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Cutaneous Lymphomas
Cutaneous Lymphomas Benjamin D. Smith, MD,* and Lynn D. Wilson, MD, MPH† The skin is the most common site of extranodal non-Hodgkin lymphoma, with a yearly incidence approaching 1 per 100,000 individuals in the United States. Skin lymphomas are classified broadly into cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma (CBCL). Within these broad categories, multiple unique pathologic entities exist with a wide array of natural histories and treatment options. Radiotherapy plays an important role in the curative treatment of localized CTCL and CBCL and may be used to palliate cutaneous and visceral symptoms associated with advanced disease. This review highlights the role of radiotherapy in the multidisciplinary management of cutaneous lymphoma. Semin Radiat Oncol 17:158-168 © 2007 Elsevier Inc. All rights reserved.
A
pproximately 27% of all non-Hodgkin lymphomas arise in extranodal sites, such as the skin, stomach, brain, small intestine, lung, and eye.1 The skin is the most common extranodal site, with a yearly incidence approaching 1 case per 100,000 individuals in the United States.2 Cutaneous lymphomas present substantial diagnostic and therapeutic challenges, given their diverse clinical manifestations and expansive, multidisciplinary treatment options. This article will review the natural history of the most common cutaneous lymphomas and will discuss treatment options with a special emphasis on the role of radiotherapy.
phoma within the same classification scheme may be inappropriate because accumulating evidence suggests that primary cutaneous lymphomas behave differently than histologically similar nodal lymphomas. To address the need for a universally accepted classification solely devoted to primary cutaneous lymphoma, the WHO-EORTC published a unified classification for primary cutaneous lymphoma in 2005.5 The entities included in the WHO-EORTC classification, along with their relative frequencies and associated 5-year diseasespecific survivals, are reported in Table 1.
World Health Organization–European Organization for the Research and Treatment of Cancer Classification
Mycosis Fungoides
The pathologic classification of cutaneous lymphoma has been a subject of much debate. In 1997, the European Organization for the Research and Treatment of Cancer (EORTC) proposed a classification scheme for primary cutaneous lymphoma.3 Although the EORTC classification borrowed terms previously used in the classification of nodal lymphoma, the EORTC terminology was not intended to apply to nodal lymphoma. In contrast, the World Health Organization (WHO) classification, proposed in 2001, was a unified system that applied similar terminology to both extranodal lymphoma (including primary cutaneous lymphoma) and nodal lymphoma.4 However, grouping cutaneous and nodal lym*United States Air Force, Wilford Hall Medical Center, Lackland AFB, TX. †Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT. Address reprint requests to Lynn D. Wilson, MD, MPH, Department of Therapeutic Radiology, Yale University School of Medicine, HRT 132, 333 Cedar Street, New Haven, CT 06520. E-mail: Lynn.wilson@ yale.edu
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Clinical Manifestations Mycosis fungoides (MF) is a malignancy of helper (CD4⫹) T-cells and accounts for nearly 50% of all cutaneous lymphomas, with a yearly incidence of approximately 5 cases per million in the United States.2,5 The EORTC classification states that the term mycosis fungoides should be reserved for those CD4⫹ cutaneous lymphomas that are “characterized by the subsequent evolution of patches to more infiltrated plaques and eventually tumors.”3 The earliest phase of MF— the premycotic phase—typically begins with skin patches that are mildly erythematous, slightly scaling, annular (ringshaped) or arcuate (arc-shaped), and classically involves sunshielded areas (Fig. 1A). Such lesions may wax and wane for years before histologic findings show definitive evidence of MF. As MF progresses, patches lose their predilection for sun-shielded areas and may become eczematous, hypopigmented, or hyperpigmented. The trunk, pelvis, and proximal extremities are most commonly involved. Patches may progress to form more generalized, deeply infiltrative, scaling plaques that have well-demarcated, palpable borders (Fig. 1B). If the neoplastic cells lose their skin-homing (epidermo-
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Table 1 The WHO-EORTC Classification for Cutaneous Lymphoma5
Histology Cutaneous T-cell and NK-cell lymphomas Mycosis fungoides Variants of mycosis fungoides Folliculotropic mycosis fungoides Pagetiod reticulosis Granulomatous slack skin Sézary syndrome Adult T-cell leukemia/lymphoma Primary cutaneous CD30ⴙ lymphoproliferative disorders Primary cutaneous anaplastic large-cell lymphoma Lymphomatoid papulosis Subcutaneous panniculitis-like T-cell lymphoma (␣/ type) Extranodal NK/T-cell lymphoma, nasal type Primary cutaneous peripheral T-cell lymphoma, unspecified Primary cutaneous aggressive epidermotropic CD8ⴙ T-cell lymphoma Cutaneous ␥/␦ T-cell lymphoma (provisional) Primary cutaneous CD4ⴙ small-/medium-sized pleomorphic T-cell lymphoma Cutaneous B-cell lymphomas Primary cutaneous marginal zone B-cell lymphoma Primary cutaneous follicle center lymphoma Primary cutaneous diffuse large B-cell lymphoma, leg type Primary cutaneous diffuse large B-cell lymphoma, other Intravascular large B-cell lymphoma Precursor hematologic neoplasm CD4ⴙ/CD56ⴙ hematodermic neoplasm (blastic NK-cell lymphoma)
tropic) properties, they enter a vertical growth phase and form cutaneous tumors (Fig. 1C). Such tumors may cause substantial morbidity because of ulceration and superinfection.
Diagnosis The diagnosis of mycosis fungoides remains challenging, even for the experienced clinician and dermatopathologist, because of both the absence of a diagnostic gold standard and the number of benign dermatoses that may mimic MF. On skin biopsy, the most notable finding of early MF is substantial epidermotropism, characterized by lymphocytes grouped along the epidermal basement membrane. Pautrier’s microabscesses, which are well-defined collections of intraepidermal lymphocytes, are considered pathognomonic for MF but are seen in less than 20% of early lesions. For clinically and histologically borderline cases, molecular studies may help to confirm a diagnosis of MF. Typically, MF shows the following immunophenotype: CD2⫹ (pan T-cell), CD3⫹ (pan T-cell), CD4⫹ (helper T-cell), CD5⫹ (pan T-cell), CD45RO⫹ (memory T-cell), CLA⫹ (cutaneous lymphoid antigen), CD8- (cytotoxic T-cell), and CD30- (activated T cell).6 An aberrant T-cell phenotype, such as loss of expression of CD2, CD3, and/or CD5, also supports the diagnosis of MF.5 Use of polymerase chain reaction to identify a clonal
Frequency (%)
5-Year Disease-Specific Survival (%)
44
88
4 <1 <1 3 —
80 100 100 24 —
Indolent Indolent Indolent Aggressive —
8 12 1 <1 2 <1
95 100 82 — 16 18
Indolent Indolent Indolent Aggressive Aggressive Aggressive
<1 2
— 75
Indolent
7 11 4 <1 <1
99 95 55 50 65
Indolent Indolent Intermediate Intermediate Intermediate
—
—
—
Clinical Behavior Indolent
T-cell receptor gene rearrangement may help to confirm the diagnosis of MF. For example, a clonal T-cell population can be identified in 50% to 80% of histologically borderline biopsies obtained from patients who subsequently develop classic MF.7,8 Other tests recommended to complete the diagnostic work up are summarized in Table 2.
Staging and Prognosis The American Joint Committee on Cancer (AJCC) staging system for MF identifies extent and character of skin lesions, extracutaneous disease, and leukemic transformation as the major determinants of poor prognosis (Tables 3 and 4).9 Patients with limited patches and plaques (stage IA, T1 N0 M0) experience 10-year survival similar to a matched control population.10 The median survival is approximately 11 years for patients with extensive patches and plaques (T2), 3.2 years for patients with tumors (T3), and 4.6 years for patients with erythroderma (T4).11 Patients with either pathologically documented lymph node involvement or visceral involvement experience a median survival of approximately 1 year.12 The AJCC also included a blood descriptor, B0 versus B1, to document the absence or presence of greater than 1,000 Sézary cells (CD4⫹, CD7⫺) per L. Among patients with erythroderma, the presence of B1 disease doubles the risk of
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Figure 1 Clinical presentation of CTCL. (A) Typical early patch with erythema and mild scale. (B) Typical plaque, with raised, palpable borders, central clearing, and overlying scale. (C) Large tumor with necrosis and ulceration. (D) Generalized erythroderma. (Reprinted with permission from Smith BD, Wilson LD: Management of mycosis fungoides. Part 1. Diagnosis, staging, and prognosis. Oncology [Huntingt] 17:1281-1288, 2003.)
death.13 Other factors that may herald a poor prognosis include age ⱖ60,14 elevated lactate dehydrogenase (LDH),14 elevated soluble interleukin-2 receptor levels,15 T-cell clonality within the cutaneous infiltrate detected by polymerase chain reaction,16,17 an identical T-cell clone in the skin and peripheral blood,18 and T-cell clonality in dermatopathic lymph nodes.19
Sézary Syndrome Sézary syndrome (SS) is defined as erythroderma (stage T4, Fig. 1D) plus evidence of malignant circulating T cells that satisfy any of the 5 criteria listed in Table 5.20 For the purposes of these criteria, the Sézary cell is defined as “any atypical lymphocyte with [a] moderately to highly infolded or grooved nucleus.”20 The pathologic link between MF and
Figure 4 Clinical presentation of CBCL. Common clinical features of CBCL include scalp involvement (C and D), red-orange hue (A), red hue (B and C), blue-purple hue (D), grouped papules (A), combined papule and patch (B), a single papule (C), and a single tumor (D). Note the absence of scale.
