Primary cutaneous CD30 + lymphoproliferative disorders (LPDs) account for approximately 25% of cutaneous lymphomas. Although these LPDs are clinically heterogeneous, they can be indistinguishable histologically. Lymphomatoid papulosis rarely requires systemic treatment; however, multifocal primary cutaneous anaplastic large cell cutaneous lymphoma and large cell transformation of mycosis fungoides are typically treated systemically. As CD30 + LPDs are rare, there is little published evidence to support a specific treatment algorithm. Most studies are case reports, small case series, or retrospective reviews. This article discusses various treatment choices for each of the CD30 + disorders and offers practical pearls to aid in choosing an appropriate regimen.
Key points
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The CD30 + cutaneous lymphoproliferative disorders can look similar both clinically and histologically. Evaluation by a clinician and dermatopathologist with expertise in cutaneous lymphomas is invaluable in the correct classification of these disorders.
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Correct classification sets the stage for choosing an appropriate treatment regimen for each of these disorders. Lymphomatoid papulosis (LyP) rarely requires systemic therapy, whereas refractory or multifocal cutaneous anaplastic large cell lymphoma (cALCL) and mycosis fungoides (MF) with large cell transformation (LCT) may require systemic therapy in combination with skin-directed therapy.
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Given the chronic nature and typical good prognosis of most CD30 + lymphoproliferative disorders (LPDs), the clinician should take into account possible deleterious long-term side effects of treatment options.
Introduction
Primary cutaneous CD30 + LPDs account for approximately 25% of cutaneous lymphomas. The peak incidence is in the fifth and sixth decades. Although these CD30 + LPDs are clinically heterogeneous, they can be indistinguishable histologically. The 2 CD30 + primary cutaneous LPDs listed in the World Health Organization European Organization for Research and Treatment of Cancer (EORTC) classification scheme are LyP and primary cALCL ; however, it is important to include LCT of MF in this discussion as these 3 CD30 + LPDs can mimic, be mistaken for, and occur concomitantly with each other. Recognizing and differentiating these CD30 + entities can be challenging, but correct classification is imperative for developing an effective treatment protocol. There is no definitive test to differentiate these 3 CD30 + LPDs; therefore, assimilating clinical and pathologic data remains the best method to date. By observing the primary lesion morphology, distribution on the body, the natural course of the lesions, the histology, and the immunohistochemical data, more often than not, one can correctly categorize the disorder.
Many different treatment strategies have been used for the CD30 + LPDs; however, given the rarity of these diseases, there are little accumulated data for evidence-based guidelines. Most studies are case reports, small series, or retrospective reviews. There are very few prospective studies. However, the EORTC, International Society for Cutaneous Lymphomas (ISCL), and the US Cutaneous Lymphoma Consortium (USCLC) recently convened an expert multidisciplinary panel and offered recommendations for treatment of LyP and cALCL based on literature analysis and discussion by clinicians. The National Comprehensive Cancer Network (NCCN) guidelines are also a great Web-based reference to aid in the workup and treatment of CD30 + LPDs ( www.nccn.org ).
The following discussion offers practical pearls to differentiate entities, addresses most of the treatment options, and addresses the treatment of MF with LCT, which was not discussed in the prior review.
Introduction
Primary cutaneous CD30 + LPDs account for approximately 25% of cutaneous lymphomas. The peak incidence is in the fifth and sixth decades. Although these CD30 + LPDs are clinically heterogeneous, they can be indistinguishable histologically. The 2 CD30 + primary cutaneous LPDs listed in the World Health Organization European Organization for Research and Treatment of Cancer (EORTC) classification scheme are LyP and primary cALCL ; however, it is important to include LCT of MF in this discussion as these 3 CD30 + LPDs can mimic, be mistaken for, and occur concomitantly with each other. Recognizing and differentiating these CD30 + entities can be challenging, but correct classification is imperative for developing an effective treatment protocol. There is no definitive test to differentiate these 3 CD30 + LPDs; therefore, assimilating clinical and pathologic data remains the best method to date. By observing the primary lesion morphology, distribution on the body, the natural course of the lesions, the histology, and the immunohistochemical data, more often than not, one can correctly categorize the disorder.
