A Spotlight on Two Main Subtypes: Mycosis Fungoides and Sézary Syndrome

 

Cutaneous T-cell lymphoma (CTCL) belongs to the non-Hodgkin lymphoma class of hematologic T-cell lymphoproliferative disorders.[1] Cutaneous T-cell lymphoma is a rare group of malignancies, with an incidence of 6.4 cases per 1 million people.[1] This form of T-cell lymphoma represents around 70% of primary cutaneous lymphomas.[2]

Cutaneous T-cell lymphoma attacks the the body’s immune system, specifically, the lymphatic system, affecting the two types of white blood cells (lymphocytes): B-cells and T-cells. Whereas the B-lymphocytes act to neutralize the pathogens, the main job of the T-lymphocytes is to attach to these foreign cells, viruses, or cancerous growths, and directly destroy them.

Compared with other T-cell lymphomas, a distinguishing feature of CTCL is implied by the name: malignant T-cells migrating to, and collecting in, cutaneous tissue. Diagnosis can be challenging, because the initial signs and symptoms are largely skin-related and overlap with those of many other dermatologic disorders. Adding to the challenge, CTCL variants present with overlapping symptomatology, and correct identification of the CTCL subtype is key to both treatment and prognosis.[2] Histopathologic features must be correlated with the clinical presentation to confirm the diagnosis.[3]

Many forms of CTCL are relatively indolent compared with other T-cell lymphomas, but there are aggressive subtypes.[1] This is illustrated by the two most common forms of CTCL: mycosis fungoides and Sézary syndrome. Although mycosis fungoides is considered a slow-growing variant, Sézary syndrome is aggressive and generally has a poor prognosis.[1] Importantly, even the indolent subtypes can progress in some patients and become difficult to manage.

PATHOPHYSIOLOGY

According to the Leukemia and Lymphoma Society, seven subtypes of CTCL exist (Table 1).[4] Like many hematologic malignancies, several of these subtypes are differentiated according to molecular markers on the surface of cancerous cells.[5] The most common subtype, mycosis fungoides, typically progresses slowly, over years.[1] However, some cases will advance to the lymph nodes, blood, and rarely, visceral organs.[1]

Sézary syndrome, the second most common type of CTCL, is more aggressive than mycosis fungoides.[2] It is characterized by Sézary cells accumulation in the skin, leading to erythroderma, as well as in the blood and lymph nodes.[3]

 

TABLE 1: CUTANEOUS T-CELL LYMPHOMA SUBTYPES[4]
Mycosis fungoides
Sézary syndrome
Cutaneous CD30+ expressing anaplastic large cell lymphoma
Panniculitis-like T-cell lymphoma
Cutaneous CD8+ expressing aggressive epidermotropic T-cell lymphoma
Gamma-delta T-cell lymphoma
Hypopigmented/vitiligenous mycosis fungoides

 

The cause of CTCL is not fully understood at this time. Although the skin manifestations are known to result from the accumulation of abnormal T-lymphocytes, the reason for the production of these mutated lymphocytes has not been identified. Genetic abnormalities are suspected, but these issues seem to be sporadic and spontaneous in nature for the most common forms of CTCL.[1] Certain chemokine receptors (e.g., CCR4)  may be implicated in the migration of the malignant T-lymphocytes to the skin.[5]

EPIDEMIOLOGY

As noted, the annual incidence of CTCL is 6.4 cases per 1 million people. Overall, the risk in men is twice that for women, and its likelihood increases with age. The median age at onset is in the fifth decade, but CTCL does occur (rarely) in children.[2]

About 70% of patients with CTCL have mycosis fungoides.[5] Its annual incidence is as high as 1 patient in 100,000 persons (the US annual incidence is estimated at 3.6 cases per 1 million).[5] Sézary syndrome is diagnosed in 3% to 5% of all CTCL cases.[1]

Significant racial differences are seen in patients with mycosis fungoides. For example, the incidence of CTCL is greater in blacks and non-Hispanic whites than in other racial cohorts.[6] Furthermore, black patients seem to present with earlier-onset and more advanced disease in comparison with white patients.[7] In a study using the US National Cancer Database, researchers found that of 4,459 patients diagnosed with mycosis fungoides from 2004 to 2014, African American race was an independent predictor of poorer overall survival (P< .001).[8] 