SS remains unclear. SS usually arises de novo without antecedent MF. Rarely, MF will evolve to an erythrodermic stage with concomitant hematologic findings that satisfy a diagnosis of SS.
Radiotherapy for Mycosis Fungoides Overview Radiation produces very high complete response rates and may be the single most effective modality in the treatment of MF.21 For patients with stage IA MF, localized, superficial radiotherapy, or total skin electron-beam therapy (TSEBT) may be curative. For patients with more advanced cutaneous
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Table 2 Diagnostic Testing for Patients With Suspected Mycosis Fungoides History and physical with attention to skin, lymph nodes, liver, and spleen Skin biopsy with attention to Histology Epidermotropic lymphocytes with medium-large, extremely convoluted nuclei Pautrier’s microabscesses Immunophenotype Classically CD2ⴙ CD3ⴙ CD4ⴙ CD5ⴙ CD45ROⴙ CD8ⴚ CD30ⴚ Rarely CD4ⴚ CD3ⴙ CD8ⴙ PCR for T-cell receptor gene rearrangement Biopsy of enlarged lymph nodes with attention to Histology, both number of atypical lymphocytes and disruption of nodal architecture In dermatopathic nodes, consider PCR for T-cell clonality and immunophenotyping to rule out occult involvement Evaluation of blood CBC with manual differential, liver function tests and serum chemistries for all patients In those with suspected stage IIB-IV disease LDH, soluble interleukin-2 receptor Flow cytometry for CD2, CD3, CD4, CD5, CD7, CD8, CD20, CD45RO. Findings suggestive of blood involvement include an elevated CD4:CD8 ratio (normal range 0.5 – 3.5), or an expanded population of CD4ⴙCD7ⴚ or CD45ROⴙ lymphocytes. PCR for T-cell receptor gene rearrangement Bone marrow aspirate and biopsy is only indicated to evaluate unexplained cytopenias Imaging Posteroanterior and lateral chest radiograph for stages IA-IB Computed tomography of chest, abdomen, and pelvis for suspected stage IIA-IV
and/or visceral disease, radiotherapy can provide meaningful and durable palliation.
Localized, Superficial Radiotherapy For treatment of an isolated lesion with localized, superficial radiotherapy, the optimal dose is ⱖ 30 Gy delivered in 1.2 to 2.0 Gy per fraction. For example, Cotter and coworkers22 reported an infield recurrence rate of 42% for those treated to a total dose ⱕ10 Gy, 32% for 10.01 to 20 Gy, 21% for 20.01 to 30 Gy, and 0% for ⬎30 Gy. In addition, Wilson and
Table 3 TNM(B) Classification for Mycosis Fungoides T1–Patches and/or plaques involving <10% body surface area T2–Patches and/or plaques involving >10% body surface area T3–One or more cutaneous tumors T4–Generalized erythroderma N0–Lymph nodes clinically uninvolved N1–Lymph nodes clinically enlarged but histologically uninvolved N2–Lymph nodes clinically nonpalpable but histologically involved N3–Lymph nodes clinically enlarged and histologically involved M0–No visceral disease present M1–Visceral disease present B0–No circulating atypical cells (<1,000 Sézary cells [CD4ⴙ CD7-]/L) B1–Circulating atypical cells present (>1,000 Sézary cells [CD4ⴙ CD7-]/L) Adapted with permission.9
coworkers23 reported local failure in 20% (4/20) of lesions treated with ⱕ20 Gy compared with 0% (0/10) of lesions treated with ⬎20 Gy. Evidence suggests that the malignant cells of MF have little ability to execute sublethal damage repair, thus supporting the use of low daily fraction sizes to minimize late toxicity without sacrificing local control.24 Approximately 5% of patients with stage IA disease present with a single skin lesion or with 2 or 3 lesions in close proximity, such that all clinically apparent disease can be encompassed within a reasonable radiotherapy portal.23 For patients with such limited disease, we recommend definitive treatment with localized, superficial radiotherapy because prior retrospective experiences have documented long-term disease-free survival in excess of 85% with this approach.23,25,26 For example, 21 patients treated at Yale University experienced a complete response rate of 97%. For those who received ⱖ20 Gy, long-term disease-free survival was 91%.23 Similarly, 18 patients treated to a median dose of 30.6 Gy at Allegheny University Hospitals experienced a 10-year disease-free survival
Table 4 Staging Classification for Mycosis Fungoides IA IB IIA IIB IIIA IIIB IVA IVB
T1 T2 T1-2 T3 T4 T4 T1-4 T1-4
N0 N0 N1 N0-1 N0 N1 N2-3 N0-3
The B descriptor is not considered in stage classification.
M0 M0 M0 M0 M0 M0 M0 M1
B.D. Smith and L.D. Wilson
162 Table 5 Proposed Hematologic Criteria for the Diagnosis of Sézary Syndrome20 1. Absolute Sézary cell count >1,000 cells/L 2. CD4/CD8 ratio > 10 due to an increase in CD3ⴙ or CD4ⴙ cells by flow cytometry 3. Aberrant expression of pan-T cell markers (CD2, CD3, CD4, CD5) by flow cytometry. Deficient CD7 expression on T cells (or expanded CD4ⴙ, CD7ⴚ cells >40%) is a tentative criterion 4. Increased lymphocyte count with T-cell clone in blood identified by Southern blot or polymerase chain reaction 5. A chromosomally abnormal T-cell clone
of 86%.25 Minimal stage IA disease should be treated with a single radiation field where possible, although abutting fields may be required at a convex surface such as the scalp, an axillary fold, breast, hand, or foot. The junction of abutting fields should be shifted weekly during the course of treatment to improve homogeneity. Field margins can be limited to only 1 to 2 cm beyond the visible (or palpable) clinical lesion.
TSEBT: Technique Consensus guidelines for delivery of TSEBT have been published by the EORTC27 (Table 6). The EORTC recommends a total dose of 31 to 36 Gy prescribed to the skin surface to produce a dose of at least 26 Gy at a depth of 4 mm in truncal skin along the central axis.27 Several retrospective experiences support these recommendations. For example, analysis of 176 patients treated at Stanford University revealed that complete response rates increased with total dose as follows: 18% for 8 to 9.9 Gy, 55% for 10 to 19.9 Gy, 66% for 20 to 24.9 Gy, 75% for 25 to 29.9 Gy, and 94% for 30 to 36 Gy.28 For patients treated at the Hamilton Regional Cancer Center, complete response rates were 64% for those who received 30 Gy (all treated between 1977 to 1980) compared with 85% for those who received 36 Gy (all treated between 1980 to 1992).29 The target volume for patients with patch/plaque disease should include the epidermis and dermis.30 The thickness of the epidermis and dermis varies from a minimum of approximately 2 mm at the trunk to a maximum of about 4.5 mm at the hands and soles of the feet.30 For TSEBT, the 80% isodose line should fall more than 4 mm deep to the skin surface to ensure that the epidermis and dermis fall with the high-dose region. Cutaneous tumors often exceed this 4-mm depth, and therefore such lesions are underdosed when treated with TSEBT alone. Patients with cutaneous tumors greater than 4-mm thick may receive boost treatments either during or after TSEBT, typically 10 Gy delivered in 2 Gy fractions with an appropriate electron energy and bolus. The treatment geometry for TSEBT used at Yale is presented in Fig. 2.31 A total of 6 treatment positions are designated: anteroposterior, right and left anterior oblique, posteroanterior, and right and left posterior oblique (Fig. 3). These positions maximize skin unfolding, thereby improving
dose homogeneity in the lateral dimension. Each treatment position is treated with both an upper and a lower field to maximize dose homogeneity in the vertical dimension. On treatment day 1, the anteroposterior, right posterior oblique, and left posterior oblique positions are treated. On treatment day 2, the posteroanterior, right anterior oblique, and left anterior oblique positions are treated with the same dose. Over the course of a 2-day treatment cycle, a patient will receive 2 Gy to the entire skin surface. This pattern continues, with patients receiving treatment 4 days a week for a total of nine weeks, thereby delivering a total dose of 36 Gy to the skin surface. By using this TSEBT technique, the soles of feet, perineum, and scalp are underdosed and require supplemental patch treatments as outlined in Table 7. Other potentially underdosed regions include the ventral penis, upper medial thighs, inframammary folds, folds under any pannus, and the lateral and flatter regions of the face and trunk. Supplemental patch fields, as guided by in vivo dosimetry or clinical suspicion, are appropriate for these regions to ensure that the surface dose is at least 50% of the prescribed TSEBT dose.32,33 The total supplemental dose given to these areas may be reduced as clinically indicated to enhance patient tolerance, provided such areas are uninvolved. The hands, wrists, ears, ankles, and dorsal penis may be overdosed and require shielding to limit the dose to ⱕ36 Gy. Detailed dosimetric measurements are typically required to determine the most appropriate shielding regimen for a particular treatment arrangement and patient geometry. The shielding regimen used at Yale and the resulting doses to various anatomic structures are presented in Tables 7 and 8.
