Review Article

Primary Cutaneous T-Cell Lymphoma: Review and Current Concepts

By Richard S. Siegel, Journal of Clinical Oncology, Vol 18, Issue 15 (August), 2000: 2908-2925

Primary cutaneous T-cell lymphomas (CTCLs) encompass a wide variety of lymphomas that are characterized by the localization of the malignant lymphocytes to the skin at presentation. Advances in molecular biologic techniques, including immunophenotyping and gene rearrangement studies to determine clonality, have led to more frequent diagnosis of CTCL as well as more consistent subclassification of these entities. However, there continues to be confusion in the classification, prognosis, and management of patients with CTCL. The purpose of this review is to present a summary of the diagnosis, prognosis, and treatment of CTCL, with specific emphasis on mycosis fungoides (MF) and Sézary syndrome (SS). We also present a detailed discussion of the entities that make up the differential diagnosis of CTCL.

 MF and SS are the most common forms of CTCL. The etiology of this disease is still unknown. Patients may go for months to years with skin abnormalities before being diagnosed. MF/SS is an indolent disease and patients with T1 disease have a normal life expectancy. Patients who undergo transformation to large-cell lymphoma (8% to 23% of patients) have a poor prognosis, with mean survival ranging from 2 to 19 months. Treatment for MF/SS continues to be palliative. There are many new therapies that are currently being investigated in clinical trials, and the DAB389IL-2 fusion protein was recently approved for the treatment of refractory MF/SS.

CUTANEOUS T-CELL lymphomas (CTCL) are a group of lymphoproliferative disorders characterized by localization of the neoplastic T lymphocytes to the skin at presentation. Although mycosis fungoides (MF) and Sézary syndrome (SS) make up the great majority of these diseases, there are many distinct entities that make up the differential diagnosis of cutaneous lymphoproliferative disorders. These entities can have quite dissimilar presentations, pathologic findings, prognoses, and treatments. It is imperative that clinicians appreciate these differences to provide appropriate management of these patients. Until recently, classification systems for lymphomas did not make the distinction between primary and secondary cutaneous lymphomas, and most classifications have been based only on histologic diagnosis. The recently published European Organization for Research and Treatment of Cancer classification for primary cutaneous lymphomas may be the most clinically relevant classification. The correct diagnosis of primary cutaneous lymphoproliferative disorders requires evaluation of the clinical presentation, histology, immunophenotyping, and gene rearrangement studies.

EORTC Classification for Primary Cutaneous Lymphomas:
   Indolent :
       MF
       MF + follicular mucinosis,  
       Pagetoid reticulosis , 
       Large-cell CTCL, CD30+
             Anaplastic
             Immunoblastic
             Pleomorphic
       Lymphomatoid papulosis
Aggressive
       SS
       Large-cell CTCL, CD30-
              Immunoblastic
              Pleomorphic
Provisional
       Granulomatous slack skin
       CTCL, pleomorphic small/medium-sized
       Subcutaneous panniculitis-like T-cell lymphoma

In this review, we present a detailed description of MF/SS, by far the most common form of CTCL. This is followed by descriptions of the other CTCLs, as well as presentations of the many diseases that make up the differential diagnosis of CTCL.

CTCLs: MF/SS

MF and SS  make up the great majority of cases of primary CTCL; therefore, a significant portion of this article will be a detailed review of these entities to illustrate concepts to the reader.

Epidemiology
MF/SS is an uncommon malignancy. The Surveillance, Epidemiology, and End Results Program evaluated the incidence of MF/SS, as well as all lymphomas, in nine population-based cancer registries in the United States from 1973 through 1984.3 They reported an incidence of 0.29 cases of MF per 100,000 population per year, which represented 2.2% of all lymphomas. A 3.2-fold increase was noted in the incidence of MF during the course of the study, and the proportion of MF cases among all lymphomas increased from 1.6% to 2.8% over the course of the study. The Surveillance, Epidemiology, and End Results Program data also demonstrated that the incidence of MF increases with age, is 2.2 times more common in men than women, and is more common in African-Americans.

Etiology
The etiology of MF/SS remains unknown. Several causative factors have been proposed and subsequently investigated. These include chronic antigenic stimulation as a result of exposure to various chemicals or cutaneous bacterial infections, smoking, medications, chronic sun exposure, and viral infections.

Clinical Presentation
MF is by far the most common CTCL. Alibert described the first case of MF in 1806 in a patient who developed a skin lesion that evolved into mushroom-like tumors, leading to the term MF. Bazin described the three classic phases of cutaneous progression in which the disease begins with an erythematous macular eruption that often originates on the trunk in non–sun-exposed areas. Biopsies at this stage are often nondiagnostic. This can last for months to years before progressing to the traditional patch phase, in which limited patches can resemble eczema or psoriasis. Biopsies of these lesions usually yield a diagnosis consistent with CTCL. If untreated, the disease may progress from more generalized patches and plaques to the development of tumor stage skin disease or erythroderma that is commonly associated with adenopathy, and possibly, visceral involvement.

