- Email: [email protected]
Primary cutaneous B-cell lymphomas
Primary cutaneous B-cell lymphomas Part II. Therapy and future directions Andrea Luısa Suarez, MD, PhD,a,e Christiane Querfeld, MD, PhD,b,e Steven Horwitz, MD,c,e Melissa Pulitzer, MD,d,e Alison Moskowitz, MD,c,e and Patricia L. Myskowski, MDa,b,e New York, New York CME INSTRUCTIONS The following is a journal-based CME activity presented by the American Academy of Dermatology and is made up of four phases: 1. Reading of the CME Information (delineated below) 2. Reading of the Source Article 3. Achievement of a 70% or higher on the online Case-based Post Test 4. Completion of the Journal CME Evaluation CME INFORMATION AND DISCLOSURES Statement of Need: The American Academy of Dermatology bases its CME activities on the Academy’s core curriculum, identified professional practice gaps, the educational needs which underlie these gaps, and emerging clinical research findings. Learners should reflect upon clinical and scientific information presented in the article and determine the need for further study. Target Audience: Dermatologists and others involved in the delivery of dermatologic care. Accreditation The American Academy of Dermatology is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. AMA PRA Credit Designation The American Academy of Dermatology designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditsÔ. Physicians should claim only the credit commensurate with the extent of their participation in the activity. AAD Recognized Credit This journal-based CME activity is recognized by the American Academy of Dermatology for 1 AAD Credit and may be used toward the American Academy of Dermatology’s Continuing Medical Education Award. Disclaimer: The American Academy of Dermatology is not responsible for statements made by the author(s). Statements or opinions expressed in this activity reflect the views of the author(s) and do not reflect the official policy of the American Academy of Dermatology. The information provided in this CME activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to the diagnostic, management and treatment options of a specific patient’s medical condition. Disclosures Editors The editors involved with this CME activity and all content validation/peer reviewers of this journal-based CME activity have reported no relevant financial relationships with commercial interest(s). Authors The authors of this journal-based CME activity have reported no relevant financial relationships with commercial interest(s). Planners Hensin Tsao, MD, has a relationship with Genentech. Robert Brodell, MD, has a relationship with Genentech. The other planners involved with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s). The editorial and education staff involved with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s). Resolution of Conflicts of Interest In accordance with the ACCME Standards for Commercial Support of CME, the American Academy of Dermatology has implemented mechanisms, prior to the planning and implementation of this Journal-based CME activity, to identify and mitigate conflicts of interest for all individuals in a position to control the content of this Journal-based CME activity. Learning Objectives After completing this learning activity, participants should be able to identify appropriate therapy for the different forms of primary cutaneous B cell
lymphomas and enlist the help of medical oncologists and radiation oncologists as indicated. Date of release: September 2013 Expiration date: September 2016 Ó 2013 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2013.06.011 Technical requirements: American Academy of Dermatology: d Supported browsers: FireFox (3 and higher), Google Chrome (5 and higher), Internet Explorer (7 and higher), Safari (5 and higher), Opera (10 and higher). d JavaScript needs to be enabled. Elsevier: Technical Requirements This website can be viewed on a PC or Mac. We recommend a minimum of: d PC: Windows NT, Windows 2000, Windows ME, or Windows XP d Mac: OS X d 128MB RAM d Processor speed of 500MHz or higher d 800x600 color monitor d Video or graphics card d Sound card and speakers Provider Contact Information: American Academy of Dermatology Phone: Toll-free: (866) 503-SKIN (7546); International: (847) 240-1280 Fax: (847) 240-1859 Mail: P.O. Box 4014; Schaumburg, IL 60168 Confidentiality Statement: American Academy of Dermatology: POLICY ON PRIVACY AND CONFIDENTIALITY Privacy Policy - The American Academy of Dermatology (the Academy) is committed to maintaining the privacy of the personal information of visitors to its sites. Our policies are designed to disclose the information collected and how it will be used. This policy applies solely to the information provided while visiting this website. The terms of the privacy policy do not govern personal information furnished through any means other than this website (such as by telephone or mail). E-mail Addresses and Other Personal Information - Personal information such as postal and e-mail address may be used internally for maintaining member records, marketing purposes, and alerting customers or members of additional services available. Phone numbers may also be used by the Academy when questions about products or services ordered arise. The Academy will not reveal any information about an individual user to third parties except to comply with applicable laws or valid legal processes. Cookies - A cookie is a small file stored on the site user’s computer or Web server and is used to aid Web navigation. Session cookies are temporary files created when a user signs in on the website or uses the personalized features (such as keeping track of items in the shopping cart). Session cookies are removed when a user logs off or when the browser is closed. Persistent cookies are permanent files and must be deleted manually. Tracking or other information collected from persistent cookies or any session cookie is used strictly for the user’s efficient navigation of the site. Links - This site may contain links to other sites. The Academy is not responsible for the privacy practices or the content of such websites. Children - This website is not designed or intended to attract children under the age of 13. The Academy does not collect personal information from anyone it knows is under the age of 13. Elsevier: http://www.elsevier.com/wps/find/privacypolicy.cws_home/privacypolicy
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The choice of therapy for primary cutaneous B-cell lymphoma (PCBCL) relies on correct histopathologic classification and the exclusion of systemic disease. In part II of this continuing medical education article, we will review the available therapies for the different types of PCBCL. Primary cutaneous follicle center lymphoma (PCFCL) and primary cutaneous marginal zone lymphoma (PCMZL) are indolent tumors with an excellent prognosis. They are managed similarly with local therapy, such as radiotherapy or surgical excision, for isolated disease and observation for asymptomatic multifocal presentations. Relapses are common in both PCFCL and PCMZL, but overall survival remains excellent. Primary cutaneous diffuse large B-cell lymphoma (both leg type and other) has a much poorer prognosis than indolent PCBCL, and it often requires an aggressive approach with radiation therapy and/or multiagent chemotherapy. Investigational approaches hold promise for the treatment of these malignancies, particularly primary cutaneous diffuse large B-cell lymphoma. ( J Am Acad Dermatol 2013;69:343.e1-11.) Key words: lymphoma; primary cutaneous B-cell lymphoma; primary cutaneous diffuse large B-cell lymphoma; primary cutaneous follicle center lymphoma; primary cutaneous marginal zone lymphoma; rituximab; therapy.
The choice of therapy for lymphoma, as determined CAPSULE SUMMARY primary cutaneous B-cell by a panel of experts, in lymphomas (PCBCLs) is limthe United States. Therapeutic approaches to primary ited by the rarity of these For the purpose of chooscutaneous B-cell lymphoma (PCBCL) tumors and the lack of proing therapy, PCBCLs may be range from localized therapies in spective, randomized studies divided into 2 types: indolent indolent types (primary cutaneous comparing existing and exand aggressive. Indolent tufollicle center lymphoma [PCFCL] and perimental therapies. Most mors include primary cutaneprimary cutaneous marginal zone data on the treatment of ous marginal zone lymphoma lymphoma [PCMZL]) to multiagent PCBCLs are limited to small (PCMZL) and primary cutanechemotherapy and immune-based retrospective studies. ous follicle cell lymphoma modalities in aggressive types (primary The European Organisation (PCFCL), while aggressive cutaneous diffuse large B-cell for Research and Treatment tumors include primary lymphomaeleg or other/nonleg type). of Cancer Cutaneous cutaneous diffuse large Lymphoma Group (EORTCB-cell lymphomaeleg type The treatment approach is further CLG) and the International (PCDLBCL-LT) and primary defined in the indolent PCBCLs by Society for Cutaneous cutaneous diffuse large B-cell whether or not the lesion is single and/or Lymphoma (ISCL) have delymphomaeother or nonleg limited to a single anatomic site. veloped uniform recommentype (PCDLBCL-non-LT). The Relapses are common in PCFCL and dations for the treatment of extent and size of nodules or PCMZL, but overall survival remains the 3 main types of PCBCL tumor lesions and the location excellent. based on the existing literaand anatomic site must also be Primary cutaneous diffuse large B-cell ture and good clinical pracconsidered when determining lymphoma carries a much poorer tice.1 Similarly, the National the ideal treatment approach.3 prognosis despite aggressive therapy. Comprehensive Cancer Network (NCCN) Guidelines THERAPY FOR on non-Hodgkin’s lymphoINDOLENT DISEASE mas includes consensus algorithms for the initial Primary cutaneous follicle center lymphoma treatment of PCBCL and secondary therapeutic Key points options in cases of refractory disease.2 The NCCN d If solitary or limited to a single site, first-line guidelines represent the most current and actreatment is radiation therapy or surgery, cepted practice for treatment of non-Hodgkin’s with curative intent d
d
d
d
From the Department of Dermatology,a New YorkePresbyterian Hospital/Weill Cornell Medical Center, the Dermatology Serviceb and Lymphoma Service,c Department of Medicine and the Department of Pathology,d Memorial Sloan-Kettering Cancer Center; and Weill Cornell Medical College,e New York. Funding sources: None. Conflicts of interest: None declared.