TSEBT: Clinical Results TSEBT is a reasonable first-line treatment option for patients with nonlocalized stage IA MF and for most patients with stage IB through III MF. However, no randomized data exist to support selection of a radiation-based strategy over Table 6 EORTC Guidelines for Total Skin Electron-Beam Therapy27 Dose inhomogeneity in air at treatment distance should be <10% within vertical and lateral dimensions 80% isodose line should be >4-mm deep to the skin surface to ensure that the epidermis and dermis fall within the high dose region. 80% isodose line should receive a minimum total dose of 26 Gy 20% isodose line should be <20 mm from the skin surface to minimize dose to underlying structures 30-36 fractions should be used to minimize acute side effects Total dose to bone marrow from photon contamination should be less than 0.7 Gy Patch treatments should be utilized to underdosed areas such as the perineum, scalp, and soles of feet Internal and external eye shields should be used to ensure that the dose to the globe is not more than 15% of the prescribed skin surface dose
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Figure 2 Treatment geometry for total skin electron-beam therapy. (Reprinted with permission from Smith BD, Jones G, Wilson LD: Mycosis fungoides, in Gunderson LL, Tepper JE [eds]: Clinical Radiation Oncology [ed 2]. Philadelphia, PA, Elsevier, 2007.) (Color version of figure is available online.)
other treatment strategies, and therefore initial treatment is strongly dependent on institutional and patient preferences. For patients presenting with limited patches and plaques (stage IA, T1 N0 M0), TSEBT produces complete response rates of at least 90%10,30 and 10-year relapse-free survival of 50%.34 For patients presenting with extensive
patches and plaques (stage IB, T2 N0 M0), TSEBT produces complete response rates of approximately 80% to 90%,27,34 but 10-year relapse-free survival is only 10%.34 For patients presenting with tumors (stage IIB, T3 N0-1 M0), TSEBT produces complete response rates ranging from 50% to 100% depending on the extent of initial skin involvement30,35,36 and
Figure 3 Treatment positions for total skin electron-beam therapy. Top row (from left to right): right anterior oblique, anteroposterior, and left anterior oblique treatment positions. Bottom row (from left to right): right posterior oblique, posteroanterior, and left posterior oblique treatment positions. (Reprinted with permission from Smith BD, Wilson LD: Management of mycosis fungoides: Part 2. Treatment. Oncology [Hunting] 17: 1419-1428; discussion 1430, 1433) (Color version of figure is available online.)
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164 Table 7 Treatment Protocol at Yale-New Haven Hospital31 Treatment cycle Day 1 Day 2 Dose Dose per cycle Cycles per week Total cycles Total dose Boosts Perineum Soles of feet Blocking External eye shields Internal eye shields Lip shield Lead mitt for hands Fingernail shield Foot block Testicular shield
AP, RPO, LPO treatment positions PA, RAO, LAO treatment positions 2 Gy 2 18 36 Gy 1 Gy/d, first 9 and last 9 treatment days 1 Gy/d, first 7 and last 7 days treatment days First 11 cycles Last 7 cycles Cycles 1-4 Every other cycle Every other cycle, alternating with mitts Cycles 1-3, 5, 7, 9, 11, 13, 15, 17, 18 Used with perineum boost only
At Yale, the scalp is boosted by an electron reflector mounted above the patient’s head. Alternatively, the scalp may be boosted with 120 kV, or electrons, typically 6 to 20 Gy over 1 to 3 weeks as guided by in vivo dosimetry. AP ⴝ anteroposterior; RPO ⴝ right posterior oblique; LPO ⴝ left posterior oblique; PA ⴝ posteroanterior; RAO ⴝ right anterior oblique; LAO ⴝ left anterior oblique.
may confer very meaningful palliation. However, long-term disease-free survival after TSEBT monotherapy for tumors is rare. For patients presenting with erythroderma (stage III, T4 N0-1 M0), TSEBT produces complete response rates of approximately 75% and may result in prolonged disease-free survival in the subset of patients without blood involvement.37 For patients with disease that has relapsed after treatment with TSEBT, a second course of TSEBT, typically to a total dose of 18 to 23 Gy, yields high complete response rates with acceptable toxicity.38,39
TSEBT: Adjuvant Therapy Because the majority of patients will develop a cutaneous relapse after TSEBT monotherapy, adjuvant therapy is recommended to maximize disease-free survival. Retrospective experiences suggest that adjuvant topical nitrogen mustard36 or psoralen plus ultraviolet A (PUVA)40 may improve diseasefree survival after TSEBT for stage IB MF. For patients with more advanced disease, many adjuvant therapies may be considered, including topical nitrogen mustard,36 photophoresis,41 interferon-␣, bexarotene, and denileukin diftitox.42
TSEBT: Toxicity Common acute toxicities from TSEBT include pruritus, dry desquamation, erythema, alopecia, xerosis, bullae of the feet, edema of the hands and feet, hypohidrosis (di-
minished perspiration),43 and loss of fingernails and toenails.34,44 Rare acute side effects include gynecomastia in men and mild epistaxis or parotiditis.34 Long-term complications are typically mild and may include permanent nail dystrophy, xerosis, telangiectasias, partial scalp alopecia, and fingertip dysesthesias.27 Young patients should be thoroughly counseled regarding risks of gonadal toxicity. Second cutaneous malignancies including squamous cell carcinoma, basal cell carcinoma, and malignant melanoma have been observed in patients treated with TSEBT, particularly in those exposed to multiple therapies that are themselves known to be carcinogenic, such as PUVA and nitrogen mustard.45
Other Therapies for Mycosis Fungoides In addition to radiation, other skin-directed therapies for MF include phototherapy (both ultraviolet B monotherapy and PUVA), nitrogen mustard, carmustine, bexarotene, and corticosteroids. Systemic treatment options include systemic chemotherapy, interferon, retinoids, bexarotene, denileukin diftitox, extracorporeal photophoresis, and agents currently under investigation. The effectiveness, toxicity, and indications for these therapies are discussed by Smith and Wilson.46
Table 8 Dose to Anatomic Sites Measured In Vivo31 Dose per Two-Day TSEBT Treatment Cycle* Central axis Top of head Forehead Eye Eyelid Lips Posterior neck Shoulder Axilla Hand Mid back Umbilicus Flank Lateral thigh Perineum Top of feet Soles of feet
Total Dose With Blocking and Boosts
Gy
%
Gy
%
2.0 2.3 2.4 0.1 — — 2.1 1.7 2.2 1.6 2.0 2.1 2.0 1.9 0.6 2.3 0
100 115 118 12 — — 104 87 109 82 100 104 99 95 31 117 0
36 41.4 42.5 2.2 24.5 30 37.4 31.3 39.2 15.6 36 37.4 35.6 34.2 29 28.5 14
100 115 118 6 68 83 104 87 109 43 100 104 99 95 81 79 39
*Dose using dual-field, 6-treatment position setup with scalp electron reflector and eye shields.
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Primary Cutaneous CD30ⴙ Lymphoproliferative Disorders After MF, primary cutaneous CD30⫹ lymphoproliferative disorders are the next most common cutaneous T-cell lymphoma. This category includes both lymphomatoid papulosis (LyP), which is a benign, self-limited entity, and cutaneous anaplastic large-cell lymphoma (C-ALCL), which is a malignant entity that may spread to extracutaneous sites.
clusively confined to the skin at diagnosis. Since the early 1990s, the reported incidence of CBCL has increased rapidly, approaching 4 cases per million in the United States.2 Risk factors for developing CBCL include advanced age, male sex, and white race.2 CBCL most commonly presents in the head and neck region2 as a unilesional or oligolesional patch, papule, plaque, or tumor, with coloration varying from red to orange to blue-purple. (Fig. 4) In contrast to CTCL, CBCLs rarely produce scale.
Classification
LyP LyP presents with grouped erythematous or violaceous papules and/or nodules at different stages of development. Individual skin lesions typically resolve spontaneously within 3 to 12 weeks, but scarring is common.47 Three different histologic subtypes have been described, with types A and C consisting of malignant CD30⫹ T cells, often with an extensive inflammatory infiltrate, and type B–simulating classical plaque-stage MF. For type C lesions, discrimination between LyP and C-ALCL may be difficult on histologic grounds, and assessment of the clinical context may be required to ensure the proper diagnosis.3 Although cytologically malignant, LyP is clinically benign with a 5-year survival of 100%.3,48 Thus, neither aggressive chemotherapy nor radiotherapy is indicated.49 Treatment options include PUVA or low-dose methotrexate, but neither is curative. In the long term, 15% to 20% of patients with LyP will develop a second malignancy, most commonly MF, C-ALCL, or Hodgkin’s disease.49,50
Cutaneous Anaplastic Large-Cell Lymphoma C-ALCL typically presents as a red- or flesh-colored nodule or tumor that may ulcerate. On biopsy, sheets of large CD30⫹, nonepidermotropic lymphocytes are noted in the dermis. In contrast to systemic CD30⫹ anaplastic large-cell lymphoma, overexpression of anaplastic lymphoma kinase is not found in C-ALCL. Patients with localized disease may be treated with radiotherapy alone, and 5-year disease-specific survival is approximately 95%.3,48
Cutaneous B-Cell Lymphoma Clinical Manifestations The term cutaneous B-cell lymphoma (CBCL) refers to a spectrum of B-cell lymphoproliferative disorders that are ex-
The pathologic classification, and correspondingly the optimal treatment of CBCL, has been a source of much confusion. One important source of confusion has been differences in the original EORTC and WHO classification schemes for CBCL. For example, the most common subtype of CBCL according to the original EORTC classification scheme was “follicle center cell lymphoma,” a lowgrade B-cell neoplasm for which definitive radiation therapy without chemotherapy was recommended. However, many lesions classified as “follicle center cell lymphoma” in the EORTC classification scheme may be classified as “diffuse large B-cell lymphoma” in the WHO classification.51 Unlike their nodal counterparts, the majority of CBCLs classified as “diffuse large B-cell lymphoma” according to WHO criteria exhibit clinically indolent behavior and may potentially be treated with definitive radiotherapy without systemic chemotherapy.51 Another source of confusion has been the EORTC category termed “large B-cell lymphoma of the leg,” defined as CBCL with a preponderance of large B cells arising in the lower extremities. Based on the original EORTC criteria, histologically identical lesions would be classified as “large B-cell lymphoma of the leg” if located on the lower extremities and “follicle center cell lymphoma” if located elsewhere. The combined WHO-EORTC pathologic classification (Table 1), published by Willemze and coworkers in 2005, has made great strides in addressing the deficiencies of the original WHO and EORTC classification schemes.5 Under this classification scheme, the category “primary cutaneous follicle center lymphoma” includes B-cell neoplasms with both follicular and diffuse architecture, thus encompassing the majority of “follicle center cell lymphomas” from the EORTC classification and “diffuse large B-cell lymphomas” from the WHO classification. Such CBCLs may be treated with definitive radiotherapy without che-
Table 9 CBCL-Prognostic Index (CBCL-PI)2 CBCL-PI Group
Histology*
Skin Site
IA IB II II III
Follicular, marginal zone, or lymphoplasmacytic Diffuse large B cell Diffuse large B cell Immunoblastic diffuse large B cell Immunoblastic diffuse large B cell
Any Head, neck, or arm Trunk, leg, disseminated Head, neck, or arm Trunk, leg, disseminated
*Histology is based on the WHO classification.
