BJD

GUIDELINES British Journal of Dermatology

British Association of Dermatologists and U.K. Cutaneous

Lymphoma Group guidelines for the management of primary
cutaneous lymphomas 2018
D. Gilson,1 S.J. Whittaker iD ,2 F.J. Child,2 J.J. Scarisbrick iD ,3 T.M. Illidge iD ,4 E.J. Parry,5 M.F. Mohd Mustapa,6
L.S.Exton,6 E. Kanfer,7 K. Rezvani,8 C.E. Dearden iD 9 and S.L. Morris10
1
Leeds Cancer Centre, St James’s University Hospital, Leeds LS9 7TF, U.K.
2
St John’s Institute of Dermatology, Guy’s and St Thomas NHS Foundation Trust, St Thomas’ Hospital, London SE1 7EH, U.K.
3
Queen Elizabeth Hospital, University Hospital Birmingham, Birmingham B15 2TH, U.K.
4
Institute of Cancer Sciences, University of Manchester, The Christie NHS Foundation Trust, Manchester M20 4BX, U.K.
5
Tameside Hospital Integrated Care NHS Foundation Trust, Ashton-under-Lyne OL6 9RW, U.K.
6
British Association of Dermatologists, Willan House, 4 Fitzroy Square, London, W1T 5HQ, U.K.
7
Haematology Department, Hammersmith Hospital, Du Cane Road, London W12 0HS, U.K.
8
The University of Texas MD Anderson Cancer Centre, Houston, TX, U.S.A.
9
Chronic Lymphocytic Leukaemia (CLL) Unit, The Royal Marsden NHS Foundation Trust, Sutton SW3 6JJ, U.K.
10
Guy’s and St Thomas’ NHS Foundation Trust, Guy’s Hospital, London SE1 9RT, U.K.

Linked Editorial: Wang and Bagot. Br J Dermatol 2019; 180:

Correspondence 1.0 Purpose and scope

Sean Whittaker.
E-mails: sean.whittaker@kcl.ac.uk; guidelines@bad.org.uk
Accepted for publication
14 September 2018
Funding sources
None.
Conflicts of interest
S.J.W. has been on advisory boards for Actelion, Takeda and Innate Pharma (specific) and has
a collaborative research agreement with Galderma. J.J.S. has been a consultant for Innate
Pharma, Actelion Pharmaceuticals, Therakos (Mallinckrodt), Takeda and 4SC (specific) and
has received honoraria and meeting sponsorship from Teva, Therakos, Johnson & Johnson and
Takeda (specific). C.E.D. has been a consultant for Genzyme (specific). T.M.I. has been a con-
sultant and invited speaker for Takeda (specific). E.J.P. has been on the advisory board for and
an invited speaker for Actelion. The other authors declare no conflicts of interest.
D.G., S.J.W., F.J.C., J.J.S., T.M.I., E.J.P., E.K., K.R., C.E.D. and S.L.M. are members of the
guideline development group, with technical support provided by L.S.E. and M.F.M.M.
These guidelines were first produced jointly by the British Association of Dermatologists and the
U.K. Cutaneous Lymphoma Group (2003); reviewed and updated 2018.
This is an updated guideline prepared for the BAD Clinical Standards Unit, which includes the
Therapy & Guidelines Subcommittee. Members of the Clinical Standards Unit who have been
involved are P.M. McHenry (Chairman Therapy & Guidelines), T.A. Leslie, S. Wakelin, R.Y.P.
Hunasehally, M. Cork, G.A. Johnston, N. Chiang, F.S. Worsnop, A. Salim, D. Buckley, G. Petrof,
N. Callachand (British National Formulary), T. Flavell (British Dermatological Nursing Group),
A.A. Salad (BAD Scientific Administrator), L.S. Exton (BAD Guideline Research Fellow) and M.F.
Mohd Mustapa (BAD Clinical Standards Manager).
DOI 10.1111/bjd.17240
NICE has renewed accreditation of the process used by the British
Association of Dermatologists to produce clinical guidelines. The
renewed accreditation is valid until 31 May 2021 and applies to
guidance produced using the processes described in the updated guid-
ance for writing a British Association of Dermatologists clinical
guideline – the adoption of the GRADE methodology 2016. The
original accreditation term began on 12 May 2010. More infor-
mation on accreditation can be viewed at www.nice.org.uk/accredi
tation.
The overall objective of the guideline is to provide up-to-date,
evidence-based recommendations on the management of pri-
mary cutaneous lymphoma in the U.K. The document aims
to: (i) offer an appraisal of all relevant literature up to Febru-
ary 2018 focusing on any key developments; (ii) address
important, practical clinical questions relating to the primary
guideline objective; (iii) provide guideline recommendations
with, where appropriate, some health economic implications;
and (iv) discuss potential developments and future directions.
The guideline is presented as a detailed review with high-
lighted recommendations for practical use in the clinic (see
section 12). A patient information leaflet on mycosis fun-
goides is available on the British Association of Dermatologists
(BAD) website: www.bad.org.uk/for-the-public/patient-inf
ormation-leaflets. Further information can also be found at
www.lymphomas.org.uk/about-lymphoma.
1.1 Exclusions
These guidelines do not cover patients presenting with or found
to have skin involvement as part of a systemic lymphoma.
2.0 Methodology
This set of guidelines has been developed using the BAD’s recom-
mended methodology1 and with reference to the Appraisal of
Guidelines Research and Evaluation (AGREE II) instrument
(www.agreetrust.org).2 The recommendations were developed
for implementation in the National Health Service using a process
of considered judgement based on the evidence (Appendix S1;
see Supporting Information). Targeted literature searches were
carried out in the PubMed, MEDLINE and Embase databases and
the Cochrane Library, for meta-analyses, randomized and

© 2018 British Association of Dermatologists British Journal of Dermatology (2018) 1

2 BAD and U.K. CLG guidelines for primary cutaneous lymphomas 2018, D. Gilson et al.
nonrandomized controlled clinical trials, case series, case reports,
open studies and cohort studies on primary cutaneous lymphoma
and specified treatments to February 2018. The search terms and
strategies are detailed in Appendix S2 (see Supporting Informa-
tion). Additional relevant references were also retrieved from
citations in the reviewed literature.
All identified English-language titles were screened and those
relevant for first-round inclusion were selected for further scrutiny.
The abstracts for the shortlisted references were then reviewed and
the full papers of relevant material were obtained; disagreements in
the final selections were resolved by discussion with the entire
Guideline Development Group (GDG). The structure of the 2003
guidelines was then discussed and re-evaluated, with headings and
subheadings revised where appropriate; different coauthors were
allocated separate subsections. Each coauthor then performed a
detailed appraisal of the selected literature with discussions within
the GDG to resolve any issues, for example the quality of evidence
and making the appropriate recommendations. All subsections
were subsequently collated, circulated within the GDG and edited
to produce the final guideline.
3.0 Introduction
3.1. Incidence and epidemiology
Primary cutaneous lymphomas represent a heterogeneous
group of extranodal non-Hodgkin lymphomas, consisting of
cutaneous B-cell lymphoma (CBCL) and cutaneous T-cell lym-
phoma (CTCL). CTCL represents around 70% and CBCL about
30% of primary cutaneous lymphomas. Primary cutaneous
lymphomas have been defined by the European Organisation
for Research and Treatment of Cancer (EORTC)–World Health
Organization (WHO) classification3,4 and incorporated into
the most recent WHO classification (Table 1).5
These guidelines are broadly consistent with U.S. National
Comprehensive Cancer Network guidelines (www.nccn.org),
and the EORTC and European Society for Medical Oncology
clinical practice guidelines.4,6,7
Mycosis fungoides (MF) and S
ezary syndrome (SS) are the
most common clinicopathological subtypes of CTCL.3 A recent
U.K. National Cancer Information Network audit of newly
diagnosed cases of CTCL from 2009 to 2013 suggests an
annual incidence of 0
7 per 100 000 U.K. population, with a
significantly higher male incidence (1
6 : 1
0) and a peak age
between 50 and 74 years. Completion of staging data was
poor (7% in 2009, 20% in 2013).8 While the peak incidence
of MF/SS occurs in the 50–74-year age group, approximately
20% of patients are diagnosed with CTCL aged 25–49 years,
and MF may rarely present in childhood. Increasing age is a
poor prognostic factor and the vast majority of younger
patients present with early-stage disease where the outlook is
excellent. However, management of younger adults with
intermediate or advanced stages of CTCL may require a more
aggressive approach than usual.
MF and SS are closely related both clinically and pathogenetically
but are distinct from other relatively rare types of primary CTCL.
British Journal of Dermatology (2018)
Table 1 World Health Organization/European Organisation for
Research and Treatment of Cancer classification of primary cutaneous
lymphomas (italics indicate provisional entities)
Cutaneous B-cell lymphoma
• Indolent clinical behaviour
○ Primary cutaneous marginal zone B-cell lymphomaa
○ Primary cutaneous follicle centre lymphoma
• Intermediate behaviour
○ Primary cutaneous diffuse large B-cell
lymphoma, leg type
Cutaneous T-cell lymphoma
• Indolent clinical behaviour
○ Mycosis fungoides (and variants)
○ Primary cutaneous CD30+ lymphoproliferative
disorder: anaplastic large cell lymphoma
○ Primary cutaneous CD30+ lymphoproliferative
disorder: lymphomatoid papulosis
○ Subcutaneous panniculitis-like T-cell lymphoma
○ Primary cutaneous CD4+ small/medium pleomorphic T-cell
lymphoproliferative disorderb
○ Primary cutaneous acral CD8+ T-cell lymphomab
○ Hydroa vacciniforme-like lymphoproliferative
disorderb
• Aggressive clinical behaviour
○ S
ezary syndrome
○ Extranodal natural killer/T-cell lymphoma, nasal type
○ Primary cutaneous aggressive epidermotropic cytotoxic
CD8+ T-cell lymphoma
○ Primary cutaneous c/d T-cell lymphoma
○ Primary cutaneous peripheral T-cell lymphoma,
unspecified
a
Classified as extranodal marginal zone lymphoma of mucosa-
associated lymphoid tissue (MALT lymphoma) in the 2016 ver-
sion. bChanges from the 2008 version.
Of these rarer CTCLs, the primary cutaneous CD30+ lymphoprolif-
erative disorders have an excellent prognosis, while some of the
other CTCL variants have poor prognosis and are more closely
related to peripheral T-cell lymphomas (PTCLs).9
CBCL is classified into three main types: the more common,
low-grade primary cutaneous follicle centre lymphoma
(PCFCL) and primary cutaneous marginal zone lymphoma
(PCMZL), which can occur at any age, and the rare, primary
cutaneous, diffuse, large B-cell lymphoma (PCLBCL) leg type,
which occurs typically in elderly female patients.3
A list of the abbreviations used in this guideline is available
in Appendix S3 (see Supporting Information).
4.0 Diagnosis, staging, prognosis and end
points
4.1 Diagnosis
The diagnosis of different cutaneous lymphoma variants is
based on an assessment of the clinical and pathological fea-
tures, which forms the basis for the National Cancer
© 2018 British Association of Dermatologists
 BAD and U.K. CLG guidelines for primary cutaneous lymphomas 2018, D. Gilson et al. 3
Information Network minimum dataset for primary cutaneous
lymphomas. MF is characterized by a distinct clinical morphol-
ogy consisting of polymorphic patches or plaques, with the
more advanced cutaneous stage associated with tumours and
erythroderma; peripheral adenopathy may or may not be pre-
sent. SS is much less common (5% of CTCL) and is defined
according to the WHO criteria by the presence of erythro-
derma, peripheral lymphadenopathy and S
ezary cells compris-
ing > 1000 cells lL1, or with a CD4 : CD8 ratio > 10 or
loss of one or more T-cell antigens on flow cytometry and a
T-cell clone (stage B2). Human T-lymphotropic virus-1 serol-
ogy should be checked in all patients to exclude adult T-cell
leukaemia/lymphoma, which can mimic CTCL. As for all new
patients with lymphoma, HIV status should also be checked,
in line with the Department of Health recommendations.10
Repeated biopsies may be required to establish the diagno-
sis, especially in MF. MF has a characteristic CD4+ epider-
motropic infiltrate of T cells, although rare CD8+ phenotypic
variants occur. T-cell receptor gene analysis is an important
diagnostic and staging technique especially in patients with
MF/SS, where analysis of peripheral blood provides critical
prognostic information. It is essential that results are always
interpreted in the context of the clinicopathological features.
Patients with other CTCL variants do not have the character-
istic polymorphic patches and plaques seen in MF and may
present with cutaneous tumours, nodules or subcutaneous
infiltration with distinctive pathology and immunophenotypic
findings.3 Lymphomatoid papulosis (LyP) represents part of a
spectrum of primary cutaneous CD30+ lymphoproliferative
disorders and is defined by a history of recurrent, self-healing
papules and nodules, and characteristic pathology.
CBCL presents with nodules, plaques and tumours with a
characteristic pathology and immunophenotype, and site local-
ization can be an important distinguishing feature. A definitive
diagnosis can only be made on a representative biopsy, prefer-
ably an excision or elliptical biopsy. Borrelia burgdorferi infection
has been reported in association with PCMZL, and serology is
indicated in all patients.11,12 Clonal IgH gene rearrangements
can aid diagnosis.13
4.2 Staging
Staging investigations should include a computed tomography
(CT) scan of the neck, chest, abdomen and pelvis in all patients
with CTCL and CBCL, with the exception of those with early
stages of MF (IA/IB) and LyP unless there is palpable lym-
phadenopathy.14,15 Positron emission tomography (PET) CT
should be considered for patients with PCLBCL leg type in keep-
ing with local policies for PET CT in aggressive B-cell lym-
phomas.16 The value of PET scans in MF/SS and other CTCL
variants remains unclear at present, although this may indicate
which nodal basin to sample.17,18 In MF and SS, morphological
assessment of peripheral blood for S
ezary cells is required (de-
fined as lymphocytes with hyperconvoluted nuclei). This should
be carried out by flow cytometry to quantify the total number
of S
ezary cells and T-cell-receptor gene analysis.
© 2018 British Association of Dermatologists
In SS, an identical clonal T-cell-receptor gene rearrangement
is detected in skin and peripheral blood in combination with
(i) a total S
ezary cell count > 1000 cells lL1, (ii) an
expanded CD4+ T-cell population with a CD4 : CD8 ratio
≥ 10 or (iii) an expanded CD4+ T-cell population with abnor-
mal immunophenotype including CD4+ CD7 (> 30%) or
CD4+ CD26 (> 40%). Bone marrow aspirate and trephine
biopsies are rarely indicated in MF, SS and LyP, unless there is
an unexplained haematological abnormality, but they are more
commonly required for other CTCL variants and for high-
grade PCLBCL leg type. Bone marrow biopsy and aspirate is
considered optional for low-grade PCMZL but should be con-
sidered for PCFCL, as systemic follicle centre lymphoma with
secondary cutaneous involvement may occur.19,20 Serum lac-
tate dehydrogenase has prognostic significance and should be
checked at diagnosis.21
Existing staging systems for nodal lymphomas are not appli-
cable for primary cutaneous lymphomas. The original TNM
(primary tumour, regional nodes, metastasis) and clinical stag-
ing system for MF and SS22 has now been replaced by an
International Society for Cutaneous Lymphomas (ISCL)–EORTC
revised staging system,23 which distinguishes patches and pla-
ques, incorporates a molecular assessment of lymph node and
peripheral blood, and provides a quantitative method for
assessing peripheral blood disease in SS (Tables S1–S3; see
Supporting Information).24 These revised staging systems have
been adopted by the American Joint Committee on Cancer.25
4.3 Prognosis
Recent studies have defined prognostic risks with CTCL and
CBCL, providing rates for overall survival (OS), disease-specific
survival and progression-free survival (PFS) (Tables 2 and
3).21,26–30
Unlike CTCL, prognosis for CBCL is determined by the type
of primary CBCL, not its stage (Table 3).3,11,31–33 Most
patients with early stages of MF, primary cutaneous CD30+
lymphoproliferative disorders, and marginal zone and follicle
centre lymphomas have a good prognosis, but disease progres-
sion and disease-specific mortality may occur. The 5- and 10-
year OS rates for MF are 80% and 57%, respectively, with dis-
ease-specific survival rates of 89% and 75% at 5 and 10 years,
respectively.27 Approximately 25% of early-stage patients
develop disease progression.30 In contrast, patients with SS
have an 11% 5-year survival, with a median survival of
32 months from diagnosis. Patients with low-grade PCMZL
and PCFCL have 5-year OS rates approaching 100%, but for
PCLBCL leg type the prognosis is poor, with 5-year OS rates
of between 36% and 45%.
Several multivariate analyses of large cohorts of patients with
MF/SS have identified potential independent prognostic factors
at diagnosis. A study of 1502 U.K. patients identified separate
prognostic models for early and advanced MF.30,34 Specifically
for early-stage disease, male sex, age (≥ 60 years), presence of
plaques (T1b/T2b), histological evidence of folliculotropic dis-
ease and palpable or histologically confirmed dermatopathic
British Journal of Dermatology (2018)
4 BAD and U.K. CLG guidelines for primary cutaneous lymphomas 2018, D. Gilson et al.

