of the dermal-epidermal junction, absence of significant papillary dermis fibrosis, and absence of a significant number of dermal, blast-like cells. However, the diagnosis can be difficult, and as mentioned previously, may be elusive for decades, despite numerous skin biopsies with histologic review. In these cases clinicopathologic correlation is essential. There are a few adjunctive tests that can be quite helpful in diagnosing MF. As mentioned above, T cell clonality is a diagnostically exploitable feature of MF. A variety of specific laboratory assays have been employed including, in increasing order of sensitivity: •Southern blotting, •alternatively taking advantage of the polymerase chain reaction (PCR) to amplify DNA, and •use of denaturing gradient gel electropheresis with PCR techniques or PCR/RNase protection assays. For both practical and biologic reasons, the PCR-based tests (without RNase protection assays) for the presence of a dominant clonal T cell receptor gene rearrangement have become standard. From a practical perspective, the PCR-based technologies are less labor intensive and less expensive. From a biologic perspective, the PCR-based technologies balance the relatively low sensitivity of Southern blotting (requires 10% of T cells present to be of the dominant clone) and the very high sensitivity of RNase protection assays, which requires only 1 in 100,000 cells to be of the dominant clone. Sensitivities at the highest level give rise to false positives as reactive infiltrates may have sufficient numbers of an offspring of a single clone to yield a positive result. The PCR-based techniques have a sensitivity of approximately 1%, which nicely balances these two extremes.37 A second approach to gaining adjunctive information to yield the diagnosis of MF is immunostaining. This less costly surrogate uses antibodies against the classes of the variable regions of the ? chain (V?) of the T cell receptor. Each clone will utilize a single V?, however, there will be many other clones and individual cells that will also utilize the same V?. However, there are no ideal tests. Not only are there false negative tests due to limitations of the PCR technique, but false positive results are also possible in such diseases as pityriasis lichenoides and lymphomatoid papulosis. Again, as noted above, MF is typically a CD2+CD3+CD4+CD7-CD8-CD45RO+ infiltrate. Additionally, keratinocyte expression of the major histocompatibility complex antigen HLA-DR can aid the diagnosis of MF. From time to time additional markers may help you diagnose MF, and quantitative differences in the expression of these markers by cells in the dermis and the epidermis can also be helpful. Immunophenotypic data can also identify whether the patient has a CD8+ variant and if so, whether it is in the high risk, CD7+ category or the low risk, CD7- category. Despite these advances, the diagnosis of MF still remains elusive in many patients. To assist in the integration of the above data, our group has proposed a scoring system that assigns relative values to clinical morphology and distribution, immunohistochemistry and T cell receptor gene rearrangement analysis. This study is currently under review. Staging System Several staging systems exist for MF. Of the ones that have been extant for some time, the TNM system proposed in 197938 is the most commonly used. (See Tables 1 and 2) Recently, a University of California, San Francisco group re-examined their cohort of 450 CTCL (MF and Sezary syndrome) patients and asked whether the above staging system was predictive of survival. Interestingly, they found that clinically positive lymph nodes with negative histology had no worse prognostic significance than did extensive patch disease and that patients with extensive plaque stage disease did have a worse prognosis than those with extensive patches. Further, erythroderma and tumor stage patients had similar survivals. They therefore suggest that the current classification be modified to divide T2 into T2a (patches >= 10% body surface area) and T2b (plaques >= 10% body surface area), and that Stage III be divided into Stage IIIa (tumors with negative nodal histology) and Stage IIIb (erythroderma with negative nodal histology).39 These results seem to be consistent with my experience and I await further validation. Prognosis and Survival Rates In general the prognosis for MF is considered to be good. Most patients present in early stages, with only skin involvement, and do not progress to lymph node or visceral disease. Refer to table three for age adjusted survivals at 5, 10 and 15 years, respectively.39 Stage IV patients have a poor prognosis with a median survival reported to be much worse and may be as low as six months. Therapy Options A variety of therapies exist for MF ranging from those with ancient roots, such as psoralen-ultraviolet A (PUVA) to cutting edge fusion proteins derived from molecular biology techniques. While cure is clearly desirable, because the prognosis of early stage disease is excellent, patient needs are adequately met with chronic therapy. We need new therapies for late-stage disease patients because of its heart-breaking prognosis. Fortunately, in the last few years several such newer therapies have come to clinical trial and a few have been approved for general use in the United States. •Skin-directed Therapies Topical steroids are frequently used to treat MF. In fact, I suspect that most MF patients are treated with topical steroids at some point. Remember that most patients have symptomatic skin disease for many years prior to diagnosis. During this time, they usually carry the diagnosis of some eczematous dermatitis and are treated