Renaissance of Low-Dose Radiotherapy Concepts for Cutaneous Lymphomas

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1 Review Article DOI: / Received: February 06, 2017 Accepted: March 13, 2017 Published online: April 6, 2017 Renaissance of Low-Dose Radiotherapy Concepts for Cutaneous Lymphomas Bouthaina Dabaja Lymphoma Section, Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Keywords Lymphoma Radiation Cutaneous B-cell T-cell Summary Primary cutaneous B- and T-cell lymphomas are rare types of non-hodgkin s lymphoma with a unique presentation. This can make it challenging for clinicians to manage these cases, and quite often the management mirrors that of other commonly seen lymphomas. This document summarizes how to manage primary cutaneous lymphoma with specific focus on the role of ultralowdose radiation S. Karger GmbH, Freiburg bearing long-term toxicity in mind. On the other hand, patients with primary cutaneous B-cell lymphoma (PCBCL) enjoy long survival in the majority of cases and have equally good prospects for relapse rescue which can be offered through a variety of therapies including low-dose radiation. Based on the latter, the following questions may help clinicians to determine when to use radiation: i) Is it systemic or local disease? ii) Is radiation given to cure or palliate the disease? iii) What is the risk of the disease coming back in- or outside the field? iv) What is the expected overall outcome of the patient? Primary Cutaneous B-Cell Lymphomas Introduction Lymphoma presenting in the skin varies considerably in pathology, clinical presentation, and treatment strategy. There are 2 major pathologies that help to give clinicians general guidelines on how to approach the disease: T-cell and B-cell origin. To understand why low-dose radiation has become part of the treatment of each category, one must recognize the clinical and pathologic presentation. The overall outcome of cutaneous lymphoma, although completely different for B-cell versus T-cell origin, is the most defining factor determining the logic behind the use of radiation in the management. In brief, we will show in the following document that using lowdose radiation in cutaneous T-cell lymphoma is mainly due to the modest role played by radiation in this disease for which there is currently no cure, except perhaps for allogeneic transplant. Owing to recurrence, which is the norm with all treatment regimens including topical therapy, immunotherapy, phototherapy, radiation therapy, and chemotherapy, these patients have to be managed PCBCL are included as a separate entity in the non-hodgkin s lymphoma classification. They form roughly 20% of all primary cutaneous lymphomas [1]. In a joint effort by the World Health Organization (WHO) and the European Organization for Research and Treatment of Cancer (EORTC) [2], PCBCL have been divides into 5 subtypes: i) primary cutaneous marginal zone B-cell lymphoma (PCMZL); ii) primary cutaneous follicle center lymphoma (PCFCL); iii) primary cutaneous diffuse large B-cell lymphoma, leg-type (PCLBCL, LT); iv) primary cutaneous diffuse large B-cell lymphoma, other (PCLBCL, O); and v) intravascular large B-cell lymphoma (IVLBCL). Within the frame of this document, we will only address the first 2 entities where definitive low-dose radiation is indicated. Primary Cutaneous Marginal Zone B-Cell Lymphoma Histopathological Diagnosis Previously designated as primary cutaneous immunocytoma, PCMZL shows nodular to diffuse infiltrates of small to medium Fax Information@Karger.com S. Karger GmbH, Freiburg Accessible online at: Bouthaina Dabaja, MD Lymphoma Section, Department of Radiation Oncology, Unit 97 The University of Texas MD Anderson Cancer Center 1515 Holcombe Blvd, Houston, TX, 77030, USA bdabaja@mdanderson.org

2 a b c Fig. 1. Examples of patients with primary cutaneous marginal zone B-cell lymphoma (PCMZL) achieving complete remission after local radiation using 4 Gy. lymphocytes composing the marginal zone B-cells and spearing the epidermis while a reactive germinal center is frequently seen. Additionally, lymphoplasmacytic and plasma cells are mixed with reactive T-cells. [3]. The marginal zone B-cells express CD20, CD79, and bcl-2, and are typically negative for CD5, CD10, and bcl 6. Unlike in marginal zone lymphoma of the stomach, translocation t(18; 21) is rather rare. On the other hand, t(14; 18)(32; 21) and t(3; 14)(p14.1;q32) [4] can be observed in some cases. The disease has been reported to be linked to Borrelia burgdorferi infection and to develop in preexisting acrodermatitis chronica atrophicans or vaccination sites. Presentation and Treatment The majority of patients (72%) present with multiple lesions [5]. Lesions are painless, non-ulcerative, red to violaceous papules, plaques, or nodules (fig. 1 a,b; first panel) occurring mainly on the trunk or the extremities. This presentation can persist for many years. Recurrence most commonly occurs in the skin, and spontaneous resolution has been reported. The indolent clinical presentation, the possible resolution without therapy, and the rarity of extracutaneous relapses make local radiation an attractive treatment option. Complete remission, as reported in the literature, can reach 99% regardless of the