Primary Cutaneous T-Cell Lymphomas

Primary cutaneous T-cell lymphomas (CTCLs) encompass a clinically and biologically heterogeneous group of non-Hodgkin lymphomas (NHLs) defined by clonal proliferation of skin-homing malignant T lymphocytes and natural killer cells. They account for up to 75% to 80% of all cutaneous lymphomas. The current WHO-EORTC classification of cutaneous lymphomas with primary cutaneous manifestations lists 13 entities (Table 1 ).¹ The most common subtypes—mycosis fungoides, Sézary syndrome, primary cutaneous anaplastic large cell lymphoma, and lymphomatoid papulosis—which represent approximately 95% of CTCLs, will be discussed in the following review. Each entity has unique biological characteristics and clinical course. Topical and/or systemic therapies are employed based on the stage of the disease and the tempo of progression.

The term mycosis fungoides was coined by Alibert, a French dermatologist, in 1806 to describe a skin eruption that developed into mushroom-like tumors. In 1938, Sézary and Bouvrain described the leukemia variant of CTCL. Later studies showed that this disease is related to the proliferation of mature, thymus derived T-cells with a predominantly CD4⁺ (helper cell) phenotype. Mycosis fungoides (MF) represents the most common type of CTCL, comprising 50% of CTCLs with a male predominance of approximately 2:1 and a preponderance of African-American patients. It has a yearly incidence of 0.36 cases per 100,000 population that has remained constant over the past decade.

MF is typically a chronic, slowly progressing disease with an indolent evolution. The disease is characterized by the development of patches, plaques or tumors (Figure 1; see Color Figures, page 513). The typical patch is a flat, annular, scaly skin lesion mimicking eczema, psoriasis, or dermatophyte infection. It is often erythematous to violaceous in color and has a predilection for sun-protected areas, including the lower abdomen, upper thighs, buttocks, and female breasts. These initial lesions may spontaneously regress and recur. Patches are highly variable and can give rise to or coexist with plaques, which are raised, palpable skin lesions (Figure 1a and 1b; see Color Figures page 513). Tumor stage may arise from patches or plaques or de novo. Tumors are thicker and deeper than plaques (Figure 1c; see Color Figures, page 513). They may necrotize and ulcerate, leading to opportunistic infections (Figure 1d; see Color Figures, page 513). Tumors correlate with deeper infiltration of malignant CD4⁺ T helper cells into the skin. Approximately 3 to 5% of all newly reported cases of CTCL are patients with Sézary syndrome. The disease is characterized by circulating, atypical, malignant T-lymphocytes with cerebriform nuclei (Sézary cells), erythroderma, and often lymphadenopathy. Severe pruritus, ectropion, alopecia, and palmar-plantar keratoderma are common associated features (Figure 2a and 2b; see Color Figures, page 513). Patients with CTCL may eventually develop visceral organ involvement with infiltration of the lymph nodes, liver, spleen, gastrointestinal tract, bone marrow, and, rarely, the brain.

Staging is based on the TNMB (tumor, node, metastasis, blood) system, which takes into account the extent of skin involvement, the presence of lymph node or visceral disease, and the detection of Sézary cells in the peripheral blood (Tables 2  and 3 ).

Patients with stage IA disease (T1, N0, M0) have limited patch/plaque disease with less than 10% of body surface area involvement. Patients are usually asymptomatic and may remain at this stage for years. Patches and plaques involving more than 10% of the body surface area indicate stage IB disease (T2, N0, M0). Stage IIA disease (T1–2, N1, M0) includes stage IA or IB disease plus the presence of lymphadenopathy. Stage IIB (T3, N0/1, M0) is associated with the development of skin tumors, which may arise de novo or in pre-existing patches or plaques with or without associated lymphadenopathy. Patients with erythroderma are classified as having stage III disease (IIIA: T4, N0, M0; IIIB: T4, N1, M0). Sézary syndrome is a distinct form of erythrodermic CTCL, characterized by exfoliative erythroderma, lymphadenopathy, lymphocytosis, intense pruritus, and circulating Sézary cells. Enlarged nodes are found in about 47% of all patients and in 83% of erythrodermic patients. Frank involvement of nodes by tumor cells (N2, N3) without visceral organ involvement is classified as stage IVA (T1–4, N2–3, M0). Patients with extracutaneous manifestations and/or bone marrow involvement are classified as stage IVB (T1–4, N0–3, M1).

