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Cutaneous T-Cell Lymphoma, Mycosis Fungoides

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Cutaneous T-Cell Lymphoma, Mycosis Fungoides

BASICS

DESCRIPTION

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.

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

Initial Tests (lab, imaging)

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; initially, therapy prior to systemic therapy. Clinical trials should be considered. Disease stage dictates the aggressiveness and type of therapy (4)[A].

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

11 Wong HK. Novel biomarkers, dysregulated epigenetics, and therapy in cutaneous T-cell lymphoma. Discov Med. 2013;16(87):71-78.22 Agar NS, Wedgeworth E, Crichton S, et al. Survival outcomes and prognostic factors in mycosis fungoides/S İzary 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):4730-4739.33 Humme D, Nast A, Erdmann R, et al. Systematic review of combination therapies for mycosis fungoides. Cancer Treat Rev. 2014;40(8):927-933.44 Jain S, Zain J, O'Connor O. Novel therapeutic agents for cutaneous T-cell lymphoma. J Hematol Oncol. 2012;5:24.55 Schlaak M, Pickenhain J, Theurich S, et al. Allogeneic stem cell transplantation versus conventional therapy for advanced primary cutaneous T-cell lymphoma. Cochrane Database Syst Rev. 2013;(8):CD008908.

  • 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 S İzary 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
  • African American incidence is greater compared with whites.
  • 0.6 cases/100,000/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.
  • 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

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 (two points if two of following are present, and one 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 (two points if both of following are present, and one point if one is present) epidermotropism without spongiosis and lymphoid atypia.
  • Molecular biologic criteria: Clonal TCR gene rearrangement is present (one 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 (one 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:EczemaParapsoriasisAtopic dermatitisPhotodermatitisDrug eruptionsPsoriasisContact dermatitis
  • Cutaneous tumorsSimilar to other cutaneous lymphomas
  • Erythroderma, although rare, can present likeAtopic dermatitisContact dermatitisDrug eruptionsErythrodermic psoriasisS İzary syndrome
  • Adult T-cell leukemia lymphoma
  • Subcutaneous panniculitis-like T-cell lymphoma
  • Primary cutaneous ALCL
  • Cutaneous B-cell lymphoma
  • Eczema
  • Parapsoriasis
  • Atopic dermatitis
  • Photodermatitis
  • Drug eruptions
  • Psoriasis
  • Contact dermatitis
  • Similar to other cutaneous lymphomas
  • Atopic dermatitis
  • Contact dermatitis
  • Drug eruptions
  • Erythrodermic psoriasis
  • S İzary syndrome

DIAGNOSTIC TESTS & INTERPRETATION

  • CBC with manual differential and S İzary 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
  • 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
  • Skin biopsy shows superficial bandlike 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.
  • S İzary syndrome (leukemic phase of CTCL) is diagnosed when S İzary cells are found in the peripheral circulation. S İzary cells are atypical lymphocytes with cerebriform nuclei. S İzary syndrome is defined by a CD4:CD8 ratio >10, a circulating clonal T-cell population is identified, a positive S İzary 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 S İzary cells) (2)[A]:T1: patches or plaques involving <10% of total BSAT2: patches, papules, and/or plaques involving ≥10% of total BSAT3: ≥1 cutaneous tumors (≥1 cm in diameter)T4: generalized erythroderma (>80% of total BSA)N0: lymph nodes clinically uninvolvedN1: lymph nodes clinically enlarged but not histologically involvedN1a clone negativeN1b clone positiveN2: lymph nodes clinically normal but histologically involvedN2a clone negativeN2b clone positiveN3: lymph nodes clinically enlarged and histologically involvedM0: no visceral organ involvementM1: visceral involvement with pathologic confirmationB0: no significant blood involvement (<5% of S İzary cells)B0a clone negativeB0b clone positiveB1: low blood tumor burden (does not meet criteria of B0 or B2)B1a clone negativeB1b clone positiveB2: high tumor burden (positive clone plus 1 of the following: >1,000/ÎĵL S İzary cells; CD4/CD8 >10; CD4+CD7- cells >40%; or CD4+CD26- cells >30%)StagingIA: T1N0M0B0-1IB: T2N0M0B0-1IIA: T1-2N1-2M0B0-1IIB: T3N0-2M0B0-1IIIA: T4N0-2M0B0IIIB: T4N0-2M0B1IVA1: T1-4N0-2M0B2IVA2: T1-4N3M0B0-2IVB: T1-4N0-3M1B0-2
  • 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 involvedN1a clone negativeN1b clone positive
  • N2: lymph nodes clinically normal but histologically involvedN2a clone negativeN2b 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 S İzary cells)B0a clone negativeB0b clone positive
  • B1: low blood tumor burden (does not meet criteria of B0 or B2)B1a clone negativeB1b clone positive
  • B2: high tumor burden (positive clone plus 1 of the following: >1,000/ÎĵL S İzary cells; CD4/CD8 >10; CD4+CD7- cells >40%; or CD4+CD26- cells >30%)
  • StagingIA: T1N0M0B0-1IB: T2N0M0B0-1IIA: T1-2N1-2M0B0-1IIB: T3N0-2M0B0-1IIIA: T4N0-2M0B0IIIB: T4N0-2M0B1IVA1: T1-4N0-2M0B2IVA2: T1-4N3M0B0-2IVB: T1-4N0-3M1B0-2
  • N1a clone negative
  • N1b clone positive
  • N2a clone negative
  • N2b clone positive
  • B0a clone negative
  • B0b clone positive
  • B1a clone negative
  • B1b clone positive
  • 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

