Current Management of Primary Cutaneous CD30+ T-cell Lymphoproliferative Disorders

Publication
Article
OncologyONCOLOGY Vol 23 No 13
Volume 23
Issue 13

The purpose of this review is to familiarize oncologists with the clinical and pathologic features of this relatively rare disease spectrum. This should enable appropriate clinical management and reassurance of patients concerned about their prognosis.

Primary cutaneous CD30+ T-cell lymphoproliferative disorders (PCLPDs) are the second most common type of cutaneous T-cell lymphoma. These disorders comprise a spectrum of clinically benign lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large-cell lymphoma (ALCL). The peak incidence of LyP is in the 5th decade of life, and the incidence of primary cutaneous ALCL peaks in the 6th decade, but children are also affected. Both LyP and primary cutaneous ALCL have an excellent prognosis. However, LyP is associated with development of malignant lymphoma (mycosis fungoides, Hodgkin lymphoma, or ALCL) in 20% of cases, and also with an increased risk of non-lymphoid cancers. The diagnosis of LyP is difficult and often delayed. Primary cutaneous ALCL must be distinguished from secondary skin lesions in systemic ALCL, which confer a poor prognosis. Correlation of clinical findings with histopathology and immunopathology (stains for ALK kinase, epithelial membrane antigen, and cutaneous lymphocyte antigen) are important to achieve a correct diagnosis. When a diagnosis of CD30+ PCLPD is established, minimal clinical staging is required. Low-dose methotrexate (10–25 mg weekly) is the most effective therapy for PCLPD but is usually reserved for aggressive cases of LyP and multifocal lesions of cutaneous ALCL. Many patients with LyP can be followed expectantly, with special attention to changes in character of the skin lesions or development of lymphadenopathy. Patients with localized cutaneous ALCL can be treated with irradiation. Extracutaneous spread of disease is an indication for multiagent chemotherapy. Other treatment alternatives are discussed.

FIGURE 1

Spectrum of LyP and PCALCL in an Individual Patient

CD30-positive primary cutaneous T-cell lymphoproliferative disorders (CD30+ PCLPDs) comprise a spectrum of closely related disorders-lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large-cell lymphoma (ALCL) (Figure 1). LyP patients have clinically benign self-healing skin papules and/or nodules that have the unexpected histopathology of a high-grade malignant lymphoma.[1] Primary cutaneous ALCL also has the histology of a high-grade lymphoma, but only 25% of lesions regress spontaneously. Because of their histologic appearance and frequent recurrence, patients with CD30+ PCLPD may be treated unnecessarily with multiagent chemotherapy. However, the prognosis for these patients is excellent. Disease-specific survival of LyP patients at 5 years is 100%, and overall survival at 5 years is 92%.[2,3] The disease-specific survival rate for primary cutaneous ALCL patients at 5 years is 85% to 90%.[2,3]

Oncologists should become familiar with these disorders to avoid overly zealous therapy. The purpose of this review is to familiarize oncologists with the clinical and pathologic features of this relatively rare disease spectrum. This should enable appropriate clinical management and reassurance of patients concerned about their prognosis.

Diagnosis

LyP is often not diagnosed correctly upon presentation; it is common for symptoms to persist for 1 to 3 years before a correct diagnosis is established. A variety of diagnoses may be entertained, most commonly insect, spider, or mosquito bite. This is likely due to the common occurrence of bites with associated erythema and central necrosis, and the fact that most patients and many clinicians are unfamiliar with LyP. Indeed, LyP is more readily recognized by dermatologists trained in academic medical centers. Oncologists are unlikely to encounter LyP or PCLPD unless consulted for chemotherapy, staging, or prognosis of the disease.

Histopathology

Tumor cells in both LyP and primary cutaneous ALCL are derived from activated T-cells that express CD30 antigen. The CD30+ cells are larger than normal lymphocytes and have basophilic cytoplasm and large nuclei with a prominent nucleolus, resembling immunoblasts. These cells are often bi- or multinucleated, giving the appearance of Reed-Sternberg cells. Mitoses are frequent and often atypical. In LyP, tumor cells are scattered throughout the upper dermis and surrounded by small lymphocytes, neutrophils, and eosinophils. In primary cutaneous ALCL, tumor cells form large clusters or sheets that generally extend from the dermal-epidermal junction down into the subcutaneous fatty tissue. Thus the distinction of LyP from ALCL largely depends on the density of CD30+ tumor cells and the extent of dermal and subcutaneous involvement.