Routine evaluation should include complete physical examination; a complete blood cell count with differential and Sézary cell count; serum chemistries, including measurement of the serum lactate dehydrogenase (LDH) concentration, a skin biopsy for histologic examination, immunophenotyping and gene rearrangement studies and lymph node biopsies in patients with enlarged nodes at presentation to establish the diagnosis and disease stage.

Diagnosis in early stages of MF has been improved due to advances in PCR gene rearrangement techniques, resulting in increased sensitivity and specificity. Imaging studies should be reserved for patients with clinical and laboratory findings suggestive of systemic disease or prominent lymphadenopathy. Bone marrow biopsy should be performed in advanced-stage disease. Serologic tests for HIV and HTLV-1 should be considered in select patients. The data obtained should be used to stage the patient with the TNMB classification. Treatment decisions should only be made after the patient has been appropriately staged.

The most important predictive factors for survival remain the T (tumor) classification, extracutaneous manifestations, and patient age. In addition, several independent adverse prognostic factors have been identified including large cell transformation, follicular mucinosis, thickness of tumor infiltrate, and increased serum LDH levels. Patients with large Sézary cells were also found to have a worse prognosis. A high Sézary cell count, loss of T-cell markers such as CD5 and CD7, existence of a T-cell clone in the blood, and chromosomal T-cell abnormalities are also independently associated with a poor outcome. The presence of cytotoxic CD8⁺ T-lymphocytes in the dermal infiltrate, as well as the density of epidermal Langerhans cells exceeding 90 cells/mm², is associated with a better prognosis. Patients with T1 disease have a normal life expectancy, whereas patients with increased tumor burden have a significantly decreased survival. The median survival time of patients with extra-cutaneous disease is approximately 25 months.

There is a spectrum of strategies employed for the management of MF/SS. Few phase III trials have been performed and, as a result, the choice of treatment is often determined by physician or patient preference. The EORTC has recently published consensus recommendations for the treatment of MF/SS based on the review of available data (Table 4 ).³ 

Phototherapy is one of the mainstay treatment modalities in CTCL. Of the available phototherapies, PUVA therapy has been widely used with established benefit in early-stage MF for more than 25 years. It involves treatment with orally administered 8-methoxypsoralen (8-MOP) that sensitizes the skin to UVA irradiation. The initial UVA dosage is approximately 0.5 J/cm² and will be increased per treatment as tolerated or up to the minimal erythema dose. Therapy is typically given 3 times a week until complete remission is achieved. Additional maintenance therapy can be administered while gradually reducing PUVA to once every 4 to 6 weeks, to maintain longer remission times. Several studies confirmed high remission rates in early stages of MF with reported complete remissions (CR) in up to 71.4% of patients.^4,5 Although being effective in clearing superficial lesions, PUVA has its limitations in clearing deeply infiltrated lesions. Disease-free survival rates for stage IA at 5 and 10 years were 56% and 30%, respectively, and for stage IB/IIA 74% and 50% have been reported.⁵ The most common reported acute side effects were erythema, pruritus, and nausea, which were usually mild at presentation and generally manageable with dose adjustments of UVA or 8-MOP or dose interruptions. Long-term exposure was associated with an increased risk for developing chronic photodamage and non-melanoma skin cancer in about one third of patients.

The efficacy of broadband UVB is limited more to patch stage, while PUVA is also effective in clearing plaques. The effects of UVB phototherapy were retrospectively evaluated in 37 patients with MF limited to patch/plaque disease.⁶ Seventy-one percent achieved CR with a median duration of 22 months. Eighty-three percent of patients with disease limited to patches achieved remission, whereas none of the patients with plaque disease achieved remission. Narrowband (NB)-UVB is considered to be less carcinogenic and may offer an alternative treatment option in early stage MF, but randomized clinical trials are needed to confirm its efficacy and long-term remission rates.

Topical corticosteroids are frequently prescribed in patients to induce clearing of skin lesions in patients with limited patches (stage IA). In an investigational trial, 79 patients were treated daily with topical class I–III steroids.⁷ Thirty-two patients (63%) of stage T1 patients and 7 (25%) of stage T2 patients achieved complete clearing. The duration of response depends on extent of disease and thickness of the targeted lesion.