Many different treatment strategies have been used for the CD30 + LPDs; however, given the rarity of these diseases, there are little accumulated data for evidence-based guidelines. Most studies are case reports, small series, or retrospective reviews. There are very few prospective studies. However, the EORTC, International Society for Cutaneous Lymphomas (ISCL), and the US Cutaneous Lymphoma Consortium (USCLC) recently convened an expert multidisciplinary panel and offered recommendations for treatment of LyP and cALCL based on literature analysis and discussion by clinicians. The National Comprehensive Cancer Network (NCCN) guidelines are also a great Web-based reference to aid in the workup and treatment of CD30 + LPDs ( www.nccn.org ).
The following discussion offers practical pearls to differentiate entities, addresses most of the treatment options, and addresses the treatment of MF with LCT, which was not discussed in the prior review.
Lymphomatoid papulosis
Whether to classify LyP as benign or malignant remains a controversy. However, most experts in the field think of LyP as an indolent cutaneous lymphoma on the same spectrum as cALCL. LyP incidence peaks in the fifth decade and has an excellent prognosis with a 10-year survival approaching 100% (LyP). Up to70% of LyP cases are associated with +TCR gene rearrangements. The classic clinical description of LyP is crops of erythematous papules (often at different stages of development) most often on the trunk or proximal extremities that progress to central necrosis and heal spontaneously over weeks to possibly months ( Fig. 1 ). The histology can be variable with predominant CD4 + or CD8 + T cells and is categorized into 5 different subtypes (A–E) ( Table 1 ), although a single patient may exhibit several of these histologic patterns. These subtypes are not predictive of clinical course or of severity of disease. However, it is important to be knowledgeable about these histologic subtypes as they mimic the histology of other more concerning LPDs and may lead to misdiagnosis and possibly more aggressive treatment than is needed.
| LyP Subtypes | Histologic Description |
|---|---|
| Type A | Wedge-shaped clusters CD30 + large atypical lymphocytes interspersed with a mixed inflammatory infiltrate of neutrophils, histiocytes, and eosinophils |
| Type B | MF-like with bandlike infiltrate and epidermotropism of smaller atypical lymphocytes that may be CD30 − |
| Type C | cALCL-like with larger clusters or sheets of large anaplastic CD30 + cells without the interspersed mixed infiltrate of Type A |
| Type D | CD8 + epidermotropic CTCL-like with large CD8 + , CD30 + lymphocytes that often stain with cytotoxic markers (TIA-1, granzyme, perforin) |
| Type E | Angioinvasive with small to large angiocentric CD30 + atypical lymphocytes that invade walls of small to medium vessels in dermis or SQ |
| Type F | Perifollicular infiltrates of CD30 + atypical cells with folliculotrophism with or without follicular mucinosis |
The most common type A LyP histology resembles wedge-shaped clusters of CD30 + large atypical lymphocytes interspersed between a mixed inflammatory infiltrate of neutrophils, histiocytes, eosinophils, and smaller lymphoctyes, and epidermotropism is typically absent. The rarer type B LyP exhibits histologic features reminiscent of MF, with a bandlike infiltrate and epidermotropism of small to medium atypical lymphocytes that may be CD30 − . Type C LyP is described as cALCL-like with larger clusters or sheets of large anaplastic CD30 + atypical lymphocytes without the mixed inflammatory infiltrate seen in type A. Type D LyP has a more worrisome histologic appearance and can mimic CD8 + aggressive epidermotropic cutaneous T-cell lymphoma (CTCL) with large CD8 + , CD30 + lymphocytes that stain for cytotoxic markers, including T-cell intracellular antigen-1 (TIA-1), granzyme, and perforin. These cases do not usually have necrosis and ulceration but may lose expression of T-cell antigens including CD2, CD3, CD5, and CD7. Recently reported type E LyP is described as angioinvasive with small, medium, and large angiocentric CD30 + atypical lymphocytes that invade the walls of small to medium vessels in the dermis and less so in the subcutis, often with associated necrosis. Clinically, the initial papules in type E LyP quickly progress to larger hemorrhagic and necrotic ulcers, but even these cases follow the typical course of LyP and spontaneously resolve. In addition, one case series describes LyP type F, which exhibits perifollicular infiltrates of CD30 + atypical cells with folliculotrophism with or without follicular mucinosis.