with topical steroids. Many of these patients are adequately treated, the disease goes into remission and the patients don? follow-up. Some of these patients actually have nascent MF. For many patients, however, topical steroids fail to be a good long-term solution. The use of topical steroids for diagnosed MF patients has been systematically studied.40 This study of 79 patients found a 49% complete response rate and a 41% partial response rate. Unfortunately, time to treatment failure was not noted, though this study does highlight that the effects (presumably lympholytic effects) of topical steroids can benefit some patients in the short term. A theoretic disadvantage might be cutaneous immunosuppression and diminished host immunity to the malignancy. Topical mechlorethamine or nitrogen mustard is a mainstay of MF therapy at most centers. It may be formulated as 10 mg dissolved in 50 cc of tap water and painted on the skin or mixed into an ointment base at 10 to 20% concentration. Daily neck-down application is standard. The main adverse effects are contact dermatitis, which can be reduced by lessening the concentration of the nitrogen mustard and then slowly increasing it as tolerated, or phototherapy to attempt to induce immunologic tolerance. The induction of secondary skin cancers is a second complication. For example, there is a relative risk of 8.6 for the development of squamous cell carcinoma in patients using topical mechlorethamine.41 On the positive side, the complete response rate at 2 years is 75.8% with a mean duration of 66 months for stage I patients and a complete response rate at 2 years of 44.6% with a mean duration of 44 months for stage II patients.42 Phototherapy including PUVA therapy is another standard therapy of MF that is familiar to most of us. For patch-plaque disease, complete response rates of 65% and partial response rates of 30% or better can be expected,43 and can frequently be achieved in 3 to 5 months. Nausea can be a problem with oral psoralen that can be addressed with topical psoralen. Secondary skin cancers, including possible risk of melanoma, are possible adverse effects. For patches, but not plaques, broadband UVB can be a more convenient option without some of the inconveniences associated with PUVA, such as oral medication and protective eyewear outside of the phototherapy cabinet. An 83% complete response rate of patch stage patients and a mean duration of remission of 22 months has been reported.44 The differential therapeutic response of patch stage and plaque stage disease adds weight to the argument to distinguish these lesion types in a modified staging scheme. Narrow band UVB is a newer modality that also has efficacy in MF, the exact place of which in the armamentarium is still to be determined, though we have had success in both patch and plaque stage disease. Radiation therapy has been employed for MF. Both electron beam and orthovoltage radiation has been utilized. Total body electron beam leads to complete remission in 84% of a mixed population of MF patients.45 This therapy requires specialized equipment and skill. Because electrons penetrate only to upper dermis there are both advantages (reduced adverse effects involving mucosal surfaces) and disadvantages (mainly in exposing all involved sites). Adverse effects include altered sweat gland function, anonychia, and alopecia. Modifications in fractionation of doses, dosing and shielding may minimize these and other adverse effects. A variety of orthovoltage regimens are utilized, usually to treat individual, problematic lesions. •Systemic Therapies Extracorporeal photochemotherapy, or photopheresis, is used for MF, though its use in disease that lacks significant blood involvement is controversial. Photopheresis is an apheresis-based therapy in which mononuclear leukocytes are isolated outside of the body. In some systems, the patient has previously ingested psoralen. In another, liquid psoralen is delivered extracorporeally to the collected leukocytes. This second approach circumvents absorption issues with oral psoralen, delivering precise drug levels to the cells to be exposed to UVA. Much lower total doses of psoralen are required (400 mcg) than with oral ingestion, the risk of ocular, GI, adverse effects or systemic photosensitization are reduced. Depending on the stage of CTCL treated, efficacy data vary. As a rule, I expect complete responses in approximately one third of patients, partial responses in one third of patients, and minimal to no response in the remaining third of patients.46, 47 Interferon therapy, particularly interferon alpha has been utilized for MF for more than a decade. Initial reports suggested modest efficacy of 10 to 27% with relapses typically within 6 months.48 Doses range from 3 million units three times a week to as much as 20 million units per day. Toxicities generally limit its use. These are flu-like symptoms of fever, anorexia, malaise, myalgia, to which patients harden, to varying degrees. Additionally neurologic, hematologic and rarely cardiac toxicities occur. In my practice, I rarely use interferon alpha as monotherapy, however, I do employ it at low doses of 1.5 to 6 million units three times a week in conjunction with PUVA, as this can induce remission in patients who are incompletely responsive to PUVA alone.49 Interferon gamma may be useful in the treatment of MF50 though the optimal use is unclear.51 Bexarotene is a recently FDA-approved therapy for MF available in both oral and topical formulations. Bexarotene is a selective retinoid X receptor-blocking agent. Typical doses are 300-400 mg/m2 po daily, for the oral agent. Response rates are reported at 45 to 54% with durati