Differential Diagnosis

The frequency of LyP in male children poses an interesting differential diagnosis with pityriasis lichenoides et variolaformis acuta (PLEVA). PLEVA can present with similar cutaneous lesions but has a different prognostic significance. In particular, there is no increased risk of developing lymphoma among patients with PLEVA, while the risk of lymphoma in LyP patients approaches 20%.[3,4] PLEVA is more common in children and young adults than in older patients, so the most difficult differential diagnosis is in the age group under 30 years old.

Skin lesions in PLEVA tend to be hemorrhagic papules, whereas LyP lesions vary from papules to small nodules, often with central whitening and ulceration due to accumulation of neutrophils in the epidermis. On histology, LyP shows more frequent large bizarre cells including bi- or multinucleated cells with basophilic cytoplasm; these cells are CD30+. Such cells are infrequent or absent in PLEVA. Necrosis of individual keratinocytes (Civatte or colloid bodies) are common in PLEVA but absent in LyP. Further, immunopathology reveals a predominance of CD4+ lymphocytes in LyP but mostly CD8+ lymphocytes in PLEVA.

Nodular scabies is also in the differential diagnosis of LyP, particularly in children. Scabies also includes CD30+ cells. It is found in the inguinal and genital areas, which can be affected in LyP. In scabies, the CD30+ cells coexpress B-cell antigens, whereas CD30+ cells in LyP express T-cell antigens.

Distinction From Systemic ALCL

TABLE 1

Comparison of CD30-Positive and Other Lymphoproliferative Disorders Affecting the Skin

Oncologists need to be aware of the distinction of CD30+ PCLPD from secondary skin lesions in patients with nodal/systemic ALCL (Table 1). Skin is the most common extranodal site of disease in nodal/systemic ALCL,[5] and skin lesions confer an increased risk of treatment failure in childhood ALCL.[6] When skin lesions are a presenting manifestation of nodal/systemic ALCL, the distinction from CD30+ PCLPD is imperative.

The distinction of skin lesions in systemic ALCL from CD30+ PCLPD can be difficult on purely clinical grounds and may also be difficult to achieve by routine histopathology. One of the most helpful approaches is to test the tumor cells for expression of the ALK protein. This is expressed in skin lesions of most patients with nodal/systemic ALCL but not in the large majority of patients with CD30+ PCLPD. Rare exceptions occur, and in such cases a panel of immunologic markers is recommended. Epithelial membrane antigen (EMA) is expressed on tumor cells in 82% of nodal/systemic ALCL but < 5% of CD30+ PCLPD.[7] Cutaneous lymphocyte antigen (CLA) also is more frequently expressed in CD30+ PCLPD (44%) than on tumor cells in nodal/systemic ALCL (18%).[7] Thus, a successful immunopathologic distinction of CD30+ PCLPD from nodal/systemic ALCL can be made in most cases.

Staging

When a diagnosis of CD30+ PCLPD is established, minimal clinical staging is required. Bone marrow involvement is rare and thus bone marrow biopsy is not indicated. Lymph node involvement is uncommon and, when it occurs, does not appear to portend a poor prognosis.[3] In my experience, peripheral lymph nodes draining areas with numerous skin lesions are the most common sites of involvement. Often this is minimal microscopic involvement with tumor cells confined to lymph node sinuses and not effacing lymph node architecture. This may be detected by immunohistochemical staining for CD30, which in combination with morphology, can reveal microscopic disease. Thoracic or abdominal lymphadenopathy is uncommon and usually occurs only as a late manifestation of disease. This is usually preceded by persistent enlarged skin tumors and accompanied by systemic symptoms (eg, fever, sweats, and weight loss). In such cases, treatment with multiagent chemotherapy and/or biologics is needed.

Etiology

Although CD30+ PCLPDs are rare, all races, ages, and both genders are affected. The prevalence of CD30+ PCLPD in the United States is unknown, but an LyP patient support group includes 850 members, indicating a prevalence approaching 3 per million. Most European studies show a male predominance, whereas our US registry has a nearly equal number of males and females. The peak age incidence of LyP appears to be in the 5th decade. However, children are also affected. In our registry, females exceed males in the group over 19 years old, whereas males exceed females in the group under 20. This could be due to biased reporting of cases by women and mothers of children with LyP. Primary cutaneous ALCL has a peak incidence after age 50 but can also affect children and young adults.

