Cutaneous T-Cell Lymphoma Guidelines

Updated: Aug 15, 2018
  • Author: Lauren C Pinter-Brown, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Guidelines

Guidelines Summary

Guidelines contributors:  Priyank P Patel, MD , Hematology/Oncology Fellow, Roswell Park Cancer Institute, University at Buffalo;  Francisco J Hernandez-Ilizaliturri, MD; Chief, Lymphoma and Myeloma Section; Professor of Medicine, Department of Medical Oncology; Director of The Lymphoma Translational Research Program; Associate Professor of Immunology, Roswell Park Cancer Institute 

NHL Classification Schemas

The three most commonly used classification schemas for non-Hodgkin lymphoma (NHL) are as follows:

  • National Cancer Institute’s Working Formulation (IWF) [120]

  • Revised European-American Classification of Lymphoid Neoplasms (REAL) [121]

  • World Health Organization (WHO) classification [122]

The Working Formulation, originally proposed in 1982, classified and grouped lymphomas by morphology and clinical behavior (ie, low, intermediate, or high grade) with 10 subgroups labeled A to J. [120] In 1994, the Revised European-American Lymphoma (REAL) classification attempted to apply immunophenotypic and genetic features in identifying distinct clinicopathologic NHL entities. [121]

The World Health Organization (WHO) classification, first introduced in 2001 and updated in 2008, further elaborates upon the REAL approach. This classification divides NHL into two groups: those of B-cell origin and those of T-cell/natural killer (NK)–cell origin. [122]

Although considered obsolete, the National Cancer Institute’s Working Formulation (IWF) classification is still used mainly for historical data comparisons. [120]

The World Health Organization–European Organization for Research and Treatment of Cancer (WHO-EORTC) classification of cutaneous T-cell lymphoma (CTCL) is divided into CTCLs with indolent clinical behavior and those with aggressive subtypes. CTCLs with indolent clinical behavior include the following [1] :

  • Mycosis fungoides

  • Mycosis fungoides variants and subtypes (eg, folliculotropic mycosis fungoides, pagetoid reticulosis, granulomatous slack skin)

  • Primary cutaneous CD30+ lymphoproliferative disorder (eg, primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis)

  • Subcutaneous panniculitis-like T-cell lymphoma (provisional)

  • Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma (provisional)

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Mycosis Fungoides/Sezary Syndrome

In addition to the guidelines from the National Comprehensive Cancer Network (NCCN) [123] , the European Organization for Research and Treatment of Cancer (EORTC) released consensus recommendations for the treatment of mycosis fungoides/Sezary syndrome (MF/SS) in 2006. [124]  In 2013, the European Society for Medical Oncology (ESMO) included treatment recommendations in its guidelines for primary cutaneous lymphoma. [125]

Diagnosis

The NCCN considers the following studies essential for establishing a diagnosis of MF/SS [123] :

  • Biopsy of suspicious skin sites (multiple biopsies may be necessary to capture the pathologic variability of disease at diagnosis)

  • Dermatopathology review of slides (including evaluation for presence of transformation or areas of folliculotropism

  • Immunohistochemistry panel of skin biopsy (CD2, CD3, CD4, CD5, CD7, CD8, CD20, CD30, CD25, CD56, TIA1, granzyme B, ßF1, TCR-CγM1)

  • Molecular analysis to detect clonal T-cell antigen receptor (TCR) gene rearrangements or other assessment of clonality

Staging

In 2007, the ISCL/EORTC released a revised tumor-node-metastasis-blood (TNMB) classification of MF/SS based on particular skin findings and extracutaneous disease. [5]  See Table 4, below.

Table 4. International Society for Cutaneous Lymphoma/European Organization for Research and Treatment of Cancer tumor-node-metastasis-blood revised classification for mycosis fungoides and Sezary syndrome (Open Table in a new window)

Skin

Involvement

Node

Involvement

Viscera

Involvement

T1

Patchy or plaquelike skin disease involving ≤10% of the skin surface area

N0

No abnormal lymph nodes

M0

No visceral organ involvement

T2

Patchy or plaquelike skin disease involving ≥10% of the skin surface area

N1

Histopathology Dutch Gr 1 or NCI LN 0-2

M1

Visceral organ involvement

T3

Tumors are present ≥1 cm in diameter

N2

Histopathology Dutch Gr 2 or NCI LN 3

MX

Abnormal visceral site; no histologic confirmation

T4

Erythroderma ≥80% of body area

N3

Histopathology Dutch Gr 3-4 or NCI LN 4

Blood

Involvement

   