Nitrogen mustard (mechlorethamine) has been widely used as a first-line treatment of early-stage MF since 1959. It may be applied locally or to the entire skin once daily.

Many investigators have demonstrated the efficacy of topical nitrogen mustard at a concentration of 0.1% to 0.2% in an aqueous or ointment base (Aquaphor) with reported CR in up to 72% of early-stage MF patients and occasional long-term remissions of more then 8 years.⁸ Skin clearance may require 6 months or longer and is followed by maintenance therapy; however, there is no evidence that prolonged maintenance is beneficial. The most common side effect was irritant contact dermatitis and hypersensitivity reaction.

Another type of topical chemotherapy that has been employed for MF is the nitrosourea alkylating agent carmustine (1,3-bis(2-chloroethyl)-I-nitrosourea, BCNU). Clearance rates in 43 (84%) of 51 T1 and 14 (37%) of 38 T2 patients appear to be similar to those with nitrogen mustard.⁹ Patients almost always develop erythema at site of application. Although irritant and/or allergic reactions occur less frequently, the cutaneous toxicity may be greater with the development of progressing teleangiectasias and reported bone marrow suppression from systemic absorption.

Bexarotene 1% gel (Targretin^®) has been approved by the Food and Drug Administration (FDA) for early-stage MF in 2000. The current expense and associated skin irritation makes it unlikely that bexarotene gel will be used in patients with more than 10% of skin involvement. Bexarotene gel is applied slightly to patches or plaques and is most effective and best tolerated when used twice daily. Topical bexarotene has been evaluated in a dose escalating trial with concentrations ranging from 0.1% to 1.0%.¹⁰ Median treatment duration with bexarotene gel was 10.5 months. The complete response (CR) rate was 21%, with a 63% overall response rate and a 75% response rate in treatment-naïve patients. The median duration of remission was 24 months.

Patients with localized tumors (stage IIB) may require systemic treatment, but mostly respond very well to localized orthovoltage radiation. Total skin electron beam treatment (TSEBT) may be used in patients with more disseminated cutaneous disease. It is a treatment in which ionizing radiation is administered to the entire skin surface penetrating to the dermis. The standard total dose is 36 Gy delivered with electrons of at least 4 MeV energy and fractionated over 8–10 weeks. Reported complete remission rates range from 40% to 98% among patients with T1 and T2 stage; however, relapse rates are high when used as the sole modality.^11 –13 Nearly all patients developed skin-related side effects including erythema, teleangiectasia, xerosis, nail dystrophy, and/or reversible alopecia.

Interferon-alpha (INF-α) is one of the most widely used first-line treatments and probably the most effective single agent in the treatment of CTCL. The available subtypes INF-α2a (Roferon^® A) and INF-α2b (Intron^® A) do not differ in their activity and have shown a wide range of biologic effects, including antiviral, antiproliferative, and immunomodulatory. Overall response rates range from 29% to 74% of patients with median durations from 4 to 42 months.^14 –16 The higher response rates and durations have been seen in early stage MF patients who have not received previous therapy.

INF-α is generally given as long-term therapy, although the optimal dose and duration in CTCL has not been established. Various dosages and treatment schedules have been used. Therapy should be initiated at low doses between 1 and 3 million units (MU) 3 times weekly with gradual escalation to 9–12 MU daily or as tolerated. The combination therapy IFN-α and PUVA, first reported by Kuzel et al in 1995, resulted in very high response rates and showed superiority to other combinations with retinoids or extracorporeal photophoresis (ECP).¹⁷ Thirty-nine patients with advanced disease (IB-IVB) were treated with INF-α2a (12 MU 3 × weekly) and PUVA (3 × weekly) with an overall response rate of 92% and CR in 62% of patients. The median duration was 28 months. Side effects are based on dosage and schedule and can be divided into acute and chronic. Initially, almost all patients develop temporary flu-like symptoms. Chronic side effects can be anorexia, fatigue, depression, alopecia, cytopenia, and impaired liver function. INF-γ has also demonstrated activity in CTCL.¹⁸ 

