Welcome to the NORD Physician Guide to Cutaneous T-Cell Lymphoma (CTCL). The NORD Online Physician Guides are written for physicians by physicians with expertise on specific rare disorders. This guide was reviewed by Oleg E. Akilov, MD, PhD, Assistant Professor of Dermatology, Director, Cutaneous Lymphoma Program, University of Pittsburgh School of Medicine. (see acknowledgements for additional information).
NORD is a nonprofit organization representing all patients and families affected by rare diseases. The information NORD provides to medical professionals is intended to facilitate timely diagnosis and treatment for patients.
Cutaneous lymphoma is a general term for cancers of the lymphocytes that primarily involve the skin. They are a subtype of non-Hodgkin lymphoma. Cutaneous lymphoma is classified as either originated from B-lymphocyte (cutaneous B-cell lymphoma) or T-lymphocyte (cutaneous T-cell lymphoma). Approximately 75% of primary cutaneous lymphomas are T-cell derived.
This Physician Guide deals with cutaneous T-cell lymphoma (CTCL).
CTCL primarily affects the skin, but in more advanced disease can also involve the blood, lymph nodes, and various internal organs.
There are many types of CTCL. The two main types are mycosis fungoides (MF) and Sézary syndrome (SS) accounting for approximately 65% of all primary CTCL. The term mycosis fungoides originally referred to the mushroom-like nodules seen in the tumor stage.
The incidence of CTCL as a whole is currently estimated to be 6.4 per every 1 million people in the general population. According to Surveillance, Epidemiology, and End Results (SEER) registry data, males and African-Americans have the highest incidence rates.
What is Cutaneous T-Cell Lymphoma (CTCL)?
The cutaneous T-cell lymphomas (CTCLs) are a clinically and biologically heterogeneous group of extranodal non-Hodgkin lymphomas (NHLs). CTCLs are characterized by the clonal proliferation of malignant T-cells that primarily target and persist in the skin. Patients develop patches, plaques, and/or tumors. The median age at diagnosis is the mid-50s. Incidence increases significantly with age and these disorders are uncommon in children and young adults. The male to female ratio is 2:1. Mycosis fungoides is the most common variant; it accounts for approximately 50% of cases.
| TABLE 1. EXPANDED CLASSIFICATION OF CTCL BASED ON THE WORLD HEALTH ORGANIZATION (WHO) AND THE EUROPEAN ORGANIZATION FOR RESEARCH AND TREATMENT OF CANCER (EORTC) |
|---|
| Cutaneous T-cell and NK-cell lymphomas |
| Mycosis fungoides and its variants |
| Sézary syndrome |
| Primary CD30+ lymphoproliferative diseases: • Lymphomatoid papulosis • Anaplastic large cell lymphoma |
| Adult T-cell leukemia/lymphoma |
| Subcutaneous panniculitis-like T-cell lymphoma |
| Aggressive cutaneous cytotoxic lymphomas: • Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma • Primary cutaneous gamma/delta T-cell lymphoma • Cutaneous extranodal natural killer/T-cell lymphoma, nasal type |
| Cutaneous peripheral T-cell lymphoma unspecified |
| Cutaneous CD4+ small-medium T-cell lymphomas: • Indolent CD8+ lymphoid proliferation of the ear (face) • Primary cutaneous T-follicular helper-cell lymphoma |
| Other cutaneous NK/T-cell lymphomas: • Angioimmunoblastic T-cell lymphoma • Hydroa vacciniforme-like lymphoma |
| From: Cerroni L. Skin Lymphoma: The Illustrated Guide, 4th Edition. Oxford, UK. Wiley Blackwell. 2014:440 |
Mycosis Fungoides
MF usually exhibits a chronic, indolent course. Since most of the patients with MF are the elderly of 65 years old and older, and it takes 15-20 years for disease to progress, visceral involvement of MF is infrequent. Seventy percent of patients have mainly cutaneous involvement. The classic three stages of development of MF lesions, patches, plaques, and tumors represent the degree of neoplastic infiltrate and may be found in the same patient.
Early MF frequently starts with well-defined erythematous patches resembling eczema. Sun protected areas are most often affected, particularly the lower trunk, buttocks, or upper thighs. The pruritus may be present but in various degree, usually of mild to moderate intensity. The patches can remain unchanged, may grow larger and become confluent or may disappear during summer time. At early stage, MF can mimic common dermatoses such as psoriasis or eczema. The MF limited to 10% of body surface can persist for months, years, or decades.
When disease progresses, thicker lesions develop on the skin. These plaques may be derived from existing patches or occur spontaneously in unaffected areas. They are well demarcated and may take geometric shapes (arcuate, annular, etc.). Plaques may spontaneously resolve or coalesce into larger plaques.
