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International Journal of

Radiation Oncology
biology

physics

www.redjournal.org

Guidelines

Modern Radiation Therapy for Primary Cutaneous


Lymphomas: Field and Dose Guidelines From
the International Lymphoma Radiation Oncology
Group
Lena Specht, MD, PhD,* Bouthaina Dabaja, MD,y Tim Illidge, MD, PhD,z
Lynn D. Wilson, MD,x and Richard T. Hoppe, MDjj, on behalf of the
International Lymphoma Radiation Oncology Group
*Departments of Oncology and Hematology, Rigshospitalet, University of Copenhagen, Copenhagen,
Denmark; yDivision of Radiation Oncology, Department of Radiation Oncology, The University of
Texas MD Anderson Cancer Center, Houston, Texas; zInstitute of Cancer Sciences, University of
Manchester, Manchester Academic Health Sciences Centre, The Christie National Health Service
Foundation Trust, Manchester, United Kingdom; xDepartment of Therapeutic Radiology, Yale
University School of Medicine, New Haven, Connecticut; and jjDepartment of Radiation Oncology,
Stanford University, Stanford, California
Received Dec 14, 2014, and in revised form Jan 6, 2015. Accepted for publication Jan 9, 2015.

Primary cutaneous lymphomas are a heterogeneous group of diseases. They often remain localized, and they generally
have a more indolent course and a better prognosis than lymphomas in other locations. They are highly radiosensitive,
and radiation therapy is an important part of the treatment, either as the sole treatment or as part of a multimodality
approach. Radiation therapy of primary cutaneous lymphomas requires the use of special techniques that form the focus
of these guidelines. The International Lymphoma Radiation Oncology Group has developed these guidelines after multinational meetings and analysis of available evidence. The guidelines represent an agreed consensus view of the International Lymphoma Radiation Oncology Group steering committee on the use of radiation therapy in primary cutaneous
lymphomas in the modern era. 2015 The Authors. Published by Elsevier Inc. This is an open access article under the
CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction
The purpose of these guidelines is to provide a consensus
position on the modern approach to the delivery of
Reprint requests to: Lena Specht, MD, PhD, Department of
Oncology, Rigshospitalet, Section 3994, Blegdamsvej 9, 2100
Copenhagen, Denmark. Tel: (45) 35453969; E-mail: lena.specht@
regionh.dk

radiation therapy (RT) in the treatment of primary cutaneous lymphomas. The present guidelines represent a
consensus viewpoint of the Steering Committee of the
International Lymphoma Radiation Oncology Group
This project was supported by The Connecticut Sports Foundation and
The Global Excellence Program of the Capital Region of Denmark.
Confict of interest: none.
AcknowledgmentsdThe authors thank Ms. Jessi Shuttleworth for
coordinating the ILROG guidelines committee.

Int J Radiation Oncol Biol Phys, Vol. 92, No. 1, pp. 32e39, 2015
0360-3016/ 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-ncnd/4.0/).
http://dx.doi.org/10.1016/j.ijrobp.2015.01.008