Retinoids are vitamin A derivatives that have important effects on cell growth, terminal differentiation, and apoptosis and have been used to treat CTCL since the early 1980s with reported benefits in several small studies. Response rates ranged from 44% to 67% with CR rates from 21% to 35% and median response duration around 8 months. Common effects consisted on skin and mucous membrane dryness. Bexarotene, a new retinoid X receptor (RXR)-selective retinoid, has been approved in 1999 for the treatment of relapsed/refractory CTCL at early and advanced stages. The approval of bexarotene capsules was based on two multicenter open-label phase II-III clinical trials in 152 patients with early and advanced stages of CTCL patients who have failed or were refractory to two or more standard therapies.^19,20 In the early stage trial, 58 patients randomized to doses of 6.5, 300 or 650 mg/m² daily achieved response rates (defined as a greater than 50% improvement in skin lesions) of 20%, 54% and 67%, respectively.¹⁹ Median time to response was 8 weeks. In the advanced stage trial with 94 patients, response rates of 45% and 55% have been observed with daily doses of 300 or 650 mg/m², respectively, and an overall response rate of 48%.²⁰ However, only 6% (6/94) of patients achieved a CR. Median duration of response was 10 months. Retrospectively collected comparison data suggest that there may be little difference in efficacy between the RXR-selective retinoid bexarotene and the retinoic acid receptor (RAR)-specific retinoid all trans-retinoic acid (ATRA).²¹ 

The most common significant side effects experienced in trials of both early- and advanced-stage disease were hypertriglyceridemia, hypercholesterolemia, central hypothyroidism, and leukopenia requiring additional treatment with lipid-lowering agents such as statins, HMG-CoA reductase inhibitors or fenofibrates, and thyroid hormone replacement.^19,20 The concomitant use of gemfibrozil (Gemcor) is contraindicated as it increases plasma concentration of bexarotene and triglyceride levels, possibly related to cytochrome P450 3A4 isoenzyme inhibition. A combined regimen with PUVA may not increase response rates but has the advantage of decreased dose requirements for both PUVA and bexarotene.

Extracorporeal photopheresis (ECP) was approved in 1988 by the FDA for the palliative treatment of patients with CTCL. Circulating mononuclear cells are separated by a leukapheresis-based method, mixed with 8-MOP (UVADEX^®), exposed to UVA light (1–2 J/cm²) that activates the 8-MOP causing crosslinking of DNA, and re-infused to the patient. One suggested mechanism of action is induction of apoptosis in circulating malignant T lymphocytes with subsequent release of tumor antigens leading to a systemic antitumor response against the malignant T-cell clone. Treatment is empirically given on 2 consecutive days every 14 to 28 days. It usually takes several months to see an improvement and is especially of benefit for both erythrodermic MF and SS with circulating neoplastic T cells. In 1987 Edelson et al reported on preliminary results of the first multicenter trial for ECP in CTCL with a partial or complete response in 27 of 37 patients (73%).²² Of the responding patients 24 had exfoliative erythroderma. Mean time to response was 22 weeks. Optimal candidates for ECP are patients with SS with less than 2 years of disease onset, modest tumor burden and circulating neoplastic cells, and almost normal counts of circulating CD8⁺ T cells and NK cells. Prolonged response rates have been reported when combined with INF-α, bexarotene, granulocyte colony-stimulating factor (G-CSF), or TESBT.^23 –25 There have been few adverse events related to ECP treatment, including catheter-related infection and hypotension caused by volume shifts.

Alemtuzumab (CamPath^® ) is a humanized IgG₁ MoAb that targets the CD52 antigen abundantly expressed on normal and malignant B and Tcells, but not on hematopoietic stem cells. It is FDA approved for the treatment of CLL. An update on alemtuzumab reported more than 50% response rates with 32% CR in two studies conducted with heavily pretreated relapsed/refractory MF/SS patients.²⁶ Results were most promising in patients with SS. Median response duration was 12 months. The compound, however, can be associated with significant hematologic toxicities and infectious complications consisting of reactivation of cytomegalovirus, herpes zoster, miliary tuberculosis, and pulmonary aspergillosis. In particular, this can be a problem when used in heavily pretreated patients. Cytopenias and prolonged immunosuppression require prophylactic antibiotic, antiviral, and antifungal treatment, and potential support with G-CSF. One group observed adverse cardiac events such as congestive heart failure, arrhythmia and LV dysfunction associated with alemtuzumab therapy.