Nx

Abnormal lymph nodes; no histologic confirmation

B0

≤5% of peripheral blood lymphocytes are Sezary cells

       

B1

>5% of peripheral blood lymphocytes are Sezary cells but do met B2 criteria

       

B2

≥1000/mcL Sezary cells or CD4/CD8 ≥10 or ≥40% CD4+/CD7- or ≥30% CD4+/CD26- cells

The ISCL/EORTC system was further modified to update clinical staging classifications. [5]  See Table 5, below.

Table 5. Staging classifications for mycosis fungoides and Sezary syndrome (Open Table in a new window)

Clinical Stage

5-Year Survival  [5]

TNM (B) Stage

IA

96-100%

T1N0M0B0

T1N0M0B1

     

IB

73-86%

T2N0M0B0

T2N0M0B1

     

IIA

49-73%

T1N1M0B0

T1N1M0B1

T1N2M0B0

T1N2M0B1

 

 

T2N1M0B0

T2N1M0B1

T2N2M0B0

T2N2M0B1

 

IIB

40-65%

T3N0M0B0

T3N0M0B1

T3N1M0B0

T3N1M0B1

 

 

T3N2M0B0

T3N2M0B1

     

IIIA

50-57%

T4N0M0B0

T4N1M0B0

T4N2M0B0

   

IIIB

T4N0M0B1

T4N1M0B1

T4N2M0B1

   

IVA

15-40%

T1N0M0B2

T2N0M0B2

T3N0M0B2

T4N0M0B2

 

 

T1N1M0B2

T2N1M0B2

T3N1M0B2

T4N1M0B2

 

 

T1N2M0B2

T2N2M0B2

T3N2M0B2

T4N2M0B2

 

 

T1N3M0B0

T2N3M0B0

T3N3M0B0

T4N3M0B0

 

 

T1N3M0B1

T2N3M0B1

T3N3M0B1

T4N3M0B1

 

 

T1N3M0B2

T2N3M0B2

T3N3M0B2

T4N3M0B2

 

IVB

0-15%

T1N0M1B0

T2N0M1B0

T3N0M1B0

T4N0M1B0

 

T1N1M1B1

T2N1M1B1

T3N1M1B1

T4N1M1B1

 

T1N2M1B2

T2N2M1B2

T3N2M1B2

T4N2M1B2

 

T1N3M1B3

T2N3M1B3

T3N3M1B3

T4N3M1B3

 

Treatment

The NCCN recommends that patients be treated at specialized centers with expertise in the management of MF/SS. Unlike other non-Hodgkin lymphoma subtypes, MF/SS criteria have not correlated with prognosis, and treatment decisions are made on a clinical basis. [123]

In 2011, the International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the EORTC issued a joint consensus statement proposing new clinical end points and response criteria for use in clinical trials of MF/SS. [126]  The NCCN includes the new criteria in its current recommendations. [123]

All three guidelines recommend treatment selection based on clinical stage. [123, 124, 125]

Mycosis fungoides

In general, topical therapies are recommended for localized disease (stages IA, IB and IIA), with systemic or combination systemic and topical therapies beginning with stage IIB. Systemic therapies may also be considered in patients with early-stage disease that does not respond to topical treatments. [123, 124, 125]

Localized therapies endorsed by the guidelines include the following [123, 124, 125]

  • Psoralens + ultraviolet A (PUVA)—For thick plaques

  • Narrow-band ultraviolet B (UVB)—For patch or thin plaques

  • Topical corticosteroids

  • Localized radiation therapy (12-36 Gy)

  • Topical chemotherapy (ie, nitrogen mustard or carmustine)

  • Topical retinoids (ie, bexarotene)

Because of the high toxicity of total skin electron beam therapy (TSEBT), both NCCN and EOTRTC recommend TSEBT only after other treatments have failed. [123, 124]

Systemic therapies recommended for advanced stages include the following [123, 124, 125]

  • Retinoids (ie, bexarotene)

  • Interferons (IFN-alpha, IFN-gamma)