CD30 signaling is known to have an effect on the growth and survival of lymphoid cells. CD30 transcription is controlled by a genetically determined polymorphic promoter. In a study published in 2005, colleagues from Western Australia and I analyzed CD30 promoter microsatellite alleles in 32 unrelated Caucasian patients diagnosed with LyP alone or LyP plus lymphoma, as well as 8 unrelated Caucasian patients with CD30+ primary cutaneous ALCL. Controls were 57 Caucasian healthy volunteers and patients with nonlymphoid malignancies. Patients and controls were gender-matched. We determined that two allelic forms of the CD30 promoter microsatellite repressive element, designated 30M377 and 30M362, are associated with the development of lymphomatoid papulosis and CD30+ lymphomas in lymphomatoid papulosis patients, respectively. These findings suggest that allele-specific differences in the control of CD30 transcription may affect the pathogenesis of the spectrum of CD30+ cutaneous lymphoproliferative disorders.[8]

In a study from Beth Israel Deaconess Medical Center and Harvard, we reported 35 cases of LyP beginning in childhood.[9] These patients had a significantly higher prevalence of atopy (relative risk [RR] = 3.1; 95% confidence interval [CI] = 2.2–4.3). Compared with the general population, patients with childhood-onset LyP had a significantly increased risk of developing non-Hodgkin lymphoma (RR = 226.2; 95% CI = 73.4–697.0). Fletcher and coauthors also reported an association of CD30+ PCLPD with atopic eczema beginning in childhood.[10] Three patients had primary cutaneous ALCL, of whom two developed systemic disease and one died. A fourth patient developed LyP type A, which resolved after withdrawal of cyclosporine therapy. We conclude that LyP presents similarly in children and adults, including the risk to develop lymphoma, and that all patients should be closely monitored for the development of lymphoma throughout their lives.

The interferon regulatory factor-4 (IFR4) gene is overexpressed in multiple myeloma and some B-cell lymphomas. IFR4 translocations occur in multiple myeloma and some B-cell lymphomas. Recently, recurrent translocations involving the IFR4 locus have been reported in 8 of 14 primary cutaneous ALCLs, indicating a role for IFR4 in the pathogenesis of primary cutaneous ALCL.[11]

Association of LyP With Malignant Lymphoma and Non-lymphoid Malignancies

A major concern of LyP patients, and parents of children with LyP, is whether the affected individual will develop a malignant lymphoma. Many individual or small series of cases have been reported, but there are few reports of large numbers of affected patients. In one series, including a review of the literature, 50 patients with LyP-associated lymphomas were evaluated.[12] Three main types of LyP-associated lymphomas were distinguished: cases associated with mycosis fungoides (19/50), Hodgkin disease (12/50), and CD30+ large-cell lymphoma (16/50). Mycosis fungoides and Hodgkin disease could develop before, after, or concurrent with LyP, but CD30+ large-cell lymphoma always developed in patients with existing LyP, often showing a slow progression from regressing LyP lesions to persistent skin tumors.

LyP patients with mycosis fungoides, Hodgkin disease, and CD30+ large-cell lymphoma limited to the skin generally had a favorable prognosis.[12] The prognosis of LyP patients developing a systemic CD30+ large-cell lymphoma was generally poor. Few LyP patients develop Hodgkin disease followed by a systemic CD30+ large-cell lymphoma, which also is associated with a poor prognosis. In a subsequent review of 118 LyP patients in the Netherlands, 23 (19%) developed malignant lymphoma-11 developed mycosis fungoides; 10, CD30+ ALCL; and 2, Hodgkin lymphoma.[3]

The relationship between LyP (a T-cell disorder) and Hodgkin disease (primarily a B-cell disorder) is poorly understood. I am aware of patients who had LyP lesions before or after Hodgkin disease. When the Hodgkin disease was treated with chemotherapy, the LyP lesions often disappeared temporarily, only to reappear shortly thereafter. In rare cases, a clonal relationship between the CD30+ cells in LyP and Hodgkin disease was shown by DNA sequencing. A clonal relationship between LyP, mycosis fungoides, and ALCL is firmly established.[13,14]