radiation dose which ranges from 10 to 45 Gy [6]. Although the use of local radiation is entirely appropriate in many instances, management continues to include local resection or systemic therapy including aggressive multi-agent chemotherapy. Others have transitioned to using interferon, rituximab, or single-agent chlorambucil. The disease responds to all of the above treatments, which is an indication of how indolent the disease is rather than of how effective the treatment is. The lymphoma-specific survival is close to 100%, while the relapse-free survival for solitary lesions is 77% versus 39% for multifocal lesions [7]. This indicates that aggressive therapy does not improve the relapse rate, and relapse does not decrease survival. Hence, based on the aforementioned evidence, the most logical next step is to deliver the least toxic and most confined therapy, which in this case is low-dose radiation with doses as low as 4 Gy. This was recently shown in a small single-institution series looking at PCBCL. 39 patients with 42 lesions (including 16 with PCFCL) received radiation as the only treatment; all lesions achieved complete remission, no in-field relapse was seen, and 7/42 patients had an out-of-field relapsed. The authors showed that doses of 12 Gy (including 4 Gy) were equally effective as doses of > 12 Gy (fig. 1 a). It is worth noting that patients who relapsed in other sites could be treated effectively with another course of 4 Gy [8]. Below are 3 examples of patients with PCMZL achieving complete remission after local radiation using 4 Gy (fig. 1 a c). Of note, guidelines published by the National Comprehensive Cancer Network (NCCN), the International Society for Cutaneous Lymphoma, and the EORTC still recommend radiation doses of Gy. Due to the rarity of the disease, it is not possible to conduct randomized trials; therefore, we have to depend on common clinical sense and retrospective studies. Finally, it is key to know that when using low-dose radiation, a noticeable clinical response might not be seen before 4 8 weeks. In the above examples, most images showing complete remission were taken 12 weeks post treatment. Haas et al. [9] previously reported the use of 4 Gy in patients with recurrent indolent lymphoma including advanced stage, and the response assessment was also carried out at 4 6 weeks. It is speculated that the effect of radiation is mostly on the microenvironment rather than on the actual malignant cells, thus explaining the long time to response. Primary Cutaneous Follicle Center Lymphoma This is a tumor of neoplastic follicle center cells, which follows the same pattern as seen in PCMZL, with nodular or diffuse infiltrates sparing the epidermis. Originally doubted to be a separate entity and merged with PCMZL, PCFCL is now recognized as a separate disease in the WHO/EOTC classification. Tumor growth starts in a follicular pattern; however, over time and when lesions mature, the follicular pattern can be erased. At an early stage, the abnormal follicles are formed of cells that are CD20+, CD79a+, and bcl6+, in a network of CD21+ or CCD35+ follicular dendritic cells. These cells become more prominent with progression, while the T-cells decrease [10]. The key pathologic feature, which may make PCFCL mistakable for aggressive large B-cell lymphoma, is the presence, especially in the later stages, of a monotonous population of large follicle center cells. Tumors rarely 256 Dabaja

3 express t(14; 18) or bcl2. Having said that, others reported a higher recurrence rate for lesions located in the lower extremities, with the presence of bcl2 expression by more than 50% of cells indicating a worse prognosis. Presentation and Treatment With a presentation similar to that of PCMZL, these 2 entities are clinically difficult to differentiate. Lesions present as non-ulcerative plaques or nodules, most commonly on the scalp, forehead, or trunk, and may persist over several years. The treatment paradigm closely follows that of PCMZL. The rate of complete remission is near 100%, and the typical radiation doses are Gy [11]. Chemotherapy with single or combined agents, interferon, rituximab, intralesional therapy, and topical therapy have all been used and are all successful. As in PCMZL, radiation therapy can achieve complete remission in 100% of cases, with a relapse-free survival of 73 89%; the majority of patients can be salvaged with local radiation. Fig. 2. Erythema (left), progressing to different plaque lesions (right). Cutaneous T-Cell Lymphoma Primary cutaneous T-cell lymphoma (CTCL) has a variety of pathologic subtypes, with the most commonly encounter in the clinic being mycosis fungoides (MF), which represents two-thirds of CTCL, followed by primary cutaneous anaplastic large cell lymphoma (PALCL). Radiation therapy forms an important treatment modality in both subtypes. Presentation and treatment will be detailed below separately for each entity. Fig. 3. Tumor presentation can vary in terms of aggressiveness. Mycosis Fungoides MF is an indolent disease, and it might take many years or even decades before a formal diagnosis can be made. This is mainly owing to the fact that MF can mimic other conditions, and it can take multiple biopsies before a pathognomonic pathology is