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 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.
Incidence
- 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.
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 (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:
- 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
- S İzary 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 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
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 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 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 S İzary 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 1 of the following: >1,000/ÎĵL S İzary 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; initially, therapy 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 light (PUVA) or narrow-band ultraviolet B (UVB)
- Radiation therapy (total skin electron beam therapy [TSEBT]) (see "Issues for Referral")
- Oral methotrexate
- T3 disease
- 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.
- T4 disease and S İzary syndrome
- 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 doxorubicin
- Second 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].
- 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 S İzary cells, and repeat imaging, as indicated
PATIENT EDUCATION
Patient information can be found at:
- American Academy of Dermatology Web site: www.aad.org
- Cutaneous Lymphoma Foundation Web site: www.clfoundation.org
PROGNOSIS
Median survival by stage:
- 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
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.
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.