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Blood Res 2023; 58(S1):

Published online April 30, 2023

https://doi.org/10.5045/br.2023.2023023

© The Korean Society of Hematology

Mycosis fungoides and Sézary syndrome

Hyewon Lee

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Division of Hemato-Oncology, Department of Internal Medicine, and Center for Hematologic Malignancy, Research Institute and Hospital, National Cancer Center, Goyang, Korea

Correspondence to : Hyewon Lee, M.D., Ph.D.
Division of Hemato-Oncology, Department of Internal Medicine, and Center for Hematologic Malignancy, Research Institute and Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang 10408, Korea
E-mail: hwlee@ncc.re.kr

Received: January 26, 2023; Revised: April 16, 2023; Accepted: April 17, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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Mycosis fungoides (MF) and Sézary syndrome (SS) are a distinct disease entity of cutaneous T-cell lymphoma with heterogenous clinical features and prognosis. MF mainly involves skin and usually shows an indolent and favorable clinical course. In patients with advanced-stage disease, extracutaneous involvement including lymph nodes, viscera, and blood, or large cell transformation may be observed. SS is a leukemic form of advanced-stage MF, characterized by generalized erythroderma. Early-stage MF can be treated with skin-directed therapy. However, patients with refractory or advanced-stage disease are associated with severe symptoms or poor prognosis, requiring systemic therapy. Recent progress in understanding the pathogenesis of MF/SS has contributed to advances in the management of these rare diseases. This review aims to describe the clinical manifestations, diagnosis, risk stratification, and treatment strategy of MF/SS, focusing on the recent updates in the management of these diseases.

Keywords Mycosis fungoides, Sézary syndrome, Cutaneous T-cell lymphoma, Diagnosis, Prognosis, Treatment

Article

Review Article

Blood Res 2023; 58(S1): S66-S82

Published online April 30, 2023 https://doi.org/10.5045/br.2023.2023023

Copyright © The Korean Society of Hematology.

Mycosis fungoides and Sézary syndrome

Hyewon Lee

Division of Hemato-Oncology, Department of Internal Medicine, and Center for Hematologic Malignancy, Research Institute and Hospital, National Cancer Center, Goyang, Korea

Correspondence to:Hyewon Lee, M.D., Ph.D.
Division of Hemato-Oncology, Department of Internal Medicine, and Center for Hematologic Malignancy, Research Institute and Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang 10408, Korea
E-mail: hwlee@ncc.re.kr

Received: January 26, 2023; Revised: April 16, 2023; Accepted: April 17, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Mycosis fungoides (MF) and Sézary syndrome (SS) are a distinct disease entity of cutaneous T-cell lymphoma with heterogenous clinical features and prognosis. MF mainly involves skin and usually shows an indolent and favorable clinical course. In patients with advanced-stage disease, extracutaneous involvement including lymph nodes, viscera, and blood, or large cell transformation may be observed. SS is a leukemic form of advanced-stage MF, characterized by generalized erythroderma. Early-stage MF can be treated with skin-directed therapy. However, patients with refractory or advanced-stage disease are associated with severe symptoms or poor prognosis, requiring systemic therapy. Recent progress in understanding the pathogenesis of MF/SS has contributed to advances in the management of these rare diseases. This review aims to describe the clinical manifestations, diagnosis, risk stratification, and treatment strategy of MF/SS, focusing on the recent updates in the management of these diseases.

Keywords: Mycosis fungoides, Sézary syndrome, Cutaneous T-cell lymphoma, Diagnosis, Prognosis, Treatment

Fig 1.

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Figure 1.Clinical manifestation and pathologic findings. Patchy (A), plaque (B), and tumor-type (C) skin lesions in a patient with advanced stage mycosis fungoides. PET scan showed FDG-uptake on large extent plaque and tumor stage lesions and axillary lymph nodes (D). Histology of plaque-type MF lesion with epidermotropic infiltration of lymphocytes, in which clonality of TCR gene rearrangement was confirmed (E). Higher resolution of E, representing grouped aggregation of large lymphocytes in the epidermis, forming early form of Pautrier’s micro-abscess (F). Generalized erythroderma in a patient with Sézary syndrome (G). Atypical lymphocyte with cerebriform nuclei, so called ‘Sézary cell’, was observed on peripheral blood smear (H).
Blood Research 2023; 58: S66-S82https://doi.org/10.5045/br.2023.2023023

Fig 2.

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Figure 2.Therapeutic options for mycosis fungoides and Sézary syndrome based on the stage of disease.
Blood Research 2023; 58: S66-S82https://doi.org/10.5045/br.2023.2023023

Table 1 . Diagnostic algorithm for early Mycosis Fungoides [38]..

CriteriaScoring system
Clinical2 points for basic criteria and two additional criteria
1 point for basic criteria and one additional criterion
Basic
Persistent and/or progressive patches/thin plaques
Additional
1. Non-sun-exposed location
2. Size/shape variation
3. Poikiloderma
Histopathologic2 points for basic criteria and two additional criteria
1 point for basic criteria and one additional criterion
Basic
Superficial lymphoid infiltrate
Additional
1. Epidermotropism without spongiosis
2. Lymphoid atypiaa)
Molecular biologic1 point for clonality
1. Clonal T cell receptor gene rearrangement
Immunopathologic1 point for one or more criteria
1. <50% CD2+, CD3+, and/or CD5+ T cells
2. <10% CD7 T cells
3. Epidermal/dermal discordance of CD2, CD3, CD5, or CD7b)

a)Lymphoid atypia is defined as cells with enlarged hyperchromatic nuclei and irregular or cerebriform nuclear contours. b)T cell antigen deficiency confined to the epidermis..