DIAGNOSIS AND STAGING

The diagnosis of CTCL is often challenging; as a result, delays in diagnosis (and subsequently work-up and treatment) can be significant. Part of the reason is the variability in how individual patients present with CTCL and its subtypes.[1] Because mycosis fungoides progresses slowly, some patients may not experience progression beyond their initial symptoms, even beyond 10 years.[1] Patients with mycosis fungoides or Sézary syndrome also have overlap in manifestations; in fact, Sézary syndrome was once classified as a malignant, leukemic variant of mycosis fungoides but is now recognized as a distinct CTCL subtype.[9]

Staging. Table 2 describes the overall clinical staging of mycosis fungoides, as published by the National Comprehensive Care Network (NCCN) guidelines.[3]

TABLE 2: CLINICAL STAGING OF MYCOSIS FUNGOIDES AND SÉZARY SYNDROME[3]
Stage Skin Involvement Lymph Node Involvement Blood Involvement Visceral Involvement
IA T1 (Patches, papules, plaque covering < 10% BSA) N0 (None) B0–B1 M0
IB T2 (Patches, papules, plaque covering ≥ 10% BSA) N0 B0–B1 M0
IIA T1-T2 N1-N2 (abnormal lymph nodes) B0–B1 M0
IIB T3 (≥ 1 tumor [≥ 1 cm in diameter]) N0-N2 (none to intermediate-grade, abnormal lymph nodes) B0–B1 M0
IIIA T4 (Erythema ≥ 80% BSA) N0-N2 B0 M0
IIIB* T4 N0-N2 B1 M0
IV1 T1-T4 N0-N2 B2 M0
IV2 T1-T4 N3 (High-grade, abnormal lymph nodes) B0–B2 M0
IVB T1-T4 N0-N3 B0–B2 M1
Reprinted from NCCN Clinical Practice Guidelines in Oncology: Primary cutaneous lymphomas. Version 2.2020. https://www.nccn.org/professionals/physician_gls/pdf/primary_cutaneous.pdf.

 

As noted in Table 2, blood involvement is variable across thestages of mycosis fungoides; Sézary syndrome is characterized by erythroderma and B2 blood involvement.[3]

Patients with stages IIB and beyond are considered to have advanced CTCL.[3] Accurate staging is critical to choosing the appropriate therapeutic approach.[3]

Skin Manifestations. Patients with mycosis fungoides may progress through three phases of skin symptoms. The first may feature little more than transient red, scaly areas of skin on the buttocks and torso.[1] The plaques may be hyper- or hypopigmented.[3]  As such, these symptoms can be easily misidentified as common skin conditions such as eczema or psoriasis.[10] The variability of signs and symptoms also adds to the challenge of making a timely, clear-cut diagnosis.

In the second phase, patients with progressing disease may develop palpable, scaly, reddish-brown plaques that appear on any portion of the body.[1] Over time, the affected areas of skin may grow, merging with other affected regions. Patients’ skin presentation during this stage can vary considerably: Some patients may experience severe pruritus or pain in these scaly bumps, which can result in sleep disturbances and other challenges to quality of life. Other patients may remain asymptomatic other than the skin’s appearance.[1]

Disease presentation is a bit more consistent in patients who have progressed to the third phase of skin symptoms. Some patients may develop mushroom-shaped skin tumors that can cause skin ulceration and infection.[1] Even for patients with mycosis fungoides reaching this phase of skin progression, malignant spread is uncommon (only 10% will experience metastases to major organs).[1]

While patients with Stage III mycosis fungoides experience widespread erythema (>80% of body surface area), erythroderma is a consistent feature of Sézary syndrome.  This rash will often be associated with severe pruritus and peeling.[2]

Other Signs. In addition to erythroderma and B2 blood involvement, patients with Sézary syndrome will typically have several other characteristic signs: generalized lymphadenopathy, opportunistic infections, and alopecia.[3] The liver and possibly the spleen will be enlarged, and patients often have very thick, coarse skin on the soles of the feet and palms of the hands (i.e., palmoplantar keratoderma).[3]