  • T1 and T2 diseaseTopical potent corticosteroidsTopical 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 light (PUVA) or narrow-band ultraviolet B (UVB)Radiation therapy (total skin electron beam therapy [TSEBT]) (see "Issues for Referral")Oral methotrexate
  • T3 diseaseSkin-directed therapy (as above)Oral bexarotene, all-transretinoic acid, isotretinoin (retinoids)Interferons (INF-alfa and INF-gamma) (immune modulators)Denileukin diftitoxChemotherapy: If the disease progresses on the above therapies, 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 S İzary syndromeSkin directed therapy (as above)Oral bexarotene (retinoid)Interferon (immune modulator)Denileukin diftitox (immune modulator, combination of IL-2 and diphtheria toxin)PhototherapyVorinostat (oral histone deacetylase inhibitor)Romidepsin (injectable histone deacetylase inhibitor)Extracorporeal photophoresisRadiotherapyAdditional chemotherapy agents (used with disease progression despite above therapies)First line: gemcitabine or liposomal doxorubicinSecond line: low-dose methotrexate, bortezomib, cyclophosphamide, and pralatrexateAllogeneic hematopoietic stem cell transplantation: Data are limited, can lead to durable remission and potentially curative (5)[A].
  • Consider referral for patients who have failed multiple systemic therapies
  • 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 light (PUVA) or narrow-band ultraviolet B (UVB)
  • Radiation therapy (total skin electron beam therapy [TSEBT]) (see "Issues for Referral")
  • Oral methotrexate
  • Skin-directed therapy (as above)
  • Oral bexarotene, all-transretinoic acid, isotretinoin (retinoids)
  • Interferons (INF-alfa and INF-gamma) (immune modulators)
  • Denileukin diftitox
  • Chemotherapy: If the disease progresses on the above therapies, 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.
  • Skin directed therapy (as above)
  • Oral bexarotene (retinoid)
  • Interferon (immune modulator)
  • Denileukin diftitox (immune modulator, combination of IL-2 and diphtheria toxin)
  • Phototherapy
  • Vorinostat (oral histone deacetylase inhibitor)
  • Romidepsin (injectable histone deacetylase inhibitor)
  • Extracorporeal photophoresis
  • Radiotherapy
  • Additional chemotherapy agents (used with disease progression despite above therapies)First line: gemcitabine or liposomal doxorubicinSecond line: low-dose methotrexate, bortezomib, cyclophosphamide, and pralatrexate
  • Allogeneic hematopoietic stem cell transplantation: Data are limited, can lead to durable remission and potentially curative (5)[A].
  • First line: gemcitabine or liposomal doxorubicin
  • Second line: low-dose methotrexate, bortezomib, cyclophosphamide, and pralatrexate

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 EDUCATION

  • American Academy of Dermatology Web site: www.aad.org
  • Cutaneous Lymphoma Foundation Web site: www.clfoundation.org

PROGNOSIS

  • Stage IA: 35.5 years
  • Stage IB: 21.5 years
  • Stage IIA: 15.8 years
  • Stage 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.

REFERENCES

ADDITIONAL READING

  • Alberti-Violetti S, Talpur R, Schlichte M, et al. Advanced-stage mycosis fungoides and S İzary syndrome: survival and response to treatment. Clin Lymphoma Myeloma Leuk. 2015;15(6):e105-e112.
  • Akilov OE, Geskin L. Therapeutic advances in cutaneous T-cell lymphoma. Skin Therapy Lett. 2011;16(2):1-5.
  • Galper SL, Smith BD, Wilson LD. Diagnosis and management of mycosis fungoides. Oncology (Williston Park). 2010;24(6):491-501.
  • Horwitz SM, Olsen EA, Duvic M, et al. Review of the treatment of mycosis fungoides and S İzary syndrome: a stage-based approach. J Natl Compr Canc Netw. 2008;6(4):436-442.
  • Hwang ST, Janik JE, Jaffe ES, et al. Mycosis fungoides and S İzary syndrome. Lancet. 2008;371(9616):945-957.
  • Olsen E, Vonderheid E, Pimpinelli N, et al. Revisions to the staging and classification of mycosis fungoides and S İzary 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.
  • Pimpinelli N, Olsen EA, Santucci M, et al. Defining early mycosis fungoides. J Am Acad Dermatol. 2005;53(6):1053-1063.
  • Prince HM, Whittaker S, Hoppe RT. How I treat mycosis fungoides and S İzary syndrome. Blood. 2009;114(20):4337-4353.

CODES

ICD10

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

ICD9

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

SNOMED

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

CLINICAL PEARLS

  • 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.