Reprints not available from the authors. Correspondence to: Patricia L. Myskowski, MD, Dermatology Service, Department of Medicine, Rockefeller Outpatient Pavilion, Memorial Sloan-Kettering Cancer Center, 160 E 53rd St, New York, NY 10022. E-mail: [email protected]. 0190-9622/$36.00
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Abbreviations used: CBCL: CHOP:
cutaneous B-cell lymphoma cyclophosphamide, doxorubicin, onvocin/vincristine, and prednisone DLBCL: diffuse large B-cell lymphoma EORTC-CLG: European Organisation for Research and Treatment of Cancer Cutaneous Lymphoma Group FISH: fluorescence in situ hybridization MALT: mucosa-associated lymphoid tissue NCCN: National Comprehensive Cancer Network PCBCL: primary cutaneous B-cell lymphoma PCDLBCL-LT: primary cutaneous diffuse large B-cell lymphoma, leg type PCFCL: primary cutaneous follicle center lymphoma PCMZL: primary cutaneous marginal zone lymphoma R-CHOP: cyclophosphamide, doxorubicin, onvocin/vincristine, and prednisone with rituximab
d
d
Skin recurrences are common after therapy, often outside of the treated site Patients with multiple lesions may be treated with observation, local therapy, radiation, topical agents, intralesional steroids, and even systemic therapy if clinically warranted
Untreated, the lesions of PCFCL may enlarge slowly, often over years. Lesions may also spontaneously regress (Fig 1). Regardless of the growth pattern—either follicular or diffuse—the 5-year survival rate of PCFCL is excellent (overall survival, 96.1% at 5 years and 88.8% at 10 years in 1 large study).4 Recurrences were common, but when confined to the skin do not appear to have an adverse effect on prognosis.4 Patients with PCFCL presenting with lesions on the legs may have higher rates of relapse and extracutaneous disease than patients without lesions on the legs.5-7 Other variables associated with shorter survival include age, female sex, and greater extent of skin lesions.4,6,7 PCFCL expressing Forkhead box protein P1 or arising on the leg may have a less favorable prognosis, and some advocate more aggressive treatment in these cases.1,7 Rarely, PCFCL may grow rapidly and extensively, and a repeat biopsy specimen should be obtained if the clinical behavior of a formerly indolent lymphoma changes. PCFCL may also undergo rapid clinical progression and histologic transformation to DLBCL (Fig 2), signaling more rapidly progressive disease and requiring more aggressive therapy. For patients with single lesions of PCFCL, curative therapy is a reasonable goal. Radiotherapy (RT) is an option, although the optimal dose and fractionation
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have not been established.1-4,8,9 The EORTC/ISCL recommendations for radiation therapy of PCFCL recommend a dose of at least 30 Gy with margin of 1 to 1.5 cm of clinically uninvolved skin.1 In the United Kingdom, the standard dose for low-grade non-Hodgkin’s lymphomas, including indolent cutaneous follicular lymphomas, is 24 Gy in 12 sessions.10,11 Data supporting the EORTC/ISCL recommendations comes from a few large studies.3,4,8,9 In 1 study, complete remission was achieved in 100% of PCFCL patients treated (n = 101) with a median dose of 40 Gy. Relapses occurred in 29 of 101 patients at a median of 12 months after initial treatment, and generally occurred outside of the irradiated area.3 While 40 Gy was the most frequent dosage used, doses as low as 30 Gy were reportedly effective.3 Solitary lesions of PCFCL on the scalp may be ideally suited for this approach (Fig 3), as may symptomatic lesions (Fig 4). Long-term side effects of RT include alopecia, radiation dermatitis, hyperpigmentation, atrophy, telangiectasia, and secondary skin cancers. Surgical excision is a reasonable option for single lesions of PCFCL.1,2 Nearly 90 patients have been treated with surgical excision in the literature.1,12 In a comparison of surgery versus RT for indolent PCBCL, 6 patients with PCFCL were treated with surgical excision with 5-mm margins and 7 PCFCL patients were treated with radiation therapy (median dose of 3000-4000 cGY, 10 fractions, for 6 weeks).12 One patient treated with radiation experienced a recurrence, whereas there were no recurrences in the surgery group. In addition, 2 patients in the radiation arm experienced chronic nonhealing ulcerations in the tumor area, and 2 patients experienced skin changes, such as erythema and edema. None of the patients in the surgical arm experienced local complications. Surgery appears to be an equally effective treatment option for PCBCL, while avoiding some local complications associated with radiation therapy.12 RT or surgery for localized disease may not be reasonable options in all patients. For example, surgical excision of PCFCL facial lesions might leave a scar after excision with the risk for disfigurement, while RT may be a better option. For large lesions, RT is a more practical approach than surgical resection. Conversely, lesions presenting at sites ill-suited for RT—such as the scalp, when hair loss is a significant cosmetic issue—may be better managed with other local means. A summary of the therapeutic options for PCFCL is shown in Table I. The NCCN guidelines for PCFCL also give consideration to topical therapies (eg, topical corticosteroids, topical nitrogen mustard, and topical
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Fig 1. Primary cutaneous follicle center lymphoma. A, Two asymptomatic pink lesions on either side of the lower back. B, Regression 1 year later.
Fig 2. Primary cutaneous follicle center lymphoma. New purple nodules on the anterior aspect of the lower leg. A biopsy specimen revealed transformation to primary cutaneous diffuse large B-cell lymphoma.
bexarotene) and intralesional steroids. Class I highpotency topical steroids are reported in the treatment of cutaneous lymphomas.2,13 We have used daily applications of topical clobetasol 0.05% cream with some success in selected, symptomatic patients (Fig 5). Intralesional corticosteroids, specifically triamcinolone (10-20 mg/mL), can also be useful in PCFCL.14 We have used intralesional corticosteroid injections to treat PCFCL in cosmetically sensitive
Fig 3. Primary cutaneous follicle center lymphoma. A, Red-purple nodules on the scalp. B, One year after radiation therapy to the scalp.
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Fig 4. Primary cutaneous follicle center lymphoma. A, Symptomatic (pruritic) purple-pink lesions on the upper aspect of the back. B, Resolution of lesions after radiation therapy.
Table I. Recommendations for the treatment of primary cutaneous follicle center lymphoma CBCL type and extent
Solitary/localized
Generalized skin disease
Initial therapy
Secondary therapy
Local radiotherapy1,2 and excision1,2 Select cases—observation,1 topical therapy (eg, steroids, imiquimod, nitrogen mustard, and bexarotene),1 and intralesional steroids1 Observation,1,2 intravenous rituximab,1,2 local radiotherapy,1,2 topical therapy (eg, steroids, imiquimod, nitrogen mustard, and bexarotene),1 and intralesional steroids1
Observation,1 intralesional interferon-alfa,2 excision,1 intralesional rituximab,2 topical therapy (eg, steroids, imiquimod, nitrogen mustard, and bexarotene),1 intralesional steroids,1 and local radiotherapy1 Chlorambucil with or without rituximab1 or CVP with or without rituximab1,2 Select cases—CVP2
CBCL, Cutaneous B-cell lymphoma; CVP, cyclophosphamide, vincristine, and prednisone.
areas on the face, where RT would have resulted in asymmetric hair loss in the beard area, and surgical excision would not have provided an equivalent result (Fig 6). We have also had success with cryotherapy as a treatment for localized disease. In 1 case of multiple small papules of PCFCL on the scalp, where RT would have resulted in unacceptable hair loss and surgical excision was not practical, we used liquid nitrogen in 2 freeze/thaw cycles of 20 seconds each with good local control (Fig 7). Because recurrence rates after initial treatment are high, alternative therapies currently pursued, and with promising outcomes, include immune-based modalities, such as rituximab, interferon, and imiquimod.13 There are a few cases in the literature of intralesional interferon-alfa (IFNa) for PCFCL, with
dosages varying from 1 million IU, 3 times per week to 6 million IU, 3 times a week for larger lesions.15-17 While responses rates were high, follow-up periods were short, limiting the conclusiveness of these studies regarding relapse rate or long-term efficacy. Imiquimod has also been used with mixed success in PCFCL.18 In 1 study, the effect of imiquimod seemed to be less potent for PCFCL than cutaneous T-cell lymphoma.19 In another report of PCFCL with simultaneous alopecia areata of the scalp, both lesions regressed with topical imiquimod and systemic steroids.20 Therefore, while imiquimod may be an additional treatment option in some cases of PCBCL, additional studies are needed. Rituximab is an anti-CD20 monoclonal antibody targeting CD20 antigens on the surface of both normal and malignant B cells.21 In vitro, lymphoma
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Fig 5. Primary cutaneous follicle center lymphoma. A, Violaceous nodules on the abdomen. B, Nodules on the abdomen after 4 months of topical clobetasol 0.05% cream daily.
cells undergo antibody-dependent, cell-mediated lysis when exposed to rituximab. In vivo, it induces antigen-specific T cell responses and sensitizes cells to the cytotoxic effects of chemotherapy.22,23 Relapsed or refractory B-cell lymphomas respond well to rituximab, and it is first-line therapy in combination with chemotherapy for low-grade and aggressive nodal B-cell lymphomas.24-27 There are reports of high response rates for PCBCL treated with rituximab.28,29 In a retrospective study of rituximab in indolent PCBCL, 10 patients with PCFCL received intravenous rituximab (375 mg/m2), with a 100% overall response rate (8/10 complete responses and 2 partial responses).28 Patients had either multiple lesions or scalp involvement. Median time to response, duration of response, and time to progression of treated patients with PCBCL was 30 days, 24 months, and 24 months, respectively. A similar study found a complete response in 100% of PCFCLs (n = 11).29 While limited by small sample sizes, these studies support rituximab as a reasonable treatment for indolent cutaneous B-cell lymphoma (CBCL) with multiple lesions, particularly where local treatment is not effective or desirable. Intravenous rituximab appears safe with relatively few side effects. Intralesional rituximab administration has also achieved favorable results but it requires a lower dose, offering a potentially more cost effective modality over the intravenous route with comparable efficacy.30-31
Fig 6. Primary cutaneous follicle center lymphoma. A, Purple plaque on the lateral aspect of the cheek. B, Lesion 6 months after intralesional triamcinolone, 0.15 mL of 10 mg/mL once.