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to define the optimal radiotherapy dose for CBCL, Smith and coworkers51 noted a trend toward improved local control for patients who received ⱖ36 Gy.51 To enhance cosmesis, particularly in the head and neck region, we recommend low daily fraction sizes on the order of 2 Gy/d. For patients with primary cutaneous follicle center lymphoma and primary cutaneous marginal zone lymphoma, radiotherapy as the sole treatment modality confers complete response rates approaching 100%. Five-year local control is approximately 90%, and 5-year relapse-free survival is approximately 50%.51,56-60 The majority of recurrences are limited to the skin and are amenable to additional salvage radiotherapy.
Conclusion
Figure 5 Relative survival stratified by CBCL-Prognostic Index Group. CBCL prognostic index groups are defined in Table 9. Relative survival indicates the expected survival compared with age-, race-, and sex-matched controls. (Reprinted with permission from the American Society of Clinical Oncology.2)
motherapy. In addition, the WHO-EORTC classification introduced a new category, “primary cutaneous large Bcell lymphoma, leg type,” which includes histologically aggressive large B-cell neoplasms arising on either the lower extremities or other skin sites, often with expression of bcl-2 and Mum-1/IRF-4. Such lesions typically exhibit a more aggressive clinical course, and systemic therapy should be strongly considered.
Staging and Prognosis The conventional AJCC staging system for non-Hodgkin lymphoma fails to provide adequate risk stratification for CBCL because patients can be grouped into only 2 categories: stage IE if skin lesions are localized and stage IVE if skin lesions are disseminated.9 To provide more detailed prognostic information, Smith and coworkers used population-based data to develop a CBCL-Prognostic Index (CBCL-PI), which predicts prognosis using skin site of involvement and lesion histology (Table 9 and Fig. 5).2 This prognostic index should be used cautiously, however, as it awaits validation. Other factors correlated with adverse prognosis include leg involvement,52,53 multiple skin lesions,52-54 bcl-2 expression,54 Mum-1 expression,55 and round cell (immunoblastic) histology.53
Radiotherapy: Technical Factors and Results Either electron therapy with appropriate bolus or orthovoltage therapy may be used in the treatment of CBCL. Typically, a 2- to 3-cm margin of normal tissue should be included in the field to account for microscopic extension of disease. When lesions are located on oblique surfaces, multiple abutting fields are required to ensure adequate tumor coverage. Although limited data exist
Skin lymphomas represent a diverse array of clinical entities with unique natural histories and treatment options. Radiation oncologists must be cognizant of these issues to provide optimal radiotherapy within a multidisciplinary context.
References 1. Groves FD, Linet MS, Travis LB, et al: Cancer surveillance series: nonHodgkin’s lymphoma incidence by histologic subtype in the United States from 1978 through 1995. J Natl Cancer Inst 92:1240-1251, 2000 2. Smith BD, Smith GL, Cooper DL, et al: The cutaneous B-cell lymphoma prognostic index: A novel prognostic index derived from a populationbased registry. J Clin Oncol 23:3390-3395, 2005 3. Willemze R, Kerl H, Sterry W, et al: EORTC classification for primary cutaneous lymphomas: A proposal from the Cutaneous Lymphoma Study Group of the European Organization for Research and Treatment of Cancer. Blood 90:354-371, 1997 4. World Health Organization Classification of Tumors, in Jaffe ES, Harris NL, Stein H (eds): Pathology and Genetics of Tumours of Hematopoietic and Lympoid Tissues. Lyon, France, IARC Press, 2001 5. Willemze R, Jaffe ES, Burg G, et al: WHO-EORTC classification for cutaneous lymphomas. Blood 105:3768-3785, 2005 6. Fung MA, Murphy MJ, Hoss DM, et al: Practical evaluation and management of cutaneous lymphoma. J Am Acad Dermatol 46:325-357, 2002 7. Ashton-Key M, Diss TC, Du MQ, et al: The value of the polymerase chain reaction in the diagnosis of cutaneous T-cell infiltrates. Am J Surg Pathol 21:743-747, 1997 8. Dadej K, Gaboury L, Lamarre L, et al: The value of clonality in the diagnosis and follow-up of patients with cutaneous T-cell infiltrates. Diagn Mol Pathol 10:78-88, 2001 9. Greene FL, Page DL, Fleming ID, et al: AJCC Cancer Staging Handbook (ed 6). New York, NY, Springer, 2002 10. Kim YH, Jensen RA, Watanabe GL, et al: Clinical stage IA (limited patch and plaque) mycosis fungoides. A long- term outcome analysis. Arch Dermatol 132:1309-1313, 1996 11. Kim YH, Hoppe RT: Mycosis fungoides and the Sezary syndrome. Semin Oncol 26:276-289, 1999 12. de Coninck EC, Kim YH, Varghese A, et al: Clinical characteristics and outcome of patients with extracutaneous mycosis fungoides. J Clin Oncol 19:779-784, 2001 13. Kim YH, Bishop K, Varghese A, et al: Prognostic factors in erythrodermic mycosis fungoides and the Sezary syndrome. Arch Dermatol 131: 1003-1008, 1995 14. Diamandidou E, Colome M, Fayad L, et al: Prognostic factor analysis in mycosis fungoides/Sezary syndrome. J Am Acad Dermatol 40:914-924, 1999 15. Wasik MA, Vonderheid EC, Bigler RD, et al: Increased serum concentration of the soluble interleukin-2 receptor in cutaneous T-cell lymphoma. Clinical and prognostic implications. Arch Dermatol 132:42-47, 1996 16. Delfau-Larue MH, Dalac S, Lepage E, et al: Prognostic significance of a polymerase chain reaction-detectable dominant T-lymphocyte clone in
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cutaneous lesions of patients with mycosis fungoides. Blood 92: 3376-3380, 1998 Guitart J, Camisa C, Ehrlich M, et al: Long-term implications of T-cell receptor gene rearrangement analysis by Southern blot in patients with cutaneous T-cell lymphoma. J Am Acad Dermatol 48:775-779, 2003 Beylot-Barry M, Sibaud V, Thiebaut R, et al: Evidence that an identical T cell clone in skin and peripheral blood lymphocytes is an independent prognostic factor in primary cutaneous T cell lymphomas. J Invest Dermatol 117:920-926, 2001 Bakels V, Van Oostveen JW, Geerts ML, et al: Diagnostic and prognostic significance of clonal T-cell receptor beta gene rearrangements in lymph nodes of patients with mycosis fungoides. J Pathol 170:249-255, 1993 Vonderheid EC, Bernengo MG, Burg G, et al: Update on erythrodermic cutaneous T-cell lymphoma: Report of the International Society for Cutaneous Lymphomas. J Am Acad Dermatol 46:95-106, 2002 Hoppe RT: Mycosis fungoides: Radiation therapy. Dermatol Ther 16: 347-354, 2003 Cotter GW, Baglan RJ, Wasserman TH, et al: Palliative radiation treatment of cutaneous mycosis fungoides—A dose response. Int J Radiat Oncol Biol Phys 9:1477-1480, 1983 Wilson LD, Kacinski BM, Jones GW: Local superficial radiotherapy in the management of minimal stage IA cutaneous T-cell lymphoma (Mycosis Fungoides). Int J Radiat Oncol Biol Phys 40:109-115, 1998 Kim JH, Nisce LZ, D’Anglo GJ: Dose-time fractionation study in patients with mycosis fungoides and lymphoma cutis. Radiology 119: 439-442, 1976 Micaily B, Miyamoto C, Kantor G, et al: Radiotherapy for unilesional mycosis fungoides. Int J Radiat Oncol Biol Phys 42:361-364, 1998 Wong R, Jones G, Farrar N, et al: Local superficial radiotherapy (LSRT) for newly diagnosed stage IA patch-plaque mycosis fungoides (MF) with only one, two, or three presenting lesions. Int J Radiat Oncol Biol Phys 57:S289-S290, 2003 (suppl 1) Jones GW, Kacinski BM, Wilson LD, et al: Total skin electron radiation in the management of mycosis fungoides: Consensus of the European Organization for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Project Group. J Am Acad Dermatol 47:364-370, 2002 Hoppe RT, Fuks Z, Bagshaw MA: The rationale for curative radiotherapy in mycosis fungoides. Int J Radiat Oncol Biol Phys 2:843851, 1977 Jones GW, Tadros A, Hodson DI, et al: Prognosis with newly diagnosed mycosis fungoides after total skin electron radiation of 30 or 35 GY. Int J Radiat Oncol Biol Phys 28:839-845, 1994 Jones GW, Hoppe RT, Glatstein E: Electron beam treatment for cutaneous T-cell lymphoma. Hematol Oncol Clin North Am 9:1057-1076, 1995 Chen Z, Agostinelli AG, Wilson LD, et al: Matching the dosimetry characteristics of a dual-field Stanford technique to a customized single-field Stanford technique for total skin electron therapy. Int J Radiat Oncol Biol Phys 59:872-885, 2004 Gamble LM, Farrell TJ, Jones GW, et al: Composite depth dose measurement for total skin electron (TSE) treatments using radiochromic film. Phys Med Biol 48:891-898, 2003 Anacak Y, Arican Z, Bar-Deroma R, et al: Total skin electron irradiation: Evaluation of dose uniformity throughout the skin surface. Med Dosim 28:31-34, 2003 Jones G, Wilson LD, Fox-Goguen L: Total skin electron beam radiotherapy for patients who have mycosis fungoides. Hematol Oncol Clin North Am 17:1421-1434, 2003 Quiros PA, Kacinski BM, Wilson LD: Extent of skin involvement as a prognostic indicator of disease free and overall survival of patients with T3 cutaneous T-cell lymphoma treated with total skin electron beam radiation therapy. Cancer 77:1912-1917, 1996 Chinn DM, Chow S, Kim YH, et al: Total skin electron beam therapy with or without adjuvant topical nitrogen mustard or nitrogen mustard
