Cutaneous T-Cell Lymphoma, Mycosis Fungoides

Basics

Cutaneous T-cell lymphoma (CTCL) is a rare and typically indolent mature T-cell lymphoma presenting primarily in the skin. This disease involves overlap of the disciplines of dermatology, medical oncology, and radiation oncology.

Description

  • A heterogeneous group of relatively uncommon extranodal non-Hodgkin lymphomas
  • This topic focuses on mycosis fungoides (MF), the most common subtype of cutaneous lymphoma. Other subtypes include Sézary syndrome and primary cutaneous anaplastic large cell lymphoma (ALCL). For other subtypes, please consult the Reference section.

Epidemiology

  • Median age at diagnosis is 55 to 60 years; however, it can occur in children and young adults.
  • Male-to-female ratio = 2:1
  • Incidence is higher in African Americans.

Incidence
  • 0.6 cases per 100,000 per year
  • ~4% of all non-Hodgkin lymphoma cases

Etiology and Pathophysiology

  • Unknown but thought to be due to genetic and epigenetic abnormalities
  • Infiltration of activated and malignant T cells in the skin
  • Cytokines, such as interleukin (IL)-4 and IL-5, which can lead to eosinophilia and atopy-like symptoms

Genetics
  • Clonal T-cell receptor (TCR) gene rearrangements are detected in most cases.
  • No recurrent, MF-specific chromosomal translocations have been identified.
  • Loss at chromosome 10q and abnormalities in the tumor suppressor genes p15, p16, and p53 are common.
  • Epigenetic changes may play an important role (1)[A].

Risk Factors

Possible risk factors include viral infection (HTLV-1, EBV) or solvent/chemical exposure.

Diagnosis

  • Diagnostic algorithm for MF is a point-based system. Points are scored for clinical, histopathologic, molecular biologic, and immunopathologic categories. A diagnosis of MF is made when a total of ≥4 points are determined.
  • Clinical criteria: Patient has persistent or progressive patches and plaques plus (2 points if two of following are present, and 1 point if one is present) lesions in a non–sun-exposed location, size/shape variation of lesions, and poikiloderma.
  • Histopathologic criteria: superficial lymphoid infiltrate present plus (2 points if both of following are present, and 1 point if one is present) epidermotropism without spongiosis and lymphoid atypia
  • Molecular biologic criteria: Clonal TCR gene rearrangement is present (1 point).
  • Immunopathologic criteria: <50% of T cells express CD2, CD3, CD5; <10% of T cells express CD7; there is discordance of the epidermal and dermal cells with regard to expression of CD2, CD3, CD5, or CD7 (1 point if any present).

Physical Exam

  • Examination of the entire skin with assessment of percentage of involved body surface area (BSA) (patient’s palm plus fingers is ~1% of BSA) and lesions found is critical.
  • Pink scaly patches or plaques, typically in sun-protected areas, such as the buttocks, thighs, and breasts; often pruritic
  • Cutaneous tumors and ulcerations
  • Generalized erythroderma
  • Alopecia
  • Palmoplantar keratoderma (thickened scaly skin on palms and soles)
  • Lymphadenopathy can be present in later stages.
  • Hepatosplenomegaly can be present at late stages.

Differential Diagnosis

  • Patches and plaques seen in MF resemble lesions of the following:
    • Eczema
    • Parapsoriasis
    • Atopic dermatitis
    • Photodermatitis
    • Drug eruptions
    • Psoriasis
    • Contact dermatitis
  • Cutaneous tumors
    • Similar to other cutaneous lymphomas
  • Erythroderma, although rare, can present like
    • Atopic dermatitis
    • Contact dermatitis
    • Drug eruptions
    • Erythrodermic psoriasis
    • Sézary syndrome
  • Adult T-cell leukemia lymphoma
  • Subcutaneous panniculitis-like T-cell lymphoma
  • Primary cutaneous ALCL
  • Cutaneous B-cell lymphoma

Diagnostic Tests & Interpretation

Initial Tests (lab, imaging)
  • CBC with manual differential and Sézary cell count and/or flow cytometry (including CD4+/CD7− or CD4+/CD26−)
  • Comprehensive metabolic profile
  • Liver function tests
  • Low-density lipoprotein (LDL)
  • TCR gene rearrangement
  • Chest x-ray alone can be considered in limited disease (stage IA and select patients with stage IB disease) in otherwise healthy asymptomatic patients.
  • CT of the neck, chest, abdomen, pelvis, or PET-CT for ≥ T2 disease (see staging system described below); MRI, if unable to obtain CT