Diagnosis is usually made with a patient history, complete physical exam, blood tests, biopsy of skin lesions, computed tomography imaging, and sometimes lymph node biopsy and/or bone marrow biopsy.[3] These methods can also be useful in determining the stage of disease, especially whether the lymph nodes have been involved and whether the cancerous cells have spread to blood and other organs. In addition to eczema and psoriasis, the differential diagnosis may include nonspecific dermatitis, lichen, lupus, pseudolymphoma, parapsoriasis, and toxidermia.[11]

MANAGEMENT AND CURRENT TREATMENTS

There are many, multimodal treatment options for the various CTCL subtypes (Table 3).[1-3] In addition to pharmacologic approaches, several other types of interventions have been used successfully, including radiation therapy, phototherapy, extracorporeal photopheresis, and in some cases, stem-cell transplant. Many of these options are dependent on the stage and extent of the disease and are often categorized as “skin-directed” and systemic agents, as in Table 3.

Table 3. Medications and Other Therapeutic Options for Treating a Patient With CTCL[1-3,10]

Medication Class Rationale Examples
Skin-Directed Treatments    
Topical Corticosteroids Suppress inflammation and pruritis symptoms in early-stage disease Hydrocortisone, desonide, fluocinolone, mometasone
Topical Retinoids Slow or halt the growth of malignant T-lymphocytes in skin Bexarotene, tazarotene
Topical Chemotherapy

Kills rapidly dividing cells (including malignant cells) nonselectively

 

Mechlorethamine* (formerly called nitrogen mustard), carmustine
Radiation therapy, including TSEBT Radiation to outer layers of skin
Phototherapy Ultraviolet light therapy (eg, PUVA , in which psoralen given prior to treatment sensitizes T-cells to light, allowing UV light exposure to kill them  
Systemic Treatments    
Targeted treatment Exploits specific, unique cell and molecular features of malignancies (e.g., cell surface markers) Alemtuzumab, brentuximab,* romidepsin, pembrolizumab, denileukin diftitox, mogamulizumab,*† vorinostat*
Systemic chemotherapy

Kills rapidly dividing cells (including malignant cells) nonselectively

 

Gemcitabine, pralatrexate, methotrexate, others
Interferon Stimulates the immune system to attack malignant cells Alpha interferon
Extracorporeal photopheresis Removes leukocytes from circulation, exposes them to UV light, then returns them to patient Therakos®*
Stem-cell transplant Chemotherapy destroys patients’ stem cells, and donated healthy stem cells are used to repopulate the bone marrow
*FDA approved to treat CTCL. Some medications treat only specific forms of CTCL. †Only drug specifically approved to treat Sézary syndrome.

Patients with mycosis fungoides are often treated with skin-directed therapies, especially in the early stages of disease. In contrast, patients with later-stage disease, disease that does not respond well to skin-directed treatments, or Sézary syndrome generally require systemic treatments.[3] Topical therapies do not have a significant impact on disease progression for advanced stages of either form of CTCL, although skin-directed treatment can play an important role in alleviating such symptoms as pain and pruritus, and most patients will require the intermittent use of topical steroids.[1]

In early-stage CTCL, patients most often visit dermatologists for the diagnosis of their skin lesions, and typically manage it using skin-directed treatment. However, as CTCL progresses, oncologists play an important, collaborative role. The oncology team will commonly manage CTCL with systemic, targeted treatments, radiation approaches, sometimes chemotherapy[11,12] for patients with Sézary syndrome, advanced disease, refractory CTCL,  and other aggressive forms. Clinical trials may also be considered.

Some of the more recent directions in treatment have focused on targeted systemic therapies or targeted monoclonal antibody treatment (e.g., CCR4 or CD30).[11] For example, brentuximab vedotin was recently approved for CD30-positive mycosis fungoides. Mogamulizumab, in contrast, targets specific receptors on the malignant cells (i.e., CCR4). It has been shown to improve progression-free survival, overall response rate, and duration of response in patients with mycosis fungoides and Sézary syndrome.[12]

PROGNOSIS

In patients diagnosed with early-stage mycosis fungoides , the most common form of CTCL, prognosis is often quite good. The slowly progressing nature of the disease and effective early-stage treatments yield 95% 10-year disease-specific survivals.[1] According to the International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer, those diagnosed as having mild or limited disease, for example, are often considered to have a low risk of progression.[2]

