What every physician needs to know:
Sézary syndrome (SS) is a leukemic form of cutaneous T-cell lymphoma (CTCL), in which patients have significant blood involvement with Sézary cells and diffuse skin erythema (erythroderma). Patients with SS often have shortened survival but life expectancy is still measured in years.
Because the disease can progress slowly and the diagnosis is not always obvious from skin biopsies of early lesions, many patients will repeatedly complain of symptoms and have tried various nonspecific topical therapies, before the diagnosis is ultimately made.
These patients often experience intractable itching (pruritus), which can be the most significant life-altering symptom, and therefore treatments that can successfully reduce pruritus, even without measurable objective response may still be a valuable option. While these patients require systemic therapy, biologic therapies are usually the initial choices with chemotherapy regimens generally reserved for patients with bulky lymph node or visceral disease, or as a later line of therapy when other options have failed.
Are you sure your patient has Sézary syndrome? What should you expect to find?
The key element of diagnosis is the skin biopsy reviewed by a dermatopathologist. However, as opposed to plaque and tumors, skin biopsies of patients with erythrodermic skin involvement often do not have easily identified or specific diagnostic features; thus, assessment of other sites of potential involvement, such as blood or lymph nodes, may help confirm the clinical diagnosis. Typical Sezary cells in measurable numbers by morphology with a corresponding immunophenotype of CD4+/CD7- or CD4+/CD26- by flow cytometry, strongly favors this diagnosis.
Lymphadenopathy is a frequent finding in patients with SS, and can range from reactive dermatopathic changes to frank involvement by lymphoma on histopathologic examination. Additional clinical findings commonly seen in SS include keratoderma, nail dystrophy, alopecia, ectropion, and skin edema (especially in the legs).
Beware of other conditions that can mimic Sézary syndrome:
Drug reactions can mimic the clinical or histologic appearance (lymphomatoid drug eruptions) and should be excluded.
The human T-lymphotropic virus type 1 (HTLV-1) associated lymphoma may present with rash and lymphocytosis. T-cell prolymphocytic leukemia can have a similar presentation, but usually presents more aggressively with a very elevated lymphocyte count (often greater than 100,000, with a rapid rise which is less common for SS).
Which individuals are most at risk for developing Sézary syndrome:
Sézary syndrome is a rare disorder typically presenting in adults with a male preponderance. Some series report that it is more common among African Americans and less common among Asians. Rare cases are described in children. While there is evidence that SS is a distinct disorder from mycosis fungoides (MF) beyond merely leukemic presentation, there are patients with MF who develop significant SS at the time of progression.
What laboratory studies should you order to help make the diagnosis and how should you interpret the results?
The following studies are advised:
Skin biopsy reviewed by experienced dermatopathologist or hematopathologist
Complete blood count with peripheral smear for Sézary cells
Flow cytometry of peripheral blood to quantify CD4+/CD7- and CD4+/CD26- cells (CD26 loss is believed to be more specific for SS than CD7 loss, as CD7 may be lost in reactive T-cell processes)
Peripheral blood evaluation for T-cell receptor rearrangement may be helpful
Serology for HTLV-1, to rule out HTLV-1 associated lymphomas if suspected
Bone marrow biopsy is usually not indicated
What imaging studies (if any) will be helpful in making or excluding the diagnosis of Sézary syndrome?
Computed tomography (CT) scan of the chest abdomen and pelvis or positron emission tomography – computed tomography (PET/CT) can identify enlarged lymph nodes for biopsy.
If you decide the patient has Sézary syndrome, what therapies should you initiate immediately?
Immediate institution of therapy is usually not needed, although pruritus may be severe, but should wait for a clear diagnosis and thorough work-up. 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.
More definitive therapies?
Therapies can be divided into skin directed therapies, milder systemic or biologic therapies, and more aggressive systemic therapies which carry a higher risk for immunosuppression. Most often patients will start on one or more biologic or non-immunosuppressive systemic therapies, which include retinoids such as: bexarotene, interferon alpha, extracorporeal photopheresis, histone deacetylase inhibitors, or low doses of methotrexate.
Skin directed therapies such as phototherapy, topical corticosteroids, and emollients are frequently added as an important part of symptom management, as well as disease treatment. More immunosuppressive therapies such as single agent chemotherapies like: gemcitabine, liposomal doxorubicin, pralatrexate, or, alemtuzumab are usually reserved for those who have not adequately responded to or progressed, after less immunosuppressive therapies.
What other therapies are helpful for reducing complications?
Because these patients may have severe, intractable pruritus, supportive anti-itch treatments such as antihistamines, gabapentin, or mirtazapine may be helpful. Aggressive topical steroid treatment (+/- occlusive wraps) can often significantly improve symptoms. Anti-Staphylococcus antibiotics are often helpful in patients with significant colonization and poorly intact skin.
What should you tell the patient and the family about prognosis?
Sézary syndrome has features of both an aggressive and chronic lymphoma. Short of allogeneic stem cell transplantation, the disease is not felt to be curable and survival is shortened for most affected patients. However, there are multiple therapies with response rates in the 30 to 50% range.