LyP may occur in conjunction with other lymphomas in about 20% of cases. There have been reported cases of LyP in association with cALCL, MF, Hodgkin disease, systemic ALCL, and other systemic lymphomas. In some of these cases, the same clone is responsible for both diseases, suggesting a possible common origin in the precursor lymphoid stem cell. The coexistence of these disorders can lead to confusing clinical presentations making accurate diagnosis challenging. In these situations, it is important to remember that performing multiple biopsies of each different primary lesion morphology and observing the course of individual lesions can be helpful in deciphering these cases. In addition, if LyP nodules begin to exceed 1 cm, one should be suspicious for progression to another subtype of cutaneous lymphoma.
Treatment of Lymphomatoid Papulosis
Despite the excellent prognosis of LyP, the recurrent nature of the lesions is typically bothersome for patients, and most desire treatment ( Box 1 ). Although topical corticosteroid therapy does not prevent lesions or change the natural history of the disease, spot treatment with a high-potency topical steroid can be helpful to reduce the size and to hasten involution of papules. For those patients with frequent outbreaks of many LyP lesions, treatment options that may prevent occurrence of new lesions are often desirable and may include single-agent systemic immunomodulators, chemotherapy, and/or phototherapy. However, given the excellent prognosis of LyP, the long-term sequela of these therapies should be considered. There is no role for multiagent chemotherapy for LyP, as the risks likely outweigh the benefits.
Skin-directed treatment options
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Observation
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Topical corticosteroids
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Phototherapy
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Topical imiquimod
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Topical nitrogen mustard
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Interferon intralesional (IL)
Systemic treatment options
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Methotrexate
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Oral retinoids
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Interferon
According to the EORTC, ISCL, and USCLC recent review, topical corticosteroids, methotrexate (MTX), and psoralen + ultraviolet A (PUVA) are all first-line therapies successful at obtaining a partial response (PR) or complete response (CR) in LyP. Thus, the decision on which of these treatments to choose depends on the extent of the patient’s disease (Is it too widespread for topical treatment?), where the patient lives (Are they within driving distance of a phototherapy unit?), their insurance situation (Are they insured and does their insurance cover the pharmacy cost of psoralen?), and their comorbidities (Is any preexisting liver disease or poor kidney function making them a poor candidate for MTX?). Other second- and third-line treatment options are also discussed.
Topical corticosteroids
Although monotherapy with topical corticosteroids does not prevent new lesions, they do typically help the lesions remain smaller and resolve faster and therefore are a good option for patients with limited and infrequent disease outbreaks. Topical corticosteroids are also used often as adjunctive treatment along with MTX or PUVA. Of the 25 patients with LyP reviewed by Kempf and colleagues, only 3 had a CR with topical corticosteroids reflecting that, although helpful, monotherapy with topical corticosteroids rarely achieve CRs in LyP. Given the chronic nature of LyP, the risks outweigh the benefits for oral systemic corticosteroids, and they have not been shown to be effective in LyP.