In rare cases, patients with PCFCL may develop disseminated skin lesions or large tumors, and require chemotherapy (ie, cyclophosphamide, doxorubicin, onvocin/vincristine, and prednisone either without [CHOP] or with rituximab [R-CHOP]).1,32 Radioimmunotherapy also shows promise from early studies. A pilot study of yttrium-90 (90 Y) ibritumomab in 10 patients with relapsed PCBCL (PCFCL and PCLBCL-LT) gave complete response rates of 100% with a median time to relapse of 12 months.33 CBCL is also an appropriate target for intralesional injection with a genetically engineered virus.34 The interferon gammaeencoding adenoviral vector, TG1042, was successfully tested for in a phase I study that included 2 CBCL patients, with 1 PCFCL showing partial response.35
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Fig 7. Primary cutaneous follicle center lymphoma. A, Small pink papules on the scalp. B, Resolution of papules 6 months after cryotherapy with liquid nitrogen.
Primary cutaneous marginal zone lymphoma Key points d Localized and/or limited disease can be treated with RT or surgery with curative intent and, in some cases, antibiotics d Relapse rates after localized treatment of PCMZL may be higher than relapse rates seen in patients with PCFCL d Treatment for multifocal disease may include observation, RT, topical agents, and intralesional steroids, along with systemic immunomodulators or chemotherapeutics PCMZL is part of the group of extranodal marginal zone B-cell lymphomas involving mucosal sites, called mucosa-associated lymphoid tissue (MALT) lymphomas. In most cases, like PCFCL, it behaves as an extremely indolent tumor with a 5-year diseasespecific survival rate approaching 99%.5,32 Recommended treatment options, which are quite similar to PCFCL, are shown in Table II. RT is highly effective in cases of PCMZL with solitary or a few contiguous lesions and offers the
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potential for a cure. However, in 1 study of 153 patients with PCBCL, relapse rates were higher for PCMZL than PCFCL after this modality (5-year relapse-free survival, 45% vs 70%, respectively).3 RT doses are the same as those used for PCFCL.1-3 Primary surgical excision can also be effective for solitary and/or localized PCMZL. In 1 large study of 39 PCMZL patients treated with surgical excision, a complete response was achieved in 97.4% of patients, but 31.6% of patients developed recurrences. Radiation therapy gave 97.6% complete response rates in 83 PCMZL patients, with recurrence rates of 46.9%.4 In a smaller study of surgery versus radiation therapy for indolent PCBCL, 3 PCMZL patients had surgical excision with 5-mm margins and 7 PCMZL patients were treated with radiation therapy (median dose, 3000-4000 cGY, 10 fractions for 6 weeks).12 Both methods appeared to be equally effective. Topical therapies are frequently used in PCMZL. Topical class 1 corticosteroids, particularly clobetasol, have been used with success in PCMZL, both alone and in combination with systemic therapy.13,36-38 Complete responses have been reported with topical corticosteroids alone.13,38 Patients must be forewarned about hypopigmentation and possible atrophy. Topical nitrogen mustard,2,36 cryotherapy,37 and intralesional triamcinolone, at a wide range of dilutions (2.5-40 mg/mL; 0.5-12 mg per lesion),39 all have been used with success in PCMZL. We have observed similar results in our patients treated with intralesional steroids (Fig 8). Intralesional IFN is another alternative for localized indolent PCBCL disease. In a study of 8 patients with localized PCMZL, intralesional injections of 3 million units of recombinant IFNa2a, administered 3 times per week, resulted in complete tumor regression after a mean of 8.5 weeks.40 Of the 2 patients who relapsed (at 4 and 12 months, respectively), tumor regression was achieved after additional cycles of intralesional IFNa2a. While intralesional IFNa2a represents a potential alternative to surgery or RT, its long-term efficacy remains to be determined. The efficacy of rituximab in other B-cell lymphomas has led to interest in its use for PCMZL.28,29 In a retrospective study of 5 PCMZL patients with multiple lesions who were treated with intravenous rituximab (375 mg/m2), 1 had a complete response and 2 had partial responses, with the remaining 2 patients with stable or progressive disease, respectively.28 In another study, intralesional rituximab yielded a complete response in 4 out of 5 patients with PCMZL.41 Likewise, chlorambucil is another systemic agent that has shown promise for treatment of disseminated lesions of PCMZL.9,13
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Table II. Recommendations for the treatment of primary cutaneous marginal zone lymphoma CBCL type and extent
Solitary/localized
Multifocal skin disease
Initial therapy
Secondary therapy
Local radiotherapy,1,2 excision,1,2 and antibiotics2* Select cases—observation,1 topical therapy (eg, steroids, imiquimod, nitrogen mustard, and bexarotene),1 and intralesional steroids1 Observation,1,2 intravenous rituximab,1,2 local radiotherapy,1,2 chlorambucil,2 antibiotics,2* topical therapy (eg, steroids, imiquimod, nitrogen mustard, and bexarotene),1 and intralesional steroids1
Observation,1 intralesional interferon-alfa,2 excision,1 intralesional rituximab,2 topical therapy (eg, steroids, imiquimod, nitrogen mustard, and bexarotene),1 intralesional steroids,1,2 and local radiotherapy1 Intralesional interferon-alfa,2 intravenous rituximab,1,2 topical steroids,2 intralesional steroids,2 chlorambucil with or without rituximab,1,2 and CVP with or without rituximab1,2 Select cases—CVP2
CBCL, Cutaneous B-cell lymphoma; CVP, cyclophosphamide, vincristine, and prednisone. *In patients with evidence of Borrelia burgdorferi infection.
Fig 8. Primary cutaneous marginal zone lymphoma. A, Pink papule on the arm. B, After 3 months of treatment with intralesional triamcinolone, 0.2 mL of 40 mg/mL once.
Given the possible association of PCMZL with Borrelia burgdorferi, there is also interest in the theoretical use of antibiotic therapy. B burgdorferi infection has been implicated in some cutaneous MALT lymphomas in subsets of patients in Europe,42-45 while others suggest that chronic immune stimulation can play a role in the pathogenesis of the PCMZLs.45 Research interests in a Borreliaelymphoma association and a role for antibiotics in treating CBCL stem from the correlation between acrodermatitis chronic atrophicans, a cutaneous manifestation of Lyme disease, and CBCL.45 It is also in this setting of chronic antigen stimulation that extranodal B-cell lymphomas,
in particular marginal zone lymphoma, can arise. Borrelia was identifiable in 10% to 42% of patients with cutaneous MALT lymphomas.45 However, these findings were not confirmed in other American, European, and Asiatic studies; the relevance of Borrelia infection in lymphoma pathogenesis is therefore controversial. While only a few cases of cutaneous MALT lymphoma respond to antibiotics, the EORTCCLG/ISCL consensus recommends attempting antibiotic therapy in Borrelia antibodyepositive cases of PCMZL before pursuing more aggressive strategies.1 Given the geographic variability in reported Borrelia-positive CBCL and questionable generalizability of this association, antibiotics are not advocated for CBCL treatment in the United States and there is no mention of their use in the NCCN guidelines.2 Very rarely, patients with PCMZL may develop disseminated skin lesions, requiring multiagent chemotherapy (eg, CHOP).1,2,4 In these cases, treatment approaches are similar to those of disseminated PCFCL.1,2,4
Primary cutaneous diffuse large B-cell lymphoma, leg-type Key points d PCDLBCL-LT has a poor prognosis, with high skin relapse rates and frequent early dissemination d RT alone or in combination with R-CHOP are first-line treatment for solitary, localized, or generalized disease d Clinical trials with investigational therapies hold promise in DLBCL PCDLBCL-LT carries a poor prognosis, with lower complete response rates to therapy, a greater number of relapses, a shorter time to progression, and more common extracutaneous spread.4,46,47 The
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Table III. Recommendations for the treatment of aggressive primary cutaneous B-cell lymphoma CBCL type and extent
Initial therapy
Secondary therapy
Solitary/localized
R-CHOP with local RT or local RT or clinical trial
Generalized
R-CHOP with or without local RT or clinical trial
R-CHOP (if not previously received) or RT to previously unirradiated tumor Local RT for palliation or radioimmunotherapy
CBCL, Cutaneous B-cell lymphoma; R-CHOP, cyclophosphamide, doxorubicin, onvocin/vincristine, and prednisone with rituximab; RT, radiotherapy.