Volume 92  Number 1  2015

(ILROG). The guidelines are based on the best available


evidence and the experience of ILROG members.
Primary cutaneous lymphoma is a distinct type of skin
lymphoma with a different clinical presentation and prognosis, requiring a different therapeutic approach, and
therefore it must be distinguished from nodal or systemic
lymphomas, for which cutaneous involvement is secondary.
In lymphoma classification, primary cutaneous lymphomas
are included as separate entities. Distinct types of cutaneous T-cell lymphoma and cutaneous B-cell lymphoma
can be distinguished (1, 2). In the Western world, cutaneous
T-cell lymphomas constitute 75% to 80% of primary
cutaneous lymphomas, with mycosis fungoides the most
common type, and cutaneous B-cell lymphomas 20% to
25%. In Asia cutaneous T-cell lymphomas other than
mycosis fungoides, in particular cutaneous natural killer
(NK)/T-cell lymphomas are much more common, whereas
cutaneous B-cell lymphomas are much more uncommon.
The guidelines address the most common variants of
primary cutaneous lymphomas:
 Cutaneous T-cell lymphomas, including mycosis fungoides, primary cutaneous anaplastic large-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma,
primary cutaneous g-d T-cell lymphoma, and primary
cutaneous NK/T-cell lymphoma, nasal type.
 Cutaneous B-cell lymphomas, including primary cutaneous follicle center lymphoma, primary cutaneous
marginal zone lymphoma, and primary cutaneous diffuse
large B-cell lymphoma, leg type. Intravascular large Bcell lymphoma may infrequently be present with disease
limited to the skin.
Because the presentation, staging, natural history, and
outcomes of primary cutaneous follicle center lymphoma and
primary cutaneous marginal zone lymphoma are in many
ways similar, these will be dealt with in the first section. In
addition, primary cutaneous anaplastic large-cell lymphoma,
although having a different biology being part of the CD30
lymphoproliferative diseases, is managed similarly and will be
included in this section as well. Primary cutaneous diffuse
large B-cell lymphoma, leg type, has a more aggressive
behavior and will be dealt with separately. The rarer cutaneous
T-cell lymphomas, subcutaneous panniculitis-like T-cell
lymphoma, primary cutaneous g-d T-cell lymphoma, and
primary cutaneous NK/T-cell lymphoma, nasal type, will be
briefly mentioned. Finally, mycosis fungoides will be
considered separately and in more detail.

Cutaneous lymphoma radiation therapy guidelines

33

Organization for Research and Treatment of Cancer (EORTC)


(3). Local control for primary cutaneous follicle center
lymphoma and primary cutaneous marginal zone lymphoma
has been well established in multiple retrospective clinical
reviews. Local control data for primary cutaneous anaplastic
large cell lymphoma are less well established, and a broader
spectrum of RT doses has been applied for this histology. Most
patients with primary cutaneous follicle center lymphoma
(Fig. 1), primary cutaneous marginal zone lymphoma (Fig. 2),
or primary cutaneous anaplastic large-cell lymphoma (Fig. 3)
who present with T1 disease are served well by local RT.
Patients who have T2 disease with a small number of lesions
may also benefit from treatment to each individual lesion.

Recommendations
 Information before treatment
B Expert dermatopathologist review of biopsy.
B Staging classification: ISCL/EORTC TNM Classification (3). In general a complete history and physical
examination, photography of the skin lesion, laboratory studies including lactate dehydrogenase, and in
selected cases serum electrophoresis to exclude a
monoclonal gammopathy, are indicated.
 Volume
B Lesions categorized as T1 (solitary) (T1a <5-cm diameter; T1b 5-cm diameter) are generally treated with
involved lesion RT. Margins beyond area of clinically
evident erythema/induration will vary depending on
lesion size and body site and must take into account
dosimetry of the beam being used. Margin sizes recommended in the literature range from 0.5 to 5.0 cm (4-8).
The EORTC/ISCL recommends a margin of 1.0 to 1.5 cm
for primary cutaneous follicle center lymphoma and
primary cutaneous marginal zone lymphoma (9), and
the ILROG agrees with that recommendation.
B The thickness of the lesions must be determined, to
ensure adequate coverage also in depth. A margin is

Primary Cutaneous Follicle Center Lymphoma,


Primary Cutaneous Marginal Zone Lymphoma,
and Primary Cutaneous Anaplastic Large-Cell
Lymphoma
The staging principles for the non-mycosis fungoides primary
cutaneous lymphomas follow the guidelines of the International
Society for Cutaneous Lymphomas (ISCL) and the European

Fig. 1. Primary cutaneous follicle center lymphoma


presenting as multiple noduli on the left arm.

34

Specht et al.