Table 2 Prognosis in mycosis fungoides/S
ezary syndrome21,26–30

Overall survival Disease-free survival Progression-free survival

Stage 5 year 10 year 5 year 10 year 5 year 10 year
IA T1a 97% 91% 100% 96% 95% 91%
T1b 91% 80% 96% 92% 88% 82%
IB T2a 85% 75% 90% 82% 85% 72%
T2b 81% 64% 86% 72% 75% 56%
IIA 78% 52% 89% 67% 83% 67%
IIB 40–65% 34% 50–80% 42% 52% 42%
IIIA 47% 37% 54% 45% 47% 38%
IIIB 40% 25% 48% 45% 18% 27%
IVA1 37% 18% 41% 20% 38% 17%
IVA2 18% 15% 23% 20% 23% 20%
IVB 18% – 18–20% – 18% –

Table 3 Prognosis in primary non-mycosis fungoides/S
ezary
syndrome cutaneous lymphomas3,11,31–33
5-Year survival Overall Disease specific
pcCD30+ anaplastic large 90% NA
cell lymphoma
pcCD30+ lymphomatoid papulosis 100% NA
pc marginal zone lymphoma MZL > 95% 100%
pc follicle centre lymphoma > 95% > 95%
pc diffuse large B-cell lymphoma 36–45% 61%
pc, primary cutaneous; NA, not available.
peripheral nodes (N1/Nx) were adverse factors for progression
and survival. For late-stage disease, nodal involvement (N2/3)
and blood and visceral disease are additional important prognos-
tic factors. Patients with stage IIB disease have a poor prognosis,
but published data show marked variation in survival, perhaps
reflecting the heterogeneous nature of tumour-stage disease in
terms of both tumour burden and biology.26,27 The probability
of survival for patients with stage III erythrodermic MF, without
evidence of lymph node or peripheral blood involvement, is
broadly similar to that for stage IIB MF.
A Cutaneous Lymphoma International Consortium study of
prognostic factors in 1275 patients with advanced MF/SS from
29 international sites confirmed similar survival probability for
patients with stage IIB and III disease, with significantly worse
survival in stage IV.21 Four independent prognostic factors
were identified, namely age > 60 years, large cell transforma-
tion in skin, raised lactate dehydrogenase and stage IV disease.
A prognostic index model combining these four factors identi-
fied three risk groups with significantly different 5-year sur-
vival rates: low risk (68%), intermediate risk (44%) and high
risk (28%).21 This prognostic index is in the process of being
prospectively validated.
4.4 Disease response and end points
Historically, most trials in cutaneous lymphomas have been ret-
rospective reports of case series or phase II studies, with no
standardized definitions of end points or response criteria. Con-
sequently, the detail and quality of response assessments have
been variable, and most studies have reported responses based
on assessment of skin disease alone. This has led to the publica-
tion of ISCL–EORTC consensus criteria for disease end points,
and assessment tools for MF/SS, which are based on utilization
of the modified Severity Weighted Assessment Tool technique
(Table S4; see Supporting Information)35 and include a global
scoring system based on responses of cutaneous and noncuta-
neous disease (Table S5; see Supporting Information).35
In addition, a similar consensus proposal is in preparation for
other primary non-MF/non-SS cutaneous lymphomas. These stan-
dards for disease assessment should now be routinely used for
monitoring clinical outcomes in all patients with primary cutaneous
lymphomas in conjunction with quality-of-life measurements.
5.0 National Institute for Health and Care
Excellence Improving Outcomes Guidance for
primary cutaneous lymphomas
5.1 Specialist multidisciplinary teams
Primary cutaneous lymphomas are rare and heterogeneous
malignancies that can present considerable diagnostic difficul-
ties. In addition, effective standard treatments have yet to be
defined for many variants, particularly those with a poor prog-
nosis. As such, it is critical that patients have effective pathways
of care that allow rapid access to centres with broad experience
of primary cutaneous lymphomas. Such pathways have been
defined in the National Institute for Health and Care Excellence
(NICE) Improving Outcomes Guidance (IOG) for skin cancers
including melanoma (Table 4).36,37 Patients outside the groups
where review by the supranetwork skin lymphoma multidisci-
plinary team (MDT) is mandated may benefit from review by
this team, especially where there is difficulty in establishing a
diagnosis or the patient’s management is proving challenging,
depending on the expertise of the specialist skin MDT.
All patients with suspected or proven primary cutaneous lym-
phomas should be reviewed at regional specialist skin cancer

British Journal of Dermatology (2018) © 2018 British Association of Dermatologists

 BAD and U.K. CLG guidelines for primary cutaneous lymphomas 2018, D. Gilson et al. 5

Table 4 Clinical pathway for cutaneous lymphomas Table 5 Supranetwork multidisciplinary teams (MDTs) in England, as
per the National Institute for Health and Care Excellence Improving
Supranetwork Outcomes Guidance for skin cancer36 and other network skin
Category Specialist MDT MDT lymphoma services in the U.K.
a
Stage IA–IIA MF Required
Stage IA–IIA MF Required Essential TSEB ECP
refractory to skin-directed Supranetwork MDTs
therapy Birmingham (Queen Yes (Coventry and Yes
Stage III–IVA1 erythrodermic Required Essential Elizabeth Hospital) Warwickshire
MF/SS University Hospital)
Stage IIB–IV MF/SS Required Essential Leeds (St James’s Yes No, referred to
pcCD30+ lymphoproliferative Required a
University Hospital) Rotherham
disorders Hospital
CTCL variants Required Essential Liverpool (Royal Yes (Clatterbridge Yes
a
CBCL Required Liverpool Hospital) Hospital, Wirral)
London (Guy’s and St Yes Yes
MF, mycosis fungoides; SS, S
ezary syndrome; pc, primary cuta-
Thomas’ Hospital)
neous; CTCL, cutaneous T-cell lymphoma; CBCL, cutaneous B-
Manchester (The Yes Yes
cell lymphoma; MDT, multidisciplinary team. aThese patients Christie Hospital)
may benefit from review by the supranetwork skin lymphoma Newcastle Yes Yes
MDT. Table adapted from the National Institute for Health and (Freeman Hospital)
Care Excellence guidance.36 Nottingham Yes Yes
(City Hospital)
Other network skin lymphoma services
Belfast Yes No, would be
MDT meetings. There must be a close working relationship
referred
between the regional specialist skin cancer and haemato-oncol- Cardiff No, referred to Guy’s No, referred to
ogy MDTs, especially for patients who develop systemic disease. and St Thomas’ Bristol University
Hospitals
Glasgow No, referred to Yes
5.2 Supranetwork multidisciplinary teams Newcastle
The NICE IOG also defines which patients with primary cuta- TSEB, total skin electron beam; ECP, extracorporeal electrophore-
neous lymphomas should be referred to supranetwork MDTs sis.
across England (Table 5), at which dermatologists, clinical
oncologists, haemato-oncologists and both dermatopatholo-
gists and haematopathologists review the patient’s diagnosis biologics, chemotherapy and stem cell transplantation. Selection
and management plan. The IOG recommends that all patients of appropriate treatment is based on the stage of disease. Follow-
with stage IIB or higher MF, and all with SS and rare CTCL ing treatment, patients with advanced disease often develop
variants should be reviewed by the supranetwork MDT. These recurrent, low-grade disease that can be responsive to SDT. There
supranetwork MDTs also provide the appropriate pathway to have been very few randomized controlled studies. Recently
review cases where diagnostic or classification difficulties arise. Quaglino et al. published a retrospective analysis of 853 patients
Patients should be reviewed at supranetwork centres to pro- with advanced MF/SS from 21 centres.38 This large, multicentre
vide access to clinical trials, which are often the standard of retrospective study showed a substantial heterogeneity of treat-
care, and to agree on use of newly approved therapies. ment approaches in advanced MF/SS between U.S. and non-U.S.
The supranetwork MDT is also responsible for reviewing centres, with up to 24 different drugs, modalities or combina-
patients who require specialist treatment options, such as total tions used as first-line treatment, but these differences did not
skin electron beam therapy (TSEB) and extracorporeal photo- influence survival outcome. However, it was observed that
pheresis (ECP). Although not stipulated in the IOG, patients chemotherapy, when used as first-line treatment, is associated
with stage IB disease that is refractory to skin-directed therapy with a higher risk of death and/or change of therapy. For the pur-
(SDT) should be referred to the supranetwork MDT to ensure poses of this guideline, separate recommendations for MF/SS
that they have appropriate access to clinical trials and TSEB. All have been made according to stage.
patients who are being considered for stem cell transplantation
should be reviewed by a supranetwork MDT.
6.1 Skin-directed treatment

zary
6.0 Treatment of mycosis fungoides/Se
syndrome
Therapeutic options range from SDT consisting of topical agents,
phototherapy and radiotherapy, to systemic treatment with
6.1.1 Topical therapies
6.1.1.1 Stage IA–IIA mycosis fungoides
There have been few randomized controlled trials (RCTs) of
topical therapies for MF. The lack of well-controlled studies

© 2018 British Association of Dermatologists British Journal of Dermatology (2018)