Plaque lesions are more erythematous than patch lesions, have well-demarcated margins, and scaling. They can arise in areas of previous patches or arise de novo. In MF, compared with other CTCLs, tumors are frequently found associated with previous patches or plaques, and in these cases, represent loss of epidermotropism with extension of the infiltrate into the deep dermis. Ulceration, with secondary infection of the tumors, is a common cause of morbidity. The D’emblee presentation signifies the appearance of the tumor stage of disease without antecedent patch or plaque disease.

SS accounts for 5% of new presentations of MF/SS. The clinical picture includes generalized erythroderma, pruritus, and circulating malignant cells (Sézary cells). There is some argument over the minimum number of atypical cells needed in the peripheral blood to make this diagnosis. This is usually expressed as an absolute number of atypical cells (>= 1,000/mL) or a percentage of the total lymphocyte count (5% to 20%).

Diagnosis/Staging
The diagnosis of MF/SS is based on the clinical findings combined with the histology of the skin biopsy. On histopathology, there is a band-like infiltrate involving the papillary dermis consisting of small, medium-sized, and sometimes large mononuclear cells with hyperchromatic, cerebriform nuclei without spongiosis. There are usually nonmalignant inflammatory cells found among the malignant cells. In early patch and plaque lesions, it can be difficult to diagnose CTCL because of the extensive inflammatory response.

Nuclear contour index is a value that can be determined by electron microscopic analysis of the degree of lymphocyte nuclear folding in skin biopsies. The nuclear contour index can differentiate MF from benign lymphoid infiltrates.

Immunophenotyping is performed on the skin biopsies. The malignant cells are usually CD3+, CD4+, CD8-, CD30-, and CD45RO+. CD7 is often deleted from early lesions, and this may predict a worse prognosis. Advanced MF/SS and some variants may lose expression of CD2, CD5, and sometimes CD4.Routine evaluation now usually includes DNA analysis of the T-cell–receptor gene rearrangement to define the clonal population. This can be performed by Southern blotting, which is 90% to 95% sensitive and analyzes the ß-chain gene rearrangement. Most T cells express the {alpha}ß receptor, whereas few cells express the {gamma}{delta} receptor. PCR, which is nearly 100% sensitive, is used to analyze the {gamma} chain, which is rearranged in all T cells, whether they express the {alpha}ß or {gamma}{delta} receptor.

Lymph node biopsies can be performed at the initial staging in advanced disease, or if nodes are found to be enlarged on physical examination, or by imaging studies. Histopathology of lymph node involvement initially affects the paracortical regions. As progression occurs, there are small to large clusters of atypical cells with preserved nodal architecture, followed by partial or total effacement of the node. Immunophenotyping and T-cell–receptor gene rearrangement analysis is helpful in evaluation of lymph nodes.

Peripheral-blood involvement is demonstrable at all stages of disease because of the normal lymphatic drainage via the thoracic duct. It is much more prevalent in tumor stage disease or SS. The level of circulating malignant cells is inversely correlated with prognosis and should be evaluated at initial presentation and routinely during follow-up. Visceral involvement occurs late in the progression of MF/SS.

Formal staging is according to the tumor-node-metastasis classification system. In a study of 43 patients, Martí  evaluated 18 clinical and pathologic predictors of prognosis. They concluded that in a clinical evaluation alone, the T stage and serum lactate dehydrogenase level were the major prognostic factors. In a clinicopathologic evaluation, T stage and thickness of the cutaneous infiltrate measured from the granular layer were major prognostic factors.

Treatment
Treatment strategies can be divided into two categories: skin-directed and systemic therapy. Skin-directed therapy includes psoralens plus ultraviolet light (PUVA), topical chemotherapy, and radiation therapy. Systemic therapy includes chemotherapy and other cytotoxic agents, photopheresis, IFN, retinoids, as well as other investigational biologic response modifiers. No studies have demonstrated superiority of any one topical therapy, and the decision of which therapy to choose usually depends on physician and patient preference.

The goals of treatment with established therapies are symptom relief and cosmetic improvement because cures are generally unattainable with standard therapies. Kaye  evaluated the use of early, aggressive therapy with total-skin electron beam therapy (TSEBT) and chemotherapy versus sequential topical therapies. Although the aggressively treated patients had a higher complete remission rate, this group also had significantly more toxicity. More importantly, there were no significant durable differences between disease-free and overall survival between the two groups.

Ultraviolet B
Ramsay have shown that ultraviolet B (UVB) therapy is effective in patients with stage I patch disease. In their retrospective study, 25 (83%) out of 30 patients with stage I patch disease achieved a complete remission at a median of 5 months after initiating therapy at a frequency of three times a week. The median duration of remission was 22 months.

PUVA
PUVA therapy, which was initially used in the treatment of refractory psoriasis, consists of the ingestion of 8-methoxypsoralen (8-MOP), a member of a family of photoactivated compounds that can inhibit both DNA and RNA synthesis through the formation of mono- or bifunctional thymine adducts, gene mutations, or sister chromatid exchanges. The drug only becomes activated when exposed to ultraviolet light, particularly in the 330- to 340-nm range.

