Phototherapy of mycosis fungoides

R E V I E W

Phototherapy of mycosis fungoidesFranz Trautinger1,2

1Karl Landsteiner Institute for Dermatological Research, St. Polten, Austria, and 2Department of Dermatology and Venereology,Landesklinikum St. Polten, Austria

Key words:cutaneous T-cell lymphomas; mycosis

fungoides; narrowband UVB; PUVA

Correspondence:Franz Trautinger, Department of Dermatology and

Venereology, Landesklinikum St. Polten, Propst-

Fuehrer-Strasse, St Polten A-3100, Austria

Tel: 143 2742 300 11909

Fax: 143 2742 300 11919

e-mail: [email protected]

Accepted for publication:20 October 2010

Conflicts of interest:None declared.

Summary

Background/purpose: Among the primary cutaneous T-cell lymphomas, mycosis fungoides (MF)

is the most common disease entity. Recently, an improved understanding of the pathology,

clinical presentation, and prognosis of MF has lead to the development of new and practically

useful classification and staging systems. In most patients, MF presents with patches and plaques

and remains confined to the skin for years and decades, making it an ideal target for

phototherapy. However, treatment schedules vary widely and this review describes the current

knowledge about phototherapy of MF focusing mainly on narrow- and broadband UVB and

8-methoxypsoralen plus UVA, its indications, practical aspects, and clinical outcome.

Methods: Review and summary of the pertinent literature.

Results and conclusions: Since 1976, when the first report on phototherapy for MF was published,

sufficient evidence has accumulated to make narrowband UVB and PUVA safe and effective

treatment options for early stages of the disease. In refractory cases or more advanced stages,

combination of phototherapy with systemic treatments including mainly interferons and

retinoids might be valuable. Additional research is required to further define the optimal

treatment schedules and the role of maintenance.

Mycosis fungoides (MF): epidemiology,classification, staging, and prognosis

Cutaneous T-cell lymphomas (CTCL) are a heterogenous group

of non-Hodgkin lymphomas (NHL), which are characterized by

their initial presentation in the skin. As with other NHL, major

progress has been made recently with the development of

classification systems that aim to define disease entities based on

pathology, clinical presentation, and prognosis (1, 2). MF (MF)

is the most common form (about 65%) of CTCL. Its age-adjusted

incidence rate in the United States has been recently estimated to

be 4.1/1 000 000 with a male predominance (1, 3, 4). Sezary

syndrome (SS) – although usually mentioned together with MF –

is a separate entity according to the European Organization

for the Research and Treatment of Cancer (EORTC)-WHO

classifications (1, 2). SS is exceedingly rare (4% of CTCL) and –

although sharing histopathological features – has a different

clinical presentation and a worse prognosis than MF (1, 5). SS

will not be mentioned here in more detail since skin-directed

therapies (SDT) – if at all – play a minor role in its treatment.

Histopathologically, MF is characterized by an epidermotropic

infiltrate of small- to medium-sized T lymphocytes with cerebri-

form nuclei. Typically, the lymphocytes display the immunopheno-

type of mature memory T-cells (CD31, CD41, CD45RO1, CD8� )

and clonal rearrangement of the T-cell receptor gene is detectable in

most cases. Clinically, the disease presents with erythematous,

sometimes poikilodermatous and scaly patches and plaques with

an occasional itch (1, 6). MF has an indolent and chronic clini-

cal course characterized by episodes of treatment-associated

remissions and subsequent relapses. In patients with early stages

(stages T1–2, N0–2, M0, B0, 1 are usually described as early stages

in the literature, see Table 1), life expectancy is not significantly

different from age-matched controls. Progression to extracutaneous

involvement is estimated to occur in up to 30% of patients and is

associated with a poor prognosis (5). There is insufficient evidence

to date to conclude that the natural course of the disease could be

modified by any type of therapy (with the exception of

hematopoietic cell transplantation in selected patients) and thus

palliation is the major goal of treatment (7, 8). Consequently,

‘expectant policy’ including careful observation without active

treatment is considered a valid option for some patients with early

disease stages (8).