6 BAD and U.K. CLG guidelines for primary cutaneous lymphomas 2018, D. Gilson et al.
Table 6 Topical therapy in mycosis fungoides
Therapy Design
40
Mechlorethamine RCT
Retrospective case series41–46
Mechlorethamine + Prospective open-label phase II47
betamethasone
Bexarotene gel Phase II50
Phase III51
Carmustine (BCNU) Case series48,49
Corticosteroids Case series39
RCT, randomized controlled trial; CAILS, Composite Assessment of Index Lesion Severity. aSee Appendix S1 in the Supporting Information.
limits the quality of evidence, although all of the topical thera-
pies listed have some clinical efficacy for patches and thin pla-
ques (Table 6). However, accurate data on end points such as
duration of response and freedom from relapse are lacking.
Many of the topical therapies reviewed remain unlicensed for
use in MF.
6.1.1.1.1 Topical corticosteroids Topical corticosteroids, especially
class 1 (very potent) compounds, are effective for patches and
plaques in some patients with early-stage IA/IB MF, but
responses are rarely complete or durable.39
6.1.1.1.2 Topical mechlorethamine (nitrogen mustard) The single lar-
gest RCT randomized 260 patients to a standard nitrogen
mustard 0
02% ointment or a novel nitrogen mustard 0
02%
gel preparation, used once daily for up to 12 months; no
adjunctive therapy was allowed. The gel preparation was sta-
tistically noninferior to the ointment, with response rates of
58
5% (gel) vs. 47
7% (ointment) as measured by the Com-
posite Assessment of Index Lesion Severity (CAILS).40 An
extension study of 98 patients who failed to achieve com-
plete response used a nitrogen mustard 0
04% gel, with a
CAILS response rate of 26% (6% complete response). Euro-
pean Medicines Agency (EMA) approval of this new gel
preparation (Ledagaâ) provides a more practical formulation
than the historical, in-house compounded ointment and
aqueous solutions.
These trials confirm that mechlorethamine is an effective
topical therapy for early-stage MF. Previous studies have been
predominantly retrospective and confounded by the use of
other therapeutic modalities.41–46 A prospective, nonrandom-
ized study of 64 patients with early-stage MF treated with a
0
02% aqueous solution of mechlorethamine followed by
betamethasone cream twice weekly for 6 months reported
58% complete responses.47
The duration of response to mechlorethamine varies, and
the efficacy of maintenance therapy and whole-body applica-
tion remains unclear, but rare patients with stage IA disease
British Journal of Dermatology (2018)
Level of
evidencea Stage Response rate
1+ IA–IIA 59% gel vs. 48% ointment
(noninferiority design by CAILS)
3 IA–IB 51–80% (IA) 26–68% (IB)
2+ IA–IB 58% complete response (duration 7
7 months)
2+ IA–IB 63%
IA–IIA 44%
3 IA–IIA 76%
3 IA–IB 94% (IA), 82% (IB)
may be cured. Irritant contact dermatitis is the most com-
mon adverse effect, occurring in 10–40% of patients,
depending on the preparation used. A recent 30-year popula-
tion-based cohort study showed no increased risk of sec-
ondary cancers (including nonmelanoma skin cancer or
melanoma) in patients treated with mechlorethamine. Mortal-
ity and cause-specific mortality were not influenced by
mechlorethamine.46
6.1.1.1.3 Topical carmustine (BCNU) Limited data suggest that
topical carmustine has similar efficacy to mechloretha-
mine.48,49 However, it is more extensively absorbed, increas-
ing the risk of bone marrow suppression, although the
incidence of irritant contact dermatitis is lower (10%).
6.1.1.1.4 Other topical therapies Topical bexarotene (1% gel) has
been shown to be effective in prospective phase I/II open
studies50 and phase III trials for refractory or persistent, early-
stage MF.51 Although approved by the U.S. Food and Drug
Administration (FDA), topical bexarotene is not licensed in
Europe. Irritant contact dermatitis is common and was
reported in 12% of patients.
Limited data from case reports and series suggest that imi-
quimod 5% cream,52–59 5-fluorouracil cream,60 topical reti-
noid preparations (tazarotene 0
1%, tretinoin 0
1%)61 and
tacrolimus 0
1% ointment62 may have efficacy in early stages
of MF. The value of simple emollient therapy in MF was high-
lighted by a 24% placebo response rate to ointment base alone
in an RCT of topical peldesine (28% response rate, difference
not statistically significant).63
6.1.1.2 Stage IIB mycosis fungoides (MF); stage III–IVA1 MF/Sezary syn-
drome (SS); stage IVA2–B MF/SS
There is no evidence to suggest that topical therapies have a
significant impact on the course of the disease for advanced
stages of MF/SS, although SDT can alleviate skin symptoms
such as pain and pruritus, and most patients will require inter-
mittent topical treatments, especially topical steroids.
© 2018 British Association of Dermatologists
 BAD and U.K. CLG guidelines for primary cutaneous lymphomas 2018, D. Gilson et al. 7
Table 7 Phototherapy in mycosis fungoides
Therapy Design (all nonrandomized) Level of evidencea
66
UVB Retrospective 2
UVB Retrospective65 2
NB UVB Retrospective68 2
NB UVB Retrospective69 2
NB UVB Retrospective91 2
PUVA Retrospective74 2
PUVA Prospective79 2+
PUVA Retrospective80 2
Regimens: psoralen–ultraviolet A (PUVA), twice weekly for 12–14 weeks; Narrowband ultraviolet B (NB UVB), two to three times weekly
for 12–14 weeks. CR, complete response. aSee Appendix S1 in the Supporting Information.
6.1.2 Phototherapy
6.1.2.1 Stage IA–IIA mycosis fungoides
Phototherapy (Table 7) is the standard of care for patients
with early stages of MF whose disease is not controlled by
topical therapy, producing high complete remission rates.64–91
However, the duration of response is often limited. Repeated
courses may be considered but the increased risk of skin can-
cer (including melanoma) limits the number of phototherapy
courses in a lifetime.
There are few comparative studies or RCTs involving pso-
ralen–ultraviolet A (PUVA), and most case series lack a vali-
dated scoring system to assess tumour burden. The critical
questions as to whether PUVA affects time to progression and
disease-specific survival remain unanswered.
6.1.2.1.1 Ultraviolet B phototherapy Both narrowband ultraviolet
(UV)B (TL-01: 311–313 nm) and broadband UVB (290–
320 nm) phototherapy can produce high complete response
rates.64–69 Responses are more likely in patients who have
only patches. There have been no prospective RCTs of nar-
rowband UVB, but a retrospective case series showed it to be
as effective as PUVA for treatment of early-stage disease, with
no difference in time to relapse.70 In a paediatric case series,
high response rates were seen (> 80%), including a number
of complete responses in children with the hypopigmented
variant of MF.71
6.1.2.1.2 Ultraviolet A phototherapy High-dose UVA1 photother-
apy (340–400 nm), which penetrates more deeply than both
UVB and UVA, has shown clinical efficacy in a small case
series.72
6.1.2.1.3 Psoralen–ultraviolet A photochemotherapy Extensive, non-
randomized and retrospective case studies have reported
high complete response rates for PUVA in early stages.73–76
Data from an RCT showed that a minority (25–30% free-
dom from relapse at 5 years) of patients achieving a com-
plete response77 may have a prolonged duration of
response. Many patients receive maintenance therapy but
the benefits are uncertain.78,79 A retrospective study of
© 2018 British Association of Dermatologists
Stage Response rate Response duration (months)
IA–IB 75% 51
IA–IB 71% 22
IA–IB 84% 12
5 weeks
IA–IB 84% (IA), 78% (IB)
IA–IB 100% > 60 (80% CR and 60% no recurrence)
IA–IB 95% 43
IA–IB 100% 20 (IA), 17 (IB)
IA–II 63% (CR) 39
long-term outcomes following complete remission from
PUVA monotherapy at a single institution reported that 30–
50% of patients had a durable remission (10-year disease-
free survival), but maintenance PUVA was given to almost
all responding patients.80 A total of 30% of patients showed
chronic photodamage and secondary skin cancers. This study
showed no significant difference in the OS rate for the non-
relapsing and relapsing patient cohorts. Recent data from a
prospective cohort study suggest that maintenance therapy
does not prevent future relapse.81,82
For PUVA, an increased risk has been identified for
patients receiving more than 250 treatments and/or
> 2000 J cm2.83,84 Based on the data available, the cumula-
tive lifetime PUVA exposure should be limited (1200 J cm2
and/or 250 sessions).85 For maintenance PUVA the risks
may outweigh the benefits, and generally this should be
avoided for those patients who achieve excellent clinical
responses, although there are some exceptional refractory
patients for whom maintenance treatment may provide
important symptomatic relief.
6.1.2.1.4 Photodynamic therapy Photodynamic therapy has been
reported as a treatment for solitary plaques that are resistant
to topical treatment. Small case series have shown durable
responses in 70–75% of patients.86,87 Photodynamic therapy
is safe and well tolerated and may be appropriate for certain
sites, but a specific therapeutic role in MF has yet to be
defined.
6.1.2.1.5 Excimer laser Several small case series have demon-
strated the efficacy of the 308-nm excimer laser in early-stage
skin disease. Treatment with an excimer laser appears to be
safe, effective and well tolerated for patches, but its precise
therapeutic role remains to be established.88–90
6.1.2.2 Stage IIB mycosis fungoides
Patients with tumours invariably have coexisting patches
and plaques and may benefit from phototherapy if individ-
ual tumours respond to other options such as localized
radiotherapy.
British Journal of Dermatology (2018)
8 BAD and U.K. CLG guidelines for primary cutaneous lymphomas 2018, D. Gilson et al.

Table 8 Combination psoralen–ultraviolet A (PUVA) in mycosis fungoides/S
ezary syndrome

Duration
Therapy Design Level of evidencea Stage ORR (CR), % Number of patients (months) 5-year RFS, %
PUVA + interferon Case studies94
2 IA–IV 89 9
PUVA + interferon Case series97 2 IA–IV 68 (45) 22 20–75
PUVA + interferon Prospective phase II96 2+ IB–IIA 98 (84) 89 14
PUVA + interferon Case studies101 2 100 (100) 5 74
PUVA + interferon Case studies93 2 IB–IVB 90 (100) 39
PUVA + interferon Prospective phase II95 2+ IA–IVA 81 (75) 63 32 75
PUVA + bexarotene RCT EORTC-2101177 1+ IB–IIA 77 (31) 87 5
8 25
PUVA + bexarotene Case series100 2 I–III 67 (29) 14 2–10
PUVA + bexarotene Case series102 2 IA–IIB 100 (63) 8

ORR, overall response rate; RFS, relapse-free survival; RCT, randomized controlled trial; EORTC, European Organisation for Research and
Treatment of Cancer. aSee Appendix S1 in the Supporting Information.

6.1.2.3 Stage III/IVA1 erythrodermic mycosis fungoides/Sezary syndrome
Patients with erythrodermic MF/SS are often intolerant of
phototherapy due to aggravation of pruritus, but they can
rarely respond.
6.1.2.4 Stage IVA2–B mycosis fungoides/Sezary syndrome
PUVA can often be used as a salvage therapy, as patients with
advanced disease often relapse or have persistent low-grade
skin disease characterized by patches and plaques following
systemic treatments.
6.1.3 Combination psoralen–ultraviolet A regimens
PUVA combined with interferon-alpha or bexarotene does not
improve overall response but may improve duration of
response and can the reduce cumulative UVA dose (Table 8).
6.1.3.1 Stage IA–IIA mycosis fungoides
6.1.3.1.1 Psoralen–ultraviolet A and interferon-alpha RCTs have estab-
lished that combined PUVA and interferon-alpha are associated
with a reduced cumulative UVA dose to best response and an
improved duration of response compared with both PUVA
alone and interferon-alpha combined with acitretin.92–94 How-
ever, overall complete response rates for PUVA and interferon-
alpha appear to be similar to those with PUVA alone.93,95–102
6.1.3.1.2 Psoralen–ultraviolet A and retinoids The combination of
PUVA and retinoids (acitretin) is associated with a reduction
in cumulative UVA dose to best response, but with no dif-
ference in response rates compared with PUVA alone.99
PUVA and bexarotene have also been combined safely, with
similar response rates to PUVA alone.100 Weaknesses of
these studies include the lack of a validated scoring system
to assess tumour burden, and data regarding the duration
of response and disease-free survival/OS. A recent RCT
(EORTC-21011) comparing PUVA with combined PUVA
and bexarotene showed no significant difference in response
rates or duration of response, but a trend for lower cumu-
lative UVA dose to achieve complete response in the combi-
nation arm was noted.77
6.1.3.2 Stage IIB mycosis fungoides (MF); stage III erythrodermic MF/
Sezary syndrome (SS); stage IVA2–B MF/SS
Although there is a lack of data, combination regimens
involving PUVA have been utilized as first-line treatment for
patients with erythrodermic MF, but patients with SS toler-
ate PUVA poorly. In contrast, combination PUVA regimens
are rarely indicated as first-line therapy for tumour or nodal
disease, but are often used as an adjuvant or salvage ther-
apy for those patients with persistent cutaneous disease fol-
lowing debulking treatment for cutaneous tumours
or nodal/visceral disease, despite a lack of supportive
evidence.
6.1.4 Radiotherapy (localized radiotherapy)
6.1.4.1 Stage IA–IIA mycosis fungoides
MF is a highly radiosensitive malignancy, and localized radio-
therapy remains an effective treatment for patients with all
stages of disease.103–105 Palliative radiotherapy is very effec-
tive for plaques and small or large tumours, which respond
to relatively low doses of radiotherapy, such as 8 Gy in two
fractions.106 The dose-fractionation regimen should take into
account the size of the treatment area, the treatment site and
potential risk of acute and late damage to adjacent organs.
MF is a multifocal disease, and while local control with
radiotherapy is readily achievable, this is usually a palliative
approach. Therefore, it is appropriate to use the minimum
dose of radiotherapy to obtain local control. Using such a
low-dose approach also facilitates, if required, repeat treat-
ment or treatment to an adjacent area where fields may over-
lap with a previous treatment field. This is especially
important for sites with relatively poor skin tolerance to
radiotherapy, such as the lower legs. Single fractions of 7–
8 Gy have been shown to be effective and convenient for
the patient, but allow less re-treatment and may not be suit-
able for areas of skin with poor tolerance.107 The use of
higher doses of radiotherapy is seldom justified. Localized
radiotherapy can be used at the same time as other SDT,
including phototherapy.

