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An Overview of Sezary Syndrome
Sezary syndrome (SS) is a rare and aggressive form of cutaneous T-cell lymphoma (CTCL), characterised by the triad of erythroderma, lymphadenopathy and presence of circulating neoplastic T-cells in the peripheral blood.
We spoke to Theresa Lowry Lehnen, PhD Clinical Nurse Specialist and Associate Lecturer South East Technological University to find out more about this rare disease.
Theresa explains, “Primary cutaneous lymphomas (PCL) are localised to the skin, without extracutaneous involvement at the time of initial diagnosis and are a subset of non-Hodgkin lymphoma (NHL). PCLs can originate from T or B lymphocytes and are called cutaneous T-cell lymphomas or cutaneous B-cell lymphomas.
“Cutaneous T-cell lymphoma is further categorised into two types: an indolent form that includes mycosis fungoides (MF), lymphomatoid papulosis, and anaplastic large T-cell primary cutaneous lymphoma; and an aggressive form that includes Sezary syndrome.
“Mycosis fungoides and Sezary syndrome are the most common forms of cutaneous T-cell lymphoma. Mycosis fungoides originates in the peripheral epidermotropic T-cells, specifically the memory T-cells (CD45RO+), which express the T-cell receptor (TCR) and CD4+ immunophenotype. Mycosis fungoides has an incidence of around 6 cases per million per year in Europe and the United States, accounting for approximately 4% of all nonHodgkin lymphoma cases.”
Theresa adds that while there is evidence that Sezary syndrome is a distinct disorder from mycosis fungoides beyond merely leukemic presentation, there are patients with MF who develop significant Sezary syndrome at the time of progression. “It is hypothesised that Sezary syndrome can evolve gradually from mycosis fungoides or occur spontaneously,” she notes.
Sezary syndrome is a rare disease, with an annual incidence rate of 1/10,000,000, accounting for approximately 3% of all cases of CTCL. It typically presents in adults over 60 years of age, with a male predominance. Initially the presentation with generalised itch and erythroderma may be nonspecific. In up to one-third of skin biopsies later confirmed as SS, the histologic picture may be nonspecific, making diagnosis difficult and consequently delayed.
The exact cause of Sezary syndrome is unknown, and an inheritance pattern has not been determined. The condition occurs in people with no family history of the disorder and is not thought to be inherited in most cases.
Pathogenesis
Theresa adds, “The exact pathogenesis of Sezary syndrome is not fully understood and involves complex interactions between neoplastic T-cells, immune dysregulation, and the microenvironment. Several molecular and cellular mechanisms contribute to the development and progression of the disease.
“The malignant T-cells in SS are typically CD4+ memory T-cells with a Th2 cytokine profile. Aberrant signalling pathways, including STAT3, NF-κB, and JAK/ STAT, play an important role in the survival and proliferation of neoplastic T-cells. The immune dysregulation in SS involves a complex interplay between neoplastic T-cells and the host immune system. The malignant T-cells evade immune surveillance and suppress the antitumor immune response through various mechanisms, including impaired antigen presentation, cytokine secretion, and recruitment of immunosuppressive cells.”
Sezary syndrome incurs significant morbidity and hallmark clinical features include generalized erythroderma, intractable pruritus, lymphadenopathy, and palmoplantar keratoderma.
Pruritus is intense and even high doses of antihistamines cannot provide relief. In more advanced cases there may be alopecia, ectropion, onychodystrophy and palmar/plantar hyperkeratosis.
The cancer can spread to the lungs, liver, spleen, and bone marrow. People with Sezary syndrome are at a higher risk of developing other types of lymphoma or cancers. The disease can also lower the function of the immune system, increasing the risk of infections.
Diagnosis
Theresa told us, “Accurate and timely diagnosis of Sezary syndrome is crucial for appropriate treatment planning and improved patient outcomes. Early identification allows for the initiation of targeted therapies and the avoidance of unnecessary interventions. The condition can be a diagnostic challenge to clinicians as it can mimic benign skin disorders.
“General practitioners rarely see CTCL, and diagnostic delay can occur through misdiagnosis and because CTCL can initially respond to topical corticosteroids like more-common skin conditions. It is usually only on progression of the illness that a dermatology referral occurs, and some general dermatologists and histopathologists may also have little CTCL experience.”