The first staging system for MF has been published in 1979 by

Bunn and Lamberg (9). Although never formally validated this

system proved to be clinically useful and until recently remained

the standard for clinical studies and patient care. Based on

advances in our knowledge and understanding of the pathology,

molecular biology, classification, and clinical course of the disease,

a modified staging system was proposed by the International

Society for Cutaneous Lymphomas and the Cutaneous Lymphoma

Task Force of the EORTC (Tables 1 and 2) (10). Recently, this

system has been validated in a cohort of 1502 patients from the

United Kingdom (5).

r 2011 John Wiley & Sons A/S � Photodermatology, Photoimmunology & Photomedicine 27, 68–7468

mailto:[email protected]

The role of phototherapy in the managementof MF

There is a lack of randomized clinical trials in MF and thus the

choice of treatment is often determined by availability, experience,

and preference of both, physician and patient. Recently, however,

treatment recommendations and reviews have been published

that try to summarize the available evidence and provide a more

rational approach to the management of MF (8, 11–13). Based on

these publications and on the results of an early seminal study, it is

now commonly accepted that early-stage MF should be initially

treated with SDT (14). Systemic and more aggressive treatments

should be reserved for higher stages (ZIIB), progression, or lack of

appropriate responses. Irrespective of disease stage and type of

treatment, maintenance of quality of life should be at the center of

therapeutic strategies. SDT that have shown clinical efficacy in MF

include topical corticosteroids, topical chemotherapy (nitrogen

mustard, carmustine), topical bexaroten (not available in Europe),

radiotherapy (total skin electron beam, superficial X-irradiation),

and phototherapy (8).

Remarkably, MF (together with other types of CTCL) is the only

malignant disease that is treated with ultraviolet (UV) radiation, the

major environmental skin carcinogen. The role of UV in the

pathogenesis of MF is unclear. On the one hand, epidemiologic

studies indicate that exposure to UV is associated with a decreased

risk for the development of NHL without allowing for a reliable

conclusion regarding NHL subtypes, including MF (15, 16). On

the other hand, McGregor et al. (17) have described UV-specific

p53 mutations in advanced MF, pointing to a role for ultraviolet B

(UVB) in the pathogenesis and progression of MF.

The first publication on phototherapy for MF appeared in 1976

when Gilchrest et al. (18) reported on the treatment of nine patients

with 8-methoxypsoralen plus UVA (PUVA) . All patients responded

favorably and complete remission was achieved in four patients.

Through shielding of one arm during the initial treatment phase,

the authors clearly demonstrated the specific efficacy of the

treatment and the absence of a relevant systemic effect of PUVA.

Since then, new light sources and treatment modalities have been

developed, and in addition to PUVA, standard phototherapy

options for MF now include narrow- and broadband UVB.

Extracorporeal photochemotherapy (photopheresis, ECP) has been

developed for the treatment of SS and MF with erythroderma (19).

During ECP, the patients’ peripheral blood leukocytes are exposed

Table 1. Tumor-node-metastasis-blood (TNMB) staging as proposed by the ISCL/EORTC (10)

Skin

T1 Limited patches, papules, and/or plaques covering o 10% of skin surfaceT2 Patches, papules, and/or plaques covering Z10% of skin surface

T3 One or more tumors (Z1 cm in diameter)

T4 Confluence of erythema covering Z80% body surface area

Node�

N0 No clinically abnormal peripheral lymph nodes, biopsy not required

N1a Clinically abnormal peripheral lymph nodes, histopathology: dermatopathic lymphadenopathy, clone negative

N1b Clinically abnormal peripheral lymph nodes, histopathology: dermatopathic lymphadenopathy, clone positive

N2a Clinically abnormal peripheral lymph nodes, histopathology: early involvement of MF, clone negativeN2b Clinically abnormal peripheral lymph nodes, histopathology: early involvement of MF, clone positive

N3 Clinically abnormal peripheral lymph nodes, histopathology: partial or complete effacement of lymph node architecture

Nx Clinically abnormal peripheral lymph nodes, no histologic confirmationVisceral

M0 No visceral organ involvement

M1 Visceral involvement

BloodB0a Absence of significant blood involvement, clone negative

B0b Absence of significant blood involvement, clone positive

B1a Low tumor burden: 4 5% of peripheral blood lymphocytes are atypical cells but does not meet the criteria of B2, clone negative

B1b Low blood tumor burden: 4 5% of peripheral blood lymphocytes are atypical cells but does not meet the criteria of B2, clone positiveB2 High blood tumor burden: � 1000/ml Sezary cells with positive clone

�For details on histopathological classification of lymph nodes in MF, see (73, 74).