British Journal of Dermatology (2018) © 2018 British Association of Dermatologists

 BAD and U.K. CLG guidelines for primary cutaneous lymphomas 2018, D. Gilson et al. 9
For treatment of large areas of skin such as the trunk, limbs
or whole scalp, smaller doses per fraction should be considered,
for example 20 Gy in 10 fractions. Regions such as the eyelids
may also benefit from smaller doses per fraction to limit acute
and long-term toxicity; 4 Gy in two fractions may produce
symptomatic benefit in this situation
To define the radiotherapy clinical target volume (CTV) a
margin of ≥ 1 cm should be allowed around the disease pla-
que or tumour (gross tumour volume), and larger margins
may be required for some techniques. Further margins need
to be added according to the local protocol and radiotherapy
mode to determine the planning target volume and field size
required to treat the area. To ensure that the full dermis (3–
5 mm thick) and a 5-mm-deep margin are being treated, the
treatment dose should be delivered to a depth of 8–10 mm
below the normal skin surface.
Rarely, MF can present as a solitary patch or plaque, and in
this setting local radiotherapy may be used with curative
intent (doses of 20–30 Gy in 2-Gy fractions).108–111
Modern radiotherapy techniques such as complex matched
electrons, intensity-modulated radiotherapy, helical Hi-ART
therapy (TomoTherapyâ) and high-dose-rate brachytherapy
mould techniques are increasingly being used to treat large
areas of disease on curved surfaces of the skin such as the
scalp, trunk and limbs, and can provide excellent durable dis-
ease control for many patients.
6.1.4.2 Stage IIB mycosis fungoides
Low-dose palliative radiotherapy (e.g. 12 Gy in three fractions)
is very effective for MF tumours. Tumours involving large areas
require smaller doses per fraction, with schedules of 20–30 Gy
in 10–15 fractions. Radiotherapy field margins on the skin
should be determined as outlined above. The treatment depth
required is determined by the thickness of the tumour and its
depth of invasion, which in turn determines the radiotherapy
mode required, for example orthovoltage X-rays, electrons or
photons. The depth of invasion may need to be assessed using
ultrasound, CT or magnetic resonance imaging.
6.1.4.3 Stage III–IVA1 erythrodermic mycosis fungoides/Sezary syndrome
Local radiotherapy may be used for patients who develop iso-
lated, symptomatic fissured lesions or tumours on a back-
ground of erythrodermic disease. It can also be useful for
treating extensive involvement of the hands and feet.
6.1.4.4 Stage IVA2–B mycosis fungoides/Sezary syndrome
Localized, peripheral nodal disease can be treated with local
external beam radiotherapy, as per standard protocols for non-
Hodgkin lymphoma. Visceral metastases can also be treated
with external beam radiotherapy using the same dosing sched-
ules. Relatively low doses or single fractions can provide effec-
tive palliation and should be considered.112 Central nervous
system disease in MF has a very poor prognosis. Palliative
low-dose, whole-brain radiotherapy can be used in patients
who are fit for treatment with a good performance sta-
tus.113,114
© 2018 British Association of Dermatologists
6.1.5 Radiotherapy: total skin electron beam therapy
TSEB is a highly effective treatment for MF with excellent
complete response rates for all stages.115–134 EORTC consensus
guidelines for the use of TSEB in CTCL have been pub-
lished.115 Critical issues to be addressed include maintenance
of response to TSEB.
6.1.5.1 Stage IA–IIA mycosis fungoides
A systematic review and meta-analysis of mostly nonrandom-
ized studies has established that the rate of complete response
in patients with early-stage disease treated with TSEB is depen-
dent on the stage of disease, skin-surface dose and energy deliv-
ered, with very high complete response rates observed.116
Greater skin-surface dose (32–36 Gy) and higher energy (4–6-
MeV electrons) are associated with a higher rate of complete
response and reasonable 5-year relapse-free survival
(Table 9).116–118 The conventional Stanford schedule of TSEB is
36 Gy delivered with a six dual-field technique to the whole
skin, delivering 2-Gy fractions per 2-day cycle over 9 weeks,
with local boost treatments to tumours and thick plaques, and
supplemental radiotherapy to a median dose of 20 Gy to ‘shad-
owed’ or self-shielding areas, such as the perineum, soles of
feet, scalp and inframammary folds.119 The standard U.K. mod-
ified Stanford protocol involved 30 Gy to the whole skin deliv-
ering 1
5-Gy fractions per 1-day cycle over 5 weeks.117 TSEB
delivering 30–36 Gy is associated with significant toxicity in
some patients. Fatigue has been reported in 38% of patients,
erythema and desquamation in 47–76%, alopecia in 95%,
lower-leg oedema in 26%, blisters in 19–52% and skin infec-
tion in 31–32%.117,120
A recent review has shown similar response rates and dura-
tion of response with lower doses of TSEB (10–30 Gy),121 but
a lower median response duration was reported following a
total dose of 10 Gy.122 Very low doses of TSEB (4 Gy) have
been tested, with reported inadequate responses.123 The results
of low-dose TSEB using 12 Gy have been reported from a
pooled analysis from three phase II trials. They showed an over-
all response rate (ORR) of 88%, with a median duration of clin-
ical benefit of 70
7 weeks.124 A series of low-dose TSEB (12 Gy
in eight fractions over 2 weeks) in 103 patients has shown a
similar very high ORR, with a median duration of response of
18 months in patients with stage IB MF and 10 months in
patients with stage IIB MF, with significantly less toxicity than
standard-dose TSEB.125 Studies of low-dose TSEB in combina-
tion with newer agents are currently under way.
One RCT comparing TSEB with topical mechlorethamine
showed similar rates of complete response and duration of
responses in early stages (IA–IB) of disease.126
The use of adjuvant PUVA and topical mechlorethamine after
TSEB has been reported, but the data are based on limited retro-
spective studies of small cohorts.127,128 It is not possible to rec-
ommend this as standard treatment, although PUVA can be used
as an effective early salvage therapy following TSEB. Further-
more, a recent report has shown no clinical advantage to the use
of topical mechlorethamine as adjuvant treatment after TSEB.119
British Journal of Dermatology (2018)
10 BAD and U.K. CLG guidelines for primary cutaneous lymphomas 2018, D. Gilson et al.

Table 9 Total skin electron beam (TSEB) therapy in mycosis fungoides/S
ezary syndrome

Therapy No. of patients Dose (Gy) Level of evidencea Stage ORR, % CR, % Median RFS/PFS (months)
127
High dose 114 30–36 2+ IA 100 97 50
High dose117,119 103, 17 30–36 2+ IB 100 59–75 18–29
High dose117,119 77, 19 30–36 2+ IIB 95–100 47 9
High dose117,131 3, 45 30–36 2+ III 100 33–60 6–9
Low dose122,134 21 10 2+ IB–IV 95 57 VGPR 5
8
Low dose124 33 12 3 IB–III 88 27 MDOCB 16–17
Low dose121 33 5 to < 10 2+ IB–III 85–100 0–25 12
Low dose121 51 10 to < 20 2+ IB–III 96–100 7–52 25
7
Low dose121 32 20 to < 30 2+ IB–III 83–100 29–37 29
3
Low dose125 103 12 2+ IB–IV 87 18 13
2
54 IB 94 20 26
5
33 IIB 97 21 8
7
12 III 50 8 10
6
4 IV 25 0 –

ORR, overall response rate; CR, complete response; RFS, relapse-free survival; PFS, progression-free survival; VGPR, very good partial remis-
sion with modified Severity Weighted Assessment Tool score < 1; MDOCB, mean duration of clinical benefit (date of TSEB to date of next
whole-skin-equivalent treatment). aSee Appendix S1 in the Supporting Information.

TSEB should be considered as second-line treatment for
stage IB MF that has relapsed or is refractory to other SDT. It
can also be considered as first-line treatment in patients with
extensive cutaneous disease (stage T2b).
6.1.5.2 Stage IIB-IVB mycosis fungoides
Patients with tumour stage IIB MF can achieve high rates of
durable complete responses to TSEB.121 One RCT included
103 patients with MF/SS (all stages) and compared TSEB and
multiagent chemotherapy (CAVE; cyclophosphamide, doxoru-
bicin, vincristine and etoposide) with sequential topical ther-
apy including superficial radiotherapy and phototherapy. It
revealed a higher complete response rate in the TSEB–
chemotherapy group (38% vs. 18%), but without a significant
difference in disease-free survival and OS.129 Nevertheless, a
combination of chemotherapy and TSEB can be invaluable for
patients with severe skin disease and late stages of disease
(stage IVA2–B). In addition, TSEB can be utilized as debulking
treatment prior to allogeneic stem cell transplantation.130
6.1.5.3 Stage III-IVA1 erythrodermic mycosis fungoides/Sezary syndrome
A retrospective study of TSEB as monotherapy for erythroder-
mic CTCL noted a higher complete response rate and lower
rate of disease progression in patients without peripheral
blood involvement (stage III disease) and in those receiving a
more intense regimen (32–40 Gy).131 These retrospective data
suggest that TSEB can be considered as second-line, and even
first-line therapy for patients with erythrodermic MF, although
patients with erythrodermic disease can be very sensitive to
radiotherapy and have severe acute radiation reactions. A
radiotherapy test dose to a limited area of skin should be used
before treatment, and careful patient selection is advised.
A retrospective study comparing TSEB alone with TSEB
followed by ECP in erythrodermic MF/SS suggests that the
combination of TSEB and ECP is associated significantly with
improved disease-free and cause-specific survival when cor-
rected for peripheral blood and nodal involvement, but
these retrospective data may be open to selection bias.132
There may be potential for TSEB to be used alone or in
combination for both skin and blood debulking in patients
with SS, but this needs further investigation in clinical
trials.133
6.2 Systemic biological therapies
6.2.1 Interferon-alpha
Interferon-alpha is licensed in the European Union for the
treatment of MF/SS (Table 10). There have been numerous,
relatively small open nonrandomized studies of interferon-
alpha in all stages of pretreated MF/SS, with variable dose
schedules (3–9 megaunits, three to seven times weekly). ORRs
> 50% and complete response rates > 20% have been
reported. Response rates are higher in early stages of disease
and with higher doses of interferon.135–137 A small, random-
ized study comparing PEGylated interferon-alpha-2b plus
PUVA with standard interferon-alpha-2b plus PUVA showed a
higher ORR with less constitutional side-effects for patients
treated with PEGylated interferon-alpha-2b plus PUVA.94
However, the patients in the PEGylated interferon arm had a
higher rate of myelosuppression and liver toxicity than those
treated with standard interferon.
6.2.1.1 Stage IA–IIA mycosis fungoides
Although higher response rates have been reported for inter-
feron in patients with early-stage MF,135–137 interferon-alpha
should not be used in patients with early-stage MF who are
responsive to SDT, as these patients have a good prognosis
and there is no evidence that interferon affects long-term
outcome.