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alone as initial treatment of T2 and T3 mycosis fungoides. Int J Radiat Oncol Biol Phys 43:951-958, 1999 Jones GW, Rosenthal D, Wilson LD: Total skin electron radiation for patients with erythrodermic cutaneous T-cell lymphoma (mycosis fungoides and the Sezary syndrome). Cancer 85:1985-1995, 1999 Wilson LD, Quiros PA, Kolenik SA, et al: Additional courses of total skin electron beam therapy in the treatment of patients with recurrent cutaneous T-cell lymphoma. J Am Acad Dermatol 35:69-73, 1996 Becker M, Hoppe RT, Knox SJ: Multiple courses of high-dose total skin electron beam therapy in the management of mycosis fungoides. Int J Radiat Oncol Biol Phys 32:1445-1449, 1995 Quiros PA, Jones GW, Kacinski BM, et al: Total skin electron beam therapy followed by adjuvant psoralen/ultraviolet-A light in the management of patients with T1 and T2 cutaneous T-cell lymphoma (mycosis fungoides). Int J Radiat Oncol Biol Phys 38:1027-1035, 1997 Wilson LD, Jones GW, Kim D, et al: Experience with total skin electron beam therapy in combination with extracorporeal photopheresis in the management of patients with erythrodermic (T4) mycosis fungoides. J Am Acad Dermatol 43:54-60, 2000 Rook AH, Kuzel TM, Olsen EA: Cytokine therapy of cutaneous T-cell lymphoma: Interferons, interleukin-12, and interleukin-2. Hematol Oncol Clin North Am 17:1435-1448, 2003 Price NM: Electron beam therapy. Its effect on eccrine gland function in mycosis fungoides patients. Arch Dermatol 115:1068-1070, 1979 Desai KR, Pezner RD, Lipsett JA, et al: Total skin electron irradiation for mycosis fungoides: Relationship between acute toxicities and measured dose at different anatomic sites. Int J Radiat Oncol Biol Phys 15:641645, 1988 Licata AG, Wilson LD, Braverman IM, et al: Malignant melanoma and other second cutaneous malignancies in cutaneous T-cell lymphoma. The influence of additional therapy after total skin electron beam radiation. Arch Dermatol 131:432-435, 1995 Smith BD, Wilson LD: Management of mycosis fungoides: Part 2. Treatment. Oncology (Huntingt) 17:1419-1428; discussion 1430, 1433, 2003 Siegel RS, Pandolfino T, Guitart J, et al: Primary cutaneous T-cell lymphoma: Review and current concepts. J Clin Oncol 18:2908-2925, 2000 Liu HL, Hoppe RT, Kohler S, et al: CD30⫹ cutaneous lymphoproliferative disorders: The Stanford experience in lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma. J Am Acad Dermatol 49:1049-1058, 2003 Cabanillas F, Armitage J, Pugh WC, et al: Lymphomatoid papulosis: A T-cell dyscrasia with a propensity to transform into malignant lymphoma. Ann Intern Med 122:210-217, 1995 Beljaards RC, Willemze R: The prognosis of patients with lymphomatoid papulosis associated with malignant lymphomas. Br J Dermatol 126:596-602, 1992 Smith BD, Glusac EJ, McNiff JM, et al: Primary cutaneous B-cell lymphoma treated with radiotherapy: A comparison of the European Organization for Research and Treatment of Cancer and the WHO classification systems. J Clin Oncol 22:634-639, 2004 Zinzani PL, Quaglino P, Pimpinelli N, et al: Prognostic factors in primary cutaneous B-cell lymphoma: The Italian Study Group for Cutaneous Lymphomas. J Clin Oncol 24:1376-1382, 2006 Grange F, Bekkenk MW, Wechsler J, et al: Prognostic factors in primary cutaneous large B-cell lymphomas: A European multicenter study. J Clin Oncol 19:3602-3610, 2001 Grange F, Petrella T, Beylot-Barry M, et al: Bcl-2 protein expression is the strongest independent prognostic factor of survival in primary cutaneous large B-cell lymphomas. Blood 103:3662-3668, 2004 Sundram U, Kim Y, Mraz-Gernhard S, et al: Expression of the bcl-6 and MUM1/IRF4 proteins correlate with overall and disease-specific survival in patients with primary cutaneous large B-cell lymphoma: A tissue microarray study. J Cutan Pathol 32:227-234, 2005 Eich HT, Eich D, Micke O, et al: Long-term efficacy, curative potential, and prognostic factors of radiotherapy in primary cutaneous B-cell lymphoma. Int J Radiat Oncol Biol Phys 55:899-906, 2003 Santucci M, Pimpinelli N, Arganini L: Primary cutaneous B-cell lym-
168 phoma: A unique type of low-grade lymphoma. Clinicopathologic and immunologic study of 83 cases. Cancer 67:2311-2326, 1991 58. Piccinno R, Caccialanza M, Berti E: Dermatologic radiotherapy of primary cutaneous follicle center cell lymphoma. Eur J Dermatol 13:4952, 2003 59. Rijlaarsdam JU, Toonstra J, Meijer OW, et al: Treatment of primary
B.D. Smith and L.D. Wilson cutaneous B-cell lymphomas of follicle center cell origin: A clinical follow-up study of 55 patients treated with radiotherapy or polychemotherapy. J Clin Oncol 14:549-555, 1996 60. Kirova YM, Piedbois Y, Le Bourgeois JP: Radiotherapy in the management of cutaneous B-cell lymphoma. Our experience in 25 cases. Radiother Oncol 52:15-18, 1999
A
pproximately 27% of all non-Hodgkin lymphomas arise in extranodal sites, such as the skin, stomach, brain, small intestine, lung, and eye.1 The skin is the most common extranodal site, with a yearly incidence approaching 1 case per 100,000 individuals in the United States.2 Cutaneous lymphomas present substantial diagnostic and therapeutic challenges, given their diverse clinical manifestations and expansive, multidisciplinary treatment options. This article will review the natural history of the most common cutaneous lymphomas and will discuss treatment options with a special emphasis on the role of radiotherapy.
phoma within the same classification scheme may be inappropriate because accumulating evidence suggests that primary cutaneous lymphomas behave differently than histologically similar nodal lymphomas. To address the need for a universally accepted classification solely devoted to primary cutaneous lymphoma, the WHO-EORTC published a unified classification for primary cutaneous lymphoma in 2005.5 The entities included in the WHO-EORTC classification, along with their relative frequencies and associated 5-year diseasespecific survivals, are reported in Table 1.
World Health Organization–European Organization for the Research and Treatment of Cancer Classification
Mycosis Fungoides
The pathologic classification of cutaneous lymphoma has been a subject of much debate. In 1997, the European Organization for the Research and Treatment of Cancer (EORTC) proposed a classification scheme for primary cutaneous lymphoma.3 Although the EORTC classification borrowed terms previously used in the classification of nodal lymphoma, the EORTC terminology was not intended to apply to nodal lymphoma. In contrast, the World Health Organization (WHO) classification, proposed in 2001, was a unified system that applied similar terminology to both extranodal lymphoma (including primary cutaneous lymphoma) and nodal lymphoma.4 However, grouping cutaneous and nodal lym*United States Air Force, Wilford Hall Medical Center, Lackland AFB, TX. †Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT. Address reprint requests to Lynn D. Wilson, MD, MPH, Department of Therapeutic Radiology, Yale University School of Medicine, HRT 132, 333 Cedar Street, New Haven, CT 06520. E-mail: Lynn.wilson@ yale.edu
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Clinical Manifestations Mycosis fungoides (MF) is a malignancy of helper (CD4⫹) T-cells and accounts for nearly 50% of all cutaneous lymphomas, with a yearly incidence of approximately 5 cases per million in the United States.2,5 The EORTC classification states that the term mycosis fungoides should be reserved for those CD4⫹ cutaneous lymphomas that are “characterized by the subsequent evolution of patches to more infiltrated plaques and eventually tumors.”3 The earliest phase of MF— the premycotic phase—typically begins with skin patches that are mildly erythematous, slightly scaling, annular (ringshaped) or arcuate (arc-shaped), and classically involves sunshielded areas (Fig. 1A). Such lesions may wax and wane for years before histologic findings show definitive evidence of MF. As MF progresses, patches lose their predilection for sun-shielded areas and may become eczematous, hypopigmented, or hyperpigmented. The trunk, pelvis, and proximal extremities are most commonly involved. Patches may progress to form more generalized, deeply infiltrative, scaling plaques that have well-demarcated, palpable borders (Fig. 1B). If the neoplastic cells lose their skin-homing (epidermo-
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Table 1 The WHO-EORTC Classification for Cutaneous Lymphoma5
Histology Cutaneous T-cell and NK-cell lymphomas Mycosis fungoides Variants of mycosis fungoides Folliculotropic mycosis fungoides Pagetiod reticulosis Granulomatous slack skin Sézary syndrome Adult T-cell leukemia/lymphoma Primary cutaneous CD30ⴙ lymphoproliferative disorders Primary cutaneous anaplastic large-cell lymphoma Lymphomatoid papulosis Subcutaneous panniculitis-like T-cell lymphoma (␣/ type) Extranodal NK/T-cell lymphoma, nasal type Primary cutaneous peripheral T-cell lymphoma, unspecified Primary cutaneous aggressive epidermotropic CD8ⴙ T-cell lymphoma Cutaneous ␥/␦ T-cell lymphoma (provisional) Primary cutaneous CD4ⴙ small-/medium-sized pleomorphic T-cell lymphoma Cutaneous B-cell lymphomas Primary cutaneous marginal zone B-cell lymphoma Primary cutaneous follicle center lymphoma Primary cutaneous diffuse large B-cell lymphoma, leg type Primary cutaneous diffuse large B-cell lymphoma, other Intravascular large B-cell lymphoma Precursor hematologic neoplasm CD4ⴙ/CD56ⴙ hematodermic neoplasm (blastic NK-cell lymphoma)
tropic) properties, they enter a vertical growth phase and form cutaneous tumors (Fig. 1C). Such tumors may cause substantial morbidity because of ulceration and superinfection.
