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Management strategies for mycosis fungoides in India

Mycosis fungoides is the most common primary cutaneous T-cell lymphoma. The approach to diagnosis and further follow-up is outlined. Evidence for interventions is based classically on a Tumor Node Metastasis Blood TNMB “stage-based” approach. The treatment options in India are limited. The options as per risk stratification and prognostic index are discussed. Early stages and low-risk patients can be managed with expectant policy or skin-directed therapies including topical steroids and phototherapy; intermediate-risk patients can be opted for interferons or retinoids or low dose methotrexate along with radiotherapy including total skin electron beam therapy while high-risk patients are managed most often with single agent or multiagent palliative chemotherapy. Patients who are intermediate- or high-risk need management by a multispecialty team at tertiary care centers.


Introduction
Primary cutaneous lymphomas are rare extranodal lymphomas defined by specific clinicopathologic features, [1] the most common being mycosis fungoides (MF). [2] The National Comprehensive Cancer Network, [3] the European Organization for Research and Treatment of Cancer (EORTC), [4] European Society for Medical Oncology, [5] and the Japanese Skin Cancer Society -Lymphoma Study Group [6] have guidelines for management, but the rarity of patients in the Indian setting and unavailability of specific drugs make treatment not standardized in the absence of resources. There is also a paucity of data globally on randomized controlled trials in available options for therapy.
The management approach is often multidisciplinary though the initial presentation is most commonly to a dermatologist. Two-thirds of all cutaneous lymphomas are MF [7] in India, so we shall restrict to the management of this particular condition only.
In this article, we discuss the approach, investigations, and treatment options available as of now in India [ Table 1].

Diagnosis
The diagnosis of MF is based on set clinicopathologic criteria. Consensus approach of early-stage MF has been proposed by the International Society of Cutaneous Lymphoma (ISCL), [1] and an updated staging system proposed by the ISCL/EORTC [8] has been adopted by the American Joint Committee on Cancer.
A majority of patients present with clinical Stage IA-IB without palpable lymphadenopathy, and their investigative work-up is limited. [2] Nevertheless, about 25% can have progressive disease. [9] The management is stage based, and the prognosis varies greatly in low-risk (Stage 1A), intermediate-risk (Stage 1B-2A) and high-risk cases (Stage 2B-4B). [9][10][11][12][13][14][15] An algorithmic stage-based management strategy for available options is demonstrated [ Figure 1]. However, there are factors besides the TNMB stages that can be important for prognosis and choice of therapy. [11] Large cell transformation (LCT) can occur in early or late MF. [14] This is one of the reasons for follow-up biopsies and a definitive indication for biopsies in sudden clinical progression. The presence of CD30+ is not necessarily LCT. LCT is defined as the presence of large cells (≥4 times the size of a small lymphocyte) in >25% of the infiltrate or these large cells forming microscopic nodules. [16] LCT marks an aggressive disease and sometimes, resistance to chemotherapy. [14] Palliative radiotherapy is an option in these patients.
An objective way of clinical assessment can be done by the modified severity weighted assessment score (Cutaneous Lymphoma Resource Tools app). [17] A prognostic index can be thereafter used to assess risk and prognosticate survival [ Table 2].