Denileukin diftitox (Ontak^®) is a recombinant fusion protein that contains the portion of IL-2 that interacts with the IL-2R, coupled to the portion of diphtheria toxin. After binding to the IL-2R on neoplastic T-cells it is internalized and induces apoptosis. The IL-2R consists of three subunits, the α-chain (CD25), β-chain (CD122), and γ-chain (CD132). Denileukin diftitox targets preferentially the intermediate (β/γ-chain) and high-affinity IL-2R (α/β/γ-chain) on malignant T-lymphocytes. The degree of CD25 expression is highly variable and dependent on the tissue site. Current anti-CD25 antibodies only recognize one component of the receptor and therefore can be inaccurate in predicting response. Denileukin diftitox has been approved by the FDA in 1999 for the treatment of patients with CTCL refractory to standard treatment options. In general, response rates in patients with relapsed and refractory MF/SS range from 30% to 37%.²⁷ Adverse effects include acute infusion-related events such as fever, rash, chills, dyspnea, and hypotension, and later effects such as myalgias, elevated serum transaminases, and vascular leak syndrome (VLS). The incidence of acute infusion-related events and VLS was significantly decreased with premedication of 8 mg dexamethasone, in addition to a significantly improved overall response rate of 60% compared to prior studies without steroids.²⁷ 

Single-agent and combination chemotherapies in advanced, refractory, and aggressive forms of CTCL have been associated with high response rates, but short-lived durations.³ Their use is limited to palliation of symptoms. Options include single-agent or multi-agent chemotherapy including steroids, methotrexate, chlorambucil (Leukeran), vincristine (Oncovin), doxorubicin (Adriamycin), pegylated doxorubicin (Doxil), cyclophosphamide (Cytoxan), etoposide (Vepesid), nucleoside analogues, and alkylators. Combination regimens include cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CVP-therapy.

The concept of high-dose combined chemotherapy followed by autologous bone marrow transplant or peripheral blood stem cell support has curative potential in various non-Hodgkin’s lymphomas, but experience in CTCL is limited. Autologous stem cell transplants (SCT) have yielded disappointing results. Despite reported effective responses, with CR in most patients treated, relapses are common and may occur rapidly. Allogeneic transplants are known to achieve much more durable CR most likely due to an immune mediated graft-versus-lymphoma (GVL) effect. Response durations as far as 6 years post transplant have been reported suggesting that it may be a curative option.²⁸ It does, however, carry a higher risk of treatment-related mortality including life-threatening infections and graft-versus-host disease. Reduced-intensity non-myeloablative (mini) allogeneic stem cell transplant potentially offers a GVL effect with lesser toxicities related to the conditioning regimen. A recent series of 3 young patients with advanced, refractory CTCL, who underwent nonmyeloablative allogeneic transplantation, demonstrated only brief periods of disease remission, despite the evidence of GVL effects, indicating that there was insufficient GVL effect to control the malignancy.²⁸ Allogeneic SCT should be a consideration in younger patients with aggressive and advanced disease resistant to standard treatment options as a potentially curative option.

Various investigational options have been designed to target disease-specific pathways in CTCL. The most recent investigations are briefly discussed.

Therapeutic effects of a chimeric (mouse/human) anti-CD4 monoclonal antibody had been observed as an active agent in MF/SS as early as 1991. HuMax-CD4 is a fully human anti-CD4 (IgG₁κ) moAb that targets the CD4 receptor expressed on T-helper/memory cells. Two ongoing phase II trials showed promising results with an acceptable toxicity rate. Clinical improvement according to Physician’s Global Assessment was reported in 36% to 55% of early-stage patients and in 30% to 38% of advanced-stage patients treated for 16 weeks. Higher response rates were achieved with greater doses in early and advanced stages (www.lymphoma-net.org).

CD30 is typically expressed in large-cell transformed MF, primary cutaneous anaplastic large T-cell lymphoma (ALCL), and lymphomatoid papulosis. SGN-30 is a chimeric anti-CD30 monoclonal antibody that has demonstrated activity against targeted malignant cell lines in vitro and in xenograft models. In phase I/II trials focused on CD30⁺ malignancies, promising responses have been witnessed. Investigators using a dose of 6 mg/kg weekly for 6 consecutive doses noted 1 CR, 1 PR, 1 stable disease (SD) and 3 progressive disease (PD) in patients with CD30⁺ ALCL. Trials in CD30⁺ lymphoproliferative disorders are ongoing.²⁹ 

Immunomodulatory cytokines are thought to enhance cytotoxic cell-mediated activity. Human recombinant IL-2 has raised interest because of its ability to induce regression in a subset of patients with CTCL. Overall response rate of 18% and median response duration of 3 months suggest that subcutaneously administered rIL-2 is modestly effective as therapy in patients with relapsed and refractory CTCL (Querfeld C, Rosen ST, et al. Manuscript submitted). Treatment with IL-12 achieved higher response rates of 43% in 23 patients.³⁰ Increased levels of CD8⁺ and/or TIA-1⁺ T cells in regressing cutaneous lesions suggested induction of a cytotoxic-T-cell antitumor response.