A total of 4 points is required for the diagnosis of mycosis fungoides based on any combination of points from the clinical, histopathologic, molecular biologic, and immunopathologic criteria..

Table 2 . Mycosis Fungoides Cooperative Group TNMB classification of cutaneous T cell lymphoma [55]..

Skin (T)
T0Absence of clinically suspicious lesions
T1Patches, plaques, papules <10% BSA
T1aPatch only lesions
T1bPlaque/papule+/- patch lesions
T2Patches, plaques, papules ≥10% BSA
T2aPatch only lesions
T2bPlaque/papule+/- patch lesions
T3One or more tumors ≥1 cm diameter
T4Confluence of erythema covering ≥80% BSA
Node (N)
N0No clinically abnormal lymph nodes; biopsy not required
N1Clinically abnormal lymph nodes; pathology Dutch grade 1 or NCI LN 0-2
N1aClone negative or equivocal
N1bClone positive and identical to skin
N2Clinically abnormal lymph nodes; pathology Dutch grade 2 or NCI LN 3
N2aClone negative or equivocal
N2bClone positive and identical to skin
N3Clinically abnormal lymph nodes; pathology Dutch grade 3-4 or NCI LN 4
N3aClone negative or equivocal
N3bClone positive and identical to skin
NxClinically abnormal peripheral or central lymph node but no pathologic determination of representative lymph nodes. Other surrogate means of determining involvement may be determined by Tri-Society consensus
Visceral (M)
M0No visceral involvement
M1Visceral involvement
M1aBM only involvement; clone positive and identical to skin, clone negative or indeterminate
M1bNon-BM visceral involvement; clone positive and identical to skin, clone negative or indeterminate
MxVisceral involvement is neither confirmed nor refuted by available pathologic or imaging assessment
Blood (B)
B0No significant blood involvement: ≤5% of Sézary cells. For clinical trials, B0 may also be defined as <250/μL Sézary cells; CD4+CD26- or CD4+CD7- cells or CD4+CD26- and CD4+CD7- cells <15 % by flow cytometry
B0aClone negative or equivocal
B0bClone positive and identical to skin
B1Low blood tumor burden: does not meet the criteria of B0 or B2
B1aClone negative
B1bClone positive
B2High blood tumor burden: positive clone plus one of the following: ≥1,000/μL Sézary cells; CD4/CD8 ≥10; CD4+CD7- cells ≥40%; or CD4+CD26- cells ≥30%. For clinical trials, B2 may also be defined as >1,000/μL CD4+CD26- or CD4+CD7- cells.

Table 3 . Clinical staging and prognosis of mycosis fungoides and Sézary syndrome [56]..

Clinical stageTNMB classificationMedian OS (yr)
IAT1N0M0B0 or B135.5
IBT2N0M0B0 or B121.5
IIAT1 or T2N1 or N2M0B0 or B115.8
IIBT3N0 to N2M0B0 or B14.7
IIIAT4N0 to N2M0B04.7
IIIBT4N0 to N2M0B13.4
IVA1T1 to T4N0 to N2M0B23.8
IVA2T1 to T4N3M0B0 to B22.1
IVBT1 to T4N0 to N3M1B0 to B21.4

Table 4 . Systemic therapies for refractory or advanced-stage mycosis fungoides and Sézary syndrome..

ReferenceAgentsPhasePrior Txa)NOutcomesComments
Duvic et al. 2001 [82]BexaroteneII/III256ORR 45% (CRR 2%)Pancreatitis, hypertriglyceridemia, thyroid dysfunction
Zinzani et al. 2000 [103]GemcitabineII344ORR 70.5% (CRR 11.5%)Myelosuppression, elevated hepatic enzyme
Dummer et al. 2012 [102]Peg-L-doxorubicinII249ORR 40.8% (CR 6.1%)Myelosuppression, gastrointestinal toxicity
Duvic et al. 2007 [93]VorinostatII533ORR 24.2% (CRR 0%)Fatigue, diarrhea, nausea, thrombocytopenia, abnormal echocardiogram
Whittaker et al. 2010 [96]RomidepsinII496ORR 38% (CR 5%)IB-IVA
GI disturbances, asthenic conditions, ECG changes
Prince et al. 2017 [99] (ALCANZA)Brentuximab vedotin vs. MTX or bexaroteneIII, RCT3131ORR4 50% vs. 10%CD30+ (≥10%) MF (SS excluded)
PFS 16.1 vs. 3.5 MPeripheral neuropathy in 66% (9% Gr3), discontinuation in 14%
Kim et al. 2018 [94] (MAVORIC)Mogamulizumab vs. vorinostatIII, RCT186ORR 28% vs. 5% (68% in blood)Stage IB-IVB MF/SS (LCT excluded)
Infusion related reaction, thrombocytopenia, drug eruption, discontinuation in 7%
Khodadoust et al. 2020 [101]PembrolizumabII424ORR 38% (CRR 8%)IIB-IV
Cutaneous flare reaction (without discontinuation)

a)Prior Tx means median number of lines of previous therapy..

Abbreviations: CRR, complete response rate; MTX, methotrexate; ORR, overall response rate..
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