Treatment is typically given three times a week during the clearing phase, and this is followed by a tapering maintenance phase ranging from once a week to once every 3 to 4 weeks. The dose of 8-MOP is 0.6 mg/kg ingested 2 hours before the UVA exposure. Early studies demonstrated high remission rates for early-stage disease. The Scandinavian study group reported a 58% complete response rate within 2 to 3 months of initiation of treatment. The duration of remission was up to 53 months with maintenance therapy. They also reported an 83% remission rate in tumor stage disease. Herrmann reported Northwestern University’s experience of PUVA therapy, including long-term follow-up. In this study, 82 patients with mostly stage I disease were treated with PUVA. Ninety-five percent of patients had at least a partial response, and 65% had a complete response. The mean duration of complete response was 43 months. The mean survival in this group was 8.5 years.PUVA therapy is usually restricted to patients with stage I and II disease.

Side effects to PUVA are well-tolerated and include nausea caused by psoralen ingestion and actinic effects of UVA exposure, including erythema and pruritus in the short term and chronic dry skin and secondary skin malignancies in the long term. There has recently been a case report published linking PUVA therapy to myelodysplasia and subsequently to acute myelogenous leukemia.

Topical Chemotherapy
Topical chemotherapy can be used with either mechlorethamine (nitrogen mustard [NM]) or carmustine (BCNU). Topical NM therapy is usually applied daily to the entire body surface with a solution of 10 mg in 50 mL of tap water. Hoppe  reported a complete response rate of 51% and an overall response rate of 88% among 43 patients with T1 disease treated with topical NM. In the same series, there was a 26% complete response rate and a 70% overall response rate among 58 patients with T2 disease. Ramsay reported a 67% complete response rate after 1 year of topical NM among 41 patients with T1 disease and a 40% complete response rate among 76 patients with T2 disease. The median time to remission in this study was 4.4 months for T1 disease and 20.4 months for T2 disease. Therefore, topical NM is an efficient and convenient treatment option.

The major side effects of topical NM include irritant or allergic contact dermatitis and secondary squamous cell and basal cell carcinomas. Delayed hypersensitivity reactions occur in up to 58% of patients, requiring therapy to be held at least temporarily and desensitization. Ointment-based NM has been associated with less cutaneous sensitivity; Price  reported that among 12 patients who had previous hypersensitivity to aqueous-based NM, only three developed contact dermatitis when subsequently treated with ointment-based NM.

In a long-term follow-up study by Vonderheid 35 (11%) out of 331 patients treated with topical NM had complete remissions lasting more than 8 years. The incidence of squamous cell carcinoma of the skin was 8.6 times that of the general population, and the incidence of basal cell carcinoma of the skin was 1.8 times that of the general population. Analysis of this study is complicated by the fact that many patients were also treated with other modalities, including local radiation, TSEBT, ultraviolet phototherapy, and systemic chemotherapy.

Topical BCNU has demonstrated similar effectiveness as NM. BCNU 10 mg is dissolved in ethanol and then mixed with 60 mL of water. The resulting solution is applied once a day to the total body-surface area, except uninvolved areas of the face, hands, genitals, and skin folds. Zacheim has reported a 92% overall response rate at 3 years among 89 patients with T1 disease and a 64% overall response rate at 3 years among 83 patients with T2 disease. The 5-year survival in these two groups was 97% and 79%, respectively. The median time to achieve a complete response was 9 weeks for patients with T1 disease and 12 weeks for those with T2 disease. Hypersensitivity reactions to BCNU are rare. The most common adverse effect of topical BCNU is erythema, which can be followed by the appearance of telangiectasias. Secondary skin cancers are not usually observed. In the above study, myelosuppression was rare at the standard 10-mg dose and was seen in less than 10% of patients treated at double the standard dose.

Radiation Therapy
CTCL is very radiosensitive. External-beam radiation is effective in controlling areas of otherwise resistant MF and in palliating bulky tumor lesions. External-beam therapy is limited by its toxicities, including marrow suppression and radiation dermatitis, which may prevent the use of therapy with other agents.

Electron beam therapy is better tolerated than external-beam, and is very effective. Electrons are delivered at an energy of 4 to 9 MeV to treat the skin only. Less than 5% of the dose travels beyond 2 cm, and the target volume for most patients does not exceed a depth of 5 mm; therefore, deep organ toxicity such as myelosuppression does not occur. Reddy  showed that patients who receive a total dose of greater than 20 Gy have a better 5-year survival and longer duration of complete response than those who receive <= 20 Gy. The standard total dose for a course of TSEBT is 36 Gy. The electrons are generated by a linear accelerator and commonly administered using dual fixed-angle six-field methods.

TSEBT results in a 56% to 96% complete response rate in patients with stage IA to IIA disease.If no adjuvant therapy is given, there is a relatively high relapse rate. The relapse-free survival rate for stage IA disease ranges from 33% to 52% at 10 years; whereas the relapse-free survival rate is only 16% for patients with stage IB disease or worse.Acute toxicity of TSEBT consists of an epithelial reaction with erythema, pain, and swelling. Hair and nail loss is also seen, as well as loss of sweat gland function, but these are reversible. A 10-day break halfway through the treatment period results in less severe skin reactions. Telangiectasias and xerosis are the most common chronic adverse effects. Skin cancers can occur, and the risk of basal cell and squamous cell carcinoma of the skin is increased in patients who subsequently receive PUVA or topical chemotherapy.There is a theoretical risk of ocular complications because it has been shown that standard eye shields are less effective with electron beam compared with orthovoltage radiation. Also, although myelosuppression is extremely rare with TSEBT, it is possible if the source is contaminated with orthovoltage radiation and local therapy is given to a site of hematopoiesis.

