Mycosis Fungoides and Sézary Syndrome: An Integrative Review of the Pathophysiology, Molecular Drivers, and Targeted Therapy
Abstract
:Simple Summary
Abstract
1. Cutaneous T-Cell Lymphoma: Description of the Main Entities
1.1. Mycosis Fungoides
1.2. Mycosis Fungoides Variants
1.2.1. Folliculotropic MF
1.2.2. Pagetoid Reticulosis
1.2.3. Granulomatous Slack Skin (GSS)
1.3. Sézary Syndrome
1.4. Mycosis Fungoides/Sézary Syndrome Staging
1.5. Mycosis Fungoides/Sézary Syndrome Prognosis
2. A Landscape of Genomic Alterations in Mycosis Fungoides/Sézary Syndrome
3. A Malignant Network of Signaling Mechanisms Drives Mycosis Fungoides/Sézary Syndrome
3.1. TCR/PLCγ1 Signaling
3.2. The PKC/NF-κB Axis
3.3. JAK/STAT Signaling
3.4. STAT3 Activation in Mycosis Fungoides/Sézary Syndrome
3.5. CCR4/CCR7 Signaling
4. Therapy for Mycosis Fungoides/Sézary Syndrome
4.1. Skin-Directed Therapies
4.1.1. Topical Corticosteroids
4.1.2. Topical Mechlorethamine
4.1.3. Ultraviolet Phototherapy
4.1.4. Total Skin Electron Beam Therapy
4.1.5. Localized Radiotherapy
4.2. Systemic Therapies
4.2.1. Retinoids
4.2.2. Interferon α
4.2.3. Extracorporeal Photopheresis
4.2.4. Chemotherapy
4.2.5. Allogenic Stem-Cell Transplantation
4.3. Targeted Therapies
4.3.1. Histone Deacetylase (HDAC) Inhibitors
4.3.2. Monoclonal Antibodies
4.3.3. Other Targeted Inhibitors
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Stage | T | N | M | B | Median OS (Years) | 5 Year OS a (%) | 5 Year DSS (%) | |
---|---|---|---|---|---|---|---|---|
Early | IA | 1 | 0 | 0 | 0–1 | |||
Limited patches or plaques <10% skin surface | No nodal involvement | No visceral involvement | <1000 atypical cells | 35.5 | N/S | 98 | ||
IB | 2 | 0 | 0 | 0–1 | ||||
Patches or plaques ≥10% skin surface | No nodal involvement | No visceral involvement | <1000 atypical cells | 21.5 | 86 | 89 | ||
IIA | 1–2 | 1–2 | 0 | 0–1 | ||||
Any patches or plaques | Aggregates of atypical cells | No visceral involvement | <1000 atypical cells | 15.8 | N/S | 89 | ||
Advanced | IIB | 3 | 0–2 | 0 | 0–1 | |||
Tumoral lesions | No involvement or aggregates of atypical cells | No visceral involvement | <1000 atypical cells | 4.7 | 62 | 56 | ||
III | 4 | 0–2 | 0 | 0–1 | ||||
Erythroderma | No involvement or aggregates of atypical cells | No visceral involvement | <1000 atypical cells | 4.7 | N/S | 56 | ||
IIIA | 4 | 0–2 | 0 | 0 | ||||
Erythroderma | No involvement or aggregates of atypical cells | No visceral involvement | <250 atypical cells | 4.7 | 60 | 54 | ||
IIIB | 4 | 0–2 | 0 | 1 | ||||
Erythroderma | No involvement or aggregates of atypical cells | No visceral involvement | 250–1000 atypical cells | 3.4 | 54 | 48 | ||
IVA1 | 1–4 | 0–2 | 0 | 2 | ||||
Any skin involvement | No involvement or aggregates of atypical cells | No visceral involvement | >1000 atypical cells + clonality | 3.8 | 52 | 41 | ||
IVA2 | 1–4 | 3 | 0 | 0–2 | ||||
Any skin involvement | Partial or complete effacement of nodal architecture | No visceral involvement | <1000 or >1000 atypical cells + clonality | 2.1 | 34 | 23 | ||
IVB | 1–4 | 0–3 | 1 | 0–2 | ||||
Any skin involvement | Any nodal involvement | Visceral involvement | <1000 or >1000 atypical cells + clonality | 1.4 | 23 | 18 |
Authors | Ref. | Number of Samples | WGS | WES | TS | RNA-Seq | scRNA-Seq | Highlighted Contribution | |