Fig 9. Primary cutaneous diffuse large B-cell lymphoma, leg type. A, Diffuse faint purple plaques on leg. B, Response to rituximab after 375 mg/m2 weekly for 4 doses. C, Recurrence as purple nodules on the leg.
recommendations for the treatment of PCDLBCL-LT are shown in Table III. A large retrospective multicenter French study identified location on the leg as the main negative prognostic factor in PCDLBCL, followed by the presence of multiple skin lesions.47 Overall disease-specific survival was 53% at 3 years and 41% at 5 years. In this study, patients with leg tumors had a 3-year disease-specific survival of 43%, compared with 77% in patients with nonleg PCDLBCL-LT, confirming previous reports of the aggressive nature of these tumors.46,48 The 3-year disease specific survival rate was 39% in patients with multiple skin lesions compared to 77% in patients with only 1 lesion, and most patients with leg involvement had multiple tumors. In PCDLBCL-LT, deletions of the CDKN2A locus on chromosome 9p21.3 also correlate with an unfavorable prognosis.49 This disease often presents in the elderly, and therefore RT or RT and rituximab are often chosen for those with localized disease in whom the toxicities of combination chemotherapy are best
avoided1,50 (Fig 9). RT alone has been used palliatively in patients who cannot tolerate systemic chemotherapy. While response rates are high, the relapse rate was [58%, and 30% of patients developed extracutaneous disease.11,46 Rituximab alone induced an objective response rate of 75% in 8 cases of PCDLBCL-LT, with a 5.25-month median diseasefree survival.50 PCDLBCL-LT is usually best managed with multiagent modalities with or without RT. R-CHOP, with or without involved-field RT, is standard therapy for systemic DLBCL and, when feasible, is the preferred first-line treatment for PCDLBCL-LT.1 Grange et al47 compared different treatment cycles in 70 patients with PCDLBCL and found more favorable short-term outcomes in patients treated with rituximab and anthracycline-based multiagent chemotherapy compared with other therapies, including RT, monochemotherapy, or multiagent chemotherapy with rituximab.47 Among the 12 patients treated with rituximab and anthracycline-based multiagent, all but 1 (91.6%) achieved complete response in
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comparison to 62% in the group receiving other therapies.47 In this study, however, there was no statistical difference in overall 2-year survival. There also are reports of complete responses with R-CHOP in PCDLBCL-other, including spindle cell and intravascular large B-cell variants.51 However, clinical trials are needed to define the best approach to PCDLBCL-LT, because effective therapies are lacking. A recent phase II clinical trial of interferon gamma gene transfer with TG1042 showed local responses in the 2 cases of CBCL examined (1 disseminated PCMZL and 1 PDLBCL-LT), lending support for further developing this novel interferongamma gene transfer in CBCL.52 In addition, intralesional TG1042 was well tolerated and there were no significant changes in levels of other cytokines or inflammatory or autoimmune markers, suggesting that this approach is not associated with any significant generalized pathologic perturbation of the immune system.52 While many successful treatments are available for low-grade PCBL, the greatest need is for effective approaches to PCDLBCL-LT.2 Lenalidomide is an oral agent targeting CD 80 and CD40 that is used in the treatment of multiple myeloma. In a study of 26 DLBCL patients, a 20% response rate was observed.53 Aurora kinase inhibitors may prove useful in DLBCL through the effects on BCL-6.53 Ofatumumab (a fully humanized immunoglobulin G1 antibody that targets a unique epitope on the extracellular loop of CD20), lumilixumab (anti-CD23), and dacetuzumab (anti-CD40) are in clinical trials and may have future use in DLBCL-LT.54
CONCLUSION PCBCL represents a heterogeneous group of malignancies. Systemic progression is uncommon, and 5-year survival rates are excellent. Advances in molecular diagnostics have better defined the distinct subsets. Treatment considerations are based on clinical presentation and morphologic evaluation. Radiation is often the preferred therapy for solitary or localized grouped lesions. Surgical excision can be considered for small lesions. Immunologic and molecular genetic studies have contributed considerably to our understanding of the biology of PCBCL, refining our approach to the classification and management of these tumors. Clinical trials with investigational therapies hold promise in DLBCL. REFERENCES 1. Senff NJ, Noordijk EM, Kim YH, Bagot M, Berti E, Cerroni L, et al. European Organization for Research and Treatment of Cancer and International Society for Cutaneous Lymphoma consensus recommendations for the management of cutaneous B-cell lymphomas. Blood 2008;112:1600-9.
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2. Zelenetz AD, Abramson JS, Advani RH, Andreadis CB, Bartlett N, Bellam N, et al. Non-Hodgkin’s lymphomas. J Natl Compr Canc Netw 2011;9:484-560. 3. Senff NJ, Hoefnagel JJ, Neelis KJ, Vermeer MH, Noordijk EM, Willemze R. Results of radiotherapy in 153 primary cutaneous B-Cell lymphomas classified according to the WHO-EORTC classification. Arch Dermatol 2007;143:1520-6. 4. Zinzani PL, Quaglino P, Pimpinelli N, Berti E, Baliva G, Rupoli S, et al. Prognostic factors in primary cutaneous B-cell lymphoma: the Italian Study Group for Cutaneous Lymphomas. J Clin Oncol 2006;24:1376-82. 5. Willemze R, Jaffe ES, Burg G, Cerroni L, Berti E, Swerdlow SH, et al. WHO-EORTC classification for cutaneous lymphomas. Blood 2005;105:3768-85. 6. Willemze R, Swerdlow SH, Harris NL, Vergier B. Primary cutaneous follicle center lymphoma. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al, editors. WHO classification of tumors of hematopiryic and lymphoid tisues. Lyon: IARC Press; 2008. pp. 227-8. 7. Senff NJ, Hoefnagel JJ, Jansen PM, Vermeer MH, van Baarlen J, Blokx WA, et al. Reclassification of 300 primary cutaneous B-cell lymphomas according to the new WHO-EORTC classification for cutaneous lymphomas: comparison with previous classifications and identification of prognostic markers. J Clin Oncol 2007;25:1581-7. 8. Piccinno R, Caccialanza M, Berti E. Dermatologic radiotherapy of primary cutaneous follicle center cell lymphoma. Eur J Dermatol 2003;13:49-52. 9. Gulia A, Saggini A, Wiesner T, Fink-Puches R, Argenyi Z, Ferrara G, et al. Clinicopathologic features of early lesions of primary cutaneous follicle center lymphoma, diffuse type: implications for early diagnosis and treatment. J Am Acad Dermatol 2011;65:991-1000. 10. Pashtan I, Mauch PM, Chen YH, Dorfman DM, Silver B, Ng AK. Radiotherapy in the management of localized primary cutaneous B-cell lymphoma. Leuk Lymphoma 2013;54: 726-30. 11. Morris SL. Skin lymphoma. Clin Oncol 2012;24:371-85. 12. Parbhakar S, Cin AD. Primary cutaneous B-cell lymphoma: role of surgery. Can J Plast Surg 2011;19:e12-4. 13. Farkas A, Kemeny L, French LE, Dummer R. New and experimental skin-directed therapies for cutaneous lymphomas. Skin Pharmacol Physiol 2009;22:322-34. 14. Perry A, Vincent BJ, Parker SR. Intralesional corticosteroid therapy for primary cutaneous B-cell lymphoma. Br J Dermatol 2010;163:223-5. 15. Kutting B, Bonsmann G, Metze D, Luger TA, Cerroni L. Borrelia burgdorferieassociated primary cutaneous B cell lymphoma: complete clearing of skin lesions after antibiotic pulse therapy or intralesional injection of interferon alfa-2a. J Am Acad Dermatol 1997;36:311-4. 16. Rubegni P, De Aloe G, Pianigiani E, Lazzi S, Fimiani M. Primary cutaneous B-cell lymphoma: treatment with low dose intralesional recombinant interferon-alpha 2A. J Eur Acad Dermatol Venereol 1999;12:70-1. 17. Zenone T, Catimel G, Barbet N, Clavel M. Complete remission of a primary cutaneous B cell lymphoma treated with intralesional recombinant interferon alpha-2a. Eur J Cancer 1994;30A:246-7. 18. Hengge UR, Benninghoff B, Ruzicka T, Goos M. Topical immunomodulators—progress towards treating inflammation, infection, and cancer. Lancet Infect Dis 2001;1:189-98. 19. Coors EA, Schuler G, Von Den Driesch P. Topical imiquimod as treatment for different kinds of cutaneous lymphoma. Eur J Dermatol 2006;16:391-3.