In a case-control study of 57 patients with biopsy-proven LyP and 67 individually matched controls, we found a significantly increased frequency of prior or co-existing lymphoproliferative disorders, an increased frequency of non-lymphoid malignancies, and exposure to radiation therapy.[15] Among patients with LyP, 3 had a history of Hodgkin disease, 3 had non-Hodgkin lymphoma, and 10 had mycosis fungoides; none of the control subjects reported such histories. Prospective study of this group of patients over an 8-year period (1988–1996) revealed that 6 LyP patients (10.5%) and 1 control (1.5%) developed nonlymphoid malignancies. Two patients and no controls developed lymphoid malignancies. The expected numbers of nonlymphoid and lymphoid malignancies in the LyP group, based on Surveillance, Epidemiology and End Results (SEER) data, were 1.93 and 0.15, respectively, yielding a relative risk of 3.11 (95% CI = 1.26–6.47) for nonlymphoid malignancies and 13.33 (2.44–44.05) for malignant lymphoma among LyP patients. There was no significant difference between observed and expected numbers of malignancies in the control group. These results confirm that LyP patients are at increased risk of developing lymphoid malignancies but for the first time revealed that they also have an increased risk of non-lymphoid malignancies.[16]

The prognosis of LyP patients developing a systemic CD30+ large-cell lymphoma is generally poor. In two such cases, we found that progression of LyP to systemic ALCL was associated with mutations of receptors for the lymphocyte growth inhibitor, transforming growth factor–beta, allowing unregulated growth of the CD30+ cells.[17,18]

Treatment

Control of LyP lesions does not appear to affect the risk of developing lymphoma. Most patients with few or infrequent papules do not require therapy. For patients with extensive papules, nodules, and/or scarring lesions, particularly on the face, hands, or legs, which are cosmetically disturbing, the most effective therapies are low-dose oral methotrexate or psoralen plus ultraviolet A or ultraviolet B (PUVA/UVB). Methotrexate is effective in controlling lesions in approximately 90% of patients and induces a permanent remission in up to 20% of patients.[19]

Vonderheid treated 45 patients with relatively severe LyP, CD30+ primary cutaneous ALCL, and interface/borderline lesions with oral methotrexate.[19] During induction, patients received 10 to 60 mg/wk (median = 20 mg/wk). Clinical improvement usually occurred quickly, typically at doses of 15 to 20 mg weekly, and satisfactory long-term control was achieved in 39 patients (87%) with maintenance doses given at 10- to 14-day intervals (range = 7–28 days). Responding patients were usually free of active lesions within 4 weeks of receiving the first dose. After methotrexate was discontinued, 10 patients remained free of CD30+ lesions for more than 24 months to more than 227 months (median = > 127 months. The median total duration of methotrexate therapy for all patients exceeded 39 months (range = 2–205 months). Adverse effects were generally mild and transient, and included fatigue (47%), nausea (22%), weight loss (13%), diarrhea or gastrointestinal cramping (10%), increased serum hepatic transaminase levels (27%), anemia (11%), or leukopenia (9%). Early hepatic fibrosis was found in 5 of 10 patients, all of whom had been treated for more than 3 years (range = 38–111 months).

Patients should be directly questioned about potential contraindications to methotrexate therapy including hepatotoxicity risk factors, renal function, reproductive issues, and concomitant medications. Diabetes and obesity are added risk factors for hepatic injury. Bangert and Costner have written a useful reference for guidance of treatment in cutaneous disorders.[20] There are few case reports of topical methotrexate therapy for CD30+ PCLPD. Topical therapy might be expected to hasten the regression of individual lesions but not to prevent new lesions.

The mechanisms of effectiveness of methotrexate in controlling CD30+ PCLPD appear to include its inhibitory effect on DNA synthesis, its anti-inflammatory effects, or both. Because the atypical lymphocytes of LyP and related CD30+ PCLPD are characterized by high mitotic activity, it is likely that methotrexate inhibits cell proliferation, particularly in the early phase of lesion development. The observation that long-lasting complete remissions occur after relatively short courses (2–5 months) of methotrexate in some patients raises the possibility that high-dose methotrexate therapy, possibly combined with leucovorin (folinic acid) rescue, might provide more than suppressive therapy for some patients. Moreover, low doses of methotrexate appear to have anti-inflammatory effects separate from its anti-proliferative effect. This may explain why LyP may improve with other drugs that have anti-inflammatory effects, including corticosteroids, tetracycline, and retinoids.