seen. Additionally, as it is a rare disease, dermatologists tend to confuse it with dermatitis, psoriasis, or lichenoid eruptions. Diagnosis will require the identification of a clonal T-cell population clustered at the basement membrane of the epidermis. Since clonal T-cells can also be found in other skin conditions, additional diagnostic tools are necessary. Typical immunophenotypes of T-cells include: loss of CD7, CD5, and CD2, dim CD3+, and mature clonal CD4+ and CD45RO+; the latter has a homing ability to the papillary dermis and epidermis, eventually leading to the typical epidermotropism [1]. As mentioned before, T-cell receptor clonality can be found in dermatoses and dermatitis; therefore, long follow-up and continuous observation for signs of MF are warranted in these cases. Presentation and clinical features are tightly related to the pathology. The homing to the skin is mediated by a surface glycoprotein cutaneous lymphoid antigen that is lacking in normal T-cells. The pruritus is related to the secretion of interleukin 5. The formation of epidermotropism and its loss at later stages of the disease are related to initially high and then low levels of interferon γ [12, 13]. Fig. 4. Bacterial infection mimicking mycosis fungoides. The clinical presentation mirrors the pathologic development; for example, changing from a patch to a tumor is the reflection of the loss of epidermotropism, where the lymphoid infiltration invades into the deeper reticular dermis and ultimately develops into a tumor. There are several variants of MF including folliculotropic MF, pagetoid reticulosis, and granulomatous slack skin. The role of radiation discussed below is independent of these variants. MF typically presents with patches, but eventually plaques and tumors with or without erythroderma will develop (fig. 2, 3). It is important to recognize that concomitant skin infections are frequently seen and should be suspected. This is thought to be due to a profound immunosuppression with aberrant T-cell repertoires, which increases the susceptibility to opportunistic infection (fig. 4) [13]. Low-Dose Radiotherapy for Cutaneous Lymphomas 257

4 Staging Staging depends on skin, blood, and internal organ involvement and follows a complicated system that helps clinicians to better identify a patient s stage and outcome [14]. Therefore, in addition to skin inspection and determining the involvement of the body surface area using the modified Severity-Weighted Assessment Tool (mswat), we need to evaluate the blood with flow cytometry, specifically to determine the CD4+/CD8+ ratio which when above 4.5/1 indicates a significant level of circulating T-cell lymphoma cells in the blood. Additionally, imaging should be performed along with a bone marrow biopsy to check for possible marrow or internal organ involvement. Within the frame of this document, we will concentrate on disease limited to the skin. The latter follows T stages where T1 and T2 are patches or plaques involving less than 10% of the skin, T3 is a tumor, and T4 is erythroderma. Principals of Treatment The clinical presentation will dictate the treatment goal and thus the radiation field and dose. To understand this correlation, it is important to keep in mind that this is an indolent and practically incurable disease, unless allogeneic transplant is considered. Consequently, these patients live for years or even decades with the disease, and with regard to treatment, long-term toxicity has to be critically considered. To formulate a kind of general guideline on this matter, clinicians are advised to understand what stage of disease the patient has and what the treatment goal is, and keep in mind that in most if not all cases radiation is not a curative modality. The same principal applies to non-radiation therapy options. Often, the initial therapy will be skin-directed and include steroids creams, topical chemotherapy, topical bexarotene gel, and phototherapy. Eventually other treatments are added including histone deacetylase inhibitors, denileukin diftitox, monoclonal antibodies, and in advanced cases cytotoxic chemotherapy. Both autologous and allogeneic transplantation have been used with reported improvements in outcome supporting the potential benefit of a graft versus lymphoma effect [16]. Radiation The choice between comprehensive total skin or local radiation depends on the percentage of skin involved. In general, an involvement of > 30% of body surface is considered time-consuming to treat with multiple electron fields, but most importantly, it is an indication that other lesions will soon appear elsewhere in the skin, thus indicating the need for a total and comprehensive way of addressing the skin. The current approach is to apply the lowest radiation dose that can induce complete remission regardless of whether total skin or local radiation is being used. The recently suggested total skin dose is Gy, as opposed to the historical dose of Gy. It is felt that this dose can offer overall control as high as 88% while having only mild and often reversible toxicities[17, 18]. Classical total skin doses of around 30 Gy are reserved for high-burden advanced disease or treatment prior to definitive therapy such as transplant. It is important to