Further disease progression accompanies enlargement of the pull of malignant lymphocytes within the skin forming visible nodules. Traditionally, those nodules in MF have been called tumors. Sometimes they make have a mushroom-like appearance (which gives the disease the name “mycosis fungoides”). These tumors can get ulcerated and secondarily infected.
In the most severe cases, the whole surface of the skin can get involved with lymphoma (erythroderma).
Mycosis Fungoides Variants
There are many variants of mycosis fungoides. They may follow a similar indolent course, but have different or unusual clinical or pathological features. A few of the most common are described below.
Folliculotropic Mycosis Fungoides
This variant of MF is characterized by a collection of malignant lymphocytes around hair follicles. By definition, the glabrous skin is affected predominantly and localization on the upper portion of the trunk (including face and scalp) is the most common. Pruritus can be significant. Alopecia is frequently present. If the lymphoma is localized to the face, eyebrow plaques with enlarged pores are a common presentation. Localized or disseminated folliculocentric papules are typical and have been described as having a keratosis pilaris-like appearance. Folliculotropic MF is as aggressive as the tumor variant of MF.
Pagetoid Reticulosis
There are two types of pagetoid reticulosis (PR): generalized or Ketron-Goodman type and localized or Woringer-Kolopp disease. The main features of this variant of MF are massive infiltration (pagetoid spread) of the epidermis by malignant lymphocytes. Localized PR is most often present as an isolated patch or plaque with a keratotic rim (“horseshoe”) on the lower extremities or affects palms and soles. Generalized PR presents as multiple tumors, but is currently classified based on the phenotype of malignant lymphocytes as aggressive epidermotropic CD8+, primary cutaneous gamma delta T cell lymphoma, NK/T-cell lymphoma or tumor MF.
Granulomatous Slack Skin
This variant of MF is characterized by lax, wrinkled skin masses, especially in the body folds. The groin and axilla are common sites of involvement. Erythema and pruritus of the affected areas can occur. Generally, the condition is considered benign. However, some researchers speculate this presentation an an unusual host reaction in particular body sites.
Sézary Syndrome
Sézary syndrome is defined as the leukemic form of CTCL and is characterized by generalized erythroderma, lymphadenopathy, and high lymphocyte count in the peripheral blood. The thickening, scaling, peeling and pruritus of the skin can be intense. Additional symptoms include ectropion, onychodystrophy, palmoplantar keratoderma, alopecia, and hepatosplenomegaly. Patients with Sézary syndrome may also exhibit general, nonspecific symptoms including fevers, unintended weight loss, chills, fatigue, and malaise.
Primary CD30+ Lymphoproliferative Diseases
This is the second most common group of CTCLs accounting for approximately 30% of cases. Lymphomatoid papulosis and anaplastic large cell lymphoma represent two ends of a spectrum without clear-cut boundaries. The histological picture could be identical, and only clinical presentation and course define the diagnosis. Lymphomatoid papulosis is characterized by the recurrent appearance of isolated highly pruritic papules in the different stage of development on the skin of the trunk, arms, and legs. The patients are usually Caucasian females. These lesions spontaneously resolve within two months, but recurrence is frequent. In 10-20% of patients, lymphomatoid papulosis is preceded, concomitant with, or followed by another type of lymphoma. Anaplastic large cell lymphoma manifests by single or multiple nodules that can become ulcerated or infected. Partial or complete spontaneous regression of the tumors has been reported. Relapse is common.
Adult T-Cell Leukemia/Lymphoma (ATLL)
ATLL is caused by HTLV-1 and endemic in southwestern Japan, the Caribbean Islands and parts of Central Africa. Four variants of clinical course are known: acute, chronic, smoldering and lymphomatous. Acute cases may present with a high level of circulating malignant cells, generalized lymphadenopathy, hepatomegaly, and hypercalcemia with or without lytic bone lesions. Chronic and smoldering cases have a mycosis fungoides-like presentation. Lymphomatous course is characterized by the absence of circulating malignant T-cells, hepatosplenomegaly, hypercalcemia, and organ, and skin involvement. Patients with ATL are immunosuppressed and at risk for opportunistic infection.
Subcutaneous Panniculitis-Like T-Cell Lymphoma (SPTCL)
Previously, several lymphomas that present with subcutaneous nodules, particularly on the extremities, were grouped under SPTCL. Currently, only αβ cytotoxic CD8 lymphoma is classified as SPTCL and others belong to different categories. Importantly, the lobular panniculitis-like pattern can be observed in various cutaneous lymphomas and is not a sufficient criterion for the diagnosis of SPTCL anymore, while phenotype is. The patients are frequently misdiagnosed with lupus panniculitis or erythema nodosum and frequently have the disease for years. Systemic symptoms including fever, fatigue, and unintended weight loss are observed in a small percentage of patients. However, disease course can be protracted and aggressive. Some patients may develop the hemophagocytic syndrome.