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20. Richmond HM, Lozano A, Jones D, Duvic M. Primary cutaneous follicle center lymphoma associated with alopecia areata. Clin Lymphoma Myeloma 2008;8:121-4. 21. Molina A. A decade of rituximab: improving survival outcomes in non-Hodgkin’s lymphoma. Annu Rev Med 2008;59: 237-50. 22. Bello C, Sotomayor EM. Monoclonal antibodies for B-cell lymphomas: rituximab and beyond. Hematology Am Soc Hematol Educ Program 2007:233-42. 23. Selenko N, Maidic O, Draxier S, Berer A, J€ager U, Knapp W, et al. CD20 antibody (C2B8)-induced apoptosis of lymphoma cells promotes phagocytosis by dendritic cells and cross-priming of CD81 cytotoxic T cells. Leukemia 2001;15: 1619-26. 24. Coiffier B. Treatment of non-Hodgkin’s lymphoma: a look over the past decade. Clin Lymphoma Myeloma 2006;7(suppl 1):S7-13. 25. Marcus R, Imrie K, Belch A, Cunningham D, Flores E, Catalano J, et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 2005;105:1417-23. 26. Habermann TM, Weller EA, Morrison VA, Gascoyne RD, Cassileth PA, Cohn JB, et al. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol 2006;24:3121-7. 27. Maloney DG. Rituximab for follicular lymphoma. Curr Hematol Rep 2003;2:13-22. 28. Morales AV, Advani R, Horwitz SM, Riaz N, Reddy S, Hoppe RT, et al. Indolent primary cutaneous B-cell lymphoma: experience using systemic rituximab. J Am Acad Dermatol 2008;59:953-7. 29. Valencak J, Weihsengruber F, Rappersberger K, Trautinger F, Chott A, Streubel B, et al. Rituximab monotherapy for primary cutaneous B-cell lymphoma: response and follow-up in 16 patients. Ann Oncol 2009;20:326-30. 30. Pe~ nate Y, Hernandez-Machın B, Perez-Mendez LI, Santiago F, Rosales B, Servitje O, et al. Intralesional rituximab in the treatment of indolent primary cutaneous B-cell lymphomas: an epidemiological observational multicentre study. The Spanish Working Group on Cutaneous Lymphoma. Br J Dermatol 2010;67:174-9. 31. Fink-Puches R, Wolf IH, Zalaudek I, Kerl H, Cerroni L. Treatment of primary cutaneous B-cell lymphoma with rituximab. J Am Acad Dermatol 2005;52:847-53. 32. Sokol L, Naghashpour M, Glass LF. Primary cutaneous B-cell lymphomas: recent advances in diagnosis and management. Cancer Control 2012;19:236-44. 33. Maza S, Gellrich S, Sassaf C, Beyer M, Spilker L, Orawa H, et al. Yttrium-90 ibritumomab tiuxetan radioimmunotherapy in primary cutaneous B-cell lymphomas: first results of a prospective, monocentre study. Leuk Lymphoma 2008;49: 1702-9. 34. Dummer R, Dreyling M. Primary cutaneous lymphoma: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2008;19(suppl 2):ii72-6. 35. Dummer R, Hassel JC, Fellenberg F, Eichmuller S, Maier T, Slos P, et al. Adenovirus-mediated intralesional interferon-gamma gene transfer induces tumor regressions in cutaneous lymphomas. Blood 2004;104:1631-8. 36. Sharon V, Mecca PS, Steinherz PG, Trippett TM, Myskowski PL. Two pediatric cases of primary cutaneous B cell lymphoma and review of the literature. Pediatr Dermatol 2009;26:34-9. 37. Kennedy-Crispin M, Myskowski PL. Cryotherapy for primary cutaneous B-cell lymphoma. J Am Acad Dermatol 2012;67: e292-4.
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38. Hoefnagel JJ, Vermeer MH, Jansen PM, Heule F, van Voorst Vader PC, Sanders CJ, et al. Primary cutaneous marginal zone B-cell lymphoma: clinical and therapeutic features in 50 cases. Arch Dermatol 2005;141:1139-45. 39. Li C, Inagaki H, Kuo TT, Hu S, Okabe M, Eimoto T. Primary cutaneous marginal zone B-cell lymphoma. A molecular and clinicopathologic study of 24 Asian cases. Am J Surg Pathol 2003;27:1061-9. 40. Cozzio A, Kempf W, Schmid-Meyer R, Gilliet M, Michaelis S, Scharer L, et al. Intra-lesional low-dose interferon alpha2a therapy for primary cutaneous marginal zone B-cell lymphoma. Leuk Lymphoma 2006;47:865-9. 41. Kyrtsonis MC, Siakantaris MP, Kalpadakis C, Dimopoulou MN, Vassilakopoulos TP, Kontopidou FN, et al. Favorable outcome of primary cutaneous marginal zone lymphoma treated with intralesional rituximab. Eur J Haematol 2006;77:300-3. 42. Cerroni L, Zochling N, Putz B, Kerl H. Infection by Borrelia burgdorferi and cutaneous B-cell lymphoma. J Cutan Pathol 1997;24:457-61. 43. Goodlad JR, Davidson MM, Hollowood K, Ling C, MacKenzie C, Christie I, et al. Primary cutaneous B-cell lymphoma and Borrelia burgdorferi infection in patients from the Highlands of Scotland. Am J Surg Pathol 2000;24:1279-85. 44. Wood GS, Kamath NV, Guitart J, Heald P, Kohler S, Smoller BR, et al. Absence of Borrelia burgdorferi DNA in cutaneous B-cell lymphomas from the United States. J Cutan Pathol 2001;28:502-7. 45. Ferreri AJ, Ernberg I, Copie-Bergman C. Infectious agents and lymphoma development: molecular and clinical aspects. J Intern Med 2009;265:421-38. 46. Grange F, Bekkenk MW, Wechsler J, Meijer CJ, Cerroni L, Bernengo M, et al. Prognostic factors in primary cutaneous large B-cell lymphomas: a European multicenter study. J Clin Oncol 2001;19:3602-10. 47. Grange F, Beylot-Barry M, Courville P, Maubec E, Bagot M, Vergier B, et al. Primary cutaneous diffuse large B-cell lymphoma, leg type: clinicopathologic features and prognostic analysis in 60 cases. Arch Dermatol 2007;143:1144-50. 48. Vermeer MH, Geelen FA, van Haselen CW, van Voorst Vader PC, Geerts ML, van Vloten WA, et al. Primary cutaneous large B-cell lymphomas of the legs. A distinct type of cutaneous B-cell lymphoma with an intermediate prognosis. Dutch Cutaneous Lymphoma Working Group. Arch Dermatol 1996;132:1304-8. 49. Grange F, Petrella T, Beylot-Barry M, Joly P, D’Incan M, Delaunay M, et al. Bcl-2 protein expression is the strongest independent prognostic factor of survival in primary cutaneous large B-cell lymphomas. Blood 2004;103:3662-8. 50. Fenot M, Quereux G, Brocard A, Renaut JJ, Dreno B. Rituximab for primary cutaneous diffuse large B-cell lymphoma-leg type. Eur J Dermatol 2010;20:753-7. 51. Yun SJ, Lee KH, Yang DW, Lee JB, Kim SJ, Lee SC, et al. Primary cutaneous spindle cell B-cell lymphoma with multiple figurate erythema-like manifestation. J Cutan Pathol 2009;36:49-52. 52. Dummer R, Eichm€ uller S, Gellrich S, Assaf C, Dreno B, Schiller M, et al. Phase II clinical trial of intratumoral application of TG1042 (adenovirus-interferon-gamma) in patients with advanced cutaneous T-cell lymphomas and multilesional cutaneous B-cell lymphomas. Mol Ther 2010;18:1244-7. 53. Roschewski M, Dunleavy K, Wilson WH. Diffuse large B cell lymphoma: molecular targeted therapy. Int J Hematol 2012; 96:552-61. 54. Quintas-Cardama A, Wierda W, O’Brien S. Investigational immunotherapeutics for B-cell malignancies. J Clin Oncol 2010;28:884-92.