TSEBT is most commonly used in patients with diffuse skin involvement of thick plaques and tumors and in patients with SS. It can also be used for lesions that have been refractory to other skin-directed therapy. Current studies are evaluating whether adjuvant therapy improves survival compared with TSEBT alone. In an evaluation of 14 patients with T1 and T2 disease who received PUVA therapy after TSEBT, Quiros  demonstrated significant improvement in disease-free survival in the PUVA group and a trend toward improved overall survival.

Photopheresis
Edelson  have described the method of photopheresis. Patients ingest oral 8-MOP. This is followed by leukapheresis with isolation of the mononuclear fraction, which is then exposed to UVA. The irradiated cells are then returned to the patient. The UVA is directly toxic to those cells that are irradiated, and in addition, the reinfused cells stimulate a selective immune response against the malignant cells.

Photopheresis is initially performed on 2 consecutive days once a month until maximal clearing has occurred. This is followed by an additional 6 months of monthly therapy and then gradually tapered to 2-month intervals and discontinuation. Edelson  reported a 73% response rate in patients with CTCL refractory to previous therapies, most of whom had SS. Patients with SS, near normal CD8+ lymphocyte counts, and a relatively short duration of advanced disease were most likely to respond. Edelson have subsequently reported a median survival of 60 months in this initial cohort of patients. Genotypic evidence of clonality was not required in that study. Fraser-Andrews  retrospectively compared a group of patients treated with photopheresis with a group not treated with photopheresis. Inclusion in their study required genotypic evidence of a peripheral-blood T-cell clone. Median survival in the patients treated with photopheresis was only 39 months and was not significantly better than the group not treated with photopheresis. There is now an investigational form of liquid 8-MOP available that is administered directly into the photopheresis machine, so patients do not have to ingest the psoralen.

Systemic Chemotherapy
Systemic chemotherapy is usually used for palliation of patients with relapsed or refractory disease after skin-directed therapies or for patients with advanced disease at presentation. Single-agent therapy with several agents has been used, including methotrexate, glucocorticoids, NM, cyclophosphamide, cisplatin, etoposide, bleomycin, doxorubicin, vincristine, and vinblastine. Single-agent therapy can attain complete response rates up to 30%, but remissions are of short duration. Prednisone alone induces partial remissions in approximately 50% of patients, and pulse dexamethasone is effective in obtaining symptomatic relief in patients with severe SS. Zackheim and Epstein reported an overall response rate of 76% and a 71% 5-year survival among a group of 17 patients who received weekly, low-dose methotrexate.

Combination chemotherapy has also been used for patients with advanced disease. Alkylating agents are used in combination with doxorubicin and/or vinca alkaloids. Although response rates of 80% to 100% are seen, there are no significant survival benefits.

Many recent studies have focused on the use of the purine analogs; 2-deoxycoformycin, 2-chlorodeoxyadenosine, and fludarabine.These agents do not have a single mechanism of action, but all of them interfere with intracellular regulation of deoxyribonucleotide pools. The response rate in studies performed to date have been higher with 2-deoxycoformycin (54% to 100%) than with the other two compounds. The major toxicities of these drugs are neurotoxicity and prolonged immunosuppression, leading to opportunistic infections.

IFNs
The most active agent in the treatment of MF is IFN{alpha}. Initial studies with heavily pretreated patients yielded complete response rates of 10% to 27% and objective response rates of 45% to 64%, with response duration of 4.5 to 5.5 months. The doses in these two initial trials ranged from 36,000,000 IU administered by intramuscular injection once a day to 50,000,000 IU administered by intramuscular injection three times a week. A study of previously untreated patients with all stages of MF/SS demonstrated an overall response rate of 79%, with 88% of patients with stage I and II disease responding. The current approach to dosing IFN{alpha} is to start at 3,000,000 IU/d and increase as tolerated, usually to a maximum of approximately 15,000,000 IU/d.

Acute adverse effects to IFN{alpha} include flu-like symptoms such as fevers, chills, and myalgias. These are usually transient. Chronic adverse effects include malaise, depression, anorexia, and weight loss, which often lead to dose-modification or cessation of therapy. Laboratory abnormalities include leukopenia, thrombocytopenia, and abnormal liver function tests. The leukopenia is mild, dose-related, and reversible. Hypothyroidism can also occur as a side effect of IFN{alpha}.

Recently, a case report was published describing a case of acrocyanosis associated with elevated antinuclear antibody titers, which was attributed to IFN{alpha} therapy for MF. Neutralizing IFN antibodies can develop during treatment. In one study, seven (41%) out of 17 patients developed IFN{alpha}-binding antibodies, and two of these neutralized the function of IFN{alpha} as demonstrated by a functional assay. The presence of anti-IFN antibodies correlated with diminished clinical response. However, the use of these assays to guide therapy is not reliable. The mechanism of resistance to IFN{alpha} in an IFN-resistant CTCL cell line has been shown to be lack of STAT1 expression, thus preventing normal signaling via the JAK/STAT pathway.

