Mycosis fungoides

Published on 19/03/2015 by admin

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Mycosis fungoides

Pierluigi Porcu and Henry K. Wong

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

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Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma (CTCL), a heterogeneous group of extranodal non-Hodgkin lymphomas (NHL) of the skin, which includes Sézary syndrome (SS) and CD30-positive lymphoproliferative disorders. The identity of the T-cell subset and the immune compartment (blood, skin, or lymph nodes) targeted by the transforming event in most CTCLs are not known; however, the tumor cell in MF is a mature, CD45RO+, CD4+, CLA+, skin-homing, memory T cell. Functional studies of this T-cell subset in patient samples have provided insight into the pathogenesis and clinical aspects of MF. Decreased production of IFN-γ and IL-12, upregulation of inhibitory molecules such as CTLA4 and PD1, and diminished T-cell immune repertoire, contribute to an increased risk of infections and of secondary malignancies. Selective skin trafficking, mediated by the chemokine receptors CCR4 and CCR10, makes the skin the dominant site of disease across all stages of MF, even though tumor cells are almost always present in the blood and the lymph nodes. Finally, in advanced stage MF, complex chromosomal abnormalities, unresponsiveness to growth-inhibitory signals, and defective apoptosis drive MF’s transformation into a highly aggressive malignancy.

MF accounts for 65–75% of all CTCL cases. MF usually presents in the sixth decade, but can affect all ages, and is more common in males and Blacks, where it may also have a more aggressive behavior. The age-adjusted incidence rates for CTCL in the US have ranged from 4 to 6.4/million person-years, but for 1998–2002 they were up to 9.6/million person-years. The current best estimate for the number of new MF cases in the US is about 3000 per year. Prevalence is much higher owing to the long survival.

Incidence of cutaneous T-cell lymphoma in the United States, 1973–2002.

Criscione VD, Weinstock MA. Arch Dermatol 2007; 143: 854–9.

These papers provide an updated view of the changing epidemiological landscape of cutaneous lymphoma (CL) in the US using the SEER database, a program of the National Cancer Institute (NCI) that collects cancer incidence and survival data from population-based registries covering approximately 28% of the US population. The incidence of CL has increased in the last decade, due in part to improved diagnosis. Inconsistencies in classification and diagnostic criteria remain a limitation in studies spanning several decades, but population-based studies are key to better understand these disorders. Incidence rates vary markedly by race and sex, supporting the notion that cutaneous lymphomas include distinct disease entities.

Diagnosis and staging

An effective treatment strategy depends on making an accurate diagnosis, which in early stage MF can be very challenging. The key diagnostic finding is epidermal invasion by atypical lymphoid cells with a convoluted ‘cerebriform’ nucleus, in the proper clinical context. The International Society for Cutaneous Lymphomas (ISCL) has developed consensus standards for diagnosis, grounded on clinical, pathologic, and immunophenotypic criteria. While not perfect, these criteria should be used to increase concordance in clinical practice. Often, multiple visits and skin biopsies are needed during the evolution of MF before the distinctive histologic features develop and the ISCL criteria are reached.

Once diagnosis is confirmed, determining the clinical stage is crucial. As in other malignancies, staging aims at defining the specific sites of involvement and the overall disease burden, drives the management strategy, and predicts outcomes. The current staging system for MF (and SS) is the product of a joint effort of the ISCL and the European Organisation for Research and Treatment of Cancer (EORTC). This system includes assessment of the peripheral blood compartment, hence TNMB. The ISCL/EORTC staging system requires the integration of clinical findings and laboratory assays, such as flow cytometry and T-cell receptor (TCR) gene rearrangement analysis. Based on this classification, for treatment decisions and discussion of survival, patients can be divided into ‘early stage’ (IA–IIA), or ‘advanced stage’ (IIB–IVB).

Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC).

Olsen E, Vonderheid E, Pimpinelli N, Willemze R, Kim Y, Knobler R, et al. Blood 2007; 110: 1713–22.

These two papers provide an updated consensus approach to the diagnosis of early stage MF and the clinical staging classification of MF/SS. The papers explicitly focus on MF/SS and exclude other types of CTCL and the cutaneous B-cell lymphomas (CBCLs), which are staged differently. A prospective, multi-institutional validation of the ISCL criteria was planned, but has not yet been completed. However, several retrospective studies of the applicability of these criteria have been published and they support the validity of the ISCL/EORTC classification across different patient populations. The two largest studies (Agar et al., Talpur et al.) are discussed below.

Natural history

MF is typically an indolent disease, with a slow and predictable progression, which can very often be inferred by the behavior and evolution of the lesions in the skin. While many patients with MF can be treated without systemic therapy, and enjoy a normal lifespan, a significant subset experiences incomplete clearance of skin lesions, progression to more advanced stages, and significant disease-specific morbidity and mortality. Long term outcome studies based on large patient populations are required to estimate true rates of disease relapse, progression, transformation, and survival.

Survival outcomes and prognostic factors in mycosis fungoides/Sézary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer staging proposal.

Agar NS, Wedgeworth E, Crichton S, Mitchell TJ, Cox M, Ferreira S, et al. J Clin Oncol 2010; 28: 4730–9.