Diagnostic Procedures/Other
  • Skin biopsy: diagnostic procedure of choice; may require multiple biopsies; immunophenotyping to include at least the following markers: CD2, CD3, CD4, CD5, CD7, and CD8; evaluation for clonality of TCR gene rearrangement
  • Lymph node biopsy with clinical or radiographically significant adenopathy
  • Bone marrow biopsy for unexplained hematologic abnormality: not required
Test Interpretation
  • Skin biopsy shows superficial band-like infiltrate, epidermotropism of lymphocytes, Pautrier microabscesses, and dermal infiltrates of atypical cells in tumors.
  • Cells are usually CD3+, CD4+, CD45RO+, CD8−, and CD30−.
  • Loss of T-cell antigens, such as CD2, CD3, CD5, and CD7, is often seen.
  • Sézary syndrome (leukemic phase of CTCL) is diagnosed when Sézary cells are found in the peripheral circulation. Sézary cells are atypical lymphocytes with cerebriform nuclei. Sézary syndrome is defined by a CD4:CD8 ratio >10, a circulating clonal T-cell population is identified, a positive Sézary cell count >1,000 cells/mm3 in peripheral blood, a CD4/CD26− ≥30% of all of the lymphocytes in the presence of a clonal T-cell population.
  • Large cell transformation of CTCL can occur. If 25% of large cells are found on a biopsy taken from an MF lesion, this represents a transformation from an indolent lymphoma, MF, to a very aggressive form of CTCL and associated with reduced survival.
  • Staging is done based on physical exam and pathology. Bone marrow biopsy is not needed for disease staging; the TNMB staging system ([T]umor, [N]ode, [M]Visceral, and [B]lood involvement with Sézary cells) (2)[A]:
    • T1: patches or plaques involving <10% of total BSA
    • T2: patches, papules, and/or plaques involving ≥10% of total BSA
    • T3: ≥1 cutaneous tumors (≥1 cm in diameter)
    • T4: generalized erythroderma (>80% of total BSA)
    • N0: lymph nodes clinically uninvolved
    • N1: lymph nodes clinically enlarged but not histologically involved
      • N1a clone negative
      • N1b clone positive
    • N2: lymph nodes clinically normal but histologically involved
      • N2a clone negative
      • N2b clone positive
    • N3: lymph nodes clinically enlarged and histologically involved
    • M0: no visceral organ involvement
    • M1: visceral involvement with pathologic confirmation
    • B0: no significant blood involvement (<5% of Sézary cells)
      • B0a clone negative
      • B0b clone positive
    • B1: low blood tumor burden (does not meet criteria of B0 or B2)
      • B1a clone negative
      • B1b clone positive
    • B2: high 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%)
    • Staging
      • IA: T1N0M0B0-1
      • IB: T2N0M0B0-1
      • IIA: T1-2N1-2M0B0-1
      • IIB: T3N0-2M0B0-1
      • IIIA: T4N0-2M0B0
      • IIIB: T4N0-2M0B1
      • IVA1: T1-4N0-2M0B2
      • IVA2: T1-4N3M0B0-2
      • IVB: T1-4N0-3M1B0-2

Treatment

General Measures

  • Most cases are managed on an outpatient basis.
  • Treatment should be individualized for each patient, based on extent of disease and side effects of possible therapies.
  • Skin lesions commonly become infected, and treatment with antibiotic may be necessary.

Medication

Treatment must be individualized and usually involves skin-directed therapy with or without systemic therapy. No universally accepted standard approach exists to treat this disease. Combination therapy has not been demonstrated to be superior to monotherapy (3)[A]. Localized therapy is preferred prior to systemic therapy. Clinical trials should be considered. Disease stage dictates the aggressiveness and type of therapy (4)[A].