Hyperacetylation of tumor suppressor genes is frequently observed in CTCL. These genes are silenced by histone deacetylases, which remove acetyl groups from histones, which form complexes with DNA (nucleosome). Histone deacetylase (HDAC) inhibitors may restore the expression of tumor suppressor and/or cell cycle regulatory genes by increasing the acetylation of histones. Depsipeptide and suberoylanilide hydroxamic acid (SAHA) (www.lymphomainfo.net)³¹ are potent HDAC inhibitors and have shown in vitro and in vivo cytotoxic activity against CTCL. In recently conducted phase II trials, depsipeptide and SAHA have been shown to be active in both MF and peripheral T-cell lymphoma.

Host immune function appears to play an integral role in mediating responses in MF. Toll-like receptor (TLR) agonists such as imiquimod (Aldara) and CpG-7909 enhance immune responses via activation of TLR-7, 8, and/or 9. CpG-7909 (CpG oligonucleotide) is a TLR-9 agonist known to induce Th1-induced immune responses via dendritic cell activation. Preliminary results demonstrate that the cytotoxic CD8⁺ T-cell population increased within tumor infiltrates after systemic administration.³² Lenalidomide (CC-5013, Revlimid^®), an oral immunomodulatory thalidomide analogue, is currently being used in clinical trials to treat various hematological malignancies and solid tumors. The immunomodulatory properties such as T cell co-stimulation with induction of Th1 cytokine production and cytotoxic activity along with anti-angiogenic, anti-proliferative, and pro-apoptotic properties provided the rationale to use this agent in patients with MF/SS. Preliminary data from an ongoing phase II trial have shown efficacy in heavily pretreated patients with advanced MF/SS.³³ 

Lymphomatoid papulosis represents a benign, chronic, recurrent, self-healing, papulonodular, and papulonecrotic CD30⁺ skin eruption³⁴ (Figure 2a; see Color Figures, page 513). However, 10–20% of patients may develop a lymphoid malignancy, but the prognosis for patients with lymphomatoid papulosis is otherwise excellent with a 100% 5-year survival. There is no curative treatment available. Lymphomatoid papulosis is managed by observation, intralesional steroid injection, topical bexarotene (targretin), Imiquimod (Aldara), ultraviolet light therapy, or low-dose methotrexate.³⁵ Trials with SGN-30 (anti-CD30 mAb) are in progress.²⁹ 

Primary systemic CD30⁺ ALCL and primary cutaneous CD30⁺ ALCL represent identical morphologic entities, but they are clinically distinct diseases.³⁶ 

The neoplastic cells of primary cutaneous CD30⁺ large T-cell lymphoma (CD30⁺ LTCL) are of the CD4⁺ helper T-cell phenotype with CD30 expression. It represents 9% of CTCLs and typically presents with solitary or localized nodules (Figure 2d; see Color Figures, page 513). This tumor has an excellent prognosis, as confirmed in several studies, in contrast to the transformation of mycosis lymphoma to a CD30⁺ large cell variant. It shows histologic and immunophenotypic overlap with lymphomatoid papulosis. In most cases, tumor cells show anaplastic features, less commonly a pleomorphic or immunoblastic appearance. However, there is no difference in the prognosis and survival rate. Primary cutaneous CD30⁺ LTCLs rarely carry the t(2;5) translocation and are usually ALK-negative. These lesions may undergo spontaneous regression, as do the lesions of lymphomatoid papulosis. The mechanism of tumor regression remains unknown. Spot radiation therapy or surgical excision is the preferred treatment, with systemic chemotherapy reserved for cases with large tumor burden and extracutaneous involvement. In addition, there has been reported efficacy of recombinant interferon and in combination with bexarotene.³⁷ Trials with SGN-30 (anti-CD30 mAb) are in progress.²⁹