Fig. 2. Primary cutaneous marginal zone lymphoma


presenting as multiple noduli in the forehead.

added to ensure treatment of microscopic disease in


the underlying tissue. The size of this margin is
theoretically of the same magnitude as the lateral
margins, but it should be modified according to the
location of the lesion and the thickness of the soft
tissues beneath the lesion. Intact bone and/or fascia
are not expected to harbor microscopic disease and
may reduce the need for depth coverage. Most lesions
can be treated effectively with electrons, usually 6 to
9 MeV (Fig. 4). Generally, bolus will be required to
avoid skin sparing. Alternatively, low energy X rays
(approximately 100 kV) may be used. For certain
situations, for example for deep and bulky tumors or
for circumferential lesions, higher-energy photon
fields and opposed field treatment (with bolus) may
be required to provide adequate coverage.

International Journal of Radiation Oncology  Biology  Physics

 RT dose
B Curative RT dose recommendations for primary
cutaneous follicle center lymphoma and primary
cutaneous marginal zone lymphoma have varied from
20 to 45 Gy, most commonly in the 24- to 40-Gy
range (4, 5, 7-10). Local control is excellent within
this dose range. Anecdotal examples of local failure
have been reported at all dose points.
B The EORTC/ISCL recommends a dose range of 20 to
36 Gy for primary cutaneous marginal zone lymphoma
and 30 Gy for primary cutaneous follicle center lymphoma (9). The NCCN recommends a dose of 24 to
30 Gy for primary cutaneous marginal zone lymphoma
(11), and a similar dose range is often recommended for
primary cutaneous follicle center lymphoma, based on
the randomized trial of 24 Gy versus 40 Gy for all patients
with indolent lymphoma (12). The ILROG recommends
24 to 30 Gy for primary cutaneous follicle center lymphoma and primary cutaneous marginal zone lymphoma.
B Palliative doses (2 Gy  2) achieve a complete
remission rate of 72%, with 30% of lesions requiring
retreatment within a median period of 6.3 months (6).
B Dose guidelines for primary cutaneous anaplastic largecell lymphoma are few, with a paucity of reported data
from large cases series (13). Doses used have been in the
range of 24 to 50 Gy. Additionally, one report recommends a dose of 40 Gy (14). A dose between 24 and
30 Gy can still achieve a durable complete remission,
and this is the dose range recommended by the ILROG
for primary definitive treatment on the basis of our
clinical experience. A multicenter review is in progress
and will hopefully clarify the issue.

Primary Cutaneous Diffuse Large B-Cell


Lymphoma, Leg Type
These are rapidly growing red to bluish tumors often
located on the lower extremity (Fig. 5). The term leg type
reflects the predominant but not exclusive anatomic location of these tumors. It is seen often in elderly patients (15).
In contrast to the indolent cutaneous lymphomas discussed
earlier, these lymphomas tend to relapse in extra-cutaneous
sites. Solitary or localized disease is treated with R-CHOP
(rituximab, cyclophosphamide, adriamycin, vincristine, and
prednisone) (16), followed by local RT. If the patient does
not tolerate chemotherapy, RT alone or combined with
rituximab alone may be used (17).

Recommendations

Fig. 3. Solitary primary cutaneous anaplastic large-cell


lymphoma.

 Clinical target volume: Pre-chemotherapy gross tumor


volume with margins of 1 to 2 cm.
 Technique: Most lesions can be treated effectively with
electrons, usually 6 to 9 MeV. Generally, bolus will be
required to avoid skin sparing. For certain body surfaces,
higher-energy photon fields and opposed-field treatment

Volume 92  Number 1  2015

Cutaneous lymphoma radiation therapy guidelines

35

Fig. 4. Electron field for the treatment of a localized cutaneous lymphoma in the skin of the forehead (left). The wire is the skin
collimation, the red is the field. An inner eye shield was used to protect the lens of the right eye. Bolus was added on top. The isodose
distribution is shown in 2 CT-scan slices (center and right).
(with bolus) may be required to provide adequate
coverage.