British Journal of Dermatology (2018) © 2018 British Association of Dermatologists

 BAD and U.K. CLG guidelines for primary cutaneous lymphomas 2018, D. Gilson et al. 11

Table 10 Biological therapies in mycosis fungoides/S
ezary syndrome

Therapy Design Level of evidenceb Stage ORR, % CR, % Duration

135
Interferon-a Case series 2 IA–IVB 45–74 10–27 NA
Interferon-a Case series136 2 IA–IIA 88 ? NA
Interferon-a Case series138 2 IIB–IVB 29–63 ? NA
Bexarotene Phase II145 2+ IA–IIA 54 0 516 days
Bexarotene Phase II148 2+ IIB–IVB 45–51 0 299 days
Brentuximab vedotin Phase II160 2+ IB–IVB 73 35 32 weeks (range 3–93)
Brentuximab vedotin Phase II161 2+ IB–IVB 70 3 54% of responders
progression free at 12 months
Brentuximab vedotin RCT Phase III162 1+ 1A–IVB 56 16 16
7 months
Denileukin diftitoxa Phase II163 2++ IB–IVA 30 10 6
9 months
Denileukin diftitoxa RCT phase III164 1+ IA–III 44 10 > 2 years (PFS)
Alemtuzumab high dose Case series151,152 2 IIB–IV 37–100 25–47 6–9 months
Alemtuzumab low dose Case series154,155 2 IIB–IV 85 21 TTF 12 months
Vorinostata Phase II165 2+ IB–IVA 24–29
7 0 106–185 days
Romidepsina Phase II166 2+ IB–IVA 34 6 13
7–14
9 months
Bortezomib Case series167 2 III–IV 70 10 7–14 months

ORR, overall response rate; CR, complete response; RCT, randomized controlled trial; NA, not available; PFS, progression-free survival; TTF,
time to treatment failure. aApproved by the U.S. Food and Drug Administration but not the European Medicines Agency. bSee Appendix S1
in the Supporting Information.

However, for patients with early-stage MF who are refractory
to SDT, interferon and PUVA can be used in combination, and
evidence suggests that this may reduce the cumulative UV dose
required to achieve a complete response.99 One RCT comparing
PUVA and interferon with interferon plus acitretin in stage I
and II patients demonstrated that PUVA and interferon were
superior, with a 70% complete response rate compared with
38% for the drug combination.92
6.2.1.2 Stage IIB mycosis fungoides (MF); stage III–IVA1 erythrodermic
MF/Sezary syndrome (SS); stage IVA2–B MF/SS
Most studies of interferon have involved patients with refrac-
tory, advanced-stage disease but have not distinguished
between patients with erythroderma and either tumour-stage
disease or nodal involvement. Responses are dose dependent
but complete response is rare.135,136,138 Responses have been
reported with combined interferon-alpha and acitretin in
patients with MF and SS resistant to interferon alone.139 Aviles
et al.140 reported good response rates (80%) at 1 year with
combinations of interferon (5 megaunits three times a week)
and methotrexate or interferon and trans-retinoic acid. Data on
combined interferon-alpha and bexarotene are currently lim-
ited to case series.141 Patients with erythrodermic MF treated
with immunosuppressive therapy such as ciclosporin for sus-
pected inflammatory disorders may have a more aggressive
disease course and worse outcome.142
time to response, and improve duration of response,143,144
although the only RCT92 suggested no benefit.
Prospective studies of bexarotene, a retinoid X receptor rex-
inoid, have shown significant efficacy and good duration of
response with low rates of disease progression in early-stage
disease.145 Bexarotene has been used in combination with
PUVA;102,146 however, the EORTC-21011 RCT in low-risk MF
comparing PUVA alone with PUVA plus bexarotene showed
no difference in response rates.77
6.2.2.2 Stage IIB mycosis fungoides (MF); stage III–IVA1 erythrodermic
MF/Sezary syndrome (SS); stage IVA2–B MF/SS
Bexarotene is licensed in the European Union for the treat-
ment of late-stage MF/SS refractory to at least one systemic
agent, and U.K. consensus guidelines for bexarotene prescrib-
ing and management have been published.147 Maximum
responses may take 6 months, and bexarotene should be con-
tinued until loss of response.
Prospective studies of bexarotene in refractory, late-stage
disease have shown encouraging ORRs and response durations
at doses of 300 mg m2 daily,148 which have been confirmed
in subsequent case series.146,149 These results suggest that bex-
arotene has a useful role, particularly for erythrodermic dis-
ease, but monotherapy is unlikely to be effective for tumours
or nodal disease. Whether adjuvant bexarotene has a role in
maintaining remission or partial responses in those patients
with pretreated advanced disease is currently unknown.

6.2.2 Retinoids and rexinoids

6.2.2.1 Stage IA–IIA mycosis fungoides
Retinoic acid receptor retinoids (acitretin) have modest effects
in early stages of MF as monotherapy, but in combination
with PUVA they may reduce the cumulative UVA dose and
6.2.3 Antibody therapies
6.2.3.1 Stage IA–IIA mycosis fungoides
At present, there is no evidence that antibody therapies should
be used for patients with early-stage disease.

© 2018 British Association of Dermatologists British Journal of Dermatology (2018)

12 BAD and U.K. CLG guidelines for primary cutaneous lymphomas 2018, D. Gilson et al.

expression appeared to correlate with tumour responses. Those

6.2.4 Alemtuzumab (CAMPATH-IH)
6.2.4.1 Stage IIB mycosis fungoides (MF); stage III–IVA1 erythrodermic
MF/Sezary syndrome (SS); stage IIVA2–B MF/SS
Phase II trials of alemtuzumab (a humanized anti-CD52 anti-
body) in small cohorts of patients with advanced MF/SS have
shown encouraging ORRs.150–156 Reported overall response
and complete remission rates are high, but typically responses
are short lived, with only a minority of patients achieving
responses for longer than 12 months. Clinical responses are
best in SS, where symptomatic benefit may be dramatic. In
contrast, recent evidence suggests that alemtuzumab is ineffec-
tive in patients with MF with tumours and large cell transfor-
mation.157
Reports of possible cardiac toxicity158 have not been con-
firmed and the safety profile has been acceptable even in
elderly patients, although infection and specifically cytomega-
lovirus reactivation remains an issue and patients need irradi-
ated blood products.155 In the majority of studies,
alemtuzumab has been administered intravenously at the stan-
dard dose of 30 mg three times per week. However, one
study examined the use of a lower-dosage subcutaneous
schedule at 10 mg three times per week, with similar efficacy
but reduction in toxicity.154 Alemtuzumab remains an impor-
tant second-line therapeutic option for patients with advanced
disease, particularly erythrodermic stage III–IVA1 MF/SS.
6.2.5 Brentuximab vedotin
Brentuximab vedotin is an antibody–drug conjugate comprised of
an anti-CD30 monoclonal antibody attached by an enzyme-cleava-
ble linker to the antimicrotubule agent, monomethyl auristatin E,
which is released upon internalization into CD30-expressing
tumour cells. It is administered intravenously at 1
8 mg kg1 over
30 min every 21 days, for a maximum of 16 cycles.159
Phase II trials demonstrated encouragingly high response
rates,160,161 where the proportion of CD30 tumour cell
with < 5% CD30 expression had a lower likelihood of global
response than did those with CD30 expression ≥ 5%.161
Further to these phase II trials, a randomized, open-label
phase III trial (ALCANZA) was designed to evaluate single-agent
brentuximab vedotin vs. a control arm of the investigator’s
choice of standard therapies, namely methotrexate or bexaro-
tene, in patients with CD30-expressing CTCL, including those
with primary cutaneous anaplastic large cell lymphoma
(pcALCL) or MF. The primary end point was objective response
lasting at least 4 months (ORR4) as assessed by Global Response
Score. Brentuximab vedotin resulted in a statistically significant
improvement in the rate of ORR4 (56
3% vs. 12
5% in the con-
trol arm). The median PFS was 16
7 months vs. 3
5 months, a
significant difference favouring brentuximab (P < 0
001).
In November 2016, the FDA granted brentuximab vedotin
Breakthrough Therapy designation for the treatment of
patients with CD30-expressing MF and pcALCL who require
systemic therapy and have received one prior systemic ther-
apy. The phase III data from this trial have also led to EMA
approval in patients with CD30+ CTCL.162 Peripheral neuropa-
thy is a frequent side-effect, occurring in over 60% of
patients, but resolution or improvement of symptoms on ces-
sation of treatment is reported.
Other biological therapies are listed in Table 10.163–167
6.3 Chemotherapy
Systemic chemotherapy (Table 11) is usually reserved for
patients with advanced disease, or disease refractory to SDT or
immunobiological therapy, and is palliative rather than cura-
tive.168–189 Although good responses are reported with both
single-agent and combination regimens, overall the results are
disappointing when compared with other lymphomas. A par-
ticular difficulty in interpreting data in this area is the variable
and largely suboptimal reporting of response assessment and
the heterogeneity of risk factors within the spectrum of the

Table 11 Chemotherapy in mycosis fungoides/S
ezary syndrome

Therapy Design Level of evidencea ORR, % CR, % Median RFS or PFS (months)
174–177,181
Pentostatin Case series 2 35–71 6–32 9
Cladribine Case series178 2 28–41 14–19 4
5
Fludarabine Case series179,188 2 30–51 11
4 5
9
Liposomal doxorubicin Case series183 2 80–88 45–66 15
Liposomal doxorubicin EORTC-21012184 2+ 40
8 6
1 6
Gemcitabine Case series180–182 2 68–75 8–22 10–15
Methotrexate Case series170 2 58 41 31
Trimetrexate Case series171 2 45 Not recorded
Pralatrexate Phase II189 2+ 45 Not recorded
Combination chemotherapy Systematic review168 2+ 81 38 5–41
Chlorambucil Case series169 2 89 36 Not recorded
EPOCH Phase II187 2+ 80 27 8

ORR, overall response rate; CR, complete response; RFS, relapse-free survival; PFS, progression-free survival; EORTC, European Organisation
for Research and Treatment of Cancer; EPOCH, etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin. aSee Appendix S1 in
the Supporting Information.

British Journal of Dermatology (2018) © 2018 British Association of Dermatologists

 BAD and U.K. CLG guidelines for primary cutaneous lymphomas 2018, D. Gilson et al. 13
patients with MF and SS who are treated. In the absence of
randomized, phase III trials, comparison of response rates
across phase II studies is fraught with difficulties of interpreta-
tion, and therefore recommendations are subject to inherent
investigator and reporting bias.
6.3.1 Stage IA–IIA mycosis fungoides
Chemotherapy is contraindicated for early stages of disease, as
low-grade disease is relatively resistant to chemotherapy and
response duration is short.
6.3.2 Stage IIB mycosis fungoides (MF); stage III–IVA1
erythrodermic MF/Se
zary syndrome (SS); stage IVA2–B
MF/SS
Quaglino et al. found treatment heterogeneity between U.S.
and non-U.S. centres but no difference in survival.38 However,
a constant geographical feature was the finding that first-line
chemotherapy was associated with a higher risk of death.
One RCT comparing combination chemotherapy and TSEB
against conservative SDT showed a better overall response in
the combination arm but greater morbidity and no improve-
ment in OS.129 A systematic review of uncontrolled open
studies of single-agent regimens in 526 patients with CTCL treated
between 1988 and 1994 revealed OR rates of 62%, with com-
plete response rates of 33% and median response durations of
3–22 months.168 Single-agent therapies showing clinical effi-
cacy in MF/SS include alkylating agents (chlorambucil and
cyclophosphamide),169 antimetabolites (methotrexate and
trimetrexate),170,171 purine analogues (pentostatin, 2-chloro-
deoxyadenosine and fludarabine),172–179 the pyrimidine
antimetabolite gemcitabine180–182 and liposomal doxoru-
bicin.183,184 A recent U.K. prospective phase II study assessing
a combination regimen incorporating gemcitabine and bexaro-
tene in advanced MF/SS (GEMBEX) showed a low response
rate following chemotherapy at 12 weeks (31%, all with par-
tial response), reducing to a 14% ORR at 24 weeks despite
bexarotene maintenance. In addition, control of hyperlipi-
daemia was challenging with this combination.185
A systematic review of different combination chemotherapy regi-
mens in patients with MF and SS stages IIB–IVB treated between
1988 and 1994 showed an OR rate of 81% in 331 patients
and a complete response rate of 38%, with response duration
ranging from 5 to 41 months.168 The most commonly
reported regimen used in MF/SS is CHOP (cyclophosphamide,
doxorubicin, vincristine, prednisone). Prospective,
Table 12 Electrophoresis (ECP) in mycosis fungoides/S
ezary syndrome (adapted from Scarisbrick et al.)196
Therapy Design Level of evidencea
ECP Systematic review 2+
ECP Systematic review 2+
ECP Multiple case series 2
ORR, overall response rate; CR, complete response; OS, overall survival. aSee Appendix S1 in the Supporting Information.
© 2018 British Association of Dermatologists
nonrandomized studies of other multiagent chemotherapy reg-
imens – VICOP-B (etoposide, idarubicin, cyclophosphamide,
vincristine, prednisolone, bleomycin) and EPOCH (etoposide,
prednisolone, vincristine, cyclophosphamide, doxorubicin) –
have revealed similar OR rates and durations of response to
those for CHOP.186,187 Overall survival rates remain
unchanged for these more intensive regimens and toxicity
may be considerable; therefore, these regimens have little clin-
ical benefit over less intensive regimens.
The patient’s quality of life should always be considered
before embarking on chemotherapy regimens with limited
efficacy. Patients with CTCL are at high risk of neutropenic
sepsis, and therapy-related mortality with combination
chemotherapy is a significant risk. Single-agent regimens
appear to have similar efficacy to combination regimens but
with lower toxicity, and therefore are preferable as palliative
therapy in late stages of MF and SS. Durable responses with
either single- or multiagent regimens are rare.
The limited data suggest that methotrexate and pentostatin
are most appropriate for erythrodermic SS, while gemcitabine
and liposomal doxorubicin are more appropriate for advanced
stages of MF. Maintenance or adjuvant treatment with bioim-
munotherapy, SDT or TSEB for patients achieving a response
with chemotherapy may be considered. Patients frequently
relapse, with early stages of disease manifested by patches and
plaques, although there is no trial evidence suggesting that
any such approach improves outcomes, and further well-
designed studies are required.
While outcomes are invariably poor for patients with
advanced disease, with median survival of < 12 months (stage
IV), for those stage IVA2 patients with a good performance sta-
tus, the aim is to achieve a durable complete or good partial
remission and to proceed to a reduced-intensity allogeneic
transplant.
6.4 Extracorporeal photopheresis
6.4.1 Stage IA–IIA mycosis fungoides
Although responses to ECP have been reported in early-stage
MF, this is based mostly on a small number of patients in
poorly controlled single-centre studies, including some in
which patients were treated with adjuvant therapies
(Table 12).190–192 The only randomized study looking at
patients with early-stage MF treated with either PUVA or ECP
showed that PUVA was more effective over a 6-month treat-
ment period.193 Therefore, there is no evidence at present to
Stage ORR, % CR, % OS (months)
IB–IV 63 20
III 35–71 14–26 39–100
III 31–86 0–33
British Journal of Dermatology (2018)
14 BAD and U.K. CLG guidelines for primary cutaneous lymphomas 2018, D. Gilson et al.
suggest that ECP should be used for patients with early-stage
disease.
6.4.2 Stage IIB mycosis fungoides
ECP is not effective for stage IIB MF.194,195
6.4.3 Stage III–IVA1 erythrodermic mycosis fungoides/

