Mycosis Fungoides

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Primary Author(s)*

Jane Scribner, MD and Daynna J. Wolff, PhD

Cancer Category/Type

Cancer Sub-Classification / Subtype

  • Mycosis Fungoides (MF)

Definition / Description of Disease

MF is a primary cutaneous T-cell lymphoma (CTCL) of epidermotropic small to medium-sized T lymphocytes presenting with skin patches that progress slowly to plaques and tumors. The disease is postulated to be caused by skin-homing mature T cells, the majority of which are CD4-positive. Sézary syndrome (SS) is often used to refer to the leukemic phase of mycosis fungoides. However, recently studies have suggested that there are major genomic and phenotypical differences between these two entities. [1]

Synonyms / Terminology

  • Cutaneous T-cell lymphoma
  • Alibert-Bazin syndrome

Epidemiology / Prevalence

  • Most common CTCL subtype (54% of CTCL)[2]
  • Incidence 4.1/1,000,000 person/years (increasing)
    • Highest in males, blacks, and those over 50 years old[3][4][5]
    • Can occur in children and adolescents[6][7]
  • Prevalence 6.4 million people

Clinical Features

  • Pruritic, erythematous or poikilodermatous and atrophic skin lesions with a fine scale
  • Progresses over years to decades from patches to plaques and less commonly to nodules/tumors
  • Rarely, MF can present with erythroderma without a diagnosis of Sézary syndrome[8]
  • May have symptoms and/or diagnosis of other inflammatory skin diseases (e.g., eczema or psoriasis) for 3 - 4 years prior to the diagnosis of MF[9]

Sites of Involvement

  • Skin
    • Typically sun protected areas: trunk, buttock, upper thighs
    • Some MF variants: head and neck, axillae and groin, or acral sites
  • Advanced disease - lymph nodes, liver, spleen, lungs and blood

Morphologic Features

Pathologic features are variable and may be non-specific with overlap with benign reactive processes.

  • Early patch stage: superficial band-like or lichenoid infiltrate of lymphocytes and histiocytes; atypical small to medium-sized lymphocytes with cerebriform nuclei confined to basilar epidermis, may have halo and "tag" the basilar layer keratinocytes
  • Plaque stage: Epidermotropism (atypical lymphocytes in epidermis without associated spongiosis); intraepidermal collections of atypical cells (Pautrier microabscesses); papillary dermal fibrosis
  • Tumor stage: Dermal infiltrate more diffuse; may lose epidermotropism

Histologic large cell transformation, defined by >25% of large lymphoid cells in the dermal infiltrate, may occur at any stage, but most commonly in tumor stage mycosis fungoides. They may be positive or negative for CD30[8]

Immunophenotype

The immunologic milieu of mycosis fungoides is predominantly that of mature memory Th2 gene expression and associated cytokine production. [10]

The aberrant loss of normal T-cell antigen expression by immunohistochemistry staining is a useful ancillary test in the diagnosis of mycosis fungoides. [11]

Finding Marker
Positive (T-cell lineage markers) CD3, CD4, CD45RO
Variable expression CD2, CD5, CD7 (often lost, significant only if 90% loss)
Markers with aberrant expression CD8 (CD4:CD8 ratio of 10:1 suggestive of mycosis fungoides), CD30 (may indicate transformation)

The majority of lymphocytes in mycosis fungoides express the αβ TCR, but rare cases have been reported that express γδ TCR.

Mycosis fungoides T-cells are T resident memory cells, exhibiting CCR4+/CLA+/L-selectin-/CCR7- expression. [12]

Chromosomal Rearrangements (Gene Fusions)

  • No consistent gene fusions
  • CD28-CTLA4 gene fusion identified, resulting in activation of TCR signaling [13]

Characteristic Chromosomal Aberrations / Patterns

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

Genomic Gain/Loss/LOH[14]

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, [15] with an observation that there is an inverse correlation between genomic complexity and survival. [16]

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. [17]

Gene Mutations (SNV/INDEL)

Although no disease specific molecular abnormalities exist in mycosis fungoides, but some changes are seen more frequently than others.[18] 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.[15] [17] Alterations in tumor suppressor genes are frequently implication the pathogenesis of mycosis fungoides, and more than 90% of variants arise from copy number alterations. [15]

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%[19]
HNRNPK Tumor Suppressor Inhibitor of JAK-STAT signaling[20]
SOCS1 Tumor Suppressor Inhibitor of JAK-STAT signaling [20]
ZEB1 Tumor Suppressor Zinc-finger transcription repressor 56-65%[17]
PDCD1 Expressing PDL1, deleted 36%[17]
TP53 Tumor Suppressor Deletion 92.5% [17]
TOX Encodes member of homeobox family, upregulated in MF[21]

Epigenomics (Methylation)

Epigenetic modifiers of DNA, including DNMT3A, are frequently mutated in mycosis fungoides. [22]

An epigenetic mediator, the writer KMT2C of the histone methyltransferases (KMT) family, is recurrently deleted in mycosis fungoides. [17]

Genes and Main Pathways Involved

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.[23] Presence of identical clones from two different biopsy sites is quit specific for mycosis fungoides[24] and may be useful in early or histologically equivocal cases. However early mycosis fungoides may commonly be negative for clonal TCR rearrangements [25] and T-cell clonality itself is not diagnostic of a T cell lymphoma as many dermatitis may have dominant T cells clones[18].

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[26] [27]. 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%[28][29].

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[30]. 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[30]. A recent study demonstrated that positive TCR gene rearrangement studies are not predictive of lymphoproliferative disorders in patients which otherwise negative phenotyping[31].

Summary of additional diagnostic and prognostic testing methods:

  • TCR gene rearrangement studies may be utilized for monitoring of residual disease[32]
  • 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[33]
  • In cases with suspected large cell transformation, staining for CD30 positivity may provide additional therapeutic options[34]
  • 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[35]
  • 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[36]

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

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) [37]. The revised TNMB staging of MF/SS determines management and treatment, and has been demonstrated to have prognostic significance. [4] 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[18]
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

Familial Forms

  • There are rare reports of familial MF, suggesting that a host genetic factor may contribute to the development of the disease[38]

Other Information

  • N/A

Links

  • N/A

References

(use "Cite" icon at top of page)

  1. Campbell, James J.; et al. (2010-08-05). "Sézary syndrome and mycosis fungoides arise from distinct T-cell subsets: a biologic rationale for their distinct clinical behaviors". Blood. 116 (5): 767–771. doi:10.1182/blood-2009-11-251926. ISSN 0006-4971. PMC 2918332. PMID 20484084.
  2. Bradford, Porcia T.; et al. (2009-05-21). "Cutaneous lymphoma incidence patterns in the United States: a population-based study of 3884 cases". Blood. 113 (21): 5064–5073. doi:10.1182/blood-2008-10-184168. ISSN 1528-0020. PMC 2686177. PMID 19279331.
  3. Criscione, Vincent D.; et al. (2007-07-01). "Incidence of Cutaneous T-Cell Lymphoma in the United States, 1973-2002". Archives of Dermatology. 143 (7). doi:10.1001/archderm.143.7.854. ISSN 0003-987X.
  4. 4.0 4.1 Agar, Nita Sally; et al. (2010-11-01). "Survival outcomes and prognostic factors in mycosis fungoides/Sézary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer staging proposal". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 28 (31): 4730–4739. doi:10.1200/JCO.2009.27.7665. ISSN 1527-7755. PMID 20855822.
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