Primary Cutaneous Gamma/Delta T-Cell Lymphoma
This is a distinct entity with a universally poor prognosis. Most patients present only with tumors from the beginning. Skin involvement could be secondary to hepatosplenic γδ T-cell lymphoma, thus, staging work-up is crucial. It is important to mention that γδ phenotype is not unique to γδ T-cell lymphomas, as it can be observed in several other types of cutaneous lymphomas including indolent variants of MF.
Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type (ENKL)
Initial symptoms are usually nasal obstruction and chronic rhinorrhea since nasopharynx is frequently involved. Epistaxis, pain and nasal septal or hard palate perforation can also occur. On the skin, ENKL is generally present with isolated necrotic rapidly evolving ulcers frequently on extremities. The prognosis is grave with a median survival time of 15 months since time of diagnosis.
Staging
CTCL is classified based upon the TNM (tumor-node-metastasis) system with an additional compartment, blood (B). This stratification of patients is considered an important prognostic tool and is used to help determine a “risk-adapted” treatment approach.
TABLE 2. TNMB (TUMOR, NODE, METASTASIS, BLOOD) RISK-STRATIFICATION CLASSIFICATION SYSTEM FOR PATIENTS WITH MF/SS.
| T (Skin): T1 – Limited patch/plaque development (<10% body surface area) T2 – Generalized patch/plaque development (>10% body surface area) T3 – Tumors T4 – Erythroderma (>80% of body surface area) |
| N (Nodes): N0 – No clinically abnormal peripheral lymph nodes N1 – Enlarged lymph nodes, dermatopathic changes on histology N2 – Enlarged lymph nodes, histological evidence of early involvement (aggregate of atypical lymphocytes) N3 – Enlarged lymph nodes, histological partially or fully replaced by lymphoma |
| M (Metastasis): M0 – No visceral involvement M1 – Visceral involvement |
| B (Blood): B0 – No circulating atypical cells (<5%) B1 – Circulating atypical cells (>5%) B2 – High tumor burden: >1000 Sézary cells/μl with positive clone |
Stages are determined according to the following table.
TABLE 3. STAGING FOR MYCOSIS FUNGOIDES AND SÉZARY SYNDROME PATIENTS
| Stage | T | N | M | B |
| IA | 1 | 0 | 0 | 0,1 |
| IB | 2 | 0 | 0 | 0,1 |
| IIA | 1,2 | 1 | 0 | 0,1 |
| IIB | 3 | 0-2 | 0 | 0,1 |
| IIIA | 4 | 0-2 | 0 | 0 |
| IIIB | 4 | 0-2 | 0 | 1 |
| IVA1 | 1-4 | 0-2 | 0 | 2 |
| IVA2 | 1-4 | 3 | 0 | 0-2 |
| IVB | 1-4 | 0-3 | 1 | 0-2 |
| Combined International Society for Cutaneous Lymphoma and European Organization for Research and Treatment of Cancer staging for mycosis fungoides and Sézary syndrome |
Patients with Stage IA, IB or IIA have an early stage disease compared to IIB (tumor), III (erythroderma), and IV (pathologically involved nodes – IVA; visceral involvement – IVB) have advanced-stage disease.
Stage I indicates the presence of cutaneous patches or plaques. There is no involvement of lymph nodes, blood or additional organ systems.
Stage III indicates erythrodermic condition:
Stage IV indicates advanced disease with extracutaneous manifestations:
Not only are the early symptoms of mycosis fungoides nonspecific and mildly symptomatic, but they may also have an indolent course. This is the reason why a delay in diagnosis of approximately three to four years is common. Since the skin presentation may be confusing, the evaluation by a dermatologist is necessary for diagnosis.
A diagnosis of CTCL requires a thorough clinical evaluation, a detailed patient history, skin biopsy with immunophenotyping, clonality testing, and flow cytometry of the peripheral blood.
Physical examination in classic cases may reveal characteristic skin lesions in a “bathing suit” distribution. The patients with early MF present with patches and/or thin plaques. The affected skin can appear mildly pruritic and scaly. These lesions vary in shape, size, and color.
