HAEM5:Mycosis fungoides

Haematolymphoid Tumours (WHO Classification, 5th ed.)

editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification

This page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:Mycosis Fungoides.

(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support.)

Primary Author(s)*

Jane Scribner, MD and Daynna J. Wolff, PhD

WHO Classification of Disease

Structure	Disease
Book	Haematolymphoid Tumours (5th ed.)
Category	T-cell and NK-cell lymphoid proliferations and lymphomas
Family	Mature T-cell and NK-cell neoplasms
Type	Primary cutaneous T-cell lymphoid proliferations and lymphomas
Subtype(s)	Mycosis fungoides

Related Terminology

Acceptable	N/A
Not Recommended	Classic mycosis fungoides (type Alibert–Bazin); Woringer–Kolopp disease

Gene Rearrangements

Put your text here and fill in the table (Instructions: Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Driver Gene	Fusion(s) and Common Partner Genes	Molecular Pathogenesis	Typical Chromosomal Alteration(s)	Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
EXAMPLE: ABL1	EXAMPLE: BCR::ABL1	EXAMPLE: The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1.	EXAMPLE: t(9;22)(q34;q11.2)	EXAMPLE: Common (CML)	EXAMPLE: D, P, T	EXAMPLE: Yes (WHO, NCCN)	EXAMPLE: The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference). BCR::ABL1 is generally favorable in CML (add reference).
EXAMPLE: CIC	EXAMPLE: CIC::DUX4	EXAMPLE: Typically, the last exon of CIC is fused to DUX4. The fusion breakpoint in CIC is usually intra-exonic and removes an inhibitory sequence, upregulating PEA3 genes downstream of CIC including ETV1, ETV4, and ETV5.	EXAMPLE: t(4;19)(q25;q13)	EXAMPLE: Common (CIC-rearranged sarcoma)	EXAMPLE: D		EXAMPLE: DUX4 has many homologous genes; an alternate translocation in a minority of cases is t(10;19), but this is usually indistinguishable from t(4;19) by short-read sequencing (add references).
EXAMPLE: ALK	EXAMPLE: ELM4::ALK Other fusion partners include KIF5B, NPM1, STRN, TFG, TPM3, CLTC, KLC1	EXAMPLE: Fusions result in constitutive activation of the ALK tyrosine kinase. The most common ALK fusion is EML4::ALK, with breakpoints in intron 19 of ALK. At the transcript level, a variable (5’) partner gene is fused to 3’ ALK at exon 20. Rarely, ALK fusions contain exon 19 due to breakpoints in intron 18.	EXAMPLE: N/A	EXAMPLE: Rare (Lung adenocarcinoma)	EXAMPLE: T		EXAMPLE: Both balanced and unbalanced forms are observed by FISH (add references).
EXAMPLE: ABL1	EXAMPLE: N/A	EXAMPLE: Intragenic deletion of exons 2–7 in EGFR removes the ligand-binding domain, resulting in a constitutively active tyrosine kinase with downstream activation of multiple oncogenic pathways.	EXAMPLE: N/A	EXAMPLE: Recurrent (IDH-wildtype Glioblastoma)	EXAMPLE: D, P, T

editv4:Chromosomal Rearrangements (Gene Fusions)

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• No consistent gene fusions
• CD28-CTLA4 gene fusion identified, resulting in activation of TCR signaling

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editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).

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• Chromosomal Rearrangements (Gene Fusions)
• Individual Region Genomic Gain/Loss/LOH
• Characteristic Chromosomal Patterns
• Gene Mutations (SNV/INDEL)

The staging system for mycosis fungoides, which also includes Sézary syndrome, was updated in 2007 by the International Society for Cutaneous Lymphomas (ISCL) and the European Organization of Research and Treatment of Cancer (EORTC) . The revised TNMB staging of MF/SS determines management and treatment, and has been demonstrated to have prognostic significance. The TNMB staging forms the basis for a risk-adapted approach to treatment of mycosis fungoides.