Low risk
Patch stage MF with <10% BSA involvement poses a low risk. Hypopigmented MF in adolescents is a classic example. The risk of progression is so low that a school of thought exists to club these as hypopigmented dermatosis and manage them with no active intervention and only clinical follow-up. [18] Few patch stage lesions can be managed with topical mid-potent steroids with or without phototherapy such as narrow band ultraviolet B (UVB) or psoralen plus ultraviolet A (PUVA) or PUVAsol in India. These patients form a majority, especially in children and young adults who are diagnosed with MF. [19] Hypopigmented MF which needs to be differentiated from vitiligo can be treated on similar lines of management with remission that lead to delayed diagnosis since both respond excellently to topical steroids and phototherapy. [20] A single patch/plaque, although rare, can be subjected to radiotherapy with expected complete response of up to 100%. [21] Intermediate risk These situations warrant multiple skin-directed and systemic treatment interventions. [22] Maintenance   systemic treatment may be necessary in early-stage disease if there is no sustained response to skin-directed treatment. [23] UVA induces better response rates compared to UVB in plaque stage disease, with complete remissions reported up to 58% in patch stage disease. [21,24] However, although PUVA phototherapy is effective, durable complete responses are rare. There is a theoretical risk of skin cancers such as squamous cell carcinoma if the total lifetime cumulative UVA dose should exceed 1000 J/cm 2 or 250 sessions. [25] There have been no reports from India of PUVA-induced malignancy in this subset of patients. UVB phototherapy has a better safety profile than PUVA and should be preferred in patients with predominant patches. PUVA would be an alternative if there is a suboptimal response or patients with extensive thick plaques. [26] The combination of PUVA and interferon-alpha (IFN-α) or bexarotene has been studied. [27,28] Since bexarotene is not available in India, combination with acitretin has been tried with variable results. [29] Our center experience (unpublished data) shows a partial response rate of 70% but not durable with UVA combined with acitretin.
Bexarotene and IFN-α have reported comparable results. [30] IFNs given daily or thrice weekly at 3-9 million unit should only be considered as a second-line therapy for early-stage disease. While pegylated IFN-α has a more convenient weekly dosing, the efficacy might be the same. [27] Low-dose methotrexate (MTX) can be a choice for patients with early stages of MF if disease is resistant to skin-directed therapies. Doses can range between 25 and 75 mg/week. Complete remission rates are as low as 12% with a median of 15 months for treatment failure in reported data. [31] Low-dose MTX has also been successfully combined with IFN-α. [32] Cutaneous lymphomas are extremely radiosensitive. Therefore, radiotherapy is a preferred palliative option for MF, especially for sanctuary sites resistant to phototherapy. [21,22,33] In most instances, the target volume is the epidermis and/or dermis, except those with tumors or deep ulcers. Hence, lesions can be treated with soft (low penetrance) beam-superficial radiograph therapy (50-145 peak kV) or 4-9 MeV electron beams. For thicker lesions, higher energy of radiotherapy can be opted.
Total skin electron beam (TSEB) therapy is an excellent treatment option for MF with a high rate of complete remissions. In TSEB therapy, the patient is exposed to either multiple field arrangements or a rotational technique (Stanford technique), with "patching" or "boosting" for areas of underdosing and self-shielding (e.g., soles of feet and perineum). The full dose regimen takes 6-10 weeks to complete. This option of management is available at selected centers in India allowing patients to benefit from TSEB.
Although with low-dose TSEB, the CR rates are lower; this choice of therapy is better because repeat courses are better tolerated and can provide excellent palliation. Follow-up treatment in intervals can be with PUVA +/− interferons/acitretin. [4,22,24] High risk These patients present with erythroderma and blood or nodal involvement. Erythrodermic MF is encountered in practice, but its leukemic variant, Sezary syndrome is somehow yet to be reported from India.
The majority of these patients are managed by hemato-oncologists rather than dermatologists since the options are mostly chemotherapy and rarely, allogeneic stem cell transplantation. Patient age, presence of lymph node disease, and peripheral blood involvement are the most essential poor prognostic markers in advanced stages, especially those with erythroderma or tumor development in the background of erythroderma. [2,4,22,24] Many centers across the world prefer immunobiologic therapy, but extracorporeal photopheresis is not available. Newer targeted biologics such as alemtuzumab or mogamulizumab have also not been available. [34,35] Single-agent chemotherapy regimens, such as liposomal doxorubicin and gemcitabine, are offered at our centers. The responses are short lived but can provide clinical relief. Single-agent low-dose oral MTX and chlorambucil are other palliative options, the former being drug most Indian dermatologists are well versed with using. Although TSEB is not very effective in erythrodermic MF, it can be used with palliative intent.
Although systemic multiagent chemotherapy is opted in advanced disease, studies demonstrate no survival benefit over "conservative" sequential therapy. [36] However, after multiagent chemotherapy, these patients can be treated with skin-directed therapies since they are mostly left with cutaneous patches and plaques.
The choice thus depends on patient factors, the disease aggressiveness, and the risks of myelosuppression with the drugs being used. Drugs include alkylating agents (cyclophosphamide and chlorambucil), anthracyclines, etoposide, and purine analogs. There is no multiagent chemotherapy regimen that has been found superior though cyclophosphamide, doxorubicin, vincristine, and prednisolone has been traditionally used.
Allogeneic transplantation in patients with advanced-stage MF can be considered as consolidation once complete or partial remission is achieved with discussed options. [37] Conclusion Patients need to have a confirmed diagnosis, workup for therapy, and prognostication. MF is an indolent disease in its early stages, but 25% can progress. Hence, if there is any suspicion of transformation, resistance to therapy, or intermediate or high risk, these patients should be referred to appropriate centers with multidisciplinary teams comprising dermatologists, hemato-oncologists, radiotherapists, and allied specialists to manage. The choice of therapy should finally depend on variables as discussed with minimal toxicities, even if they result in partial remission. Further studies into biology and availability of newer and targeted drugs will enable physicians in India to treat their patients with MF better.

Financial support and sponsorship
Nil.

Conflicts of interest
There are no conflicts of interest.

What is new?
• Risk based approach practical over TNMB alone. • Therapeutic options including TSEB are vital for patients in India who have limited access to newer drugs. • Need for a national registry for epidemiological data for MF.