She adds that a multidisciplinary team is needed for complete diagnosis and management, comprising a CTCL-experienced dermatologist, a dermato-and haemato-pathologist experienced in skin and lymphoma, respectively, and an oncologist experienced in delivering CTCLtailored treatments.
“The need for specialist nurses to support patients and liaise with nursing care closer to home is important. The diagnosis of Sezary syndrome requires a comprehensive evaluation involving various diagnostic modalities. SS should be differentiated from mycosis fungoides, psoriasis, pityriasis rubra pilaris, dermatitis, hypereosinophilic syndrome, and adult T-cell leukaemia. Primary skin disorders like scabies, and adverse drug reactions are also considered in the differential.”
A detailed patient medical history and physical examination is carried out. Tests include a full blood count with differential, Sezary blood cell count, HIV test and skin biopsy. More than one skin biopsy may be needed. Other tests that may be carried out include:
• Immunophenotyping using antibodies to identify cancer cells based on the types of antigens or markers on the surface of the cells. Immunophenotyping is used to help diagnose specific types of lymphoma.
• Flow cytometry, a laboratory test that measures the number of cells in a sample, the percentage of live cells in a sample, and certain characteristics of the cells, such as size, shape, and the presence of tumour or other markers on the cell surface. The cells from a sample of a patient’s blood, bone marrow, or other tissue are stained with a fluorescent dye, placed in a fluid, and then passed one at a time through a beam of light. Test results are based on how the cells that were stained with the fluorescent dye react to the beam of light. Flow cytometry is used to help diagnose and manage certain types of cancers, such as leukaemia and lymphoma.
• T-cell receptor (TCR) gene rearrangement test, in which cells in a sample of blood or bone marrow are checked to see if there are certain changes in the genes that make receptors on T cells. Testing for these gene changes can identify whether large numbers of T cells with a certain T-cell receptor are being made.
“After mycosis fungoides or Sezary syndrome has been diagnosed, further tests are necessary to determine if cancer cells have spread from the skin to other parts of the body,” Theresa adds. “Tests include, chest x-ray, CT scan, PET scan, bone marrow aspiration and biopsy, and lymph node biopsy. Excisional lymph node biopsy is preferred, and it can show reactive changes or dermatopathic changes or features suggestive of lymphoma. Secondary skin infections are common because of frequent scratching and compromised skin. Starting antibiotics and taking cultures to rule out methicillin-resistant Staphylococcus aureus may be indicated at diagnosis.”
Staging and Prognosis
The prognosis of patients with mycosis fungoides and Sezary syndrome is based on the TNMB staging system, which considers the extent of skin, lymph node and visceral organ involvement, and blood tumour burden. “The presence of lymphadenopathy and involvement of peripheral blood and viscera increase in likelihood with worsening cutaneous involvement and define poor prognostic groups,” she notes.
Stage I Mycosis Fungoides
Stage I is divided into stages IA and IB:
• Stage IA: Patches, papules and/ or plaques cover less than 10% of the skin surface.
• Stage IB: Patches, papules, and/or plaques cover 10% or more of the skin surface. There may be a low number of Sezary cells in the blood.
Stage II Mycosis Fungoides
Stage II is divided into stages IIA and IIB:
• Stage IIA: Patches, papules and/ or plaques cover any amount of skin surface. Lymph nodes are abnormal, but they are not cancerous.
• Stage IIB: One or more tumours that are 1 centimetre or larger are found on the skin.
Lymph nodes may be abnormal, but they are not cancerous. There may be a low number of Sezary cells in the blood.
Stage III Mycosis Fungoides
In stage III, 80% or more of the skin surface is reddened and may have patches, papules plaques, or tumours. Lymph nodes may be abnormal, but they are not cancerous. There may be a low number of Sezary cells in the blood.
Stage IV Mycosis Fungoides/ Sezary Syndrome
When there is a high number of Sezary cells in the blood, the disease is called Sezary syndrome. Stage IV is divided into stages IVA1, IVA2, and IVB depending on the presence of nodal and visceral involvement.