PUVA Plus IFN{alpha}
At Northwestern University, a study combining the use of IFN{alpha} with PUVA in 39 patients with all stages of MF/SS demonstrated an overall response rate of 88%, with a complete response rate of 62% and median response duration of 28 months. The IFN{alpha} dose was started at 3,000,000 IU/ three times a week and escalated over a 6 to 8 week period to 12,000,000 IU/ three times a week, which was demonstrated to be the maximum-tolerated dose in the preceding phase I trial.

Retinoids
Retinoids are derivatives of vitamin A and have been shown to have antiproliferative and differentiating effects in several malignancies. The prime example is the successful use of all-trans-retinoic acid in acute promyelocytic leukemia. There have been several studies that have evaluated the effectiveness of various retinoids in CTCL. Kessler  demonstrated a 44% response rate for isotretinoin (13-cis-retinoic acid) in 25 patients with at least T2 disease. Molin  reported a 68% response rate in a group of 28 patients with MF/SS. However, many of these responses were short-lived. The most common toxicity is drying of the skin and mucous membranes. Other adverse effects include conjunctivitis, fatigue, arthralgias, mental status changes, and headaches. Elevated triglyceride levels are also commonly seen. Still, given the unique side effect profile and demonstrated activity, there are a number of ongoing clinical trials evaluating these agents.

IL-2 Fusion Protein
DAB389IL-2 is a fusion protein that combines the cytotoxic A-chain and translocation B chain of diptheria toxin with recombinant IL-2, thus targeting cells that express the IL-2 receptor. CTCL, Hodgkin’s lymphoma, and non-Hodgkin’s lymphoma express the high affinity IL-2 receptor at relatively high frequencies. Saleh  reported the results of a phase I trial using this novel protein. In the 102 patients screened, 59% stained positive for the presence of IL-2 receptor (CD25). Treatment consisted of daily infusions for 5 days given every 3 weeks for up to six cycles. Thirty patients with MF/SS were treated, as were five patients with CTCL other than MF/SS. Among these 35 patients, there was a complete response rate of 14% and an overall response rate of 37%. Adverse effects of DAB389IL-2 in this study included fever/chills, hypotension, nausea/vomiting, and elevated transaminases. In the pivotal phase III trial of DAB389IL-2, which compared two different doses of the fusion toxin in a heavily pretreated population, the overall response rate was 29.5%. DAB389IL-2 is now Federal Drug Administration–approved for the treatment of MF/SS at a dose of 18 µg/kg/d for 5 consecutive days given in 21 day cycles. In the future, administration of IL-1{alpha} before infusion of DAB389IL-2 may increase the response rate, as laboratory models and in vitro human studies have shown that this cytokine upregulates expression of the high-affinity IL-2 receptor. In fact, neoplastic lymphocytes from patients with MF/SS display increased susceptibility to DAB389IL-2 when pretreated with IL-1{alpha}.

Investigational Agents
Retinoids combined with other therapies. Dreño reviewed four trials that combined IFN{alpha} with etretinate and found an overall response rate of 56%. This included a trial in which 11 (42%) out of 26 patients had not responded to low-dose IFN{alpha} alone but responded to the combination.

In a small study comparing chemotherapy with chemotherapy plus etretinate in patients with advanced disease, there was no difference in response rate. The etretinate group did have a median response duration of 6 months compared with 3 months in the chemotherapy-only group.

IL-2. Marolleau  published a series of seven patients with CTCL (six with MF/SS) that were treated with high doses of IL-2. Treatment consisted of an induction phase consisting of a 5-day continuous infusion given every 2 weeks for three cycles at a dose of 20,000,000 IU/m2/d and a consolidation phase consisting of 5 monthly cycles of 2-day infusions. The response rate in the MF/SS group was 67%, with two complete responses and two partial responses. Similar to IFN{alpha}, the most common side effects of IL-2 are fatigue, flu-like symptoms, and depression.

IL-12. As previously mentioned, MF/SS seems to be a disease mediated by TH2 helper cells. Rook  have shown that peripheral-blood mononuclear cells (PBMCs) from patients with MF/SS are deficient in the production of IFN{gamma} and IL-12, which is consistent with the cytokine milieu seen in this disease. Rook have also shown that IL-12 is a potent stimulus for IFN{gamma} production in in vitro studies using PBMCs from patients with SS. This has important therapeutic implications because the revived capacity of IFN{gamma} production could potentially reverse many of the immunologic abnormalities in patients with MF/SS. IL-12 may also be important in the therapeutic benefit of retinoids, and it also stimulates cell-mediated cytotoxicity in PBMCs from SS patients.

Other investigational agents. Knox  published the results of a phase I trial of chimeric anti-CD4 monoclonal antibody in which seven of eight patients with MF had at least a minor response, with an average freedom from progression of 25 weeks. Horikoshi  reported one case of a woman with refractory MF who had a complete response of at least 6 years after administration of IFN{gamma}. In a phase II trial, five (31%) of 16 patients responded to IFN{gamma}. In a phase II study of CAMPATH-1H, a monoclonal antibody directed against CD52, four out of eight patients with MF had significant responses, including two complete responses. Also, an anti-idiotype vaccine has been tested in a few patients, with a major response in one patient. Hypericin is a photodynamic compound that is activated by UVA or white light, and in vitro studies have shown that it inhibits the proliferation of neoplastic T cells in patients with CTCL. If effective in trials, treatment with hypericin may prove to be less toxic than standard PUVA because of the ability to use visible light.