  • T1 and T2 disease
    • Topical potent corticosteroids
    • Topical mechlorethamine (nitrogen mustard)
    • Topical bischloronitrosourea (BCNU, carmustine) (alkylating agent)
    • Topical bexarotene or tazarotene (retinoid)
    • Topical tacrolimus (immunosuppressant)
    • Topical imiquimod (immune modulator)
    • Phototherapy: psoralen ultraviolet A (PUVA) light or narrow-band ultraviolet B (UVB)
    • Radiation therapy (total skin electron beam therapy [TSEBT]) (see “Issues for Referral”)
    • Oral low-dose methotrexate
  • T3 disease
    • Skin-directed therapy (as above)
    • Systemic retinoids: oral bexarotene, isotretinoin interferon (INF-alfa) (immune modulators)
    • Denileukin diftitox
    • Chemotherapy: If the disease progresses on the above therapies, single-agent gemcitabine or liposomal doxorubicin is usually used first line. If the disease continues to progress, low-dose methotrexate, bortezomib, cyclophosphamide, and pralatrexate are options as second-line therapy. Stem cell transplantation can also be used in certain cases; see below.
  • T4 disease and Sézary syndrome
    • Skin-directed therapy (as above)
    • Systemic retinoids
    • Interferon denileukin diftitox (immune modulator, combination of IL-2 and diphtheria toxin)
    • Phototherapy
    • Histone deacetylase inhibitor: vorinostat (oral) or romidepsin (injectable)
    • Extracorporeal photophoresis
    • Radiotherapy
    • Additional chemotherapy agents (used with disease progression despite above therapies)
      • First line: gemcitabine or liposomal doxorubicin
      • Second line: low-dose methotrexate, bortezomib, cyclophosphamide, and pralatrexate
      • Combination chemotherapy for patients with very aggressive disease
        • Cyclophosphamide (Cytoxan), hydroxydaunorubicin (doxorubicin), oncovin (vincristine), and prednisone (Deltasone) (CHOP)
        • Cyclophosphamide, vincristine, prednisone (CVP)
    • Allogeneic hematopoietic stem cell transplantation: Data is limited, can lead to durable remission and potentially curative (5)[A]. Consider referral for patients who have failed multiple systemic therapies.

Issues For Referral

  • Dermatology manages early disease.
  • Hematology oncology is involved for recurrent or advanced-stage diseases.
  • Radiation oncology can be referred for local or TSEBT.

Ongoing Care

Follow-up Recommendations

Patient Monitoring
Must be individualized; includes routine physical exam with attention to skin lesions, lymphadenopathy, organomegaly; laboratory tests, including CBC with evaluation for Sézary cells, and repeat imaging, as indicated

Patient Education

Patient information can be found at:

Prognosis

Median survival by stage:

  • Stage IA: 35.5 years
  • Stage IB: 21.5 years
  • Stage IIA: 15.8 years
  • Stages IIB and IIIA: 4.7 years
  • Stage IIIB: 3.4 years
  • Stage IVA1: 3.8 years
  • Stage IVA2: 2.1 years
  • Stage IVB: 1.4 years

Complications

  • Immunosuppression from the disease and treatments can lead to infections.
  • Long-term use of topical corticosteroids may lead to skin atrophy.
  • High-potency topical corticosteroids may be systemically absorbed, leading to numerous adverse effects.

Additional Reading

  • Akilov OE, Geskin L. Therapeutic advances in cutaneous T-cell lymphoma. Skin Therapy Lett. 2011;16(2):1–5. [PMID:21591544]
  • Alberti-Violetti S, Talpur R, Schlichte M, et al. Advanced-stage mycosis fungoides and Sézary syndrome: survival and response to treatment. Clin Lymphoma Myeloma Leuk. 2015;15(6):e105–e112. [PMID:25817937]
  • Galper SL, Smith BD, Wilson LD. Diagnosis and management of mycosis fungoides. Oncology (Williston Park). 2010;24(6):491–501. [PMID:20568590]
  • Horwitz SM, Olsen EA, Duvic M, et al. Review of the treatment of mycosis fungoides and Sézary syndrome: a stage-based approach. J Natl Compr Canc Netw. 2008;6(4):436–442. [PMID:18433609]
  • Hwang ST, Janik JE, Jaffe ES, et al. Mycosis fungoides and Sézary syndrome. Lancet. 2008;371(9616):945–957. [PMID:18342689]
  • Olsen E, Vonderheid E, Pimpinelli N, et al; for ISCL/EORTC. Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood. 2007;110(6):1713–1722. [PMID:17540844]
  • Pimpinelli N, Olsen EA, Santucci M, et al; for International Society for Cutaneous Lymphoma. Defining early mycosis fungoides. J Am Acad Dermatol. 2005;53(6):1053–1063. [PMID:16310068]
  • Prince HM, Whittaker S, Hoppe RT. How I treat mycosis fungoides and Sézary syndrome. Blood. 2009;114(20):4337–4353. [PMID:19696197]