• Stage IVA1: Patches, papules, plaques, or tumours may cover any amount of the skin surface, and 80% or more of the skin surface may be reddened. The lymph nodes may be abnormal, but they are not cancerous. There is a high number of Sezary cells in the blood.
• Stage IVA2: Patches, papules, plaques, or tumours may cover any amount of the skin surface, and 80% or more of the skin surface may be reddened. The lymph nodes are very abnormal, or cancer has formed in the lymph nodes. There may be a high number of Sezary cells in the blood.
• Stage IVB: Cancer has spread to other organs in the body, such as the spleen or liver. Patches, papules, plaques, or tumours may cover any amount of the skin surface, and 80% or more of the skin surface may be reddened. The lymph nodes may be abnormal or cancerous. There may be a high number of Sezary cells in the blood.
“For people with early-stage MF, the life span may be normal. Patients with stage IA disease have a median survival of 20 years or more.”
She adds, “Prognosis for Sezary syndrome is generally poor, with a median survival of 2 to 4 years, however, survival has improved with newer treatments. Prognosis can vary depending on age, disease stage, and response to therapy.”
Treatment Strategies
The management of Sezary syndrome requires a multimodal approach, including skin-directed therapies, systemic therapies, and supportive care measures. Skindirected therapies include topical corticosteroids, phototherapy, and electron beam radiation.
Theresa says, “Systemic treatments include interferonalpha, retinoids, histone deacetylase inhibitors, and novel immunotherapies targeting immune checkpoints, such as PD-1 inhibitors. 7 Besides diseasedirected treatment options, pruritis is a major concern in patients with Sezary syndrome.
“Various local and/or systemic options can be used to try and control the pruritis. Patients with Sezary syndrome are very susceptible to infections from poorly intact skin, colonization, indwelling catheters, and immunosuppression from therapy. Good skin care and avoidance of indwelling catheters are important for minimising these risks.
“Given the leukemic involvement in Sezary syndrome, the treatment is generally systemic. Specific treatment for individual patients is based on a variety of factors, including the patient’s general health and stage of disease.”
Treatments for SS include:
• Phototherapy: PUVA (ultraviolet-A light is directed onto the skin and the patient is given the drug psoralen); UVB (skin directed ultraviolet-B light); NBUVB (skin directed narrow band ultraviolet-B light).
• Biologic or immunotherapy therapy used to stimulate a patient’s own immune system to fight the cancer.
• Retinoids, to slow certain types of cancer cells. Examples are Interferon alpha and Bexarotene.
• Extracorporeal photopheresis (ECP), a procedure used to expose the blood to ultraviolet light.
• Radiation therapy, using high energy X-rays or other types of radiation to kill cancer cells or prevent them from growing.
• Advanced disease treatment can involve chemotherapy, given either orally or through an intravenous infusion to stop the growth of rapidly dividing cancer cells. While the response may be quick, it can be short-lived and require maintenance therapy.
• Haematopoietic stem cell transplant.
Theresa concludes. “Sezary syndrome is generally an incurable condition, and the primary aims of treatment are symptom control and remission induction. While CTCL is currently deemed incurable, remission has been achieved for some following allogeneic stem cell transplant (ASCT). With new potential therapeutic options on the horizon, it is hoped that these agents will bring improved outcomes and a better quality of life for patients.
“Since the publication of the first WHO-EORTC classification in 2005, much progress has been made, and the 2018 update continues to be a useful guide for clinicians involved in the care of patients with cutaneous lymphomas. Genome-wide genetic studies have contributed to a better understanding of the molecular pathways involved in the pathogenesis of the different types of cutaneous lymphomas and resulted in the recognition of additional diagnostic and prognostic criteria and new potential therapeutic targets
“Although genetic markers are becoming increasingly important, integration of histologic, immunophenotypic, genetic, and cutaneouslymphomas clinical data remain essential for an accurate diagnosis. In recent years, a multidisciplinary approach with collaboration among pathologists, dermatologists, haematologists, and radiation oncologists has been crucial for defining new entities and classifications and is the best guarantee for further progress in the diagnosis, treatment, and management of patients with a cutaneous lymphoma.
“More information, support, and the establishment of national and international patient CTCL advice and support groups is necessary for patients with Sezary syndrome and CTCL, who can feel isolated, especially when most people have never even heard of their disease.”