This paper presents data on a multicenter cohort of 1502 CTCL patients observed over a 30-year period (1980–2009) and classified per ISCL/EORTC criteria. The large size of the cohort and the long term follow-up allowed a better estimate of rates of progression (34%) and disease-specific mortality (26%). These rates suggest that, in the long term, the morbidity and mortality of MF/SS may be greater than expected. In particular, the rate of progression in patients with stage IA and IB at 20 years may be higher than previously recognized (18% and 47%, respectively). Furthermore, a significant difference in survival and progression was noted for patients with early-stage disease having patches alone (T1a/T2a) compared with those having patches and plaques (T1b/T2b). Multivariate analysis also showed that advanced skin (T) stage, presence of the tumor clone in the blood (B0b), increased LDH, and folliculotropic MF were independent predictors of survival and progression.

Long-term outcomes of 1263 patients with mycosis fungoides and Sézary syndrome from 1982 to 2009.

Talpur R, Singh L, Daulat S, Liu P, Seyfer S, Trynosky T, et al. Clin Cancer Res 2012; 18: 5051–60.

Another recent large outcome study based on a cohort of 1263 MF/SS patients at the MD Anderson Cancer Center between 1982 and 2009. The mean age at diagnosis (~55 years) and the fraction of patients with early stage (~71%) was almost identical to the study by Agar et al. Rates of disease progression for early stage patients (12%), and disease-specific mortality for the entire cohort (8.1%) were lower than those observed by Agar et al. The median overall survival was ~24 years and the median progression-free survival was 16 years. Risk factors associated with progression or deaths were advanced age, plaque stage, LDH, and tumor area.

Second lymphomas and other malignant neoplasms in patients with mycosis fungoides and Sézary syndrome: evidence from population-based and clinical cohorts.

Huang KP, Weinstock MA, Clarke CA, McMillan A, Hoppe RT, Kim YH. Arch Dermatol 2007; 143: 45–50.

Patients with MF/SS have an increased risk of second malignancies. This study analyzed Stanford (1973–2001) and SEER-9 registry data (1984–2001), for a cumulative population of >2200 patients and estimated relative risk for various malignancies, excluding non-melanoma skin cancers. A higher relative risk for all malignancies was observed in the SEER-9 but not the Stanford cohort. However, in both cohorts there was a very significant increase in the risk of Hodgkin lymphoma. The risk of non-Hodgkin lymphoma was increased in the SEER-9 cohort. The cumulative incidence of second malignancies in the Stanford cohort was estimated to be 10% at 8.6 years. Therefore, updated SEER (population based) and Stanford (clinic based) data confirm earlier findings of increased risk of lymphoma in patients with MF/SS.

Management strategies

Patients with MF should ideally be managed by a multidisciplinary team including a dermatologist, a medical oncologist, a pathologist familiar with skin lymphoma, and a radiation oncologist. The availability of nursing staff with expertise in dealing with skin malignancies is also desirable. This approach minimizes the risk of management errors and has been shown to increase patient satisfaction. An initial consultation at a comprehensive cancer center with an experienced cutaneous lymphoma team should be strongly considered. Finally, optimal patient support and education are paramount for an effective treatment strategy in MF, and all new patients should be encouraged to contact patient advocacy organizations that provide those resources.

The objectives of treatment depend on the stage of the patient at diagnosis. For patients presenting with early stage MF (IA–IIA), the goals are to control symptoms, to clear all visible disease in the skin, to slow or prevent progression, and to minimize distress, costs, and side effects. Avoidance of therapies with immune suppressive effects is a key objective. In a few patients, this can be achieved with minimal topical therapy. In most patients, however, this will require a coordinated effort and a sequence of skin-directed treatments to induce, and then maintain, a response. Finally, in some patients this objective will only be achieved with combinations of skin-directed and systemic therapies.

With the many modalities now available for skin-directed and systemic therapy, there is often more than one option for disease management, and the strategy chosen for each individual patient may depend on the availability and accessibility of specific treatments. The goal is to initiate a treatment plan that the patient can adhere to reliably. Whether cure is achievable in early stage MF remains to be determined as the duration of complete clinical clearance in the skin varies and long term follow-up is often lacking. While occasional patients do not have recurrence of the disease after 5-10 years, or longer, in most cases the disease recurs. The lesions may reappear in the skin as patches or plaques and are often responsive again to skin-directed treatments. Re-institution of treatments that were previously effective is a wise and effective approach in early stage MF and is currently recommended by the National Comprehensive Center Network (NCCN).

For patients with advanced stage MF (IIB–IVB) the goal of therapy is to induce remission, avoid any further reduction of immune competence, and prevent infections. Inability to realize these goals is likely to result in disease progression, severe morbidity, and death. In these patients, treatment decisions are complex, and effective options for therapy are limited. Patients with SS are particularly challenging, due to drug resistance, intractable pruritus, greater risk of infections, and difficulty with venous access.

A look at the National Comprehensive Cancer Network guidelines for cutaneous lymphomas.

Porcu P. Clin Lymph Myelom Leuk 2010; 10(Suppl 2): S109–11.

These two articles stress the importance of a multidisciplinary approach in the management of MF/SS and the general strategy of gradual escalation of systemic therapy, starting with biologics, and leaving cytotoxic drugs for later. In addition, the strategy of ‘looping back’ is integral to the NCCN guidelines. Disease relapse or progression in MF/SS does not necessarily imply advancement to a higher stage (i.e., from T1 to T2, or T3). Rather, patients who start with T1 disease and achieve remission may relapse back to T1 disease. In that case, resuming the treatment initially adopted may be more appropriate (loop back), rather than switching to more aggressive therapies.

Specific investigations

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