CTCL VARIANTS

CD30+ Primary Cutaneous Large-Cell Lymphoma
Patients with primary cutaneous CD30+ large-cell lymphomas have a favorable prognosis. Willemze and Beljaards have published a classification scheme on behalf of the European Organization for Research and Treatment of Cancer for this subgroup of lymphoproliferative disorders that includes lymphomatoid papulosis and primary cutaneous Hodgkin’s disease.CD30+ CTCLs usually present with solitary nodules that frequently ulcerate. Lymph node involvement is present up to 25% of the time. The clinical definition includes predominance (> 75%) of CD30+ blast cells or large clusters of such cells, no clinical evidence of lymphomatoid papulosis, no history of MF, and no evidence of extracutaneous disease at presentation.Some patients have partial or complete spontaneous regression of their lesions. Such lesions used to be called regressing atypical histiocytosis. Radiation therapy is the standard treatment, except in the rare patients with generalized skin lesions, when chemotherapy is given. Prognosis is good, with a 90% 4-year survival rate. Most patients have anaplastic histology, however, no differences in survival have been seen between the anaplastic and nonanaplastic (immunoblastic and pleomorphic) forms of this disease.

Pleomorphic and Immunoblastic CTCL
Primary CTCLs that are not MF/SS or CD30+ CTCL make up a heterogeneous group. Beljaards  reviewed 35 such cases. In that series, most of the pleomorphic lymphomas had diffuse, dense infiltrates in the dermis, and epidermotropism was only seen in approximately 30% of the cases. Five patients had infiltrates centered around large blood vessels in the deep dermis and subcutis and were termed angiocentric. Clinically, most patients had generalized plaques and/or tumors. The tumors were classified as pleomorphic small-cell, pleomorphic medium-cell, pleomorphic large-cell, and immunoblastic. The large-cell classification required at least 30% large cells. Overall, this group had poor survival, with a 2-year survival rate of 53% and a 4-year survival rate of 22%. Five of the patients had partial or complete spontaneous regression, and this finding was most common in the angiocentric type of lesion. The authors found a significantly more favorable survival rate for the small and medium cells when grouped together in comparison to the large-cell/immunoblastic group.

Subcutaneous Panniculitis-Like T-Cell Lymphoma
Subcutaneous panniculitis-like T-cell lymphoma is an extremely rare disease that can initially be confused with inflammatory panniculitides. Patients present with subcutaneous nodules and plaques and often complain of constitutional symptoms, including fevers, fatigue, and anorexia.Histology reveals a subcutaneous infiltrate of variable-sized pleomorphic T cells mixed with benign macrophages. Tumor-cell necrosis, karyorrhexis, and erythrophagocytosis are common findings. Infiltration of deep blood vessels can be seen in some cases. Differential diagnosis includes the frequently fatal but nonneoplastic cytophagic histiocytic panniculitis. The prognosis for this entity is poor despite use of aggressive chemotherapy.

RELATED CONDITIONS AND LOW-GRADE MALIGNANT VARIANTS

Small-Plaque (digitate) Parapsoriasis (SPP)
Patients with SPP  present with generalized oval-shaped patches and plaques ranging from 2 to 6 cm. The eponym digitate comes from the characteristic fingerprint-shaped, yellowish lesion that follows the lines of cleavage in the skin. These lesions are located preferentially on the lateral aspect of the trunkand are usually asymptomatic. There is some controversy as to whether this entity is actually MF or a benign variation. Ackerman asserts that both SPP and large-plaque parapsoriasis (LPP) have been shown to be MF "by virtue of precise correlation of clinical and histopathological findings." However, other authors disagree and state that SPP is not related to MF because of its frequently indolent natural history.In a review of the natural history of SPP and LPP, Samman differentiates the two entities based on the entirely benign nature of SPP and the potentially malignant nature of LPP.

Histopathology of SPP reveals spongiosis with focal areas of hyperkeratosis, parakeratosis, and exocytosis. The dermis contains a mild superficial perivascular, lymphohistiocytic infiltrate, and dermal edema. There is no progression of histologic features with time.

SPP patients should be reassessed with follow-up examinations every 6 months to every year to confirm the clinical impression of SPP. Patients can be treated with lubrication, topical steroids, UVB irradiation, PUVA, and/or topical NM.

LPP
LPP is often indistinguishable from an early-stage MF, and it may represent a precursor lesion. The lesions of LPP are usually oval or irregularly shaped patches or plaques that can have discrete margins or blend imperceptibly into the surrounding skin. These lesions are erythematous to brown, usually greater than 6 cm, and are located mainly on the buttocks and intertriginous areas.Histopathology in early lesions reveals a mildly acanthotic and hyperkeratotic epidermis with spotty parakeratosis. Dermal lymphocytic infiltrates tend to be perivascular and scattered, with delicate fibroplasia of the papillary dermis. In more indurated lesions, interface infiltrates are seen with definite epidermotropism. Treatment options for LPP include topical steroids, UVB, PUVA, and/or topical NM. Patients with LPP should be frequently monitored for possible transformation into CTCL. Patients with the retiform variant of LPP or with widespread epidermal atrophy have the greatest likelihood of developing CTCL. Suspicious lesions should be biopsied repeatedly, especially when there is a change in the appearance of the lesion(s). In a review of 89 patients with LPP seen at Northwestern University from 1970 to 1985, 30% eventually developed MF.