For patients with stage IIB disease (considered advanced disease, marked by the appearance of cutaneous tumors), the 10-year disease-specific survival is 42%. In those with generalized erythroderma (stage III), the 10-year survival is still around 45%. Median overall survival in patients with stage IIIA disease is 4.7 years. Patients with stage IVB disease, wherein the malignancy has spread to the lymph nodes or organs, have a median overall survival of less of 1.5 years and a 10-year disease-specific survival of less than 20%.[1]

In patients with Sézary syndrome, the 5-year disease-specific survival is 24%, and median survival is reported to be 2.9 years.[13]

CLINICAL TRIAL INFORMATION

A check of www.clinicaltrials.gov in April 2020 revealed 53 studies actively recruiting patients with various forms of CTCL.

 

RESOURCES

National Organization for Rare Disorders (NORD): Provides a unified voice for the 30 million people who wake up every day to fight the battle with a rare disease, including parents and caregivers.

Cutaneous Lymphoma Foundation: An independent, non-profit patient advocacy organization dedicated to supporting every person affected by cutaneous lymphoma.

Cancer.Net: The American Society of Clinical Oncology’s patient web resource on CTCL.

Lymphoma Research Foundation: A lymphoma-focused health organization devoted to improving care through education and support services and improving outcomes through investment in the most promising lymphoma research.

REFERENCES
  1. Wilcox RA. Cutaneous T-cell lymphoma: 2017 update on diagnosis, risk-stratification, and management. Am J Hematol. 2017;92:1085-1102.
  2. Gilson D, Whittaker SJ, Child FJ, et al. British Association of Dermatologists and U.K. Cutaneous Lymphoma Group guidelines for the management of primary cutaneous lymphomas 2018. Br J Dermatol.2019;180:496-526.
  3. Primary cutaneous lymphomas. National Comprehensive Cancer Network April 10, 2020. https://www.nccn.org/professionals/physician_gls/pdf/primary_cutaneous.pdf. Accessed May 7, 2020.
  4. Cutaneous T-cell lymphoma facts. Leukemia and Lymphoma Society of America. June 2014 https://www.lls.org/sites/default/files/file_assets/cutaneoustcelllymphoma.pdf. Accessed August 3, 2020.
  5. Wu X-S, Londsdorf AS, Hwang ST. Cutaneous T-cell lymphoma: roles for chemokines and chemokine receptors. J Invest Dermatol. 2009;129:1115-1119.
  6. Bradford PT, Devesa SS, Anderson WF, Toro JR. Cutaneous lymphoma incidence patterns in the United States: A population-based study of 3884 cases. Blood. 2009;113:5064-5073.
  7. Geller S, Lebowitz E, Pulitzer M, Myskowski PL. Understanding racial disparities in mycosis fungoides through international collaborative studies. Br J Dermatol. 2019;180:1263-1264.
  8. Su C, Nguyen KA, Bai HX, et al. Racial disparity in mycosis fungoides: An analysis of 4495 cases from the US National Cancer Database. J Am Acad Dermatol. 2017;77:497-502.
  9. Kelati A, Gallouj S, Tahiri L, Harmouche T, Mernissi FZ. Defining the mimics and clinico-histological diagnosis criteria for mycosis fungoides to minimize misdiagnosis. Int J Womens Dermatol. 2017;3:100‐106.
  10. Cutaneous T-cell lymphoma: Diagnosis and treatment. American Academy of Dermatology 2019. https://www.aad.org/public/diseases/skin-cancer/types/common/ctcl/treatment. Accessed April 10, 2020.
  11. Horowitz SM. Clinical update: A new target in CTCL: Treating the skin, blood, and lymph nodes. Clin Adv Hematol Oncol 2019;17:40-43.
  12. Kim YH, Bagot M, Pinter-Brown L, et al. Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC): An international, open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2018;19:1192-1204.
  13. Olsen EA, Rook AH, Zic J, et al. Sézary syndrome: Immunopathogenesis, literature review of therapeutic options, and recommends for therapy by the United States Cutaneous Lymphoma Consortium. J Am Acad Dermatol. 2011;64:352-404.

 

This Cutaneous T-Cell Lymphoma (CTCL) Learning Page is supported by Kyowa Kirin. This content was developed by CheckRare; the supporter did not influence the final article or editorial themes of this article. For more information on CheckRare’s editorial policy and focus, click here.

Articles