zary syndrome
Se
A systematic review of nonrandomized and mostly retrospective
studies of ECP in 650 patients from 30 published studies
showed an ORR of 63% and a complete response rate of
20%.196 Response rates are highest in those with erythrodermic
stage III–IVA1 MF/SS.190,197–200 Treatment is given on two
consecutive days and repeated every 4 weeks, but it may be
given more frequently (e.g. every 2 weeks) in those with a
high blood-tumour burden.194,196,201 Responses may take up
to 6 months to develop and therapy should continue until loss
of response. The U.K. consensus guidelines for ECP in CTCL
recommend ECP as first-line systemic treatment in patients with
erythrodermic CTCL with evidence of blood involvement, treat-
ing with one to two cycles per month. The guidelines were
recently updated in 2017 with the recommendation that ECP
treatment should be continued until loss of response.196,202
A recent U.K. audit report of 97 patients with CTCL treated
since 2010 found that 45% had received ECP as the first-line
systemic agent.203 The response rate at 6 months was 61%
and the median length of treatment was 9 months. There have
been numerous small case series of erythrodermic patients
treated with combinations of ECP, interferon-alpha and/or
retinoids, as well as bexarotene, which suggest that combina-
tion therapy can be highly effective, as both clinical and
molecular remissions have been documented.196,204–213
Although these studies were uncontrolled, the evidence sug-
gests that ECP can be an effective and well-tolerated therapy
for patients with erythrodermic stage III–IVA1 MF/SS and that
such patients may benefit from combination regimens com-
bining ECP with other systemic therapies. ECP is an FDA-
approved treatment for MF/SS. In contrast, there is a lack of
evidence for use of ECP in stage IVA2–B MF/SS.
6.5 Systemic therapies (Food and Drug Administration
but not European Medicines Agency approved)
6.5.1 Toxin therapies (denileukin diftitox: diphtheria
interleukin-2 fusion toxin; Ontak)
Denileukin diftitox is a fusion protein targeting the interleukin-
2 receptor (CD25). Large RCTs have shown significant efficacy
and improved PFS in all stages of disease (Table 9). Denileukin
diftitox is FDA but not EMA approved for MF/SS, but it is cur-
rently not available in the U.S.A. because of a manufacturing
change, and results of an ongoing trial are awaited. Toxicity
includes hypersensitivity reactions and vascular leak.
British Journal of Dermatology (2018)
6.5.1.1 Stage IA–IIA mycosis fungoides
Toxin therapies should not be used for early-stage disease in
view of potential adverse effects, but denileukin diftitox can
be effective for early-stage patients who are resistant to SDT.
6.5.1.2 Stage IIB mycosis fungoides (MF); stage III–IVA1 erythrodermic
MF/Sezary syndrome (SS); stage IVA2–B) MF/SS
Denileukin diftitox (18 lg kg1 per day for 5 days, as a 21-
day cycle) is effective in heavily pretreated patients with late
stages of disease,163,164,214 and efficacy may be improved by
combining with bexarotene.215
6.5.2 Histone deacetylase inhibitors
Histone deacetylase (HDAC) inhibitors are an emerging class of
drugs that increase acetylation of histones and nonhistone pro-
teins affecting gene transcription, which results in cell-cycle
arrest and apoptosis. Several phase II studies have established
that HDAC inhibitors have clinical efficacy in all stages of MF/
SS, with an acceptable safety profile.165,166,216,217 These studies
led to FDA approval for vorinostat (suberoylanilide hydroxamic
acid) and romidepsin for the treatment of refractory MF/SS.
Neither HDAC inhibitor is licensed for use in Europe.
6.5.2.1 Stage IA–IIA mycosis fungoides
HDAC inhibitors should not be used for early-stage MF but
can be effective for patients resistant or refractory to SDT.
6.5.2.2 Stage IIB mycosis fungoides (MF); stage III–IVA1 erythrodermic
MF/Sezary syndrome (SS); stage IVA2–B MF/SS
Phase II studies of vorinostat and romidepsin have shown sim-
ilar ORRs in advanced disease including stage III
patients.165,166,216,217 Evaluation of patients on vorinostat for
over 2 years provides evidence of long-term safety and tolera-
bility.218 One study also showed a significant improvement in
pruritus in 43% of patients, including those who had no
objective clinical response.166
6.5.3 Other systemic chemotherapies
Pralatrexate belongs to a class of folate analogues, known as
the 10-deazaaminopterins, and is emerging as a promising
new agent in the treatment of T-cell lymphomas, including
CTCL. Phase II trials have demonstrated good response rates,
although adverse effects, including mucositis, are a con-
cern.219 A further study, using a lower dose of pralatrexate,
reported better tolerance but similar response rates.189
6.6 Systemic therapies (not Food and Drug
Administration or European Medicines Agency approved)
Bortezomib, a proteasome inhibitor, has shown clinical efficacy
in a small series of patients with advanced stages of CTCL,167
but its clinical role remains to be established. Temozolomide
has also been reported to be effective in a minority of patients
© 2018 British Association of Dermatologists
 BAD and U.K. CLG guidelines for primary cutaneous lymphomas 2018, D. Gilson et al. 15
in a small multicentre study of patients with advanced MF/
SS220 and those with central nervous system progression.114
6.7 Autologous or allogeneic peripheral blood or bone
marrow stem cell transplant
Autologous haemopoietic stem cell transplant (HSCT) appears
to be associated with only short-term remission and is there-
fore difficult to justify.221–223 In contrast, allogeneic HSCT is a
complex form of immunotherapy aimed at consolidating treat-
ment of advanced MF/SS to produce a durable complete
remission.224 A retrospective study from the European Group
for Blood and Marrow Transplant (EBMT) included a hetero-
geneous group of patients who received both myeloablative
and reduced-intensity conditioning (RIC) regimens. The study
showed an estimated 3-year survival rate of 54%.225 However,
the treatment-related mortality of 25% at 1 year for CTCL was
a concern. The EBMT data suggested that alemtuzumab should
not be used as part of the pretransplant conditioning regimen
because of a higher rate of early relapse and increased treat-
ment-related mortality.225
A number of other case reports and small retrospective
series have also described clinical responses and durable
remissions of more than 3 years following myeloablative
allo-HSCT226–229 and reduced-intensity conditioning allo-
HSCT.229–234 A single-centre report described outcomes in 19
recipients of allo-HSCT using an RIC regimen that included
TSEB irradiation prior to transplant. Eleven patients achieved
sustained complete remissions, some of which were following
donor lymphocyte infusion, immunosuppression withdrawal
and/or chemotherapy.130 An update of this study utilizing
pretransplant TSEB in the majority of patients showed that
60% achieved complete skin remission as a result.235
A more recent analysis of the EBMT cohort (60 patients
with MF/SS) in 2014 reported an OS of 46% and PFS of 32%
at 5 years.236 Relapse or progression occurred in 45% at a
median of 3
8 months following HSCT, but many patients
were rescued with donor lymphocyte infusions. Nonrelapse
mortality was 22%, with the last nonrelapse death occurring
14 months following HSCT. Multivariate analysis confirmed
worse outcomes for myeloablative conditioning regimens and
transplants from unrelated donors.236 A meta-analysis of allo-
geneic or autologous SCT in MF and SS supports the view that
allogeneic transplantation provides a better survival and dis-
ease-free outcome than autologous transplantation.237
There is increasing enthusiasm for RIC allograft approaches
for a number of reasons. CTCL affects older patients, many of
whom have chronically infected skin tumours, and the risk of
life-threatening sepsis is lower with reduced-intensity allo-
grafts. Allogeneic transplant is successful in part because of
the graft-versus-lymphoma effect of the donor graft, indepen-
dent of the conditioning regimen, but this has to be balanced
against the morbidity associated with chronic graft-versus-host
disease.225 In addition, and relevant to the above, a major risk
following allogeneic transplant is disease relapse. Clearly,
some patients can be salvaged with donor lymphocyte
© 2018 British Association of Dermatologists
infusion, but this in turn may lead to significant graft-versus-
host disease.
Maximal benefit from RIC-HSCT is observed when it is per-
formed before patients develop highly refractory disease and
when there is low disease bulk at the time of transplanta-
tion.225 Appropriate data registration is required to identify
the optimal conditioning regimen for allo-HSCT and to define
clinical outcomes. Considering the numerous biological agents
that are becoming available and the potential efficacy of allo-
HSCT, younger patients with stage IIB–IV disease and poor
prognostic factors or aggressive disease should be reviewed at
supranetwork MDTs and, if appropriate, referred early to a
specialist transplant centre.
6.8 Future perspectives
FDA-approved therapies include topical bexarotene gel,
mechlorethamine gel, oral bexarotene, denileukin diftitox,
photopheresis and the HDAC inhibitors vorinostat and romi-
depsin.
In contrast, only topical mechlorethamine ointment for all
stages of MF, and interferon-alpha, brentuximab and oral bex-
arotene for late-stage refractory MF/SS, are EMA approved.
Currently, there is an unmet need for improved treatments in
CTCL and an urgent need for well-designed RCTs with appro-
priate clinical end points.
Until recently, denileukin diftitox was not available world-
wide because of manufacturing problems, although new clini-
cal trials have commenced.
Recommendations
• The diagnosis of MF and SS is based on a combination
of clinical and pathological criteria and requires close
MDT collaboration between different specialities.
(Strength of recommendation D (GPP))
• All patients with early-stage MF refractory to SDT and
late-stage MF/SS should be reviewed by supranetwork
MDTs to agree a management plan and provide the
opportunity for consideration in appropriate clinical
trials. (Strength of recommendation D (GPP))
• The aim of treatment is to control the patient’s disease
and symptoms with the minimum of intervention.
Management may range from an expectant policy
through to nonmyeloablative allogeneic stem cell trans-
plantation. (Strength of recommendation D (GPP))
• SDTs, including phototherapy and local radiotherapy,
are the standard of care for patients with early-stage
IA–IIA MF. (Strength of recommendation C)
• Patients with stage IA–IIA MF who are refractory to
SDT often require TSEB and systemic biological thera-
pies. There is no evidence to support the use of main-
tenance phototherapy. (Strength of recommendation C)
• Patients with stage IIB MF can have an unpredictable
clinical course: some patients develop only small and
infrequent skin tumours and often obtain durable
British Journal of Dermatology (2018)
16 BAD and U.K. CLG guidelines for primary cutaneous lymphomas 2018, D. Gilson et al.
responses to localized radiotherapy and other SDT
options for persistent patches and plaques; other
patients develop extensive bulky skin tumours and
rapidly progressive disease requiring TSEB and systemic
chemotherapy. (Strength of recommendation C)
• Following treatment, patients with advanced MF may
develop recurrent, low-grade disease where SDT is a
treatment option. (Strength of recommendation D (GPP))
• Patients with erythrodermic MF (stage III) and SS
(stage IVA1) often require single or combination sys-
temic therapies such as methotrexate, photopheresis,
bexarotene and interferon-alpha as first-line treatment.
(Strength of recommendation C)
• Options for SS (stage IVA1–2) also include clinical tri-
als and alemtuzumab. (Strength of recommendation C)
• For stage IVA2–B MF/SS, radiotherapy (including TSEB
for selected stage IV patients) and single-agent
chemotherapy regimens are the preferred option, but
response duration is often short. (Strength of recommenda-
tion C)
• Brentuximab offers an effective option for refractory
stage IB disease and advanced stages of MF/SS with
tumour CD30 expression. (Strength of recommendation B)
• All patients with early-stage MF refractory to SDT and
stage IIB–IV MF/SS should be offered the opportunity
to participate in well-designed clinical trials. (Strength of
recommendation D (GPP))
• Autologous HSCT should not be considered for
advanced stages of MF/SS. (Strength of recommendation A)
• Reduced-intensity allogeneic HSCT should be considered
for selected groups of patients with advanced MF/SS to
consolidate treatment responses. (Strength of recommendation B)
• The conditioning regimens and outcomes of RIC allo-
HSCT should be collected through data registries such
as the EBMT registry. (Strength of recommendation D (GPP))
7.0 Treatment of non-mycosis fungoides/
Se
zary syndrome primary cutaneous T-cell
lymphomas
7.1 Primary cutaneous CD30+ lymphoproliferative
disorders
Primary cutaneous CD30+ lymphoproliferative disorders rep-
resent a spectrum of disorders, and the diagnosis is depen-
dent on careful assessment of both clinical and pathological
features. Specifically, MF must be excluded by a clinical
evaluation that fails to identify pre-existing or coexistent
polymorphic patches and plaques in a characteristic limb-
girdle distribution. There is only one RCT involving this
condition, and the evidence is based on the EORTC, ISCL
and United States Cutaneous Lymphoma Consortium consen-
sus statement,15 which is the appropriate source for refer-
ences supporting all the treatment recommendations below.
British Journal of Dermatology (2018)
7.1.1 Primary cutaneous CD30+ anaplastic large cell
lymphoma
pcALCL is characterized by solitary tumours, grouped tumours
or thick plaques of disease. Rarely, patients present with gener-
alized multifocal lesions. Partial regression may occur but it is
rarely complete, and this clinical feature helps to distinguish
pcALCL from LyP. The tumour phenotype is CD30+ ALK, and
this CTCL variant is biologically distinct from its nodal counter-
part. The prognosis is excellent, with 5-year survival rates of
96%.31 Staging is based on the non-MF/SS staging recommen-
dations,24 and CT scans and bone marrow trephine biopsies are
required to confirm that the skin disease is not a manifestation
of a systemic lymphoma. Primary cutaneous CD30+ ALK+ ALCL
has been rarely described but there is no evidence that such
patients have a worse prognosis.
7.1.1.1 Surgery
Surgical excision can be an effective treatment for solitary
tumours. If the lesion has been completely excised with clear
histological margins, it may be appropriate to manage the
patient with adjuvant radiotherapy or active surveillance.
7.1.1.2 Radiotherapy
Radiotherapy is an effective treatment modality for pcALCL,
with very high complete remission rates reported. Cutaneous
recurrences have been reported in 41–64% of patients.15
International consensus recommends a dose of 24–30 Gy.238
7.1.1.3 Chemotherapy
Doxorubicin-based, multiagent chemotherapy regimens are
effective with high complete response rates, but response
duration is limited with relapses in > 60% of patients.15 Vin-
blastine has been effective as a single agent in pcALCL.239
There are only limited reports of single-agent chemotherapy
agents such as methotrexate, etoposide and gemcitabine.
7.1.1.4 Antibodies
The fusion toxin brentuximab vedotin (SGN-35) in a large
phase III RCT in pcALCL has shown significant benefit in
terms of durable response and improved PFS compared with
methotrexate or bexarotene.162
7.1.2 Lymphomatoid papulosis
LyP is characterized by recurrent, papulonodular eruptions that
resolve spontaneously to leave varioliform scars. The pathology
shows variable proportions of CD30+ large cells (type A–D).