ISCL, International Society for Cutaneous Lymphomas; EORTC, European Organization for the Research and Treatment of Cancer; MF, mycosis

fungoides.

Table 2. Staging classification based on the updated tumor-node-metastasis-blood (TNMB) staging as proposed by the ISCL/EORTC (10)

T N M B

IA 1 0 0 0, 1

IB 2 0 0 0, 1II 1.2 1.2 0 0, 1

IIB 3 0–2 0 0.1

III 4 0–2 0 0, 1

IIIA 4 0–2 0 0IIIB 4 0–2 0 1

IVA1 1–4 0–2 0 2

IVA2 1–4 3 0 0–2

IVB 1–4 0–3 1 0–2

ISCL, International Society for Cutaneous Lymphomas; EORTC,

European Organization for the Research and Treatment of Cancer.

69r 2011 John Wiley & Sons A/S � Photodermatology, Photoimmunology & Photomedicine 27, 68–74

Phototherapy of mycosis fungoides

to 8-methoxypsoralen and UVA. Comprehensive reviews on ECP

have been published recently and the treatment will not be covered

here (20, 21). Other modalities where only small case series have

been published to date include photodynamic therapy, excimer

laser, and UVA1 (22–29). These treatments have not found

widespread application in MF because they are either limited to

the irradiation of very limited skin areas, or the equipment is

expensive and not widely available, or both.

PUVA

As mentioned above, the first report on the use of PUVA for MF

appeared in 1976 (18). The authors concluded that ‘methoxsalen

photochemotherapy may prove to be a valuable addition to

therapies currently available for MF and may obviate some of the

problems associated with conventional management of this

disorder’. Although 4 30 years have passed and although in the

meantime a variety of other treatment forms for MF have been

introduced, PUVA has still retained its value in the treatment

of MF. This is supported by the results from a large number of

reports, which – taken together – might allow for a reliable

estimate of response rates. A comprehensive list of these studies

has been recently published (30). As is often the case with studies

on diseases that are rare and run a chronic course, the available

data suffer from a wide heterogeneity regarding patient selection,

treatment protocols, outcome measures, observation periods,

concomitant treatments, sample size, and general quality.

However, based on the data of five studies and a total of 244

patients, Hermann and colleagues have calculated the rate of

complete remission after an initial course of PUVA to be 90% for

IA, 76% for stage IB, 78% for stage IIA, 59% for stage IIB%, and

61% for stage III (staging according to (9)) and similar figures

have been reported by others (31, 32).

Less well investigated, however, is the long-term outcome

regarding relapse rates and disease-free survival. In a follow-up

study of 44 patients, Honigsmann et al. (33) reported that five of

nine (stage IA) and 10 of 26 (stage IB) patients remained in

remission for an observation period of up to 79 months. All patients

with T3 disease experienced relapses. Mean disease-free survival

was 20 months for stage IA and 17 months for stage IB. In a more

recent study, 66 patients with stages IA to II who achieved complete

remission after initial PUVAwere followed up for up to 242 months

(34). 5- and 10-year disease-free survival rates for patients with T1

disease were reported to be 56% and 30%, respectively, and 74%

and 50% for T2. Actuarial survival rates at 5, 10, and 15 years did

not differ between the nonrelapse and relapse groups.

In summary, there is good evidence that PUVA is effective

for the clearing of skin lesions, particularly in early stages of

the disease, and that long-term remissions can be achieved in a

certain percentage of patients. How PUVA in this indication

compares with other treatment modalities has not been formally

investigated. Retrospective data published for topical chemo-

therapy and total skin electron beam radiation show very similar

outcomes as described above for PUVA (35–37). Thus, as long

as no data from comparative studies are available, the choice

of treatment in early MF can be made on availability, experience

of the physician, and preference of the patient.

Important open questions regarding the use of PUVA in MF

relate to the duration of treatment, dose escalation, maintenance

therapy, combination therapies, and short- and long-term toxicity.

Technically, PUVA in MF is generally performed according to the

guidelines established for the treatment of psoriasis (38, 39).