---|---|---|---|---|---|---|---|---|---|
MF | SS | ||||||||
Lee et al., 2012 | [45] | 24 | 3 | 27 | SS-associated lncRNAs | ||||
Vaqué et al., 2014 | [32] | 45 | 8 | 53 | PLCG1, JAK mutants, and NFAT activation (IHC) | ||||
Sekulic et al., 2015 | [33] | 1 | 1 | 1 | CTLA4:CD28 gene fusion | ||||
McGirt et al., 2015 | [25] | 30 | 5 | 25 | JAK mut. and JAK inhibitors; C > T | ||||
Ungewickell et al., 2015 | [34] | 41 | 32 | 11 | 73 | TNFR2 mut. and recurrent CTLA4:CD28 gene fusion | |||
Choi et al., 2015 | [27] | 40 | 2 | 40 | CNVs as drivers (STAT5B and PRKCQ amplification); C > T | ||||
Kiel et al., 2015 | [35] | 66 | 6 | 66 | JAK1, 3/STAT3, 5B and ARID1A mut. | ||||
Pérez et al., 2015 | [36] | 35 | JAK mut. and JAK inhibitors | ||||||
Da Silva Almeida et al., 2015 | [37] | 8 | 25 | 42 | Mutational landscape: CARD11 and cGKIβ mut. | ||||
Wang et al., 2015 | [26] | 37 | 37 | 37 | 32 | TCR signaling and IL32, IL2RG expression; C > T | |||
Prasad et al., 2016 | [28] | 12 | 12 | 10 | ITPR1, 2, PKHD1L1 and DSC1 mut. and fusion genes; C > T | ||||
Woollard et al., 2016 | [38] | 101 | 10 | 101 | POT1 mut., BRCA2 del. and PRKCQ, STAT3/5B amp; C > T | ||||
Izykowska et al., 2017 | [39] | 9 | 9 | TOX and MYC amp. and deregulated expression | |||||
Litvinov et al., 2017 | [46] | 181 | 181 a | Single-cell heterogeneity and transcriptional signatures for prognosis | |||||
Park et al., 2017 | [40] | 220 b | RLTPR (NF-κB), CSNK1A1 and RHOA mut. | ||||||
Chang et al., 2018 | [44] | 18 c | 121 c | Mutually exclusive mut. within the NF-κB pathway | |||||
Bastidas Torres et al., 2018 | [40] | 9 | 9 | 8 | HNRNPK and SOCS1 del. (JAK/STAT pathway) | ||||
Buus et al., 2018 | [47] | 11 | 11 | Single-cell heterogeneity and surface marker expression | |||||
Perez et al., 2019 | [41] | 95 | 95 | P-STAT3 (IHC) in advanced vs. initial MFs | |||||
Borcherding et al., 2019 | [48] | 1 | 1 | Intra-patient heterogeneity | |||||
Gaydosik et al., 2019 | [49] | 5 | 5 | Patient-specific heterogeneity and clustering | |||||
Iyer et al., 2019 | [50] | 27 | 10 d | 27 | Clonotypic heterogeneity | ||||
Iyer et al., 2020 | [43] | 31 | 31 | Divergent evolution of cancer subclones |
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García-Díaz, N.; Piris, M.Á.; Ortiz-Romero, P.L.; Vaqué, J.P. Mycosis Fungoides and Sézary Syndrome: An Integrative Review of the Pathophysiology, Molecular Drivers, and Targeted Therapy. Cancers 2021, 13, 1931. https://doi.org/10.3390/cancers13081931
García-Díaz N, Piris MÁ, Ortiz-Romero PL, Vaqué JP. Mycosis Fungoides and Sézary Syndrome: An Integrative Review of the Pathophysiology, Molecular Drivers, and Targeted Therapy. Cancers. 2021; 13(8):1931. https://doi.org/10.3390/cancers13081931
Chicago/Turabian StyleGarcía-Díaz, Nuria, Miguel Ángel Piris, Pablo Luis Ortiz-Romero, and José Pedro Vaqué. 2021. "Mycosis Fungoides and Sézary Syndrome: An Integrative Review of the Pathophysiology, Molecular Drivers, and Targeted Therapy" Cancers 13, no. 8: 1931. https://doi.org/10.3390/cancers13081931
APA StyleGarcía-Díaz, N., Piris, M. Á., Ortiz-Romero, P. L., & Vaqué, J. P. (2021). Mycosis Fungoides and Sézary Syndrome: An Integrative Review of the Pathophysiology, Molecular Drivers, and Targeted Therapy. Cancers, 13(8), 1931. https://doi.org/10.3390/cancers13081931