Skin biopsies are necessary to confirm the clinical diagnosis. Biopsies can reveal the presence of atypical small- to medium-sized lymphocytes with dense hyperchromatic, elaborately indented (cerebriform) nuclei that are percolating through the epidermis (epidermotropism) in the setting of the absence of other epidermal changes. The papillary dermis may have diffuse lymphocytic infiltration. Immunophenotyping for antigens on the surface of white blood cells or cellular proteins is used to specify the types of atypical lymphocytes which help to sub-classify the cutaneous lymphoma. However, these findings may not be present early in the disease, and initial biopsies may give unclear or contradictory results. It is recommended that multiple biopsies from multiple sites over a period of time be taken to support the clinical impression of MF.
T-cell receptor gene rearrangement analysis (TCRGR) can be performed to support the diagnosis of CTCL by PCR or by sequencing. This test can help identify a clonal population of T-cells within the dermal infiltrate of the skin or the peripheral blood.
The diagnosis of ATLL can be confirmed by the presence of HTLV-1 via serology (antibody assessment) or PCR (virus presence).
A bone marrow aspiration and biopsy may be used in some cases, but is usually not necessary.
The spread and extent of the disorder can be assessed by specialized imaging techniques such as computed tomography, magnetic resonance imaging, and positron emission tomography scans. The choice of imaging study is dependent on the overall involvement of skin, lymph nodes, and blood.
There is no standard of care for CTCL. Since these types of lymphomas are extremely rare, large clinical trials are practically impossible to conduct with CTCL patients. The approach is consensus based and choice of therapeutic modality depends on the disease stage; number of tumors; specific subtype of CTCL; the presence of co-morbidities; an individual’s age and general health. A wide variety of treatment options exist for individuals with CTCL including topical steroids and chemotherapy, phototherapy, radiation therapy, vitamin A derivatives (retinoids), and chemotherapy. These treatments may be used alone or in combination.
Organizations have put out consensus guidelines for physicians treating patients with CTCL.
Below, you can find information which is primarily geared toward MF and Sézary syndrome. More detailed treatment guidelines for rarer forms of CTCL are available in the documents noted in the previous paragraph.
The majority of patients with MF presents with patch or plaque stage disease and have an excellent prognosis. Treatment is aimed at improving cutaneous symptoms; maintaining quality of life and avoiding complications of specific therapeutic interventions. Physicians may recommend that no therapy be given until symptoms appear (watch and wait). Patients will receive regular checkups to detect disease progression. Patients with early stage mycosis fungoides may remain symptom-free for many years.
Treatment for CTCL can be broadly broken down into skin-based and systemic therapies. Early-stage disease confined to the skin often responds well to skin-directed therapies. Such therapies include:
Because of the aggressive nature of some types of lymphomas and advanced stage MF/SS, a combination of topical and systemic therapies can be required. Often, treatment is undertaken by a multidisciplinary team consisting of a hematologist/oncologist, dermatologist, and radiation oncologist.
Systemic therapies used to treat advanced CTCL include:
As of April 2016, a variety of drugs are being studied as potential treatments for CTCL. These include drugs that have been FDA approved for certain subtypes of CTCL, but are being studied in other subtypes. Specific new medications being studied include monoclonal antibodies such as mogamulizumab and pembrolizumab; alkylating agents such as temozolomide; proteasome inhibitors such as bortezomib; topical histone deacetylase inhibitors; lenalidomide.
Clinical Trial Information
Information on current clinical trials is posted at www.clinicaltrials.gov.
All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
The Cutaneous Lymphoma Foundation posts information about clinical trials here:
http://www.clfoundation.org/research/clinical-trials/usa
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
NORD does not endorse or recommend any particular studies.
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18. Ni X, Jorgensen JL, Goswami M, et al. Reduction of regulatory T cells by Mogamulizumab, a defucosylated anti-CC chemokine receptor 4 antibody, in patients with aggressive/refractory mycosis fungoides and Sézary syndrome. Clin Cancer Res. 2015;21(2):274-285. http://clincancerres.aacrjournals.org/content/21/2/274.long
19. Olsen E, Vonderheid E, Pimpinelli N, et al. Revisions to the staging and classification of mycosis fungoides and Sézary 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. http://www.bloodjournal.org/content/110/6/1713.long
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Cutaneous Lymphoma Foundation
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Web: http://www.clfoundation.org
International Society for Cutaneous Lymphomas
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Telephone: 630-578-3991
Email: info@cutaneouslymphoma.org
Web: http://www.cutaneouslymphoma.org
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|
Oleg E. Akilov, MD, PhD NORD gratefully acknowledges Dr. Akilov’s medical expertise in his writing and reviewing of this report. |
This NORD Physician Guide was made possible by an educational grant from Therakos Inc., now a part of Mallinckrodt Pharmaceuticals.
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