Although bath PUVA with 8-methoxypsoralen has been shown

in a retrospective analysis to be effective, its use in MF is not

generally accepted because the head is usually not exposed to the

photosensitizer and relapses might preferentially occur in non-

treated areas (40). Treatment is usually applied until complete

clinical clearing is achieved. A confirmatory biopsy of a previously

exposed site is often recommended at this point, although the

implication of clinical remission without pathological clearance is

unclear. Thus, a more reasonable approach seems to be to biopsy

only lesions, which are clinically equivocal to guide further

treatment decisions.

In a recent multinational survey among dermatologists, 88% of

the respondents indicated that they use some form of PUVA

maintenance after clearance has been achieved (30). This result is

in line with the published practice, because most studies included

some form of maintenance. There is, however, no agreement on

duration, frequency, and UVA-dose and a wide range of schedules

are in use. In summary, there is insufficient evidence for the benefit

of PUVA maintenance. In the light of the carcinogenic risk associated

with PUVA, which has been clearly documented in patients with

psoriasis, and the consequent recommendation to minimize expo-

sure, the recently published consensus of the EORTC suggested to

avoid maintenance (8, 41–43). A practical approach might be to

reserve maintenance for patients who experience an early relapse

after an initial course of PUVA and to adapt the schedule as to

minimize interference with the patients’ quality of life (e.g. once

weekly without further dose increments for 3–6 months).

Through combination with systemic treatments, it is aimed to

enhance the efficacy of PUVA in later disease stages or in patients

with insufficient response to PUVA alone. The most commonly

used combination partners are interferon-a (IFN-a) and

retinoids (isotretinoin, etretinate, acitretin). These drugs have

shown some efficacy as monotherapy in the treatment of MF and

through combination with PUVA an additive effect seemed likely

(44–49). More recently, bexarotene, a new retinoid that binds to

the nuclear retinoid� receptor (R� R), has been specifically

developed for the treatment of MF (50). The drug has shown

efficacy as monotherapy in randomized clinical trials and an

increasing number of case series and smaller studies indicate that

its combination with PUVA might be safe and feasible (51–58).

In general, however, the questions as to whether any PUVA

combination is superior to PUVA alone in terms of clinically

relevant endpoints (e.g. overall survival, disease-free survival,

toxicity) remain unsolved. Studies are either retrospective, too

small, lacking appropriate controls, or used surrogate endpoints

(e.g. duration of treatment or total UVA dose). A randomized trial

that compared acitretin combined with either PUVA or IFN-a in

patients with stages I and II found out that the PUVA combination

is more efficient in inducing remissions after at least 4 weeks of


Trautinger

treatment (59). Information on remission-free periods and long-

term outcomes were not reported. Thus, because it is still unclear

whether any combination is superior to monotherapy, it is a

reasonable recommendation to start with phototherapy alone and

combine it with one of the above mentioned drugs (depending on

individual contraindications and tolerability) in case of insufficient

response or early relapse. For patients with higher stages of

the disease (e.g. tumor stage or lymph node involvement),

combination of PUVA with a systemic treatment might be a

primary choice to provide palliation of the skin symptoms at the

same time with control of the systemic involvement.

Acute side effects of PUVA include nausea, pruritus, and

phototoxic reactions, presenting as painful erythema, edema,

and sometimes blistering. These reactions do not differ between

MF and other skin diseases treated with PUVA. Sometimes, MF-

lesions appear more pronounced during the initial treatment

phase, which might be mistakenly attributed to overdose.

Regarding long-term safety, PUVA has been shown to be a

carcinogen and treatment is dose dependently associated with

the risk of squamous cell carcinomas. This has been convincingly

demonstrated in a large cohort of patients with psoriasis (43).

Although similar studies are not available for MF, the pertinent

literature indicates that there is also a similar risk in these patients

for the development of nonmelanoma skin cancer (60). This has

to be taken into account when PUVA is considered and when

obtaining a patient’s informed consent.

UVB phototherapy

With the development of fluorescent light bulbs that emit in the

UVB range, phototherapy with these lamps was introduced

initially mainly for psoriasis and vitiligo (61). The treatment

had the advantages of being easy to use and suitable for

outpatient or even home treatment. The first report of UVB-

phototherapy for MF appeared in 1982 (62). In this study, 31

patients were treated and in 61% reportedly complete remissions

were achieved. In a long-term follow-up of the same patient

cohort, it was reported that 23% of the patients remained in

remission for prolonged periods even, after discontinuation

of maintenance (63). Because this initial observation, similar

results have been reported in a number of other studies. A

comprehensive list and summary of these studies have been

recently published elsewhere (32). A technical innovation that

specifically changed phototherapy was the development of the

TL-01 fluorescent lamp (64). This lamp emits within a narrow

spectrum of around 311 nm and thus according to the available

action spectra should be ideally suitable for the clearance of

psoriatic lesions with a minimized erythema risk (65).