Follicular Mucinosis (Alopecia Mucinosa)
Patients with follicular mucinosis  present with grouped follicular papules and often with alopecia. Patches, plaques, and nodules are also seen.These lesions usually involve the face, neck, and scalp but may appear anywhere on the body. Histopathology reveals mucinous degeneration of the pilosebaceous units and can also include periappendigeal, perivascular, and interstitial infiltrates. Several authors have noted that many patients with follicular mucinosis also have CTCL. Mehregan  reviewed their series of 33 patients at the Mayo Clinic and found that nine of these patients also had MF. There was no particular histologic finding in their series that could distinguish follicular mucinosis from MF, although a predominance of eosinophils was suggestive of a benign course.

Pagetoid Reticulosis
Pagetoid reticulosis  is a rare and questionable entity characterized by an atypical lymphoid infiltrate almost exclusively involving the intraepidermal compartment. The localized variant, Woringer-Kolopp, is probably a reactive, rather than a neoplastic, process. Both the localized and disseminated forms have the histologic appearance of an epidermal infiltrate consisting of atypical medium- to large-sized lymphocytes with abundant cytoplasm. The infiltrate displays a pagetoid pattern of solitary infiltrating cells interspersed between the keratinocytes. The localized form of pagetoid reticulosis presents as solitary or very few keratotic plaques that seldom change appearance and never progresses to extracutaneous disease. Radiation or surgical excision cures this localized form.Some authors believe that the term pagetoid reticulosis should only be used to describe the localized form.

The disseminated form of pagetoid reticulosis presents with generalized lesions of the same appearance as in Woringer-Kolopp disease, and the course can be more aggressive. Some patients die of this disease in months, whereas others have normal life expectancy. There is little data available regarding the treatment of disseminated pagetoid reticulosis, although there is evidence that PUVA is effective.

Granulomatous Slack Skin (GSS)
GSS is a rare skin disorder in which patients present with large, indurated plaques that very slowly progress to form erythematous masses with a cutis laxa-like appearance. These lesions occur most frequently in the skin flexural areas, especially the inguinal and axillary regions. Histologically, GSS lesions initially consist of a dermal infiltrate of small- to medium-sized T cells, macrophages, and eosinophils. As the lesions progress, cells with cerebriform nuclei appear in the midst of tumor-infiltrating lymphocytes. Characteristic epithelioid and giant-cell granulomas are also present, and elastic fibers disappear, giving the lesions their cutis laxa–like appearance. Gene rearrangement studies have shown clonality in these patients, suggesting that GSS may be an indolent CTCL.

In approximately half of the cases, GSS is associated with other lymphoproliferative malignancies, with the malignancy being diagnosed either before or subsequent to the diagnosis of GSS. MF and Hodgkin’s disease are the most common associated malignancies. Only 34 cases of GSS have been described in the literature, so there is no standard therapy. Many treatment modalities have been tried in patients with GSS, including PUVA, topical and systemic corticosteroids, IFN{alpha}, multiagent systemic chemotherapy, retinoids (etretinate), and surgical excision. However, none of these treatments have been successful in attaining complete remissions.118

Lymphomatoid Papulosis (LyP)
First described by Macaulay, LyP belongs to a group of entities that are clinically benign, histologically malignant, continuing self-healing eruptions. The disease usually occurs in the third or fourth decade and may be more common in the white population.

Clinically, the appearance of the lesions in LyP varies. They usually appear on the trunk and extremities. Initially, scattered erythematous papules form, which often progress to brown, hemorrhagic, and/or necrotic lesions over days to weeks. These lesions usually ulcerate, and eventually resolve spontaneously, often leaving scars. The entire course for a cluster of lesions usually lasts 2 to 8 weeks. The intensity and frequency of the outbreaks is variable.

Histopathology of LyP lesions reveals a superficial and deep dermal infiltrate that is both perivascular and interstitial and contains a heterogeneous population of lymphocytes, histiocytes, eosinophils, and atypical small- and large-sized lymphoid cells. LyP is commonly divided into two variants, although these variants often overlap. Type A lesions consist of large cells, which can resemble Reed-Sternberg cells, whereas type B lesions are made up of smaller lymphoid cells that are similar to the atypical cells described in MF. Atypical lymphocytes stain for CD30 and are usually positive for HLA-DR and CD25. T-cell receptor analysis often demonstrates clonality.

The diagnosis of LyP versus CD30+ primary cutaneous lymphoma is often difficult because of the similar clinical and histologic presentation. The definition of LyP is a natural history that is benign, with chronic outbreaks that spontaneously resolve. Therefore, a period of observation may be required in difficult cases to determine whether or not the skin lesions will spontaneously resolve. Thirty percent of patients with LyP eventually develop lymphoma. Cabanillas suggest that the cumulative risk of developing lymphoma after 15 years approaches 80%. Hodgkin’s disease and MF are the most common malignancies associated with LyP, and Davis  demonstrated the same clonal origin in a patient that had these three conditions. Treatment for LyP is cosmetic, and transiently effective but does not alter the natural course of the disease. PUVA is commonly used to treat LyP.