In patients who do not respond to methotrexate by either enteral of parental administration, photo(chemo)therapy should be considered. Although conventional ultraviolet phototherapy (UVB) may be effective, PUVA administered at dosages ranging from 50 to 480 J/cm twice weekly results in complete clearing or improvement of lesions in most patients.

Alternative Therapies

Lymphomatoid Papulosis-Although topically administered steroids may be useful in controlling symptoms of LyP (eg, pruritus), steroid therapy has not been proven to control disease progression or induce remission. Similarly, antibiotic therapy has not been shown to alter the course of LyP, although anecdotally, tetracycline has benefited a few patients. In such patients, the role of tetracycline may be related to its anti-inflammatory effect rather its antimicrobial effects. In children with symptomatic LyP, a prolonged trial of tetracycline therapy may be used initially, particularly if there are concerns regarding side effects from methotrexate, photo(chemo)therapy, or other therapies. Nevertheless, neither steroid nor antibiotic therapy can be recommended as routine LyP management options.

Interferon-alpha and interferon-gamma (Actimmune) have been used successfully to treat LyP in some patients. The rationale for the use of interferon was provided by Japanese investigators who showed that CD30+ cells in LyP and cutaneous lymphoma have features of Th2 cells, and that skin lesions could be suppressed by local and intravenous injection of interferon-gamma a Th1 cytokine.[21] Austrian dermatologists treated five patients with interferon-alpha subcutaneously three times per week and compared them with a group of six patients receiving photochemotherapy, antibiotics, topical corticosteroids, or surgery in an open trial. Four patients in the interferon group showed a complete remission, and one a partial remission, within 6 weeks. Two patients developed recurrent disease after discontinuation of short-term interferon therapy (5–7 months), and one patient remained in partial remission. In the control group, one patient went into spontaneous remission, two patients had a partial remission (after which one developed progressive disease), and three patients had recurrent disease despite treatment. Although interferon-alpha can alter the clinical course, it does not induce stable remissions after short-term treatment.[22]

Retinoids can induce apoptosis of T cells. Investigators at M.D. Anderson Cancer Center reported the use of bexarotene (Targretin), a rexinoid with selectivity for intracellular retinoid X receptors in treating LyP. Ten patients with chronic and symptomatic LyP were treated prospectively with bexarotene, three orally and seven with topical gel formulations. A favorable response with decreased numbers or duration of lesions was seen in all patients, with objective responses in eight patients.[23] In patients with localized skin disease, oral bexarotene had a 54% overall response rate at an optimal dose of 300 mg/m2/d (approximately 10 mg/kg). Topical bexarotene 1.0% gel was effective in producing remissions of individual lesions, with an overall response rate of 68%.

Other topical agents that have been used historically for treatment of LyP include mechlorethamine and carmustine. There is no role for multiagent systemic chemotherapies in LyP because LyP recurs quickly and predictably in affected patients who have received such treatments.[24]

REFERENCE GUIDE

Therapeutic Agents
Mentioned in This Article

Bexarotene (Targretin)
Carmustine
Cyclophosphamide
Doxorubicin
Etoposide
Imiquimod (Aldara)
Interferon-alpha
Interferon-gamma (Actimmune)
Interleukin-12
Leucovorin
Mechlorethamine
Methotrexate
Pentostatin
Prednisone
Vincristine

Brand names are listed in parentheses only if a drug is not available generically and is marketed as no more than two trademarked or registered products. More familiar alternative generic designations may also be included parenthetically.

• Primary Cutaneous Anaplastic Large-Cell Lymphoma-While spontaneous regression is characteristic of LyP, only 25% of primary cutaneous ALCL lesions will regress.[3] Nevertheless, this number is sufficiently high to warrant as initial management expectant follow-up for a period of 4 to 6 weeks. If spontaneous regression occurs, therapy is not indicated, and such patients should be observed for possible disease recurrence. A small number of patients whose disease spontaneously regresses will not have recurrence of their disease. Therefore, observation for spontaneous regression is an appropriate first step in managing this disease.[3,24,25]

Unfortunately, most patients with primary cutaneous ALCL have disease that does not regress spontaneously.[24-26] For these patients, choice of therapy depends on disease distribution and whether the lesions are singular or multiple. An exception to this approach may arise when other associated lymphoproliferative disorders such as mycosis fungoides or symptomatic LyP are simultaneously encountered, in which case the therapeutic approach should be directed against both diseases.[14]

Solitary lesions respond to local radiotherapy.[25,27] Although surgical excision represents an alternative approach, excision specimens may contain margins involved by disease.[23,25] For this reason, radiotherapy is the preferred treatment for solitary lesions. Radiotherapy consists of electron-beam irradiation (4–10 million eV) with a total radiation dose of 40 Gy. Because electron-beam therapy penetrates only to the dermis, there are no systemic effects, although side effects include alopecia, atrophy of sweat glands and skin, radio-dermatitis and edema.