Accordingly, narrowband UVB (NB-UVB) has been shown to be

better than broadband UVB and similarly effective as PUVA in the

treatment of psoriasis (66). As a consequence to date, TL-01

lamps have replaced broadband UVB sources in many photo-

therapy wards. According to a recent survey among dermatolo-

gists, who use office-based phototherapy to treat patients with

MF, NB-UVB turned out to be first choice for T1 disease in

phototypes I and II (30). In this clinical situation, two out of 26

respondents only recommended broadband UVB. In later stages

or darker skin phototypes, PUVA took over as first choice, but

again broadband UVB was recommended by almost none of the

dermatologists participating in the survey. The efficacy of NB-

UVB has been addressed by a number of studies and case series.

In a study by Hofer et al. (67), complete remissions in 19 out of

20 patients has been achieved by a treatment course of 5–10

weeks with three to four exposures per week. Similar remission

rates have been published by others and from the cumulated data

it can be concluded, that NB-UVB – as the other modalities

described above – can induce high rates of complete remissions

in early MF (30, 32). Evidence is poor, however, regarding the

question how NB-UVB compares with other treatments.

Diederen et al (68) published a retrospective analysis of 56

patients treated with NB-UVB (n = 21) or PUVA (n = 35).

Complete remission rates were similar (81% for NB-UVB, 71%

for PUVA) and mean relapse-free intervals were almost identical

(24.5 and 22.8 months, respectively). The authors concluded

that due to the practical advantages of NB-UVB it might be a

reasonable approach to a patient with early MF to start with NB-

UVB and in case of lack of progression or lack of response switch

to PUVA. Similarly, Ahmad et al. (69) reported in 2007 from a

retrospective analysis of the records of 40 patients that both,

PUVA and NB-UVB, are effective in the treatment of early MF.

Acute toxicity from NB-UVB is almost negligible with only mild

erythema that usually fades within 24 h. Although it is likely that

NB-UVB is associated with a risk for skin cancer, this has not yet

been quantified (70) and is probably well below that of PUVA.

Areas of uncertainty

After 4 30 years of experience in the treatment of MF, it is

evident that the various forms of phototherapy are potent tools to

clear superficial skin lesions in early MF. It is, however, still

unclear whether these treatment are able to modify the natural

course of the disease. Evidence from sufficiently powered,

randomized, controlled trials on the efficacy of phototherapy in

terms of the clinically most relevant endpoints, namely disease-

free survival and long-term safety, is still lacking (overall survival

is almost uncompromised in early MF and thus can not be

reasonably used as an outcome measure in these patients). The

newly developed classification and staging systems for the first

time provide the basis that such studies can be performed on

well-defined target populations. Furthermore, there are insufficient

data to conclude based on a higher level of evidence which type

of phototherapy and which schedule (e.g. in terms of dose

increments, frequency, etc.) might be optimal. The same is true

for maintenance treatments, for which – although widely used in

clinical practice – efficacy has not yet been proven (71).

Conclusions and recommendations

Phototherapy with (NB-)UVB and PUVA are useful and highly

effective in inducing remission of patches and plaques in patients



with MF. Treatment should be used according to the guidelines for

phototherapy as published by various national and international

dermatological societies (39, 70). The choice of treatment largely

depends on availability, patient history (in terms of earlier

treatment responses), and experience of the physician. It has

become a widely accepted consensus that in patients with patches

and thin plaques NB-UVB should be preferentially used and that

PUVA should be reserved for patients with thick plaques (including

follicular mucinosis), with photoypes ZIII, and insufficient

response to UVB (8).

Our understanding of the disease has significantly increased

recently and ongoing research is likely to yield new insights

into its pathology as well as new forms of treatment (72). It is,

however, not likely that phototherapy of MF will become

obsolete in the foreseeable future, because new therapeutic

developments will rather supplement than replace it, as can be

seen from the example of bexarotene.

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Phototherapy of mycosis fungoides