Many of the milder or biologic therapies listed above, if active for an individual, can be used in an ongoing or maintenance fashion, to provide months to years of disease control. Thus, there is guarded optimism for long term disease control with relatively well tolerated approaches. If these therapies are ineffective or stop working, other therapies can provide good disease control, although durable remissions are rare.
In selected cases, allogeneic stem cell transplantation can result in long term or permanent remissions.
What if scenarios.
Patients with Sézary 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 goes are important for minimizing these risks.
Studies using low doses of alemtuzumab appear to confer a lower risk of infection in patients with Sézary syndrome as compared to full dose alemtuzumab.
Sézary syndrome is a malignancy of clonal mature T-cell, with a predilection for the skin and the blood. Its cause is unknown.
What other clinical manifestations may help me to diagnose Sézary syndrome?
Drug reactions can cause erythroderma and rare Sézary cells (as opposed to Sézary syndrome) may be seen in individuals without the disease. Similarly several other T-cell lymphomas may present with lymphocytosis and rash. Patients with Sézary syndrome usually, but not always provide a history of rash and pruritus going back many months, if not years.
What other additional laboratory studies may be ordered?
Human leukocyte antigen (HLA) typing, if allogeneic stem cell transplantation is planned.
Peripheral blood flow cytometry for CD52 in alemtuzumab is being considered as a therapy.
What’s the evidence?
Kim, YH, Liu, HL, Mraz-Gernhard, S. “Long-term outcome of 525 patients with mycosis fungoides and Sézary syndrome: clinical prognostic risk factors for disease progression”. Arch Dermatol.. vol. 139. 2003. pp. 857-866. [Large series on the treated natural history of MF and SS.]
Olsen, E, Vonderheid, E, Pimpinelli, N. “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.. vol. 110. 2007. pp. 1713-1722. [Provides specific definitons of Sézary syndrome incorporating morphology, flow cytometry, and molecular diagnostics.]
Vonderheid, EC, Bigler, RD, Greenberg, AS. “Extracorporeal photopheresis and recombinant interferon alfa 2b in Sézary syndrome. Use of dual marker labeling to monitor therapeutic response”. Am J Clin Oncol.. vol. 17. 1994. pp. 255-263. [Description of the use of combination biologic therapy with photopheresis.]
Kaye, FJ, Bunn, PA, Steinberg, SM. “A randomized trial comparing combination electron-beam radiation and chemotherapy with topical therapy in the initial treatment of mycosis fungoides”. N Engl J Med.. vol. 321. 1989. pp. 1784-1790. [Older randomized study showing that early aggressive chemotherapy approaches do not result in long term benefit in MF and SS and may cause short term increased toxicity.]
Wollina, U, Dummer, R, Brockmeyer, NH. “Multicenter study of pegylated liposomal doxorubicin in patients with cutaneous T-cell lymphoma”. Cancer.. vol. 98. 2003. pp. 993-1001. [Small study demonstrating very high response rates to liposomal doxorubicin, this is an active agent although response rates seen in this study are higher than observed on clinical practice.]
Duvic, M, Talpur, R, Wen, S. “Phase II evaluation of gemcitabine monotherapy for cutaneous T-cell lymphoma”. Clin Lymphoma Myeloma.. vol. 7. 2006. pp. 51-58. [Phase II experience with gemcitabine.]
Bernengo, MG, Quaglino, P, Comessatti, A. “Low-dose intermittent alemtuzumab in the treatment of Sézary syndrome: clinical and immunologic findings in 14 patients”. Haematologica.. vol. 92. 2007. pp. 784-794. [Study exploring an alternative and likely less toxic dosing of alemtuzumab for SS. I generally follow this approach when using alemtuzumab for these patients.]
Molina, A, Zain, J, Arber, DA. “Durable clinical, cytogenetic, and molecular remissions after allogeneic hematopoietic cell transplantation for refractory Sézary syndrome and mycosis fungoides”. J Clin Oncol.. vol. 23. 2005. pp. 6163-6171. [Small series of highly slelected patients who did exceedingly well with allogeneic stem cell transplantation. It is a proof of principle that this treatment is potentially curative for these patients.]
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- Sézary syndrome
- What every physician needs to know:
- Are you sure your patient has Sézary syndrome? What should you expect to find?
- Beware of other conditions that can mimic Sézary syndrome:
- Which individuals are most at risk for developing Sézary syndrome:
- What laboratory studies should you order to help make the diagnosis and how should you interpret the results?
- What imaging studies (if any) will be helpful in making or excluding the diagnosis of Sézary syndrome?
- If you decide the patient has Sézary syndrome, what therapies should you initiate immediately?
- More definitive therapies?
- What other therapies are helpful for reducing complications?
- What should you tell the patient and the family about prognosis?
- What if scenarios.
- What other clinical manifestations may help me to diagnose Sézary syndrome?
- What other additional laboratory studies may be ordered?
- What’s the evidence?