7.1.2.1 Expectant policy
For patients with limited disease and infrequent eruptions, an
active monitoring policy is acceptable.
7.1.2.2 Phototherapy
Phototherapy is effective in LyP but there is a lack of data on
dosage, and relapse is common when treatment is withdrawn.
© 2018 British Association of Dermatologists
 BAD and U.K. CLG guidelines for primary cutaneous lymphomas 2018, D. Gilson et al. 17
7.1.2.3 Chemotherapy
Weekly low-dose oral methotrexate is highly effective in LyP,
but only a minority of patients experience a durable remission
following treatment withdrawal.15
7.1.2.4 Radiotherapy
Radiotherapy can be very effective especially for patients with
regional LyP, and responses can be durable.15
7.1.2.5 Immunobiological therapy
There are very limited data on retinoids, interferon-alpha and
bexarotene, but responses have been reported with all of these
agents in LyP. Brentuximab is effective.160
7.2 Rare cutaneous T-cell lymphoma variants
There are various rare and aggressive CTCL variants including
cd CTCL and PTCL (not otherwise specified, NOS), which can
primarily involve cutaneous tissues. The diagnosis in such
cases requires careful evaluation of the clinical features, stag-
ing investigations and pathology. Human T-lymphotropic
virus-1 virology should be considered to exclude a cutaneous
presentation of adult T-cell leukaemias/lymphoma; there are
no controlled trial data. Treatment options are the same as
those recommended in the British Committee for Standards in
Haematology 2013 guidelines.240
Rare CTCL variants such as subcutaneous panniculitis-like T-
cell lymphoma (SPTCL), CD4+ small/medium T-cell lympho-
proliferative disorder, acral CD8+ T-cell lymphoma and
aggressive epidermotropic cytotoxic CD8+ CTCL are character-
ized by distinct clinical and/or pathological features and, with
the exception of the latter, have an excellent prognosis.
7.2.1 Subcutaneous panniculitis-like T-cell lymphoma
SPTCL is a rare CTCL variant characterized by subcutaneous
plaques and tumours and cytologically atypical CD8+ T cells
rimming fat lobules.241 Localized disease may respond to
radiotherapy. Patients may be steroid responsive but are
likely to relapse, although immunosuppressive drug therapy
has been more effective than chemotherapy for some
patients.242 Patients with haemophagocytic syndrome and
steroid-resistant disease respond to doxorubicin-based
chemotherapy regimens (CHOP), with durable remissions
reported.241 Durable responses have also been reported fol-
lowing high-dose chemotherapy and stem cell transplanta-
tion.243 Ciclosporin may be effective in patients failing
cytotoxic chemotherapy.244
7.2.2 CD4+ small/medium pleomorphic T-cell
lymphoproliferative disorder and primary cutaneous CD8+
acral T-cell lymphoma
Primary cutaneous small/medium CD4+ lymphoproliferative
disorder has an excellent prognosis, although it can be
© 2018 British Association of Dermatologists
difficult to distinguish from reactive lymphoid proliferations.
Surgical excision and local radiotherapy are acceptable treat-
ment options.245 Rare CD8+ acral CTCL variants also have an
excellent prognosis and can also be treated with surgical exci-
sion or radiotherapy.246 However, the disease may follow a
more aggressive path in patients who present with large
rapidly progressive tumours or multifocal disease; this requires
treatment as for PTCLs.247
7.2.3 CD8+ aggressive epidermotropic cytotoxic cutaneous
T-cell lymphoma and primary cutaneous cd T-cell
lymphoma
These rare CTCL variants are diagnosed on the basis of typical
clinicopathological features with usually widespread ulcerated
plaques. Systemic dissemination (central nervous system) is
common. Multiagent chemotherapy options such as CHOP-like
regimens are appropriate, and TSEB can be an effective pallia-
tive approach. Transplant options should be considered for eli-
gible patients.
Recommendations
• Primary cutaneous CD30+ lymphoproliferative disor-
ders are diagnosed on the basis of careful clinicopatho-
logical correlation. Staging investigations are not
appropriate for LyP but are essential for ALCL or bor-
derline cases. (Strength of recommendation D (GPP))
• Treatment for LyP ranges from an expectant policy for
patients with limited disease to phototherapy, radio-
therapy, low-dose methotrexate or interferon-alpha for
patients with extensive disease. (Strength of recommendation
C)
• Treatment for CD30+ pcALCL consists of surgical exci-
sion and/or radiotherapy for localized disease. (Strength
of recommendation B)
• Combination chemotherapy or brentuximab may be
appropriate for patients with CD30+ pcALCL with
extensive cutaneous disease or those with systemic pro-
gression. (Strength of recommendation B)
• Treatment of rare CTCL variants depends on the sub-
type, as some (SPTCL, CD4+ small/medium pleomor-
phic, CD8+ acral T-cell lymphoma) are indolent with
an excellent prognosis, while others are aggressive and
may require chemotherapy and consideration for stem
cell transplant in line with recommendations for sys-
temic PTCL (NOS). (Strength of recommendation C)
• Primary cutaneous PTCLs (NOS) are rare and heteroge-
neous in behaviour. Some present with limited skin
disease that can be managed with skin-directed options
such as radiotherapy, while others present with exten-
sive or bulky skin disease and will require treatment
options as for systemic PTCL (NOS). (Strength of recom-
mendation C)
British Journal of Dermatology (2018)
18 BAD and U.K. CLG guidelines for primary cutaneous lymphomas 2018, D. Gilson et al.
8.0 Treatment of primary cutaneous B-cell
lymphomas
For the purpose of this guideline, separate recommendations
have been made for low-grade lymphomas (PCMZL and
PCFCL), high-grade PCLBCL and the rare PCLBCL (NOS).
PCMZL and PCFCL have an excellent prognosis, and although
cutaneous relapses are frequent, systemic spread is rare.
PCLBCLs are aggressive lymphomas with considerable mortal-
ity and require systemic chemotherapy in most instances.
There are no RCTs but there are published EORTC consensus
guidelines.11
8.1 Primary cutaneous marginal zone and follicle centre
lymphoma
8.1.1 Excision
Complete surgical excision may be considered for small
lesions for both diagnosis and therapy, but there is no litera-
ture to guide margins of resection. In patients with PCMZL
and PCFCL treated with complete excision, over 40% are
reported to relapse.11 Where the lesion has been excised com-
pletely, a policy of monitoring or radiotherapy to the scar
with a 1
5-cm margin to CTV around the scar238 can be con-
sidered to reduce the risk of local recurrence. In larger lesions
where complete excision would result in a significant cosmetic
scar or functional defect, a diagnostic biopsy should be per-
formed and followed by radiotherapy.
8.1.2 Antibiotics
In patients with PCMZL and positive B. burgdorferi serology
there are reports of complete response following antibiotic
treatment.11 The U.K. Health Protection Agency guidance on
treatment for Borrelia with oral antibiotics should be followed
before considering other therapies.
8.1.3 Radiotherapy
Radiotherapy is the standard treatment for both PCMZL and
PCFCL. The EORTC consensus recommendations11 reported data
on 132 patients with PCMZL and 460 with PCFCL treated with
radiotherapy. Of the patients with PCMZL, 99% achieved com-
plete remission and only 46% of patients showed one or more
relapses. Extracutaneous progression was reported in only three
of 132 patients, one of whom died of lymphoma. The radio-
therapy doses reported varied from 10 Gy to 50 Gy, and most
studies used a treatment margin around the tumour of 1–5 cm.
Of the patients with PCFCL, almost all achieved complete
response with radiotherapy. Three major studies in PCFCL
combining 147 patients reported a relapse rate of 30% when
margins > 2 cm were used.248–250 This differs from the
relapse rate of 67% in a small study that used margins of 0
5–
1 cm, where frequent in-field and marginal recurrences were
reported.251 On the basis of this evidence, it is recommended
British Journal of Dermatology (2018)
that the radiotherapy CTV should be the tumour plus a 1
5-
cm margin of normal skin around the tumour.238
In the U.K., the standard radiotherapy dose for indolent
non-Hodgkin lymphoma is 24 Gy in 12 fractions, based on
the results of a multicentre, prospective RCT comparing 40 Gy
vs. 24 Gy in 2-Gy fractions for indolent follicular and mar-
ginal zone lymphoma.252 Lower doses or shorter fractionation
schedules (e.g. 8 Gy in two fractions for multiple lesions;
15 Gy in five fractions for solitary lesions) have been used in
many centres with good results.253 The Leiden group have
reported complete response rates of 72% and re-treatment
rates of 29% with 4 Gy in two fractions, and complete
response achieved in all patients retreated with 20 Gy in eight
fractions.106 A U.K. RCT has shown that 4 Gy in two fractions
can be effective in the palliative setting, with an ORR of
74
1% (complete response rate 44
3%). However, this was
significantly inferior to 24 Gy in 12 fractions, with an ORR of
81% and complete response rate of 60
3%.254 The OS rate
was the same with both fractionations but there were fewer
patients with PCMZL or PCFCL in this study.
8.1.4 Intralesional interferon
There are limited data on the use of interferon-alpha. Vandersee et al.
reported a 67% response rate in 15 patients, with 90% of responders
relapsing. The median time to relapse was 15
5 months.255
8.1.5 Rituximab
The limited data on rituximab are based on case reports and
small case series. Treatment is either as systemic therapy
375 mg m2 intravenously weekly for 4–8 weeks, or as
intralesional therapy 5–30 mg one to three times per week.
For intralesional therapy, the complete response rates for both
PCMZL and PCFCL are reported to be 70–90%, with relapse
rates of 40–60%.256 Systemic therapy is preferred for more
widespread disease. For systemic therapy, the complete
response rates for PCMZL and PCFCL are similar, ranging from
67% to 87
5%, but again the relapse rates are relatively high,
with a median time to relapse of 25 months.257,258
8.1.6 Chemotherapy
There are relatively little data published on the results of
chemotherapy for PCMZL and PCFCL. For PCMZL, chlorambu-
cil for multifocal skin lesions is associated with a complete
response rate of 64% and relapse rate of 33%, based on
reports of 14 patients. CHOP is associated with a complete
response rate of 85% and relapse rate of 57%.11
For PCFCL, cumulative data on 104 patients from eight
studies treated with CHOP or CHOP-like regimens for wide-
spread skin lesions or high skin tumour burden give a com-
plete response rate of 85% with a relapse rate of 48%.11 Only
five patients received chemotherapy without an anthracycline
(COP or CVP; see section 6
3
2). There is a lack of data on
the efficacy of rituximab–CVP and rituximab–bendamustine,
© 2018 British Association of Dermatologists
 BAD and U.K. CLG guidelines for primary cutaneous lymphomas 2018, D. Gilson et al. 19
which are the most commonly used regimens in nodal or sys-
temic indolent lymphomas, in disease confined to the skin.
As for systemic indolent lymphomas, it is appropriate to
manage patients with disease confined to the skin with watch-
ful waiting. Current evidence supports a role for single-agent
chemotherapy or rituximab for those patients with extensive
cutaneous disease and no systemic involvement. Patients with
systemic disease or high disease burden failing to respond to
single-agent systemic therapy should be managed according to
local guidelines for the management of systemic disease.
Recommendations
• Solitary lesions should be treated with the intention of
cure. (Strength of recommendation B)
• Small individual skin lesions can be completely excised
and monitored, but treatment with radiotherapy (tu-
mour or scar with a 2-cm margin of skin to define
CTV) is preferred to reduce the risk of local relapse.
(Strength of recommendation B)
• Following a diagnostic biopsy, the first-line treatment
for individual skin lesions should be radiotherapy. The
radiotherapy CTV should be the tumour plus a 1
5-cm
margin of normal skin around the tumour. (Strength of
recommendation B)
• Active monitoring is an option for patients with
asymptomatic disease. (Strength of recommendation D (GPP))
• Systemic chemotherapy should be reserved for
patients with widespread extensive lesions or high
tumour burden (stage T2c–T3), or patients with
nodal or visceral progression. Treatment is palliative,
and for disease confined to the skin consideration
should be given to single-agent rituximab, or chlo-
rambucil, as this is well tolerated and effective. Fur-
ther choice of chemotherapy should be in line with
local guidelines for the management of indolent lym-
phomas. (Strength of recommendation C)
• Patients who relapse with nodal or visceral lymphoma
should be treated according to local and national man-
agement guidelines for systemic lymphoma. (Strength of
recommendation B)
8.2 Primary cutaneous diffuse large B-cell lymphoma
8.2.1 Primary cutaneous diffuse large B-cell lymphoma leg
type
The number of reported cases of PCLBCL is small. The
response rate to radiotherapy alone is high, but relapse rates
are ≥ 58% with a significant risk of extracutaneous
recurrences.11 Data on CHOP-like chemotherapy, R-CHOP
and R-CHOP plus local radiotherapy are limited to small
numbers of patients and short follow-up periods. In a
© 2018 British Association of Dermatologists
review of 32 patients from eight separate studies treated
with CHOP-like chemotherapy, 81% achieved complete
response but 56% relapsed.11 Rituximab as a single treat-
ment has an ORR of 75% in eight reported cases but all
patients relapsed, with a median disease-free survival of
5
25 months.259 Current international consensus and guideli-
nes recommend that PCLBCL leg type should be treated like
a systemic diffuse large B-cell lymphoma (DLBCL), with
three to six cycles of R-CHOP and local radiotherapy of
30–36 Gy.6
8.2.2 Primary cutaneous diffuse large B-cell lymphoma
(not otherwise specified)
PCLBCL (NOS) includes rare morphological variants of DLBCL
such as anaplastic lymphoma, plasmablastic lymphoma, T-
cell/histiocyte rich large B-cell lymphoma and intravascular
large B-cell lymphoma, which may rarely present primarily in
the skin.3 These variants should be treated with systemic lym-
phoma chemotherapy protocols.
Recommendations
• PCLBCL leg type should be treated with R-CHOP
chemotherapy followed by local radiotherapy as per
local guidelines for systemic DLBCL. Current protocols
recommend three to six cycles of R-CHOP chemother-
apy followed by 30–36 Gy in 2-Gy fractions of local
radiotherapy. (Strength of recommendation B)
• Palliative radiotherapy alone can be considered for
patients unfit for chemotherapy. (Strength of recommenda-
tion D)
• PCLBCL (NOS) should be treated as per local guidelines
for systemic DLBCL. (Strength of recommendation B)
Future research recommendation
• Future trials should concentrate on improving clinical
outcomes for patients with PCLBCL. (Strength of recommen-
dation D (GPP))
9.0 Economic and practical considerations
• Primary cutaneous lymphomas are rare and consequently
the economic costs of treatment are modest, especially for
early stages of CTCL and primary cutaneous B-cell lym-
phomas. In contrast, advanced cutaneous T-cell lym-
phomas require complex and expensive interventions,
often with only palliative intent.
• There has been a growing difference between the U.S.A.
and European Union for approval of novel drugs. How-
ever, the emergence of several pharmaceutically sponsored
phase III RCTs in the last few years suggests that this issue
is likely to be resolved, allowing U.K. patients to have
access to these new treatments.
British Journal of Dermatology (2018)
20 BAD and U.K. CLG guidelines for primary cutaneous lymphomas 2018, D. Gilson et al.