TNMB Stages

Skin
T1	Limited patches, papules, and/or plaques covering <10% of the skin surface.  May futher stratify to T1a (patch only) vs T1b (plaque +/- patch)
T1a	Patches only < 10% of skin surface
T1b	Plaques +/- patches < 10% of skin surface
T2	Patches, papules or plaques covering > 10% of skin surface.  May further stratify to T2a (patch only) vs T2b (plaque +/- patch)
T2a	Patches only > 10% of skin surface
T2b	Plaques +/- patches > 10% of skin surface
T3	One or more tumors (> 1-cm diameter)
T4	Confluence of erythema covering > 80% body surface area
Node
N0	No clinically abnormal peripheral lymph nodes (firm, irregular, clustered, fixed, or 1.5 cm or larger), biopsy not required
N1	Clinically abnormal peripheral lymph nodes; histopathology Dutch grade 1 or NCI LN0-2
N1a	Clone negative (defined by PCR or Souther blod analysis of T-cell receptor gene)
N1b	Clone positive defined by PCR or Souther blod analysis of T-cell receptor gene)
N2	Clinically abnormal peripheral lymph nodes; histopathology Dutch grade 2 or NCI LN3
N2a	Clone negative
N2b	Clone positive
N3	Clinically abnormal peripheral lymph nodes; histopathology Dutch grades 3 - 4 or NVI LN4 (clone positive or negative)
Nx	Clinically abnormal peripheral lymph nodes; no histologic confirmation
Visceral
M0	No visceral organ invovlement
M1	Visceral invovlement (must have pathology confirmation, for spleen and liver may be diagnosed by imaging criteria; specify organ involved)
Blood
B0	Absence of significant blood invovlement: , 5% of peripheral blood lymphocytes are atypical (Sezary) cells
B0a	Clone negative
B0b	Clone positive
B1	Low blood tumor burdern: > 5% of peripheral blood lymphocytes are atypical (Sezary) cells but does not meet the criteria of B2
B1a	Clone negative
B1b	Clone positive
B2	High blood tumor burdern: > 1000/µL Sezary cells with positive clone

The above listed chromosome rearrangement and several gene mutations provide the rational for the use of targeted therapy in mycosis fungoides. These are summarized in the table below.

Review of molecular biomarkers as therapeutic targets for CTCL

Molecular marker/mutation	Targeted therapy
CD30	Brentuximab
CTLA4	Ipilimumab
CD28-CTLA4 fusion	Ipilimumab
CCR4	Mogamulizumab
NFkB	Bortezomib
TNFRSF1B	Bortezomib
CD158k/KIR3DL2	IPH4102
JAK/STAT pathway	Ruxolitinib (JAK 1/3), Tofacitinib (JAK 1/2)
PDCD1	Pembrolizumab

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Individual Region Genomic Gain/Loss/LOH

Put your text here and fill in the table (Instructions: Includes aberrations not involving gene rearrangements. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Can refer to CGC workgroup tables as linked on the homepage if applicable. Please include references throughout the table. Do not delete the table.)

Chr #	Gain, Loss, Amp, LOH	Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]	Relevant Gene(s)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
EXAMPLE: 7	EXAMPLE: Loss	EXAMPLE: chr7	EXAMPLE: Unknown	EXAMPLE: D, P	EXAMPLE: No	EXAMPLE: Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add references).
EXAMPLE: 8	EXAMPLE: Gain	EXAMPLE: chr8	EXAMPLE: Unknown	EXAMPLE: D, P		EXAMPLE: Common recurrent secondary finding for t(8;21) (add references).
EXAMPLE: 17	EXAMPLE: Amp	EXAMPLE: 17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb]	EXAMPLE: ERBB2	EXAMPLE: D, P, T		EXAMPLE: Amplification of ERBB2 is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined.

editv4:Genomic Gain/Loss/LOH

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Mycosis fungoides does not have a defining disease specific molecular abnormality. However, the molecular profile of mycosis fungoides and other CTCLs continues to be investigated.