recognize that the radiation-induced response will take up to 8 weeks to emerge; in the meantime, clinicians should wait and give the lesions time to heal. Fig. 5. Severe fibrosis of the hand that would eventually lead to amputation. a b c d Fig. 6. Examples of local treatment with low radiation doses. Patients can present with few lesions that might need local radiation, and lower radiation doses as per the published data on total skin have made their way into the clinic. Although general guidelines still suggest using doses of Gy, it appears sensible to follow the same low-dose approach used for total skin. In clinical practice, a dose ranging from 4 to 12 Gy is capable of achieving local complete remission. The key is to wait long enough for the lesion/ulcer to diminish and the area to heal and return to normal. This process takes at least 4 weeks and in some cases up to 12 weeks. Along the same lines, when treating with local fields, only the area of interest should be included, with a margin that accounts only for the beam penumbra. The low radiation dose should not include unaffected areas since we can never cover or predict the next lesion. The use of ultralow radiation doses of as low as 4 Gy 258 Dabaja

5 Fig. 7. A patient who developed graft-versus-host disease in the skin after allogeneic transplant causing skin fibrosis. Fig. 9. Skin collimation to spare critical organs. a Fig. 8. Electron beam therapy: cm margin to account for electron beam penumbra. can potentially address this problem while causing little to no toxicity, and the treatment can be potentially repeated in the future. The wisdom behind lowering the radiation dose is to avoid excess radiation toxicity on skin that has been compromised by disease, infection, and previous treatment. Patients will live long enough to suffer the side effects of large radiation doses in years to come. Figure 5 shows a patient with severe fibrosis of the hand which would eventually lead to amputation. Figure 6 demonstrates several examples of local treatment with low radiation doses. Figure 7, although an extreme case, shows a patient who developed graft-versus-host disease in the skin after allogeneic transplantation causing skin fibrosis. In this case, using a low radiation dose is necessary to avoid further damage. Electron beam therapy is an appealing option in most cases. For clinical set up, drawing on the skin can be easily used. A cm margin is needed to account for the electron beam penumbra (fig. 8). Margins are measured from the edge of the skin lesion. To treat a patch or a plaque, 9 MeV energy is sufficient to capture most of the skin area at risk including the dermis. Higher energy levels should be used when treating tumors. Additionally, treatment planning computed tomography should be used when treating an area where an organ at risk such as the salivary glands must be avoided. An alternative option for critical organs is to use skin collimation (fig. 9). The latter will produce a shaper penumbra and avoid critical organs by reducing the margin needed. b c Fig. 10. Primary anaplastic large cell lymphoma (PALCL). Primary Anaplastic Large Cell Lymphoma The primary site of involvement with this disease is the skin, and it can present along with MF in the same patient. PALCL has a distinct clinical presentation with deeper involvement of the skin and quite often associated ulcerative lesions (fig. 10 a, b). Low-Dose Radiotherapy for Cutaneous Lymphomas 259

6 Diagnosis can be challenging: the main mark of the disease is the presence of large cells with strong CD30 expression. This quite often is confused with large cell transformation; however, the clinical presentation should guide clinicians towards recognizing the disease. Contrary to systemic anaplastic large cell lymphoma, anaplastic lymphoma kinase (ALK) positivity is found in 70 80% of cases. In some cases, chromosomal translocation t(2; 5) can be found. The radiation dose has classically followed an aggressive pattern, the reason being that these lesions are tricky and look aggressive and ulcerative and the pathology includes large cells. However, in reality, the lesions respond to radiation doses as low as 6 Gy, but clinicians will need to wait long enough for lesions to heal and ulcers to close, which can take a long time. Support for low radiation doses comes from a multi-institutional study done by the International Lymphoma Radiation Oncology Group (ILROG), which showed that complete response of local tumors was achieved independently of the radiation dose [19]. Below is an example of the treatment of a patients with PALCL using a low radiation dose (fig. 10 b, c). In summary, the use of radiation in the treatment of MF and PALCL is effective even when applying ultralow doses. It represents an approach with minimal side effects that can be repeated multiple times and offers a readily effective option for these patients who can survive for long a time and may be exposed to countless different types of therapy along with the associated toxicity. Disclosure Statement The author did not provide a disclosure statement. References 1 Willemze R, Jaffe ES, Burg G, et al.: WHO-EORTC classification for cutaneous lymphomas. 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