Actinic Reticuloid
Actinic reticuloid is a rare, severe, chronic photosensitivity disorder. Men are affected 10 times more frequently than women. Patients present clinically with erythematous plaques on sun-exposed areas, and as time progresses, the patients’ skin becomes increasingly sensitive to light. Erythroderma is often a sequela, and this can mimic SS.The histopathology of the lesions in actinic reticuloid may be indistinguishable from MF, with the presence of a dense band of lymphocytes infiltrating the papillary dermis. Epidermotropism is often seen, and the lymphocytes can demonstrate cytologic atypia and form Pautrier-like microabscesses.

Actinic reticuloid is completely reversible and does not transform into lymphoma. In a recent study, Bakels showed that gene rearrangement analysis can be useful in differentiating actinic reticuloid (zero of 12 patients with a clonal population) from SS (19 of 21 samples with a clonal population). Light testing is useful in demonstrating photosensitivity. Immunophenotyping often shows a population of suppressor T cells, as opposed to helper T cells more commonly seen in MF/SS. UVB is given in gradually increasing doses to induce tolerance to light and is an effective treatment for actinic reticuloid.

Cutaneous Pseudo–T-Cell Lymphoma
Patients with cutaneous pseudo–t-cell lymphoma represent a heterogeneous group of patients with lesions that histologically resemble CTCL but whose clinical picture is consistent with a benign process, which is often drug-induced. Clinically, patients with pseudolymphoma can present with solitary lesions or diffuse erythroderma shortly after starting a medication.Anticonvulsants are the most common cause of pseudolymphoma, but angiotensin-converting enzyme inhibitors, beta-blockers, cyclosporine, penicillin, and others have also been implicated.

Two patterns have been described histologically. One pattern is a subepidermal band-like infiltrate that resembles MF and consists of lymphocytes with medium-sized cerebriform nuclei. Epidermotropism and Pautrier’s microabscesses are rare in this histologic pattern of pseudolymphoma and may be helpful in differentiating these two processes. Medium-sized blast cells can also be seen in pseudolymphoma.

Pseudolymphoma can also mimic pleomorphic CTCL with a nodular pattern. This pattern is characterized by lymphocytes with medium- to large-sized cerebriform nuclei mixed with large blast-like lymphocytes. There are frequently large numbers of histiocytes with occasional granuloma formation seen in this pattern of pseudolymphoma.

Most of the lymphocytic infiltrate in pseudolymphomas consists of CD4+ cells, with a smaller number of CD8+ cells. The only definitive way to distinguish pseudolymphoma from CTCL is to demonstrate disappearance of the lesion with cessation of the offending drug. Bakels  recently demonstrated that gene rearrangement studies and immunophenotyping may be useful in distinguishing between these two entities. None of the 10 pseudolymphoma lesions they examined demonstrated clonality or aberrant expression of T-cell antigens, whereas clonality was demonstrated in 88% and aberrant phenotype was seen in 71% of CTCLs. Recently, Brady used PCR to prove clonality in two out of 14 patients with lymphomatoid hypersensitivity. Bakels  also demonstrated that the presence of CD8+ T cells, B cells, and macrophages were a characteristic finding in pseudolymphoma. There have been rare cases of hydantoin-induced pseudolymphoma that have progressed to a true cutaneous lymphoma.125 In cases of drug-induced pseudo–T-cell lymphoma, the skin lesions usually resolve completely within 4 to 6 weeks of stopping the offending drug.

Adult T-Cell Leukemia/Lymphoma (ATLL)
ATLL  is a lymphoproliferative disease caused by the HTLV-I virus. HTLV-I infection and ATLL are endemic in southwestern Japan, the Caribbean region, Central and South America, and some parts of Africa. Seropositivity to HTLV-I is found in up to 37% of healthy adults over the age of 40 in endemic areas of Japan, but only 2% to 4% of carriers develop ATLL during their lifetime.

The clinical presentation is variable but usually includes lymphadenopathy, hepatosplenomegaly, cutaneous lesions, and/or hypercalcemia. There are four clinical types described based on prognosis and clinicopathologic features; acute, lymphoma, chronic, and smoldering. Patients with the acute type have a median survival of 6.2 months, whereas patients with the chronic type have a median survival of 24 months. Most cases present with some peripheral-blood involvement. Skin lesions are present up to 60% of the time and can strongly resemble lesions of MF or SS. A classic example of the similarity of these lesions is demonstrated by the fact that HTLV-I was first isolated by Poiesz  as stated previously, from a patient that was initially diagnosed with MF.

Traditionally, therapy has consisted of anthracycline-containing chemotherapy and/or alternating chemotherapy regimens. This approach yields a complete response rate of 17% to 42%. Standard chemotherapy does not significantly affect survival. More recently, the combination of IFN{alpha} and zidovudine has been shown to be effective, attaining a major response rate of 66% in 29 patients.