lymphomas and enlist the help of medical oncologists and radiation oncologists as indicated. Date of release: September 2013 Expiration date: September 2016 Ó 2013 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2013.06.011 Technical requirements: American Academy of Dermatology: d Supported browsers: FireFox (3 and higher), Google Chrome (5 and higher), Internet Explorer (7 and higher), Safari (5 and higher), Opera (10 and higher). d JavaScript needs to be enabled. Elsevier: Technical Requirements This website can be viewed on a PC or Mac. We recommend a minimum of: d PC: Windows NT, Windows 2000, Windows ME, or Windows XP d Mac: OS X d 128MB RAM d Processor speed of 500MHz or higher d 800x600 color monitor d Video or graphics card d Sound card and speakers Provider Contact Information: American Academy of Dermatology Phone: Toll-free: (866) 503-SKIN (7546); International: (847) 240-1280 Fax: (847) 240-1859 Mail: P.O. Box 4014; Schaumburg, IL 60168 Confidentiality Statement: American Academy of Dermatology: POLICY ON PRIVACY AND CONFIDENTIALITY Privacy Policy - The American Academy of Dermatology (the Academy) is committed to maintaining the privacy of the personal information of visitors to its sites. Our policies are designed to disclose the information collected and how it will be used. This policy applies solely to the information provided while visiting this website. The terms of the privacy policy do not govern personal information furnished through any means other than this website (such as by telephone or mail). E-mail Addresses and Other Personal Information - Personal information such as postal and e-mail address may be used internally for maintaining member records, marketing purposes, and alerting customers or members of additional services available. Phone numbers may also be used by the Academy when questions about products or services ordered arise. The Academy will not reveal any information about an individual user to third parties except to comply with applicable laws or valid legal processes. Cookies - A cookie is a small file stored on the site user’s computer or Web server and is used to aid Web navigation. Session cookies are temporary files created when a user signs in on the website or uses the personalized features (such as keeping track of items in the shopping cart). Session cookies are removed when a user logs off or when the browser is closed. Persistent cookies are permanent files and must be deleted manually. Tracking or other information collected from persistent cookies or any session cookie is used strictly for the user’s efficient navigation of the site. Links - This site may contain links to other sites. The Academy is not responsible for the privacy practices or the content of such websites. Children - This website is not designed or intended to attract children under the age of 13. The Academy does not collect personal information from anyone it knows is under the age of 13. Elsevier: http://www.elsevier.com/wps/find/privacypolicy.cws_home/privacypolicy
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The choice of therapy for primary cutaneous B-cell lymphoma (PCBCL) relies on correct histopathologic classification and the exclusion of systemic disease. In part II of this continuing medical education article, we will review the available therapies for the different types of PCBCL. Primary cutaneous follicle center lymphoma (PCFCL) and primary cutaneous marginal zone lymphoma (PCMZL) are indolent tumors with an excellent prognosis. They are managed similarly with local therapy, such as radiotherapy or surgical excision, for isolated disease and observation for asymptomatic multifocal presentations. Relapses are common in both PCFCL and PCMZL, but overall survival remains excellent. Primary cutaneous diffuse large B-cell lymphoma (both leg type and other) has a much poorer prognosis than indolent PCBCL, and it often requires an aggressive approach with radiation therapy and/or multiagent chemotherapy. Investigational approaches hold promise for the treatment of these malignancies, particularly primary cutaneous diffuse large B-cell lymphoma. ( J Am Acad Dermatol 2013;69:343.e1-11.) Key words: lymphoma; primary cutaneous B-cell lymphoma; primary cutaneous diffuse large B-cell lymphoma; primary cutaneous follicle center lymphoma; primary cutaneous marginal zone lymphoma; rituximab; therapy.
The choice of therapy for lymphoma, as determined CAPSULE SUMMARY primary cutaneous B-cell by a panel of experts, in lymphomas (PCBCLs) is limthe United States. Therapeutic approaches to primary ited by the rarity of these For the purpose of chooscutaneous B-cell lymphoma (PCBCL) tumors and the lack of proing therapy, PCBCLs may be range from localized therapies in spective, randomized studies divided into 2 types: indolent indolent types (primary cutaneous comparing existing and exand aggressive. Indolent tufollicle center lymphoma [PCFCL] and perimental therapies. Most mors include primary cutaneprimary cutaneous marginal zone data on the treatment of ous marginal zone lymphoma lymphoma [PCMZL]) to multiagent PCBCLs are limited to small (PCMZL) and primary cutanechemotherapy and immune-based retrospective studies. ous follicle cell lymphoma modalities in aggressive types (primary The European Organisation (PCFCL), while aggressive cutaneous diffuse large B-cell for Research and Treatment tumors include primary lymphomaeleg or other/nonleg type). of Cancer Cutaneous cutaneous diffuse large Lymphoma Group (EORTCB-cell lymphomaeleg type The treatment approach is further CLG) and the International (PCDLBCL-LT) and primary defined in the indolent PCBCLs by Society for Cutaneous cutaneous diffuse large B-cell whether or not the lesion is single and/or Lymphoma (ISCL) have delymphomaeother or nonleg limited to a single anatomic site. veloped uniform recommentype (PCDLBCL-non-LT). The Relapses are common in PCFCL and dations for the treatment of extent and size of nodules or PCMZL, but overall survival remains the 3 main types of PCBCL tumor lesions and the location excellent. based on the existing literaand anatomic site must also be Primary cutaneous diffuse large B-cell ture and good clinical pracconsidered when determining lymphoma carries a much poorer tice.1 Similarly, the National the ideal treatment approach.3 prognosis despite aggressive therapy. Comprehensive Cancer Network (NCCN) Guidelines THERAPY FOR on non-Hodgkin’s lymphoINDOLENT DISEASE mas includes consensus algorithms for the initial Primary cutaneous follicle center lymphoma treatment of PCBCL and secondary therapeutic Key points options in cases of refractory disease.2 The NCCN d If solitary or limited to a single site, first-line guidelines represent the most current and actreatment is radiation therapy or surgery, cepted practice for treatment of non-Hodgkin’s with curative intent d
d
d
d
From the Department of Dermatology,a New YorkePresbyterian Hospital/Weill Cornell Medical Center, the Dermatology Serviceb and Lymphoma Service,c Department of Medicine and the Department of Pathology,d Memorial Sloan-Kettering Cancer Center; and Weill Cornell Medical College,e New York. Funding sources: None. Conflicts of interest: None declared.
Reprints not available from the authors. Correspondence to: Patricia L. Myskowski, MD, Dermatology Service, Department of Medicine, Rockefeller Outpatient Pavilion, Memorial Sloan-Kettering Cancer Center, 160 E 53rd St, New York, NY 10022. E-mail: [email protected]. 0190-9622/$36.00
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Abbreviations used: CBCL: CHOP:
cutaneous B-cell lymphoma cyclophosphamide, doxorubicin, onvocin/vincristine, and prednisone DLBCL: diffuse large B-cell lymphoma EORTC-CLG: European Organisation for Research and Treatment of Cancer Cutaneous Lymphoma Group FISH: fluorescence in situ hybridization MALT: mucosa-associated lymphoid tissue NCCN: National Comprehensive Cancer Network PCBCL: primary cutaneous B-cell lymphoma PCDLBCL-LT: primary cutaneous diffuse large B-cell lymphoma, leg type PCFCL: primary cutaneous follicle center lymphoma PCMZL: primary cutaneous marginal zone lymphoma R-CHOP: cyclophosphamide, doxorubicin, onvocin/vincristine, and prednisone with rituximab
d
d
Skin recurrences are common after therapy, often outside of the treated site Patients with multiple lesions may be treated with observation, local therapy, radiation, topical agents, intralesional steroids, and even systemic therapy if clinically warranted
Untreated, the lesions of PCFCL may enlarge slowly, often over years. Lesions may also spontaneously regress (Fig 1). Regardless of the growth pattern—either follicular or diffuse—the 5-year survival rate of PCFCL is excellent (overall survival, 96.1% at 5 years and 88.8% at 10 years in 1 large study).4 Recurrences were common, but when confined to the skin do not appear to have an adverse effect on prognosis.4 Patients with PCFCL presenting with lesions on the legs may have higher rates of relapse and extracutaneous disease than patients without lesions on the legs.5-7 Other variables associated with shorter survival include age, female sex, and greater extent of skin lesions.4,6,7 PCFCL expressing Forkhead box protein P1 or arising on the leg may have a less favorable prognosis, and some advocate more aggressive treatment in these cases.1,7 Rarely, PCFCL may grow rapidly and extensively, and a repeat biopsy specimen should be obtained if the clinical behavior of a formerly indolent lymphoma changes. PCFCL may also undergo rapid clinical progression and histologic transformation to DLBCL (Fig 2), signaling more rapidly progressive disease and requiring more aggressive therapy. For patients with single lesions of PCFCL, curative therapy is a reasonable goal. Radiotherapy (RT) is an option, although the optimal dose and fractionation
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have not been established.1-4,8,9 The EORTC/ISCL recommendations for radiation therapy of PCFCL recommend a dose of at least 30 Gy with margin of 1 to 1.5 cm of clinically uninvolved skin.1 In the United Kingdom, the standard dose for low-grade non-Hodgkin’s lymphomas, including indolent cutaneous follicular lymphomas, is 24 Gy in 12 sessions.10,11 Data supporting the EORTC/ISCL recommendations comes from a few large studies.3,4,8,9 In 1 study, complete remission was achieved in 100% of PCFCL patients treated (n = 101) with a median dose of 40 Gy. Relapses occurred in 29 of 101 patients at a median of 12 months after initial treatment, and generally occurred outside of the irradiated area.3 While 40 Gy was the most frequent dosage used, doses as low as 30 Gy were reportedly effective.3 Solitary lesions of PCFCL on the scalp may be ideally suited for this approach (Fig 3), as may symptomatic lesions (Fig 4). Long-term side effects of RT include alopecia, radiation dermatitis, hyperpigmentation, atrophy, telangiectasia, and secondary skin cancers. Surgical excision is a reasonable option for single lesions of PCFCL.1,2 Nearly 90 patients have been treated with surgical excision in the literature.1,12 In a comparison of surgery versus RT for indolent PCBCL, 6 patients with PCFCL were treated with surgical excision with 5-mm margins and 7 PCFCL patients were treated with radiation therapy (median dose of 3000-4000 cGY, 10 fractions, for 6 weeks).12 One patient treated with radiation experienced a recurrence, whereas there were no recurrences in the surgery group. In addition, 2 patients in the radiation arm experienced chronic nonhealing ulcerations in the tumor area, and 2 patients experienced skin changes, such as erythema and edema. None of the patients in the surgical arm experienced local complications. Surgery appears to be an equally effective treatment option for PCBCL, while avoiding some local complications associated with radiation therapy.12 RT or surgery for localized disease may not be reasonable options in all patients. For example, surgical excision of PCFCL facial lesions might leave a scar after excision with the risk for disfigurement, while RT may be a better option. For large lesions, RT is a more practical approach than surgical resection. Conversely, lesions presenting at sites ill-suited for RT—such as the scalp, when hair loss is a significant cosmetic issue—may be better managed with other local means. A summary of the therapeutic options for PCFCL is shown in Table I. The NCCN guidelines for PCFCL also give consideration to topical therapies (eg, topical corticosteroids, topical nitrogen mustard, and topical
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Fig 1. Primary cutaneous follicle center lymphoma. A, Two asymptomatic pink lesions on either side of the lower back. B, Regression 1 year later.