Diagnosis The diagnosis of mycosis fungoides remains challenging, even for the experienced clinician and dermatopathologist, because of both the absence of a diagnostic gold standard and the number of benign dermatoses that may mimic MF. On skin biopsy, the most notable finding of early MF is substantial epidermotropism, characterized by lymphocytes grouped along the epidermal basement membrane. Pautrier’s microabscesses, which are well-defined collections of intraepidermal lymphocytes, are considered pathognomonic for MF but are seen in less than 20% of early lesions. For clinically and histologically borderline cases, molecular studies may help to confirm a diagnosis of MF. Typically, MF shows the following immunophenotype: CD2⫹ (pan T-cell), CD3⫹ (pan T-cell), CD4⫹ (helper T-cell), CD5⫹ (pan T-cell), CD45RO⫹ (memory T-cell), CLA⫹ (cutaneous lymphoid antigen), CD8- (cytotoxic T-cell), and CD30- (activated T cell).6 An aberrant T-cell phenotype, such as loss of expression of CD2, CD3, and/or CD5, also supports the diagnosis of MF.5 Use of polymerase chain reaction to identify a clonal
Frequency (%)
5-Year Disease-Specific Survival (%)
44
88
4 <1 <1 3 —
80 100 100 24 —
Indolent Indolent Indolent Aggressive —
8 12 1 <1 2 <1
95 100 82 — 16 18
Indolent Indolent Indolent Aggressive Aggressive Aggressive
<1 2
— 75
Indolent
7 11 4 <1 <1
99 95 55 50 65
Indolent Indolent Intermediate Intermediate Intermediate
—
—
—
Clinical Behavior Indolent
T-cell receptor gene rearrangement may help to confirm the diagnosis of MF. For example, a clonal T-cell population can be identified in 50% to 80% of histologically borderline biopsies obtained from patients who subsequently develop classic MF.7,8 Other tests recommended to complete the diagnostic work up are summarized in Table 2.
Staging and Prognosis The American Joint Committee on Cancer (AJCC) staging system for MF identifies extent and character of skin lesions, extracutaneous disease, and leukemic transformation as the major determinants of poor prognosis (Tables 3 and 4).9 Patients with limited patches and plaques (stage IA, T1 N0 M0) experience 10-year survival similar to a matched control population.10 The median survival is approximately 11 years for patients with extensive patches and plaques (T2), 3.2 years for patients with tumors (T3), and 4.6 years for patients with erythroderma (T4).11 Patients with either pathologically documented lymph node involvement or visceral involvement experience a median survival of approximately 1 year.12 The AJCC also included a blood descriptor, B0 versus B1, to document the absence or presence of greater than 1,000 Sézary cells (CD4⫹, CD7⫺) per L. Among patients with erythroderma, the presence of B1 disease doubles the risk of
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Figure 1 Clinical presentation of CTCL. (A) Typical early patch with erythema and mild scale. (B) Typical plaque, with raised, palpable borders, central clearing, and overlying scale. (C) Large tumor with necrosis and ulceration. (D) Generalized erythroderma. (Reprinted with permission from Smith BD, Wilson LD: Management of mycosis fungoides. Part 1. Diagnosis, staging, and prognosis. Oncology [Huntingt] 17:1281-1288, 2003.)
death.13 Other factors that may herald a poor prognosis include age ⱖ60,14 elevated lactate dehydrogenase (LDH),14 elevated soluble interleukin-2 receptor levels,15 T-cell clonality within the cutaneous infiltrate detected by polymerase chain reaction,16,17 an identical T-cell clone in the skin and peripheral blood,18 and T-cell clonality in dermatopathic lymph nodes.19
Sézary Syndrome Sézary syndrome (SS) is defined as erythroderma (stage T4, Fig. 1D) plus evidence of malignant circulating T cells that satisfy any of the 5 criteria listed in Table 5.20 For the purposes of these criteria, the Sézary cell is defined as “any atypical lymphocyte with [a] moderately to highly infolded or grooved nucleus.”20 The pathologic link between MF and
Figure 4 Clinical presentation of CBCL. Common clinical features of CBCL include scalp involvement (C and D), red-orange hue (A), red hue (B and C), blue-purple hue (D), grouped papules (A), combined papule and patch (B), a single papule (C), and a single tumor (D). Note the absence of scale.
SS remains unclear. SS usually arises de novo without antecedent MF. Rarely, MF will evolve to an erythrodermic stage with concomitant hematologic findings that satisfy a diagnosis of SS.
Radiotherapy for Mycosis Fungoides Overview Radiation produces very high complete response rates and may be the single most effective modality in the treatment of MF.21 For patients with stage IA MF, localized, superficial radiotherapy, or total skin electron-beam therapy (TSEBT) may be curative. For patients with more advanced cutaneous
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Table 2 Diagnostic Testing for Patients With Suspected Mycosis Fungoides History and physical with attention to skin, lymph nodes, liver, and spleen Skin biopsy with attention to Histology Epidermotropic lymphocytes with medium-large, extremely convoluted nuclei Pautrier’s microabscesses Immunophenotype Classically CD2ⴙ CD3ⴙ CD4ⴙ CD5ⴙ CD45ROⴙ CD8ⴚ CD30ⴚ Rarely CD4ⴚ CD3ⴙ CD8ⴙ PCR for T-cell receptor gene rearrangement Biopsy of enlarged lymph nodes with attention to Histology, both number of atypical lymphocytes and disruption of nodal architecture In dermatopathic nodes, consider PCR for T-cell clonality and immunophenotyping to rule out occult involvement Evaluation of blood CBC with manual differential, liver function tests and serum chemistries for all patients In those with suspected stage IIB-IV disease LDH, soluble interleukin-2 receptor Flow cytometry for CD2, CD3, CD4, CD5, CD7, CD8, CD20, CD45RO. Findings suggestive of blood involvement include an elevated CD4:CD8 ratio (normal range 0.5 – 3.5), or an expanded population of CD4ⴙCD7ⴚ or CD45ROⴙ lymphocytes. PCR for T-cell receptor gene rearrangement Bone marrow aspirate and biopsy is only indicated to evaluate unexplained cytopenias Imaging Posteroanterior and lateral chest radiograph for stages IA-IB Computed tomography of chest, abdomen, and pelvis for suspected stage IIA-IV
and/or visceral disease, radiotherapy can provide meaningful and durable palliation.
Localized, Superficial Radiotherapy For treatment of an isolated lesion with localized, superficial radiotherapy, the optimal dose is ⱖ 30 Gy delivered in 1.2 to 2.0 Gy per fraction. For example, Cotter and coworkers22 reported an infield recurrence rate of 42% for those treated to a total dose ⱕ10 Gy, 32% for 10.01 to 20 Gy, 21% for 20.01 to 30 Gy, and 0% for ⬎30 Gy. In addition, Wilson and
Table 3 TNM(B) Classification for Mycosis Fungoides T1–Patches and/or plaques involving <10% body surface area T2–Patches and/or plaques involving >10% body surface area T3–One or more cutaneous tumors T4–Generalized erythroderma N0–Lymph nodes clinically uninvolved N1–Lymph nodes clinically enlarged but histologically uninvolved N2–Lymph nodes clinically nonpalpable but histologically involved N3–Lymph nodes clinically enlarged and histologically involved M0–No visceral disease present M1–Visceral disease present B0–No circulating atypical cells (<1,000 Sézary cells [CD4ⴙ CD7-]/L) B1–Circulating atypical cells present (>1,000 Sézary cells [CD4ⴙ CD7-]/L) Adapted with permission.9
coworkers23 reported local failure in 20% (4/20) of lesions treated with ⱕ20 Gy compared with 0% (0/10) of lesions treated with ⬎20 Gy. Evidence suggests that the malignant cells of MF have little ability to execute sublethal damage repair, thus supporting the use of low daily fraction sizes to minimize late toxicity without sacrificing local control.24 Approximately 5% of patients with stage IA disease present with a single skin lesion or with 2 or 3 lesions in close proximity, such that all clinically apparent disease can be encompassed within a reasonable radiotherapy portal.23 For patients with such limited disease, we recommend definitive treatment with localized, superficial radiotherapy because prior retrospective experiences have documented long-term disease-free survival in excess of 85% with this approach.23,25,26 For example, 21 patients treated at Yale University experienced a complete response rate of 97%. For those who received ⱖ20 Gy, long-term disease-free survival was 91%.23 Similarly, 18 patients treated to a median dose of 30.6 Gy at Allegheny University Hospitals experienced a 10-year disease-free survival
Table 4 Staging Classification for Mycosis Fungoides IA IB IIA IIB IIIA IIIB IVA IVB
T1 T2 T1-2 T3 T4 T4 T1-4 T1-4
N0 N0 N1 N0-1 N0 N1 N2-3 N0-3
The B descriptor is not considered in stage classification.