In general, radiotherapy is impractical for patients with multiple non-regressing lesions, although total-skin electron-beam therapy may be a consideration if other diseases, like mycosis fungoides, are present. For this reason, systemic therapy is the treatment of choice for this group of patients.[28] Because long-term remissions are generally not achieved with multiagent chemotherapy, less toxic, single-agent therapies are preferred. As in LyP, methotrexate can be effective in inducing remissions, but higher weekly doses of methotrexate may be necessary.[17] In affected patients whose disease is refractory or progressive on methotrexate, oral etoposide has been shown to be safe and effective therapy for primary cutaneous ALCL.[29] Other potential therapies are purine nucleoside analogs (eg, pentostatin), retinoids, interferon-gamma, interleukin-12, imiquimod (Aldara), and monoclonal antibody against CD30.[24,30,31]

Finally, it is important to monitor patients for potential dissemination of primary cutaneous ALCL to lymph nodes and systemic organs, as well as development of associated malignancies, particularly mycosis fungoides, Hodgkin lymphoma, and B-cell non-Hodgkin lymphoma. Patients who develop systemic ALCL should be considered for multiagent systemic chemotherapies similar to those used in treatment of systemic ALCL, eg, cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like regimens.[25,27] High-dose chemotherapy followed by stem cell rescue may be indicated in affected patients who are at high risk.[25,27] Determination of high risk may be based on prognostic factors for survival in the International Prognostic Index.[32]

Personal Approach to Patients With CD30+ PCLPD

Patients are often frustrated because of the delay in establishing the correct diagnosis. They are also fearful of their prognosis because of the association of LyP with development of other lymphomas and the high-grade histology of their lesions. My priority is to reassure the patient about his or her favorable prognosis and to answer any questions about the disease. If the lesions scar or interfere with normal activity, I discuss alternatives to expectant treatment. I explain that low-dose methotrexate is the most effective treatment but is not indicated for women of childbearing age who expect to become pregnant, people with a history of liver disease, or those with blood dyscrasias. I discuss other options including PUVA/UVB and topical treatments.

I notify LyP patients of their increased risk for developing skin lesions of mycosis fungoides and ALCL, or enlarged lymph nodes of Hodgkin disease or non-Hodgkin lymphoma, and of the need to immediately bring these symptoms to the attention of their physician. For patients with suspected primary cutaneous ALCL, I confirm that appropriate clinical and pathologic studies have been done to exclude nodal/systemic ALCL. I recommend irradiation of localized skin tumors and methotrexate for multifocal cutaneous lesions. Follow-up of skin lesions should be carried out by a dermatologist and consultation by an oncologist when additional irradiation or multiagent chemotherapy is required.

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

Acknowledgement:Dr. Kadin is supported by NIH grant P20RR018757

References:

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3. Bekkenk MW, Geelen FAMJ, Vader PC, et al: Primary and secondary cutaneous CD30+ lymphoproliferative disorders: Report from the Dutch Cutaneous Lymphoma group on the long-term follow-up data of 219 patients and guidelines for diagnosis and treatment. Blood 95:3653-3661, 2000.
4. Wang HH, Myers T, Lach LJ, et al: Increased risk of lymphoid and non-lymphoid malignancies in patients with lymphomatoid papulosis. Cancer 86:1240-1245,1999.
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7. De Bruin PC, Beljaards RC, van Heerde P, et al: Differences in clinical behavior and immunophenotype between primary cutaneous and primary nodal anaplastic large cell lymphoma of T-cell or null-cell phenotype. Histopathology 23:127-135, 1993.
8. Franchina M, Kadin ME, Abraham LW: Polymorphism of the CD30 promoter microsatellite repressive element is associated with development of primary cutaneous lymphoproliferative disorders. Cancer Epidemiol Biomarkers Prev 14:1322-1325, 2005.
9. Njisten T, Curiel C, Kadin ME: Lymphomatoid papulosis in children. Arch Dermatol 240:306-311, 2004.
10. Fletcher CL, Orchard GE, Hubbard V, et al: CD30(+) cutaneous lymphoma in association with atopic eczema. Arch Dermatol 140:449-454, 2004.
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13. Chott A, Vonderheid EC, Olbricht S, et al: The same dominant T cell clone is present in multiple regressing skin lesions and associated T cell lymphomas of patients with lymphomatoid papulosis. J Invest Dermatol 106:696-700,1996.
14. Basarab T, Fraser-Andrews EA, Orchard G, et al: Lymphomatoid papulosis in association with mycosis fungoides: A study of 15 cases. Br J Dermatol 139:680-688, 1998.
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16. Wang HH, Myers T, Lach LJ, et al: Increased risk of lymphoid and non-lymphoid malignancies in patients with lymphomatoid papulosis. Cancer 86:1240-1245, 1999.
17. Knaus P, Lindemann D, De Coteau JF, et al: A dominant inhibitory mutant of the type II TGF- ß receptor in the malignant progression of a cutaneous T-cell lymphoma. Mol Cell Biol 16:3480-3489, 1996.
18. Schiemann WP, Pfeifer WM, Levi E, et al: A deletion in the gene for transforming growth factor-beta type I receptor abolishes growth regulation by transforming growth factor-beta in a cutaneous T cell lymphoma. Blood 94:2854-2861, 1999.
19. Vonderheid EC, Sajjadian A, Kadin ME: Methotrexate is effective therapy for lymphomatoid papulosis and other primary cutaneous CD30-positive lymphoproliferative disorders. J Am Acad Dermatol 34:470-481, 1996.
20. Bangert CA, Costner MI: Methotrexate in dermatology. Dermatol Ther 20:216-228, 2007.
21. Yagi H, Tokura Y, Furukawas F, et al: Th2 cytokine mRNA expression in primary cutaneous CD30-postiive lymphoproliferative disorders: Successful treatment with recombinant interferon-gamma. J Invest Dermatol 107:827-832, 1996.
22. Schmuth M, Topar G, Illersperger B, et al: Therapeutic use of interferon-alpha for lymphomatoid papulosis. Cancer 89:1603-1610, 2000.
23. Krathen RA, Ward S, Duvic M: Bexarotene is a new treatment option for lymphomatoid papulosis. Dermatology 206:142-147, 2003.
24. Drews R, Samel A, Kadin ME: Lymphomatoid papulosis and anaplastic large cell lymphomas of the skin. Semin Cutan Med Surg 19:109-117, 2000.
25. Willemze R, Beljaards RC: Spectrum of parimary cutaneous CD30 (Ki-1)- positive lymphoproliferative disorders. A proposal for classification and guidelines for management and treatment. J Am Acad Dermatol 28:973-980,1993.
26. Beljaards RC, Kaudewitz P, Berti E, et al: Primary cutaneous CD30-positive large cell lymphoma: Definition of a new type of cutaneous lymphoma with a favorable prognosis. A European Multicenter Study of 47 patients. Cancer 71:2097-2104, 1993.
27. Paulli M, Berti E, Rosso R, et al: CD30/Ki-1+ lymphoproliferative disorders of the skin: Clinicopathologic correlation and statistical analysis of 86 cases. J Clin Oncol 12:1343-1354, 1995.
28. Brice R, Cazals D, Mounier N, et al: Primary cutaneous large-cell lymphoma. Analysis of 49 patients included in the LNH87 prospective trial of polychemotherapy for high-grade lymphomas. Groupe d’Etude des Lymphomas de l’Adulte. Leukemia 12:213-219, 1998.
29. Rijlaarsdam JU, Hijgens PC, Beljaards RC, et al: Oral etoposide in treatment of cutaneous T-cell lymphoma. Br J Dermatol 127:524-528,1992.
30. Didona B, Benucci R, Amerio P, et al. Primary cutaneous CD30+ T-cell lymphoma responsive to topical imiquimod (Aldara). Br J Dermatol 150:1198-201, 2004.
31. Duvic M, Reddy SA, Pinter-Brown L, et al: A phase II study of SGN-30 (anti-CD30 monoclonal antibody) in cutaneous anaplastic large cell lymphoma and related lymphoproliferative disorders. Clin Cancer Res 15:6217-6224, 2009.
32. Shipp MA: Prognostic factors in aggressive non-Hodgkin’s lymphoma: Who has “high-risk” disease? Blood 83:1165-1173, 1994.

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