Large-scale genomic analysis using array comparative genomic hybridization and next generation sequencing including whole genome, transcriptome and exome sequencing, reveals significant genomic complexity in mycosis fungoides, with an observation that there is an inverse correlation between genomic complexity and survival.

Chromosome Number	Gain/Loss/Amp/LOH	Percent of cases	Consequence
1p	Loss	38%	Minimal region of deletion at D1S228; other candidate genes in mycosis fungoides map to 1p12p26
17p	Loss	21%	Disease progression by inactivation of genes on 17p, including p53
4/4q	Gain	18%	Oncogenes on chromosome 4: hPTTG, TBC1D1, FGFR3, KIT, PDGFRA
10q/10	Loss	15%	Minimal region of deletion at 10q26; cancer-related genes mapped to 10q: PTEN, LG11, DMBT1, FAS
19	Loss	15%
18	Gain	15%
17q/17	Gain	12%

Chromothripsis has been observed in up to 65% of CTCLs. Most events occur in chromosomes 10, 2, and 1. It is possible that these events may be the mechanism for simultaneous inactivation of multiple tumor suppressor genes see in mycosis fungoides.

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Characteristic Chromosomal or Other Global Mutational Patterns

Put your text here and fill in the table (Instructions: Included in this category are alterations such as hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis; microsatellite instability; homologous recombination deficiency; mutational signature pattern; etc. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Chromosomal Pattern	Molecular Pathogenesis	Prevalence - Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
EXAMPLE: Co-deletion of 1p and 18q	EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).	EXAMPLE: Common (Oligodendroglioma)	EXAMPLE: D, P
EXAMPLE: Microsatellite instability - hypermutated		EXAMPLE: Common (Endometrial carcinoma)	EXAMPLE: P, T

editv4:Characteristic Chromosomal Aberrations / Patterns

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Complex chromosomal abnormalities have been identified in mycosis fungoides, usually in tumor stage. Specific translocations have not been identified.

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Gene Mutations (SNV/INDEL)

Put your text here and fill in the table (Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Gene	Genetic Alteration	Tumor Suppressor Gene, Oncogene, Other	Prevalence - Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
EXAMPLE:EGFR	EXAMPLE: Exon 18-21 activating mutations	EXAMPLE: Oncogene	EXAMPLE: Common (lung cancer)	EXAMPLE: T	EXAMPLE: Yes (NCCN)	EXAMPLE: Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references).
EXAMPLE: TP53; Variable LOF mutations	EXAMPLE: Variable LOF mutations	EXAMPLE: Tumor Supressor Gene	EXAMPLE: Common (breast cancer)	EXAMPLE: P		EXAMPLE: >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.
EXAMPLE: BRAF; Activating mutations	EXAMPLE: Activating mutations	EXAMPLE: Oncogene	EXAMPLE: Common (melanoma)	EXAMPLE: T

Note: A more extensive list of mutations can be found in cBioportal, COSMIC, and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

editv4:Gene Mutations (SNV/INDEL)

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Although no disease specific molecular abnormalities exist in mycosis fungoides, but some changes are seen more frequently than others. Single copy number variations (SCNV) are important mutational drivers for CTCLs and mycosis fungoides and are seen with greater frequency than somatic single nucleotide variations (SSNV) when compared to other cancers with significantly higher SCNV/SSNV ratios. Alterations in tumor suppressor genes are frequently implication the pathogenesis of mycosis fungoides, and more than 90% of variants arise from copy number alterations.

Gene	Mutation	Oncogene/Tumor Suppressor/Other	Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)	Prevalence (COSMIC/TCGA/Other)
TNFRSF1B	Thr377Ile		Recurrent point mutation; constitutive activation of NFkB signaling pathway	18%
HNRNPK		Tumor Suppressor	Inhibitor of JAK-STAT signaling
SOCS1		Tumor Suppressor	Inhibitor of JAK-STAT signaling
ZEB1		Tumor Suppressor	Zinc-finger transcription repressor	56-65%
PDCD1			Expressing PDL1, deleted	36%
TP53		Tumor Suppressor	Deletion	92.5%
TOX			Encodes member of homeobox family, upregulated in MF

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Epigenomic Alterations

Epigenetic modifiers of DNA, including DNMT3A, are frequently mutated in mycosis fungoides.