M0 M0 M0 M0 M0 M0 M0 M1
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162 Table 5 Proposed Hematologic Criteria for the Diagnosis of Sézary Syndrome20 1. Absolute Sézary cell count >1,000 cells/L 2. CD4/CD8 ratio > 10 due to an increase in CD3ⴙ or CD4ⴙ cells by flow cytometry 3. Aberrant expression of pan-T cell markers (CD2, CD3, CD4, CD5) by flow cytometry. Deficient CD7 expression on T cells (or expanded CD4ⴙ, CD7ⴚ cells >40%) is a tentative criterion 4. Increased lymphocyte count with T-cell clone in blood identified by Southern blot or polymerase chain reaction 5. A chromosomally abnormal T-cell clone
of 86%.25 Minimal stage IA disease should be treated with a single radiation field where possible, although abutting fields may be required at a convex surface such as the scalp, an axillary fold, breast, hand, or foot. The junction of abutting fields should be shifted weekly during the course of treatment to improve homogeneity. Field margins can be limited to only 1 to 2 cm beyond the visible (or palpable) clinical lesion.
TSEBT: Technique Consensus guidelines for delivery of TSEBT have been published by the EORTC27 (Table 6). The EORTC recommends a total dose of 31 to 36 Gy prescribed to the skin surface to produce a dose of at least 26 Gy at a depth of 4 mm in truncal skin along the central axis.27 Several retrospective experiences support these recommendations. For example, analysis of 176 patients treated at Stanford University revealed that complete response rates increased with total dose as follows: 18% for 8 to 9.9 Gy, 55% for 10 to 19.9 Gy, 66% for 20 to 24.9 Gy, 75% for 25 to 29.9 Gy, and 94% for 30 to 36 Gy.28 For patients treated at the Hamilton Regional Cancer Center, complete response rates were 64% for those who received 30 Gy (all treated between 1977 to 1980) compared with 85% for those who received 36 Gy (all treated between 1980 to 1992).29 The target volume for patients with patch/plaque disease should include the epidermis and dermis.30 The thickness of the epidermis and dermis varies from a minimum of approximately 2 mm at the trunk to a maximum of about 4.5 mm at the hands and soles of the feet.30 For TSEBT, the 80% isodose line should fall more than 4 mm deep to the skin surface to ensure that the epidermis and dermis fall with the high-dose region. Cutaneous tumors often exceed this 4-mm depth, and therefore such lesions are underdosed when treated with TSEBT alone. Patients with cutaneous tumors greater than 4-mm thick may receive boost treatments either during or after TSEBT, typically 10 Gy delivered in 2 Gy fractions with an appropriate electron energy and bolus. The treatment geometry for TSEBT used at Yale is presented in Fig. 2.31 A total of 6 treatment positions are designated: anteroposterior, right and left anterior oblique, posteroanterior, and right and left posterior oblique (Fig. 3). These positions maximize skin unfolding, thereby improving
dose homogeneity in the lateral dimension. Each treatment position is treated with both an upper and a lower field to maximize dose homogeneity in the vertical dimension. On treatment day 1, the anteroposterior, right posterior oblique, and left posterior oblique positions are treated. On treatment day 2, the posteroanterior, right anterior oblique, and left anterior oblique positions are treated with the same dose. Over the course of a 2-day treatment cycle, a patient will receive 2 Gy to the entire skin surface. This pattern continues, with patients receiving treatment 4 days a week for a total of nine weeks, thereby delivering a total dose of 36 Gy to the skin surface. By using this TSEBT technique, the soles of feet, perineum, and scalp are underdosed and require supplemental patch treatments as outlined in Table 7. Other potentially underdosed regions include the ventral penis, upper medial thighs, inframammary folds, folds under any pannus, and the lateral and flatter regions of the face and trunk. Supplemental patch fields, as guided by in vivo dosimetry or clinical suspicion, are appropriate for these regions to ensure that the surface dose is at least 50% of the prescribed TSEBT dose.32,33 The total supplemental dose given to these areas may be reduced as clinically indicated to enhance patient tolerance, provided such areas are uninvolved. The hands, wrists, ears, ankles, and dorsal penis may be overdosed and require shielding to limit the dose to ⱕ36 Gy. Detailed dosimetric measurements are typically required to determine the most appropriate shielding regimen for a particular treatment arrangement and patient geometry. The shielding regimen used at Yale and the resulting doses to various anatomic structures are presented in Tables 7 and 8.
TSEBT: Clinical Results TSEBT is a reasonable first-line treatment option for patients with nonlocalized stage IA MF and for most patients with stage IB through III MF. However, no randomized data exist to support selection of a radiation-based strategy over Table 6 EORTC Guidelines for Total Skin Electron-Beam Therapy27 Dose inhomogeneity in air at treatment distance should be <10% within vertical and lateral dimensions 80% isodose line should be >4-mm deep to the skin surface to ensure that the epidermis and dermis fall within the high dose region. 80% isodose line should receive a minimum total dose of 26 Gy 20% isodose line should be <20 mm from the skin surface to minimize dose to underlying structures 30-36 fractions should be used to minimize acute side effects Total dose to bone marrow from photon contamination should be less than 0.7 Gy Patch treatments should be utilized to underdosed areas such as the perineum, scalp, and soles of feet Internal and external eye shields should be used to ensure that the dose to the globe is not more than 15% of the prescribed skin surface dose
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Figure 2 Treatment geometry for total skin electron-beam therapy. (Reprinted with permission from Smith BD, Jones G, Wilson LD: Mycosis fungoides, in Gunderson LL, Tepper JE [eds]: Clinical Radiation Oncology [ed 2]. Philadelphia, PA, Elsevier, 2007.) (Color version of figure is available online.)
other treatment strategies, and therefore initial treatment is strongly dependent on institutional and patient preferences. For patients presenting with limited patches and plaques (stage IA, T1 N0 M0), TSEBT produces complete response rates of at least 90%10,30 and 10-year relapse-free survival of 50%.34 For patients presenting with extensive
patches and plaques (stage IB, T2 N0 M0), TSEBT produces complete response rates of approximately 80% to 90%,27,34 but 10-year relapse-free survival is only 10%.34 For patients presenting with tumors (stage IIB, T3 N0-1 M0), TSEBT produces complete response rates ranging from 50% to 100% depending on the extent of initial skin involvement30,35,36 and
Figure 3 Treatment positions for total skin electron-beam therapy. Top row (from left to right): right anterior oblique, anteroposterior, and left anterior oblique treatment positions. Bottom row (from left to right): right posterior oblique, posteroanterior, and left posterior oblique treatment positions. (Reprinted with permission from Smith BD, Wilson LD: Management of mycosis fungoides: Part 2. Treatment. Oncology [Hunting] 17: 1419-1428; discussion 1430, 1433) (Color version of figure is available online.)
B.D. Smith and L.D. Wilson
164 Table 7 Treatment Protocol at Yale-New Haven Hospital31 Treatment cycle Day 1 Day 2 Dose Dose per cycle Cycles per week Total cycles Total dose Boosts Perineum Soles of feet Blocking External eye shields Internal eye shields Lip shield Lead mitt for hands Fingernail shield Foot block Testicular shield
AP, RPO, LPO treatment positions PA, RAO, LAO treatment positions 2 Gy 2 18 36 Gy 1 Gy/d, first 9 and last 9 treatment days 1 Gy/d, first 7 and last 7 days treatment days First 11 cycles Last 7 cycles Cycles 1-4 Every other cycle Every other cycle, alternating with mitts Cycles 1-3, 5, 7, 9, 11, 13, 15, 17, 18 Used with perineum boost only
At Yale, the scalp is boosted by an electron reflector mounted above the patient’s head. Alternatively, the scalp may be boosted with 120 kV, or electrons, typically 6 to 20 Gy over 1 to 3 weeks as guided by in vivo dosimetry. AP ⴝ anteroposterior; RPO ⴝ right posterior oblique; LPO ⴝ left posterior oblique; PA ⴝ posteroanterior; RAO ⴝ right anterior oblique; LAO ⴝ left anterior oblique.