  • Histone deacetylase (HDAC)-inhibitors (vorinostat, romidenpsin)—not approved in Europe

  • Extracorporeal photopheresis (ECP)

  • Methotrexate (≤100 mg/wk)

All three guidelines recommend IFN-alpha and PUVA or PUVA and retinoids (including bexarotene) as second-line combination therapies for MF stages IA, IB, and IIA. [123, 124, 125]

Other NCCN recommended combination therapies for advanced disease include the following [123] :

  • PUVA and ECP

  • TSEBT and ECP

  • Retinoids and interferons

  • ECP and retinoids

  • ECP and interferons

  • ECP and retinoids and interferons

Sezary syndrome and erythrodermic mycosis fungoides

Participation in a clinical trial as a treatment option for all patients with SS or advanced-stage MF is recommended by both the NCCN and EOTRTC.  [123, 124]  Treatment for SS or erythrodermic MF (stage IV) is palliative. The preferred modality is ECP, either alone or in combination with other treatments. [123, 124, 125]

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Primary Cutaneous CD30+ T-Cell Lymphoproliferative Disorders

In 2011, the the European Organization for Research and Treatment of Cancer (EORTC), the International Society for Cutaneous Lymphoma (ISCL), and the US Cutaneous Lymphoma Consortium (USCLC) published joint consensus recommendations for the management of primary cutaneous CD30+ T-Cell lymphoproliferative disorders (CD30+LPDs). [127]

Classification

Under the WHO-EORTC classification system for cutaneous lymphomas, primary CD30+LPDs represent a wide spectrum of disease, with lymphomatoid papulosis (LyP) at the benign end of the spectrum and primary cutaneous anaplastic large cell (PC-ALCL) lymphoma at the malignant end. Borderline lesions lie somewhere in between, with overlapping clinical and histopathologic features. [1]

Diagnosis

The National Comprehensive Cancer Network (NCCN) recommendations to establish a diagnosis of CD30+LPDs include the following [123] :

  • Differentiation of LyP and PC-ALCL from other forms of cutaneous T-cell lymphoma and secondary cutaneous involvement by nodal Hodgkin lymphoma or systemic ALCL requires careful clinicopathologic correlation

  • Mycosis fungoides can be comorbid

  • Clinical features include solitary or localized nodules or tumors (often ulcerated); multifocal lesions occur in about 20% of cases; extracutaneous disease occurs in about 10% of cases, usually involving regional lymph nodes

  • Immunohistochemistry (IHC) panel of skin biopsy specimen: CD3, CD4,CD8, CD20, CD30, CD56, βF1, ALK1

  • Expanded IHC: CD2, CD5, CD7, CD25,TIA1, granzyme B, perfornin, GM1, EBER-ISH

  • Histologically characterized by diffuse, cohesive sheets of large CD30-positive (in >75%) cells with anaplastic, pleomorphic, or immunoblastic appearance

  • Molecular analysis of skin biopsy: TCR gene rearrangements

  • Excisional or incisional biopsy of suspicious lymph nodes (in absence of definitive skin diagnosis)

  • Assessment of HTLV-1 serology in at-risk populations to identify CD30+ adult T-cell leukemia/lymphoma (ATLL)

  • Bone marrow biopsy only in cases of multifocal tumors, unexplained hematologic results, or presence of where extracutaneous disease

Staging

EORTC, ISCL, and USCLC guidelines recommend staging according to the 2007 tumor-node-metastasis (TNM) ISCL/EORTC staging of cutaneous lymphomas other than mycosis fungoides/Sezary syndrome. [27, 127]

Treatment

Both guidelines give similar treatment recommendations for PC-ALCL, as follows [123, 127] :

  • For solitary or grouped lesions, surgical excision or radiation therapy for first-line treatment

  • Relapses are equally frequent after both treatments; if confined to the skin, treatment can be repeated

  • For multifocal lesions, low-dose methotrexate may be used, based on expert consensus; retinoids and interferon alpha are alternative treatments for multifocal disease that is not responsive to other therapies, but data are limited on effectiveness. Newer promising agents include pralatrexate and CD30 antibody-drug conjugate brentuximab vedotin [104, 128]

  • Multi-agent chemotherapy is not recommended for multifocal or relapsing PC-ALCL limited to the skin; it is recommended only for extracutaneous spread

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