An epigenetic mediator, the writer KMT2C of the histone methyltransferases (KMT) family, is recurrently deleted in mycosis fungoides.

Genes and Main Pathways Involved

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Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
EXAMPLE: BRAF and MAP2K1; Activating mutations	EXAMPLE: MAPK signaling	EXAMPLE: Increased cell growth and proliferation
EXAMPLE: CDKN2A; Inactivating mutations	EXAMPLE: Cell cycle regulation	EXAMPLE: Unregulated cell division
EXAMPLE: KMT2C and ARID1A; Inactivating mutations	EXAMPLE: Histone modification, chromatin remodeling	EXAMPLE: Abnormal gene expression program

editv4:Genes and Main Pathways Involved

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Genetic Diagnostic Testing Methods

A definitive diagnosis of mycosis fungoides may be made on the basis of clinical, histopathologic and immunohistochemical features alone.

Assessment of aberrant loss of T-cell antigen expression by immunohistochemical staining for CD2, CD3, CD5, and CD7 are useful ancillary studies.

Demonstration of T-cell receptor clonality often facilitates diagnosis and serves as an adjunct to the diagnosis. Presence of identical clones from two different biopsy sites is quit specific for mycosis fungoides and may be useful in early or histologically equivocal cases. However early mycosis fungoides may commonly be negative for clonal TCR rearrangements and T-cell clonality itself is not diagnostic of a T cell lymphoma as many dermatitis may have dominant T cells clones.

There are various methods to assess TCR clonality, with different techniques and sensitivities. PCR based assays have sensitivities ranging from 50-90% in various studies . The use of Next generation sequencing (NGS)/high throughput sequencing has improved the sensitivity of detection of TCR clonality, and may be as high as 85%.

In 2020, the American Society of Clinical Pathology, the College of American pathologists, and the American Society of Hematology released a statement from an expert panel convened to develop evidence-based guidelines for appropriate evaluation process for adult patients with suspected lymphomas. In their summary, it is stated that clinical care providers should not routinely use up-front PCR-based clonality studies of antigen receptor genes (i.e., T-cell receptor) in the initial investigation of lymphoma. However, there may be a confirmatory role of these tests in certain settings. Providers should rely on immunophenotyping by flow cytometry and/or IHC in addition to morphology for the evaluation of specimens for the diagnosis and sub-classification of lymphoma. A recent study demonstrated that positive TCR gene rearrangement studies are not predictive of lymphoproliferative disorders in patients which otherwise negative phenotyping.

Summary of additional diagnostic and prognostic testing methods:

• TCR gene rearrangement studies may be utilized for monitoring of residual disease
• Tumor clone frequency as determined by high throughput sequencing of TCRβ gene has been investigated as a marker for progression and overall survival in mycosis fungoides
• In cases with suspected large cell transformation, staining for CD30 positivity may provide additional therapeutic options
• Recent diagnostic panels of gene expression profiling of MF/SS have been developed. A 17 gene signature panel including IL2RA, CCR4, STAT5A and TOX has been described to identify patients at risk for progression of disease
• microRNA profiling may have a role in diagnosis and management of mycosis fungoides, with potential 95% sensitivity and specificity in differentiating early mycosis fungoides from benign lesions

Familial Forms

• There are rare reports of familial MF, suggesting that a host genetic factor may contribute to the development of the disease

Additional Information

• N/A

Links

• N/A

References

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Notes

*Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the Associate Editor or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.

Prior Author(s):

*Citation of this Page: “Mycosis fungoides”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 07/3/2025, https://ccga.io/index.php/HAEM5:Mycosis_fungoides.