Mycosis fungoides and Sézary syndrome

Hyewon Lee

doi:10.5045/br.2023.2023023

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Blood Res 2023; 58(S1):

Published online April 30, 2023

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

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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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

Article

Review Article

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

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

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

Abstract

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

Abstract

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]..

Criteria	Scoring system
Clinical	2 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
Histopathologic	2 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 atypia^a)
Molecular biologic	1 point for clonality
1. Clonal T cell receptor gene rearrangement	1 point for clonality
Immunopathologic	1 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 CD7^b)

^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)
T0	Absence of clinically suspicious lesions
T1	Patches, plaques, papules <10% BSA
T1a	Patch only lesions
T1b	Plaque/papule^+/- patch lesions
T2	Patches, plaques, papules ≥10% BSA
T2a	Patch only lesions
T2b	Plaque/papule^+/- patch lesions
T3	One or more tumors ≥1 cm diameter
T4	Confluence of erythema covering ≥80% BSA

Node (N)
N0	No clinically abnormal lymph nodes; biopsy not required
N1	Clinically abnormal lymph nodes; pathology Dutch grade 1 or NCI LN 0-2
N1a	Clone negative or equivocal
N1b	Clone positive and identical to skin
N2	Clinically abnormal lymph nodes; pathology Dutch grade 2 or NCI LN 3
N2a	Clone negative or equivocal
N2b	Clone positive and identical to skin
N3	Clinically abnormal lymph nodes; pathology Dutch grade 3-4 or NCI LN 4
N3a	Clone negative or equivocal
N3b	Clone positive and identical to skin
Nx	Clinically 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)
M0	No visceral involvement
M1	Visceral involvement
M1a	BM only involvement; clone positive and identical to skin, clone negative or indeterminate
M1b	Non-BM visceral involvement; clone positive and identical to skin, clone negative or indeterminate
Mx	Visceral involvement is neither confirmed nor refuted by available pathologic or imaging assessment

Blood (B)
B0	No 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
B0a	Clone negative or equivocal
B0b	Clone positive and identical to skin
B1	Low blood tumor burden: does not meet the criteria of B₀ or B₂
B1a	Clone negative
B1b	Clone positive
B2	High 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 stage	TNMB classification				Median OS (yr)
IA	T1	N0	M0	B0 or B1	35.5
IB	T2	N0	M0	B0 or B1	21.5
IIA	T1 or T2	N1 or N2	M0	B0 or B1	15.8
IIB	T3	N0 to N2	M0	B0 or B1	4.7
IIIA	T4	N0 to N2	M0	B0	4.7
IIIB	T4	N0 to N2	M0	B1	3.4
IVA1	T1 to T4	N0 to N2	M0	B2	3.8
IVA2	T1 to T4	N3	M0	B0 to B2	2.1
IVB	T1 to T4	N0 to N3	M1	B0 to B2	1.4

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

Reference	Agents	Phase	Prior Tx^a)	N	Outcomes	Comments
Duvic et al. 2001 [82]	Bexarotene	II/III	2	56	ORR 45% (CRR 2%)	Pancreatitis, hypertriglyceridemia, thyroid dysfunction
Zinzani et al. 2000 [103]	Gemcitabine	II	3	44	ORR 70.5% (CRR 11.5%)	Myelosuppression, elevated hepatic enzyme
Dummer et al. 2012 [102]	Peg-L-doxorubicin	II	2	49	ORR 40.8% (CR 6.1%)	Myelosuppression, gastrointestinal toxicity
Duvic et al. 2007 [93]	Vorinostat	II	5	33	ORR 24.2% (CRR 0%)	Fatigue, diarrhea, nausea, thrombocytopenia, abnormal echocardiogram
Whittaker et al. 2010 [96]	Romidepsin	II	4	96	ORR 38% (CR 5%)	IB-IVA
Whittaker et al. 2010 [96]	Romidepsin	II	4	96	ORR 38% (CR 5%)	GI disturbances, asthenic conditions, ECG changes
Prince et al. 2017 [99] (ALCANZA)	Brentuximab vedotin vs. MTX or bexarotene	III, RCT	3	131	ORR4 50% vs. 10%	CD30+ (≥10%) MF (SS excluded)
Prince et al. 2017 [99] (ALCANZA)	Brentuximab vedotin vs. MTX or bexarotene	III, RCT	3	131	PFS 16.1 vs. 3.5 M	Peripheral neuropathy in 66% (9% Gr3), discontinuation in 14%
Kim et al. 2018 [94] (MAVORIC)	Mogamulizumab vs. vorinostat	III, RCT		186	ORR 28% vs. 5% (68% in blood)	Stage IB-IVB MF/SS (LCT excluded)
Kim et al. 2018 [94] (MAVORIC)	Mogamulizumab vs. vorinostat	III, RCT		186	ORR 28% vs. 5% (68% in blood)	Infusion related reaction, thrombocytopenia, drug eruption, discontinuation in 7%
Khodadoust et al. 2020 [101]	Pembrolizumab	II	4	24	ORR 38% (CRR 8%)	IIB-IV
Khodadoust et al. 2020 [101]	Pembrolizumab	II	4	24	ORR 38% (CRR 8%)	Cutaneous flare reaction (without discontinuation)