 Dose: 36 to 40 Gy is recommended. If no systemic


treatment is given, a dose of 40 Gy is recommended.

Subcutaneous Panniculitis-Like T-Cell


Lymphoma
Patients with the a/b T-cell phenotype and solitary skin
lesions should be treated with RT, usually with electrons.
Little information on dose is available, but doses 40 Gy
have been used.

Primary Cutaneous g-d T-Cell Lymphoma


Patients often present with generalized skin lesions. They
respond poorly to systemic treatment. Local control may be
achieved with RT to doses of 24 to 30 Gy, but patients tend
to relapse.

Primary Cutaneous NK/T-Cell Lymphoma, Nasal


Type
In patients with localized skin disease, RT is the first choice
of treatment. Recommended doses are as for NK/T-cell
lymphoma in the upper aerodigestive tract: 50 Gy to the
initial lesion and a boost of 5 to 10 Gy to residual disease.

Mycosis Fungoides

Fig. 5. Primary cutaneous large B-cell lymphoma, leg


type, presenting as multiple nodules on the right leg. Before
treatment (top), after 2 cycles of R-CHOP (rituximab,
cyclophosphamide, adriamycin, vincristine, and prednisone) (middle), and 2 months after radiation therapy.

Making a diagnosis of mycosis fungoides is of paramount


importance, to distinguish it from benign skin diseases such
as parapsoriasis, or a self-limiting disease like lymphomatoid papulomatosis, or an aggressive disease with worse
clinical outcome like epidermotropic CD8 cutaneous Tcell lymphoma. Establishing a robust diagnosis can be
difficult, may require multiple biopsies, and always requires clinico-pathologic correlation.

36

Specht et al.

Fig. 6.

International Journal of Radiation Oncology  Biology  Physics

Mycosis fungoides with widespread patches.

Patients should be staged and stratified according to


established prognostic factors (18). Therapy can then be
personalized according to the determined approximate
survival, patient comorbidities, and preferences. Therapy
can vary from skin-directed therapy, local RT, to total skin
RT, systemic biologics, or chemotherapy, and in some cases
associated with poor prognosis, allogeneic stem cell
transplantation may be recommended.
Both the folliculotropic variant and large-cell transformation carry an inferior outcome (19-23).
When the disease is limited to patches (Fig. 6) and
plaques (Fig. 7) with no extra-cutaneous involvement, skin-

Fig. 8. Mycosis fungoides with numerous tumors, before


treatment (top) and 6 months after total skin electron beam
therapy with boost to thicker lesions (bottom).
directed therapy is usually the preferred option. When tumors are present, excellent local control can usually be
achieved with RT (Fig. 8). With advanced-stage disease,
specifically with Sezary syndrome, systemic biologics,
chemotherapy, photopheresis, or allogeneic transplant is
indicated.
Radiation therapy is a highly effective treatment
approach for mycosis fungoides, and local treatment is
effective for eradication of uni-lesional disease or palliation
of multisite disease. Comprehensive programs of total skin
electron beam therapy (TSEBT) may be used for effective
palliation, and these patients may often have long-term
disease-free intervals (Fig. 9).

Recommendations

Fig. 7.

Mycosis fungoides with numerous plaques.

 RT dose
B Local palliation: Although exquisitely radiosensitive,
ultralow doses (2 Gy  2) achieve a complete
response rate <30%, and higher doses (8 Gy) are
recommended, which achieve complete response
rates >90% (6). Doses in the range of 8 to 12 Gy
allow retreatment. However, tumor stage or large-cell
transformation requires higher doses. Although 8 Gy
may be given in a single fraction with good results