Fig 1. Treatment guidelines for mycosis fungoides. EBRT, external beam radiotherapy with photons or electrons for lymph node, soft tissue or
visceral lymphoma; ECP, extracorporeal photopheresis; IFN, interferon; MTX, methotrexate; PD, progressive disease; RIC-allo-SCT, reduced-
intensity allogeneic stem cell transplantation; SDT, skin-directed therapy (topical steroids, ultraviolet B, psoralen–ultraviolet A, skin radiotherapy,
topical nitrogen mustard); TSEB, total skin electron beam radiotherapy. Skin radiotherapy indicates superficial radiotherapy or EBRT to skin
patches, plaques and tumours. #Supranetwork: refers to the supranetwork multidisciplinary team (MDT) meeting for treatment decision. *PD and
exhausted first- and second-line options. **Chemotherapy as recommended by the supranetwork MDT. ***Consider only if the patient has
durable complete response. ↔ indicates that after treatment, patients may respond to treatments included in earlier ‘line’ options. Patients can
move between first- and second-line options.

British Journal of Dermatology (2018) © 2018 British Association of Dermatologists

 BAD and U.K. CLG guidelines for primary cutaneous lymphomas 2018, D. Gilson et al. 21

Fig 2. Treatment guidelines for S
ezary syndrome. Palliative skin-directed therapy can be used for symptom control if required. Chemotherapy is as directed
by the supranetwork multidisciplinary team (MDT). EBRT, external beam radiotherapy; ECP, extracorporeal photopheresis; IFN, interferon; MTX,
methotrexate; PD, progressive disease; RIC-allo-SCT, reduced-intensity allogeneic stem cell transplantation; WCC, white cell count, 9 109. #Supranetwork: refer
to the supranetwork MDT meeting for treatment decision. †PD and exhausted first- and second-line options. ††May be used in combination.

• Because of disease rarity, few large RCTs have been con- • There is an urgent need for the identification of novel tar-
cluded. This situation is now improving as both the FDA gets in CTCL based on improved understanding of disease
and EMA have adopted the same approach for orphan drug pathogenesis.
indications, but for some interventions such as stem cell
transplantation the evidence base will develop only 11.0 Recommended audit points
through consistent use of data registries.
In the last 20 consecutive patients seen with primary cuta-
neous T-cell lymphoma:
10.0 Future directions
1 Was the WHO 2016 classification used in recording the
• Low-risk, early-stage IA–IIA MF: future trials should
following?
address the need to improve duration of response without
increasing toxicity following PUVA and TSEB. a Cutaneous lymphoma subtype.
• Early-stage IA–IIA MF refractory to SDT: future trials b Tumour phenotype.
should address the need to improve specific clinical end c Folliculotropism in MF.
points such as time to relapse or progression, PFS and OS. d Large cell transformation in MF.
• High-risk advanced-stage IIB–IV MF/SS: future trials are
2 Were patients staged appropriately?
required to address an urgent need to improve PFS and OS.
3 Is there a record of performance status?
• The conditioning regimens and outcomes of RIC allo-
4 Is there a record of S
ezary cell count, CD4 : CD8 ratio or
HSCT for selected groups of patients with advanced disease
abnormal T-cell phenotype on flow cytometry at diagno-
should be collected through data registries such as the
sis and clinical evolution?
EBMT registry, and large cohort studies should be pub-
5 Is there an annual log of a cumulative treatment
lished with adequate follow-up.
summary?

© 2018 British Association of Dermatologists British Journal of Dermatology (2018)

22 BAD and U.K. CLG guidelines for primary cutaneous lymphomas 2018, D. Gilson et al.

Fig 3. Treatment guidelines for other cutaneous T-cell lymphoma (CTCL). LyP, lymphomatoid papulosis; NK, natural killer; NOS, not otherwise
specified; pc, primary cutaneous; SDT, skin-directed therapy (topical steroids, ultraviolet B, psoralen–ultraviolet A, skin radiotherapy).

The audit recommendation of 20 cases per department is to

reduce variation in the results due to a single patient, and to
allow benchmarking between different units. However,
departments unable to achieve this recommendation may
choose to audit all cases seen in the preceding 12 months.
12.0 Summary
Figures 1–4 show treatment guidelines for MF, SS, other
CTCLs and CBCL, respectively. See the manuscript for details
of the evidence.
13.0 Stakeholder involvement and peer review
The GDG consisted of consultant clinical dermatologists, haema-
tologists and oncologists. The draft document was circulated to
the BAD membership and the British Society for Haematology,
Royal College of Pathologists, British Dermatological Nursing
Group, Primary Care Dermatological Society, Royal College of
Radiologists, British Lymphoma Pathology Group, British Soci-
ety for Dermatopathology, U.K. Lymphoma Association and
Guy’s & St Thomas’ NHS Foundation Trust Skin Lymphoma Dis-
cussion Group for comments, and was peer reviewed by the

British Journal of Dermatology (2018) © 2018 British Association of Dermatologists

 BAD and U.K. CLG guidelines for primary cutaneous lymphomas 2018, D. Gilson et al. 23

Fig 4. Treatment guidelines for cutaneous B-cell lymphoma. PCFCL, primary cutaneous follicle centre lymphoma; PCLBCL, primary cutaneous
diffuse large B-cell lymphoma; PCMZL, primary cutaneous marginal zone lymphoma; R-bendamustine, rituximab with bendamustine; RCVP,
rituximab, cyclophosphamide, vincristine and prednisolone; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone.
§
Treatment is palliative; further therapy should be in line with local guidelines for the management of indolent lymphomas. §§In line with local
guidelines for systemic diffuse large B-cell lymphoma.

Clinical Standards Unit of the BAD (made up of the Therapy &

Guidelines Subcommittee) prior to publication.
14.0 Limitations of the guidelines
This document has been prepared on behalf of the BAD and is
based on the best data available when the document was pre-
pared. Please check the BAD website for any updates (http://
www.bad.org.uk/healthcare-professionals/clinical-standards/
clinical-guidelines).260 It is recognized that under certain con-
ditions it may be necessary to deviate from the guidelines
and that the results of future studies may require some of
the recommendations herein to be changed. Failure to
adhere to these guidelines should not necessarily be consid-
ered negligent, nor should adherence to these recommenda-
tions constitute a defence against a claim of negligence.
Limiting the review to English-language references was a
pragmatic decision but the authors recognize this may
exclude some important information published in other
languages.
15.0 Plans for guideline revision
The proposed revision date for this set of recommendations is
scheduled for 2023; where necessary, important interim
changes will be updated on the BAD website: http://
www.bad.org.uk/healthcare-professionals/clinical-standards/
clinical-guidelines.
Acknowledgments
We are very grateful to Dr Jennie Wimperis (British Society
for Haematology) for her input and our U.K. CLG colleagues
Eve Gallop Evans, Eleanor James and Richard Cowan, as well
as everyone including the patient organizations who com-
mented on the draft during the consultation period.
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© 2018 British Association of Dermatologists
Supporting Information
Additional Supporting Information may be found in the online
version of this article at the publisher’s website:
Appendix S1 Levels of evidence and strength of recom-
mendation.
Appendix S2 Search strategy.
Appendix S3 List of abbreviations.
Table S1 Staging system for mycosis fungoides/S
ezary syn-
drome.
Table S2 Staging for mycosis fungoides/S
ezary syndrome
adapted from Olsen et al.23
Table S3 The International Society for Cutaneous Lym-
phomas–European Organisation for Research and Treatment of
Cancer staging system for non-mycosis fungoides/non-S
ezary
syndrome primary cutaneous lymphomas.24
Table S4 Modified Severity Weighted Assessment Tool
(mSWAT) in mycosis fungoides/S
ezary syndrome.
Table S5 Skin and global response in mycosis fungoides/
S
ezary syndrome.
British Journal of Dermatology (2018)