may confer very meaningful palliation. However, long-term disease-free survival after TSEBT monotherapy for tumors is rare. For patients presenting with erythroderma (stage III, T4 N0-1 M0), TSEBT produces complete response rates of approximately 75% and may result in prolonged disease-free survival in the subset of patients without blood involvement.37 For patients with disease that has relapsed after treatment with TSEBT, a second course of TSEBT, typically to a total dose of 18 to 23 Gy, yields high complete response rates with acceptable toxicity.38,39
TSEBT: Adjuvant Therapy Because the majority of patients will develop a cutaneous relapse after TSEBT monotherapy, adjuvant therapy is recommended to maximize disease-free survival. Retrospective experiences suggest that adjuvant topical nitrogen mustard36 or psoralen plus ultraviolet A (PUVA)40 may improve diseasefree survival after TSEBT for stage IB MF. For patients with more advanced disease, many adjuvant therapies may be considered, including topical nitrogen mustard,36 photophoresis,41 interferon-␣, bexarotene, and denileukin diftitox.42
TSEBT: Toxicity Common acute toxicities from TSEBT include pruritus, dry desquamation, erythema, alopecia, xerosis, bullae of the feet, edema of the hands and feet, hypohidrosis (di-
minished perspiration),43 and loss of fingernails and toenails.34,44 Rare acute side effects include gynecomastia in men and mild epistaxis or parotiditis.34 Long-term complications are typically mild and may include permanent nail dystrophy, xerosis, telangiectasias, partial scalp alopecia, and fingertip dysesthesias.27 Young patients should be thoroughly counseled regarding risks of gonadal toxicity. Second cutaneous malignancies including squamous cell carcinoma, basal cell carcinoma, and malignant melanoma have been observed in patients treated with TSEBT, particularly in those exposed to multiple therapies that are themselves known to be carcinogenic, such as PUVA and nitrogen mustard.45
Other Therapies for Mycosis Fungoides In addition to radiation, other skin-directed therapies for MF include phototherapy (both ultraviolet B monotherapy and PUVA), nitrogen mustard, carmustine, bexarotene, and corticosteroids. Systemic treatment options include systemic chemotherapy, interferon, retinoids, bexarotene, denileukin diftitox, extracorporeal photophoresis, and agents currently under investigation. The effectiveness, toxicity, and indications for these therapies are discussed by Smith and Wilson.46
Table 8 Dose to Anatomic Sites Measured In Vivo31 Dose per Two-Day TSEBT Treatment Cycle* Central axis Top of head Forehead Eye Eyelid Lips Posterior neck Shoulder Axilla Hand Mid back Umbilicus Flank Lateral thigh Perineum Top of feet Soles of feet
Total Dose With Blocking and Boosts
Gy
%
Gy
%
2.0 2.3 2.4 0.1 — — 2.1 1.7 2.2 1.6 2.0 2.1 2.0 1.9 0.6 2.3 0
100 115 118 12 — — 104 87 109 82 100 104 99 95 31 117 0
36 41.4 42.5 2.2 24.5 30 37.4 31.3 39.2 15.6 36 37.4 35.6 34.2 29 28.5 14
100 115 118 6 68 83 104 87 109 43 100 104 99 95 81 79 39
*Dose using dual-field, 6-treatment position setup with scalp electron reflector and eye shields.
Cutaneous lymphomas
165
Primary Cutaneous CD30ⴙ Lymphoproliferative Disorders After MF, primary cutaneous CD30⫹ lymphoproliferative disorders are the next most common cutaneous T-cell lymphoma. This category includes both lymphomatoid papulosis (LyP), which is a benign, self-limited entity, and cutaneous anaplastic large-cell lymphoma (C-ALCL), which is a malignant entity that may spread to extracutaneous sites.
clusively confined to the skin at diagnosis. Since the early 1990s, the reported incidence of CBCL has increased rapidly, approaching 4 cases per million in the United States.2 Risk factors for developing CBCL include advanced age, male sex, and white race.2 CBCL most commonly presents in the head and neck region2 as a unilesional or oligolesional patch, papule, plaque, or tumor, with coloration varying from red to orange to blue-purple. (Fig. 4) In contrast to CTCL, CBCLs rarely produce scale.
Classification
LyP LyP presents with grouped erythematous or violaceous papules and/or nodules at different stages of development. Individual skin lesions typically resolve spontaneously within 3 to 12 weeks, but scarring is common.47 Three different histologic subtypes have been described, with types A and C consisting of malignant CD30⫹ T cells, often with an extensive inflammatory infiltrate, and type B–simulating classical plaque-stage MF. For type C lesions, discrimination between LyP and C-ALCL may be difficult on histologic grounds, and assessment of the clinical context may be required to ensure the proper diagnosis.3 Although cytologically malignant, LyP is clinically benign with a 5-year survival of 100%.3,48 Thus, neither aggressive chemotherapy nor radiotherapy is indicated.49 Treatment options include PUVA or low-dose methotrexate, but neither is curative. In the long term, 15% to 20% of patients with LyP will develop a second malignancy, most commonly MF, C-ALCL, or Hodgkin’s disease.49,50
Cutaneous Anaplastic Large-Cell Lymphoma C-ALCL typically presents as a red- or flesh-colored nodule or tumor that may ulcerate. On biopsy, sheets of large CD30⫹, nonepidermotropic lymphocytes are noted in the dermis. In contrast to systemic CD30⫹ anaplastic large-cell lymphoma, overexpression of anaplastic lymphoma kinase is not found in C-ALCL. Patients with localized disease may be treated with radiotherapy alone, and 5-year disease-specific survival is approximately 95%.3,48
Cutaneous B-Cell Lymphoma Clinical Manifestations The term cutaneous B-cell lymphoma (CBCL) refers to a spectrum of B-cell lymphoproliferative disorders that are ex-
The pathologic classification, and correspondingly the optimal treatment of CBCL, has been a source of much confusion. One important source of confusion has been differences in the original EORTC and WHO classification schemes for CBCL. For example, the most common subtype of CBCL according to the original EORTC classification scheme was “follicle center cell lymphoma,” a lowgrade B-cell neoplasm for which definitive radiation therapy without chemotherapy was recommended. However, many lesions classified as “follicle center cell lymphoma” in the EORTC classification scheme may be classified as “diffuse large B-cell lymphoma” in the WHO classification.51 Unlike their nodal counterparts, the majority of CBCLs classified as “diffuse large B-cell lymphoma” according to WHO criteria exhibit clinically indolent behavior and may potentially be treated with definitive radiotherapy without systemic chemotherapy.51 Another source of confusion has been the EORTC category termed “large B-cell lymphoma of the leg,” defined as CBCL with a preponderance of large B cells arising in the lower extremities. Based on the original EORTC criteria, histologically identical lesions would be classified as “large B-cell lymphoma of the leg” if located on the lower extremities and “follicle center cell lymphoma” if located elsewhere. The combined WHO-EORTC pathologic classification (Table 1), published by Willemze and coworkers in 2005, has made great strides in addressing the deficiencies of the original WHO and EORTC classification schemes.5 Under this classification scheme, the category “primary cutaneous follicle center lymphoma” includes B-cell neoplasms with both follicular and diffuse architecture, thus encompassing the majority of “follicle center cell lymphomas” from the EORTC classification and “diffuse large B-cell lymphomas” from the WHO classification. Such CBCLs may be treated with definitive radiotherapy without che-
Table 9 CBCL-Prognostic Index (CBCL-PI)2 CBCL-PI Group
Histology*
Skin Site
IA IB II II III
Follicular, marginal zone, or lymphoplasmacytic Diffuse large B cell Diffuse large B cell Immunoblastic diffuse large B cell Immunoblastic diffuse large B cell
Any Head, neck, or arm Trunk, leg, disseminated Head, neck, or arm Trunk, leg, disseminated
*Histology is based on the WHO classification.
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166
to define the optimal radiotherapy dose for CBCL, Smith and coworkers51 noted a trend toward improved local control for patients who received ⱖ36 Gy.51 To enhance cosmesis, particularly in the head and neck region, we recommend low daily fraction sizes on the order of 2 Gy/d. For patients with primary cutaneous follicle center lymphoma and primary cutaneous marginal zone lymphoma, radiotherapy as the sole treatment modality confers complete response rates approaching 100%. Five-year local control is approximately 90%, and 5-year relapse-free survival is approximately 50%.51,56-60 The majority of recurrences are limited to the skin and are amenable to additional salvage radiotherapy.
Conclusion
Figure 5 Relative survival stratified by CBCL-Prognostic Index Group. CBCL prognostic index groups are defined in Table 9. Relative survival indicates the expected survival compared with age-, race-, and sex-matched controls. (Reprinted with permission from the American Society of Clinical Oncology.2)
motherapy. In addition, the WHO-EORTC classification introduced a new category, “primary cutaneous large Bcell lymphoma, leg type,” which includes histologically aggressive large B-cell neoplasms arising on either the lower extremities or other skin sites, often with expression of bcl-2 and Mum-1/IRF-4. Such lesions typically exhibit a more aggressive clinical course, and systemic therapy should be strongly considered.
Staging and Prognosis The conventional AJCC staging system for non-Hodgkin lymphoma fails to provide adequate risk stratification for CBCL because patients can be grouped into only 2 categories: stage IE if skin lesions are localized and stage IVE if skin lesions are disseminated.9 To provide more detailed prognostic information, Smith and coworkers used population-based data to develop a CBCL-Prognostic Index (CBCL-PI), which predicts prognosis using skin site of involvement and lesion histology (Table 9 and Fig. 5).2 This prognostic index should be used cautiously, however, as it awaits validation. Other factors correlated with adverse prognosis include leg involvement,52,53 multiple skin lesions,52-54 bcl-2 expression,54 Mum-1 expression,55 and round cell (immunoblastic) histology.53
Radiotherapy: Technical Factors and Results Either electron therapy with appropriate bolus or orthovoltage therapy may be used in the treatment of CBCL. Typically, a 2- to 3-cm margin of normal tissue should be included in the field to account for microscopic extension of disease. When lesions are located on oblique surfaces, multiple abutting fields are required to ensure adequate tumor coverage. Although limited data exist
Skin lymphomas represent a diverse array of clinical entities with unique natural histories and treatment options. Radiation oncologists must be cognizant of these issues to provide optimal radiotherapy within a multidisciplinary context.
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168 phoma: A unique type of low-grade lymphoma. Clinicopathologic and immunologic study of 83 cases. Cancer 67:2311-2326, 1991 58. Piccinno R, Caccialanza M, Berti E: Dermatologic radiotherapy of primary cutaneous follicle center cell lymphoma. Eur J Dermatol 13:4952, 2003 59. Rijlaarsdam JU, Toonstra J, Meijer OW, et al: Treatment of primary
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