Codes

ICD-10

  • C84.00 Mycosis fungoides, unspecified site
  • C84.01 Mycosis fungoides, lymph nodes of head, face, and neck
  • C84.02 Mycosis fungoides, intrathoracic lymph nodes
  • C84.03 Mycosis fungoides, intra-abdominal lymph nodes
  • C84.04 Mycosis fungoides, lymph nodes of axilla and upper limb
  • C84.05 Mycosis fungoides, nodes of inguinal region and lower limb
  • C84.06 Mycosis fungoides, intrapelvic lymph nodes
  • C84.07 Mycosis fungoides, spleen
  • C84.08 Mycosis fungoides, lymph nodes of multiple sites
  • C84.09 Mycosis fungoides, extranodal and solid organ sites

ICD-9

  • 202.10 Mycosis fungoides, unspecified site, extranodal and solid organ sites
  • 202.11 Mycosis fungoides, lymph nodes of head, face, and neck
  • 202.12 Mycosis fungoides, intrathoracic lymph nodes
  • 202.13 Mycosis fungoides, intra-abdominal lymph nodes
  • 202.14 Mycosis fungoides, lymph nodes of axilla and upper limb
  • 202.15 Mycosis fungoides, lymph nodes of inguinal region and lower limb
  • 202.16 Mycosis fungoides, intrapelvic lymph nodes
  • 202.17 Mycosis fungoides, spleen
  • 202.18 Mycosis fungoides, lymph nodes of multiple sites

SNOMED

  • 118618005 Mycosis fungoides (disorder)
  • 188627002 mycosis fungoides of lymph nodes of multiple sites (disorder)
  • 94707004 mycosis fungoides of intra-abdominal lymph nodes (disorder)
  • 94709001 mycosis fungoides of intrathoracic lymph nodes (disorder)
  • 94710006 Mycosis fungoides of lymph nodes of axilla AND/OR upper limb (disorder)
  • 94711005 mycosis fungoides of lymph nodes of head, face AND/OR neck (disorder)
  • 94712003 mycosis fungoides of lymph nodes of inguinal region AND/OR lower limb (disorder)
  • 94715001 mycosis fungoides of extranodal AND/OR solid organ site (disorder)

Clinical Pearls

  • CTCL is a rare and typically indolent mature T-cell lymphoma presenting primarily in the skin; infiltration of activated and malignant T cells in the skin
  • MF, the most common subtype of cutaneous lymphoma
  • If MF is suspected, patients should have repeat biopsies if initial biopsies are negative.
  • Impaired immunity and poor skin integrity place these patients at high risk for bacterial infections. Most systemic treatment options affect immune function and can further increase the risk for infection.
  • Patients are at increased incidence of second malignancies, specifically lymphoma.
  • Early stage MF is usually treated with skin-directed therapy. Advanced-stage disease is usually treated with a combination of skin-directed therapy and systemic therapy.

Authors


Annie Lee Oh, MD
Nicole Gerardo, PharmD

Bibliography

  1. Wong HK. Novel biomarkers, dysregulated epigenetics, and therapy in cutaneous T-cell lymphoma. Discov Med. 2013;16(87):71–78.  [PMID:23998443]
  2. Agar NS, Wedgeworth E, Crichton S, et al. 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. J Clin Oncol. 2010;28(31):4730–4739.  [PMID:20855822]
  3. Humme D, Nast A, Erdmann R, et al. Systematic review of combination therapies for mycosis fungoides. Cancer Treat Rev. 2014;40(8):927–933.  [PMID:24997678]
  4. Jain S, Zain J, O’Connor O. Novel therapeutic agents for cutaneous T-cell lymphoma. J Hematol Oncol. 2012;5:24.  [PMID:22594538]
  5. Duarte RF, Boumendil A, Onida F, et al. Long-term outcome of allogeneic hematopoietic cell transplantation for patients with mycosis fungoides and Sézary syndrome: a European Society for Blood and Marrow Transplantation lymphoma working party extended analysis. J Clin Oncol. 2014;32(29):3347–3348.  [PMID:25154828]


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