Phototherapy
There is a lack of published data on the use of phototherapy (PUVA) for LyP, but there is ample anecdotal evidence and small case series to strongly support its use as a first-line treatment modality for LyP. Kempf and colleagues reported in their review of 19 patients with LyP published in the literature that 68% had a PR and 27% had a CR with PUVA therapy. Relapses occurred in all patients shortly after discontinuing light therapy. An example of a typical PUVA regimen for patients with LyP or MF begins with treatments 3 times weekly according to institution protocols and skin type of the patient. Once the patient has substantial improvement, PUVA frequency can be decreased to twice per week, then to once per week, then to once every other week, then once every third week, and so on until reaching the minimum maintenance dose appropriate to keep that patient’s disease not 100% clear but rather well controlled. Discussing realistic expectations with patients is important. It may take a year or more to reach the desired maintenance frequency with PUVA. The minimum frequency of PUVA maintenance therapy is typically once every 8 weeks.
There are also reports of effectiveness with ultraviolet B (UVB) phototherapy in 6 of 7 children with LyP. Although UVB therapy does not penetrate to the depth that PUVA reaches to treat thicker lesions, it still may be effective for thinner LyP lesions. Broadband UVB (BBUVB) and narrowband UVB (NBUVB) also typically start with a 3-times-per-week treatment regimen until the patient substantially improves. Then one can further decrease the frequency to twice per week, then to once per week, and then every other week. Further decreases in BBUVB and NBUVB may lead to loss of efficacy and increased potential for phototoxicity. This every-other-week maintenance UVB regimen may be safely continued for extended periods in an effort to control disease. Although PUVA is associated with increased risk of both melanoma and nonmelanoma skin cancers, NBUVB does not have this same association.
One case report heralded the success in treating refractory LyP lesions with methyl aminolevulinate photodynamic therapy (MAL PDT) with a 630-nm light source after 3 hours of incubation under occlusion. MAL PDT was repeated 1 week later, and refractory lesions resolved 7 days after the second treatment without recurrence of lesions in the treated area during an 11-month follow-up period. PDT treatment may prove useful as field treatment in patients with recurrent or refractory lesions of LyP within a localized area.
The 308-nm excimer laser has been used for the treatment of localized LyP lesions. A total of 13 treatments given 3 times weekly with a maximum fluence of 500 mJ/cm 2 induced clearance in 75% of treated lesions in one report; however, duration of response was not addressed.
In one LyP case, extracorporeal photopheresis with 8-methoxypsoralen was used on 2 consecutive days once monthly to achieve a PR, albeit temporary, in this refractory case of diffuse LyP.
Methotrexate
MTX is a folate antagonist that inhibits purine and pyrimidine synthesis. Despite few published reports, MTX is an accepted first-line treatment of CD30 + LPDs, and there are ample anecdotal successes in controlling CD30 + LPDs with low-dose MTX. Effective doses range from 10 to 25 mg oral once weekly typically with concomitant folic acid, 1 mg, each day. The largest study using MTX included cALCL as well as LyP. Of 45 patients, 39 (87%) had satisfactory long-term control of their disease. Doses in some patients reached 60 mg per week; however, the investigators found that patients responded equally well with lower doses in the range of 15 to 20 mg per week. The patients typically responded within 4 weeks of beginning therapy. Once improvement was seen, MTX frequency was reduced in an effort to retain control of disease while reducing risk of drug toxicity. In some patients MTX could be reduced to once every 10 to 28 days with good control of CD30 + lesions but with less control of the MF patches (in the patients with coexisting MF). Median total duration of MTX therapy exceeded 39 months (range, 2–205 months). After MTX was discontinued, 10 patients remained free of disease from 24 to 227 months. The most common side effects reported were fatigue (47%), elevated liver transaminase levels (27%), and nausea (22%). Of 10 patients treated with MTX for more than 3 years, 5 had evidence of hepatic fibrosis.
Subcutaneous (SQ) administration of MTX can be considered in patients not responding to oral dosing. There is one report of topical MTX use in a patient with LyP who moistened his MTX tablet with tap water and applied it to some of his LyP lesions. He essentially used his other LyP lesions as a control and found that the lesions treated with topical MTX resolved faster and stayed smaller than the controls. MTX is known to have poor percutaneous systemic absorption; therefore, the effect of the MTX is thought to be local in this case. Given the issues with cutaneous absorption, no commercially available topical MTX exists, making this treatment modality difficult to replicate; however, a previous phase 1/2 trial of a topical MTX-laurocapram topical hydrophilic gel did show some efficacy in CTCL, and similar compounds may hold promise for the future.