Fig 2. Primary cutaneous follicle center lymphoma. New purple nodules on the anterior aspect of the lower leg. A biopsy specimen revealed transformation to primary cutaneous diffuse large B-cell lymphoma.
bexarotene) and intralesional steroids. Class I highpotency topical steroids are reported in the treatment of cutaneous lymphomas.2,13 We have used daily applications of topical clobetasol 0.05% cream with some success in selected, symptomatic patients (Fig 5). Intralesional corticosteroids, specifically triamcinolone (10-20 mg/mL), can also be useful in PCFCL.14 We have used intralesional corticosteroid injections to treat PCFCL in cosmetically sensitive
Fig 3. Primary cutaneous follicle center lymphoma. A, Red-purple nodules on the scalp. B, One year after radiation therapy to the scalp.
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Fig 4. Primary cutaneous follicle center lymphoma. A, Symptomatic (pruritic) purple-pink lesions on the upper aspect of the back. B, Resolution of lesions after radiation therapy.
Table I. Recommendations for the treatment of primary cutaneous follicle center lymphoma CBCL type and extent
Solitary/localized
Generalized skin disease
Initial therapy
Secondary therapy
Local radiotherapy1,2 and excision1,2 Select cases—observation,1 topical therapy (eg, steroids, imiquimod, nitrogen mustard, and bexarotene),1 and intralesional steroids1 Observation,1,2 intravenous rituximab,1,2 local radiotherapy,1,2 topical therapy (eg, steroids, imiquimod, nitrogen mustard, and bexarotene),1 and intralesional steroids1
Observation,1 intralesional interferon-alfa,2 excision,1 intralesional rituximab,2 topical therapy (eg, steroids, imiquimod, nitrogen mustard, and bexarotene),1 intralesional steroids,1 and local radiotherapy1 Chlorambucil with or without rituximab1 or CVP with or without rituximab1,2 Select cases—CVP2
CBCL, Cutaneous B-cell lymphoma; CVP, cyclophosphamide, vincristine, and prednisone.
areas on the face, where RT would have resulted in asymmetric hair loss in the beard area, and surgical excision would not have provided an equivalent result (Fig 6). We have also had success with cryotherapy as a treatment for localized disease. In 1 case of multiple small papules of PCFCL on the scalp, where RT would have resulted in unacceptable hair loss and surgical excision was not practical, we used liquid nitrogen in 2 freeze/thaw cycles of 20 seconds each with good local control (Fig 7). Because recurrence rates after initial treatment are high, alternative therapies currently pursued, and with promising outcomes, include immune-based modalities, such as rituximab, interferon, and imiquimod.13 There are a few cases in the literature of intralesional interferon-alfa (IFNa) for PCFCL, with
dosages varying from 1 million IU, 3 times per week to 6 million IU, 3 times a week for larger lesions.15-17 While responses rates were high, follow-up periods were short, limiting the conclusiveness of these studies regarding relapse rate or long-term efficacy. Imiquimod has also been used with mixed success in PCFCL.18 In 1 study, the effect of imiquimod seemed to be less potent for PCFCL than cutaneous T-cell lymphoma.19 In another report of PCFCL with simultaneous alopecia areata of the scalp, both lesions regressed with topical imiquimod and systemic steroids.20 Therefore, while imiquimod may be an additional treatment option in some cases of PCBCL, additional studies are needed. Rituximab is an anti-CD20 monoclonal antibody targeting CD20 antigens on the surface of both normal and malignant B cells.21 In vitro, lymphoma
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Fig 5. Primary cutaneous follicle center lymphoma. A, Violaceous nodules on the abdomen. B, Nodules on the abdomen after 4 months of topical clobetasol 0.05% cream daily.
cells undergo antibody-dependent, cell-mediated lysis when exposed to rituximab. In vivo, it induces antigen-specific T cell responses and sensitizes cells to the cytotoxic effects of chemotherapy.22,23 Relapsed or refractory B-cell lymphomas respond well to rituximab, and it is first-line therapy in combination with chemotherapy for low-grade and aggressive nodal B-cell lymphomas.24-27 There are reports of high response rates for PCBCL treated with rituximab.28,29 In a retrospective study of rituximab in indolent PCBCL, 10 patients with PCFCL received intravenous rituximab (375 mg/m2), with a 100% overall response rate (8/10 complete responses and 2 partial responses).28 Patients had either multiple lesions or scalp involvement. Median time to response, duration of response, and time to progression of treated patients with PCBCL was 30 days, 24 months, and 24 months, respectively. A similar study found a complete response in 100% of PCFCLs (n = 11).29 While limited by small sample sizes, these studies support rituximab as a reasonable treatment for indolent cutaneous B-cell lymphoma (CBCL) with multiple lesions, particularly where local treatment is not effective or desirable. Intravenous rituximab appears safe with relatively few side effects. Intralesional rituximab administration has also achieved favorable results but it requires a lower dose, offering a potentially more cost effective modality over the intravenous route with comparable efficacy.30-31
Fig 6. Primary cutaneous follicle center lymphoma. A, Purple plaque on the lateral aspect of the cheek. B, Lesion 6 months after intralesional triamcinolone, 0.15 mL of 10 mg/mL once.
In rare cases, patients with PCFCL may develop disseminated skin lesions or large tumors, and require chemotherapy (ie, cyclophosphamide, doxorubicin, onvocin/vincristine, and prednisone either without [CHOP] or with rituximab [R-CHOP]).1,32 Radioimmunotherapy also shows promise from early studies. A pilot study of yttrium-90 (90 Y) ibritumomab in 10 patients with relapsed PCBCL (PCFCL and PCLBCL-LT) gave complete response rates of 100% with a median time to relapse of 12 months.33 CBCL is also an appropriate target for intralesional injection with a genetically engineered virus.34 The interferon gammaeencoding adenoviral vector, TG1042, was successfully tested for in a phase I study that included 2 CBCL patients, with 1 PCFCL showing partial response.35
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Fig 7. Primary cutaneous follicle center lymphoma. A, Small pink papules on the scalp. B, Resolution of papules 6 months after cryotherapy with liquid nitrogen.
Primary cutaneous marginal zone lymphoma Key points d Localized and/or limited disease can be treated with RT or surgery with curative intent and, in some cases, antibiotics d Relapse rates after localized treatment of PCMZL may be higher than relapse rates seen in patients with PCFCL d Treatment for multifocal disease may include observation, RT, topical agents, and intralesional steroids, along with systemic immunomodulators or chemotherapeutics PCMZL is part of the group of extranodal marginal zone B-cell lymphomas involving mucosal sites, called mucosa-associated lymphoid tissue (MALT) lymphomas. In most cases, like PCFCL, it behaves as an extremely indolent tumor with a 5-year diseasespecific survival rate approaching 99%.5,32 Recommended treatment options, which are quite similar to PCFCL, are shown in Table II. RT is highly effective in cases of PCMZL with solitary or a few contiguous lesions and offers the
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potential for a cure. However, in 1 study of 153 patients with PCBCL, relapse rates were higher for PCMZL than PCFCL after this modality (5-year relapse-free survival, 45% vs 70%, respectively).3 RT doses are the same as those used for PCFCL.1-3 Primary surgical excision can also be effective for solitary and/or localized PCMZL. In 1 large study of 39 PCMZL patients treated with surgical excision, a complete response was achieved in 97.4% of patients, but 31.6% of patients developed recurrences. Radiation therapy gave 97.6% complete response rates in 83 PCMZL patients, with recurrence rates of 46.9%.4 In a smaller study of surgery versus radiation therapy for indolent PCBCL, 3 PCMZL patients had surgical excision with 5-mm margins and 7 PCMZL patients were treated with radiation therapy (median dose, 3000-4000 cGY, 10 fractions for 6 weeks).12 Both methods appeared to be equally effective. Topical therapies are frequently used in PCMZL. Topical class 1 corticosteroids, particularly clobetasol, have been used with success in PCMZL, both alone and in combination with systemic therapy.13,36-38 Complete responses have been reported with topical corticosteroids alone.13,38 Patients must be forewarned about hypopigmentation and possible atrophy. Topical nitrogen mustard,2,36 cryotherapy,37 and intralesional triamcinolone, at a wide range of dilutions (2.5-40 mg/mL; 0.5-12 mg per lesion),39 all have been used with success in PCMZL. We have observed similar results in our patients treated with intralesional steroids (Fig 8). Intralesional IFN is another alternative for localized indolent PCBCL disease. In a study of 8 patients with localized PCMZL, intralesional injections of 3 million units of recombinant IFNa2a, administered 3 times per week, resulted in complete tumor regression after a mean of 8.5 weeks.40 Of the 2 patients who relapsed (at 4 and 12 months, respectively), tumor regression was achieved after additional cycles of intralesional IFNa2a. While intralesional IFNa2a represents a potential alternative to surgery or RT, its long-term efficacy remains to be determined. The efficacy of rituximab in other B-cell lymphomas has led to interest in its use for PCMZL.28,29 In a retrospective study of 5 PCMZL patients with multiple lesions who were treated with intravenous rituximab (375 mg/m2), 1 had a complete response and 2 had partial responses, with the remaining 2 patients with stable or progressive disease, respectively.28 In another study, intralesional rituximab yielded a complete response in 4 out of 5 patients with PCMZL.41 Likewise, chlorambucil is another systemic agent that has shown promise for treatment of disseminated lesions of PCMZL.9,13
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Table II. Recommendations for the treatment of primary cutaneous marginal zone lymphoma CBCL type and extent
Solitary/localized
Multifocal skin disease
Initial therapy
Secondary therapy
Local radiotherapy,1,2 excision,1,2 and antibiotics2* Select cases—observation,1 topical therapy (eg, steroids, imiquimod, nitrogen mustard, and bexarotene),1 and intralesional steroids1 Observation,1,2 intravenous rituximab,1,2 local radiotherapy,1,2 chlorambucil,2 antibiotics,2* topical therapy (eg, steroids, imiquimod, nitrogen mustard, and bexarotene),1 and intralesional steroids1
Observation,1 intralesional interferon-alfa,2 excision,1 intralesional rituximab,2 topical therapy (eg, steroids, imiquimod, nitrogen mustard, and bexarotene),1 intralesional steroids,1,2 and local radiotherapy1 Intralesional interferon-alfa,2 intravenous rituximab,1,2 topical steroids,2 intralesional steroids,2 chlorambucil with or without rituximab,1,2 and CVP with or without rituximab1,2 Select cases—CVP2
CBCL, Cutaneous B-cell lymphoma; CVP, cyclophosphamide, vincristine, and prednisone. *In patients with evidence of Borrelia burgdorferi infection.