Volume 92  Number 1  2015

Cutaneous lymphoma radiation therapy guidelines

37

Fig. 9. Mycosis fungoides with tumors and plaques, before treatment (left) and 7 years after total skin electron beam
therapy (right).
(24), fractionation should be determined on the basis
of the normal tissue complication probability,
considering the irradiated volume, the condition of
the skin, prior RT to the site, and whether TSEBT is
considered. Often, patients will require reirradiation,

and smaller fractions may be preferred. Fraction


sizes of 3 to 5 Gy are generally very well tolerated.
Uni-lesional mycosis fungoides: Dose range in the
few reported series has been 6 to 40 Gy, with local
recurrence unusual above 24 Gy (25, 26). A

Fig. 10. Patient positions for total skin electron beam therapy, 6-field technique. The straight anterior, right posterior
oblique, and left posterior oblique fields are treated on one day. The straight posterior, right anterior oblique, and left anterior
oblique fields are treated the next day.

38

Specht et al.

reasonable dose range is 24 to 30 Gy. Because the


majority of patients respond to lower radiation
doses, we encourage the use of doses of 20 to
24 Gy.
B Total skin treatment: Considering the dose range 8 to
36 Gy, higher total doses have been associated with
higher complete response rates (27). However, complete responses, even in the higher range, often are
not durable. Recent attention has been focused on the
potential value of lower-dose (10-12 Gy) TSEBT,
which has the benefits of being briefer in duration,
with fewer side effects, and the opportunity for
retreatment if required (28-30).
 RT technique
B Local palliation: Treatment includes the lesion of
interest plus 1.0- to 2.0-cm margins.
B Uni-lesional mycosis fungoides: Given the curative
nature of this treatment, margins 2 cm are generally
used (25, 26).
B TSEBT: This is technically challenging and requires
careful attention to dosimetric technique (31, 32). A
variety of techniques may be used to ensure total skin
coverage (33), including large electron field techniques (34-36), rotational techniques (37-39), and
techniques involving patient or beam movement
during irradiation (40, 41). Generally, these require
treating patients in the standing position on a rotating
platform or else assuming multiple different positions
to expose as much as possible all body surfaces. The
6-field large electron field technique developed at
Stanford is the most commonly used (36). The 6
positions used for this technique are shown in
Figure 10.
- Shadowed areas, especially if they are involved by
mycosis fungoides, require supplemental treatment.
This may include the top of the scalp, soles, and perineum, as well as areas under the breasts, beneath a
panniculus, etc.
- Supplemental boost treatment may be delivered to tumors early during the course of TSEBT, to decrease their
thickness and enhance penetration by the TSEBT.
- As appropriate for individuals, shielding of the eyes may
be with either internal or external shields. The scalp may
be shielded selectively.
 RT beam quality
B Palliation or uni-lesional mycosis fungoides: Generally, treatment with electrons is the beam of choice.
Patches are treated effectively with 6-MeV electrons
(plus bolus). Plaques may be treated with 6- to 9MeV electrons (plus bolus), but exophytic tumors
may require even higher energy electrons, depending
on their thickness. Alternatively, low energy X rays
may be used (approximately 100 kV). Occasional
localizations of disease on extremities or very complex contoured surfaces may require treatment with
higher-energy photons (approximately 6 MV) and

International Journal of Radiation Oncology  Biology  Physics

multiple field arrangements to ensure homogeneity of


dose distribution.
TSEBT: Techniques for degrading electron beams to
make them suitable for total skin treatment vary. The
ultimate goal is to achieve dose homogeneity in the
coronal plane, a Dmax at the skin surface (where the
dose is prescribed), and an 80% dose at 0.7- to 1.0cm depth.

Conclusion
Radiation therapy for primary cutaneous lymphomas is a
highly individualized treatment, depending on the histologic type of lymphoma and the location and extent of
involvement of the skin. Electron therapy (or even lowenergy X rays) is often indicated, to avoid unnecessary
irradiation of deeper structures. Special techniques such as
TSEBT may be needed to cover more extensive lesions.
The unique histopathologic classification and clinical
course of primary cutaneous lymphomas must be taken into
account when determining the overall treatment strategy.
Radiation therapy to skin lesions plays a major role in the
treatment of these lymphomas.

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