Bexarotene
Bexarotene is an oral retinoid with a high affinity for the retinoid X receptor (RXR). It was approved by the US Food and Drug Administration (FDA) for the treatment of CTCL in 1999. In a prospective study of 10 patients with LyP treated with either topical or oral bexarotene, 300 mg/m 2 /d, all patients had a response in regards to decreased number or duration of lesions, with an objective response seen in 8 of 10 patients (1 CR in a patient using oral bexarotene, with all lesions clearing and no new lesions during continued therapy; 1 CR and 5 PRs in treated lesions in patients using bexarotene gel; and 1 PR in a patient using both oral and topical bexarotene). The use of bexarotene gel was associated with more rapid disappearance (average of 3 days to resolve compared with 2–4 months for lesion resolution), less necrosis, and overall fewer lesions than before the patient started using bexarotene gel. One patient with recurrent LyP lesions in a localized area experienced a reduction of new lesions after field treating the area with bexarotene gel, suggesting that bexarotene gel may be useful in treating active lesions as well as preventing new lesions. Bexarotene gel can cause an intense retinoid dermatitis in some patients; therefore, counseling patients on what to expect, allowing a reduction from the recommended 4 times a day dosing for MF, and prescribing a topical corticosteroid to calm retinoid dermatitis can encourage patient compliance and continued therapy.
A more extensive review of bexarotene is offered by Dr. Huen AO; however, it is important to mention here the central hypothyroidism and hypertriglyceridemia seen with oral bexarotene. Thyroid-stimulating hormone remains low throughout oral bexarotene therapy because of central hypothyroidism; therefore, it is the free T4 that must be followed to titrate the thyroid supplementation dose. Communicating with the patient’s primary doctor is of utmost importance in patients administered oral bexarotene so that there is joint understanding of the thyroid tests used to monitor these patients. For lipid control, a fenofibrate or statin should be administered at the same time as oral bexarotene with subsequent monitoring of the fasting lipid panel to adjust these medications as needed.
Interferon
There are little published data about the use of interferons (IFNs) for CD30 + LPDs. In an open trial of patients with LyP, 5 patients were treated with IFN-α SQ injection 3 times per week for 6 weeks (1 with 15 million units (MU) 3 times per week, 4 with 3 MU 3 times per week). There were 4 CRs and 1 PR. The 2 of 5 patients who had recurrent disease shortly after IFN discontinuation were only treated with 5 to 7 months of IFN suggesting that it is difficult to alter the chronic recurring nature of LyP with only short-term IFN use. One of these patients was then able to regain CR with subsequent additional 17 months of IFN therapy and has maintained remission for 3 years. The other patient with recurrent disease was treated with an additional 12 months of IFN and still has stable disease 31 years later. The other 3 patients were treated for longer 12- to 13-month intervals with IFN and were able to maintain their remission throughout the follow-up period after drug discontinuation (from 1 to 11 years) and did not require any retreatment, suggesting that treating with IFN for at least 1 year may yield better long-term results.
Intralesional IFN has been used successfully for larger, more refractory lesions. One report described 1 MU intralesional injection of IFN-α2b into 3 LyP lesions (3 MU total) 3 times weekly. Lesions smaller than 0.5 cm resolved after 3 injections. The larger lesions took up to 3 to 10 intralesional injections. After resolution of lesions, maintenance therapy was continued with 3 MU SQ injection into the abdomen 3 times weekly. The patient reported some skin recurrences; however, overall number and size of skin lesions were reduced while on IFN therapy.