Fig 8. Primary cutaneous marginal zone lymphoma. A, Pink papule on the arm. B, After 3 months of treatment with intralesional triamcinolone, 0.2 mL of 40 mg/mL once.
Given the possible association of PCMZL with Borrelia burgdorferi, there is also interest in the theoretical use of antibiotic therapy. B burgdorferi infection has been implicated in some cutaneous MALT lymphomas in subsets of patients in Europe,42-45 while others suggest that chronic immune stimulation can play a role in the pathogenesis of the PCMZLs.45 Research interests in a Borreliaelymphoma association and a role for antibiotics in treating CBCL stem from the correlation between acrodermatitis chronic atrophicans, a cutaneous manifestation of Lyme disease, and CBCL.45 It is also in this setting of chronic antigen stimulation that extranodal B-cell lymphomas,
in particular marginal zone lymphoma, can arise. Borrelia was identifiable in 10% to 42% of patients with cutaneous MALT lymphomas.45 However, these findings were not confirmed in other American, European, and Asiatic studies; the relevance of Borrelia infection in lymphoma pathogenesis is therefore controversial. While only a few cases of cutaneous MALT lymphoma respond to antibiotics, the EORTCCLG/ISCL consensus recommends attempting antibiotic therapy in Borrelia antibodyepositive cases of PCMZL before pursuing more aggressive strategies.1 Given the geographic variability in reported Borrelia-positive CBCL and questionable generalizability of this association, antibiotics are not advocated for CBCL treatment in the United States and there is no mention of their use in the NCCN guidelines.2 Very rarely, patients with PCMZL may develop disseminated skin lesions, requiring multiagent chemotherapy (eg, CHOP).1,2,4 In these cases, treatment approaches are similar to those of disseminated PCFCL.1,2,4
Primary cutaneous diffuse large B-cell lymphoma, leg-type Key points d PCDLBCL-LT has a poor prognosis, with high skin relapse rates and frequent early dissemination d RT alone or in combination with R-CHOP are first-line treatment for solitary, localized, or generalized disease d Clinical trials with investigational therapies hold promise in DLBCL PCDLBCL-LT carries a poor prognosis, with lower complete response rates to therapy, a greater number of relapses, a shorter time to progression, and more common extracutaneous spread.4,46,47 The
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Table III. Recommendations for the treatment of aggressive primary cutaneous B-cell lymphoma CBCL type and extent
Initial therapy
Secondary therapy
Solitary/localized
R-CHOP with local RT or local RT or clinical trial
Generalized
R-CHOP with or without local RT or clinical trial
R-CHOP (if not previously received) or RT to previously unirradiated tumor Local RT for palliation or radioimmunotherapy
CBCL, Cutaneous B-cell lymphoma; R-CHOP, cyclophosphamide, doxorubicin, onvocin/vincristine, and prednisone with rituximab; RT, radiotherapy.
Fig 9. Primary cutaneous diffuse large B-cell lymphoma, leg type. A, Diffuse faint purple plaques on leg. B, Response to rituximab after 375 mg/m2 weekly for 4 doses. C, Recurrence as purple nodules on the leg.
recommendations for the treatment of PCDLBCL-LT are shown in Table III. A large retrospective multicenter French study identified location on the leg as the main negative prognostic factor in PCDLBCL, followed by the presence of multiple skin lesions.47 Overall disease-specific survival was 53% at 3 years and 41% at 5 years. In this study, patients with leg tumors had a 3-year disease-specific survival of 43%, compared with 77% in patients with nonleg PCDLBCL-LT, confirming previous reports of the aggressive nature of these tumors.46,48 The 3-year disease specific survival rate was 39% in patients with multiple skin lesions compared to 77% in patients with only 1 lesion, and most patients with leg involvement had multiple tumors. In PCDLBCL-LT, deletions of the CDKN2A locus on chromosome 9p21.3 also correlate with an unfavorable prognosis.49 This disease often presents in the elderly, and therefore RT or RT and rituximab are often chosen for those with localized disease in whom the toxicities of combination chemotherapy are best
avoided1,50 (Fig 9). RT alone has been used palliatively in patients who cannot tolerate systemic chemotherapy. While response rates are high, the relapse rate was [58%, and 30% of patients developed extracutaneous disease.11,46 Rituximab alone induced an objective response rate of 75% in 8 cases of PCDLBCL-LT, with a 5.25-month median diseasefree survival.50 PCDLBCL-LT is usually best managed with multiagent modalities with or without RT. R-CHOP, with or without involved-field RT, is standard therapy for systemic DLBCL and, when feasible, is the preferred first-line treatment for PCDLBCL-LT.1 Grange et al47 compared different treatment cycles in 70 patients with PCDLBCL and found more favorable short-term outcomes in patients treated with rituximab and anthracycline-based multiagent chemotherapy compared with other therapies, including RT, monochemotherapy, or multiagent chemotherapy with rituximab.47 Among the 12 patients treated with rituximab and anthracycline-based multiagent, all but 1 (91.6%) achieved complete response in
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comparison to 62% in the group receiving other therapies.47 In this study, however, there was no statistical difference in overall 2-year survival. There also are reports of complete responses with R-CHOP in PCDLBCL-other, including spindle cell and intravascular large B-cell variants.51 However, clinical trials are needed to define the best approach to PCDLBCL-LT, because effective therapies are lacking. A recent phase II clinical trial of interferon gamma gene transfer with TG1042 showed local responses in the 2 cases of CBCL examined (1 disseminated PCMZL and 1 PDLBCL-LT), lending support for further developing this novel interferongamma gene transfer in CBCL.52 In addition, intralesional TG1042 was well tolerated and there were no significant changes in levels of other cytokines or inflammatory or autoimmune markers, suggesting that this approach is not associated with any significant generalized pathologic perturbation of the immune system.52 While many successful treatments are available for low-grade PCBL, the greatest need is for effective approaches to PCDLBCL-LT.2 Lenalidomide is an oral agent targeting CD 80 and CD40 that is used in the treatment of multiple myeloma. In a study of 26 DLBCL patients, a 20% response rate was observed.53 Aurora kinase inhibitors may prove useful in DLBCL through the effects on BCL-6.53 Ofatumumab (a fully humanized immunoglobulin G1 antibody that targets a unique epitope on the extracellular loop of CD20), lumilixumab (anti-CD23), and dacetuzumab (anti-CD40) are in clinical trials and may have future use in DLBCL-LT.54
CONCLUSION PCBCL represents a heterogeneous group of malignancies. Systemic progression is uncommon, and 5-year survival rates are excellent. Advances in molecular diagnostics have better defined the distinct subsets. Treatment considerations are based on clinical presentation and morphologic evaluation. Radiation is often the preferred therapy for solitary or localized grouped lesions. Surgical excision can be considered for small lesions. Immunologic and molecular genetic studies have contributed considerably to our understanding of the biology of PCBCL, refining our approach to the classification and management of these tumors. Clinical trials with investigational therapies hold promise in DLBCL. REFERENCES 1. Senff NJ, Noordijk EM, Kim YH, Bagot M, Berti E, Cerroni L, et al. European Organization for Research and Treatment of Cancer and International Society for Cutaneous Lymphoma consensus recommendations for the management of cutaneous B-cell lymphomas. Blood 2008;112:1600-9.
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