Imiquimod
Imiquimod is a Toll-like receptor 7 and 8 agonist. This topical immune response modifier enhances the T H 1 response leading to increased production of IFN-α, interleukin 12, IFN-γ, and other cytokines thereby having an antitumor effect and balancing the T H 2 profile of CTCL. One report of topical imiquimod application 3 times a week in a patient with LyP, who was already administered low-dose MTX, noted a faster regression of lesions from his typical 2 months down to 2 weeks. Imiquimod seemed to have only a local effect as new lesions appeared elsewhere in the patient, but this topical immunomodulator provides a good option for adjunctive treatment of refractory LyP lesions.
Topical nitrogen mustard
Despite a lack of published data, topical nitrogen mustard is used often in clinical practice for refractory LyP lesions. A review of CD30 + LPD treatments found that only 1 of 17 patients with LyP had a sustained response with topical nitrogen mustard. However, sustained responses are often not plausible in this chronic, relapsing, and remitting disease, and nitrogen mustard should be considered in the armamentarium of LyP treatments. More studies need to be done to assess whether its use leads to faster resolution of lesions.
Primary cutaneous anaplastic large cell lymphoma
Primary cALCL typically presents as a solitary or few tumor nodules without evidence of extracutaneous disease at the time of diagnosis ( Fig. 2 ). These nodules may progress to ulceration, and, although up to 25% to 44% may show partial regression over time, they less commonly completely resolve on their own. Despite various treatment strategies, up to 60% of patients with cALCL have recurrences of skin nodules. Regional lymph node involvement may infrequently occur and is typically not associated with a worse prognosis. Widespread systemic involvement is rare, and when it occurs, the patient would be considered to have systemic ALCL. cALCL has an excellent prognosis of more than 90% 10-year survival; however, patients with multifocal cALCL (lesions in more than 1 anatomic area) are more at risk for extracutaneous spread. In addition, extensive extremity involvement can prove refractory to therapy and may be associated with a worse prognosis. Histologically, these tumors comprise large sheets of anaplastic, pleomorphic, or immunoblastic T cells with irregularly shaped nuclei and pale cytoplasm, which extend into the deep dermis or SQ tissue and are CD30 + and anaplastic lymphoma kinase (ALK-1) negative. Surrounding eosinophils and small reactive lymphocytes may be seen at the periphery of the infiltrate. By definition, CD30 is expressed by greater than 75% of the large tumor cells.
Treatment of Cutaneous Anaplastic Large Cell Lymphoma
Approximately one-fourth of cALCL lesions may spontaneously improve or even resolve ( Box 2 ). Surgical excision and/or local radiation therapy are reasonable options for the treatment of solitary or localized cALCL. There is no literature to suggest that radiation following excision has a better outcome than either treatment modality alone. However, despite these 2 treatment options, cALCL recurs in about 40% of patients either in the same or in a new location. Multifocal lesions or frequent recurrences leading to multiple surgical excisions and radiation exposures become less appealing. In these situations, moving from a skin-directed to a systemic single-agent immunomodulator or chemotherapeutic treatment regimen offers a good alternative. Low-dose MTX, oral retinoids (isotretinoin, acitretin, or bexarotene), brentuximab vedotin, gemcitabine, IFN, or etoposide have data to support their efficacy in this condition and are discussed in detail.
Skin-directed treatment options
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Excision
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Radiation
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Topical imiquimod
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Phototherapy
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Interferon intralesional (IL)
Systemic treatment options
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Brentuximab vedotin
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Methotrexate
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Retinoids
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Interferon
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Gemcitabine
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Etoposide
Related posts:
Cutaneous Lymphoma
Radiation Therapy for Cutaneous T-Cell Lymphomas
The Role of Systemic Retinoids in the Treatment of Cutaneous T-Cell Lymphoma
The Use of Interferons in the Treatment of Cutaneous T-Cell Lymphoma
Other Chemotherapeutic Agents in Cutaneous T-Cell Lymphoma
Hematopoietic Stem Cell Transplant for Mycosis Fungoides and Sézary Syndrome
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