Sézary Syndrome

Introduction

In 1806, the term mycosis fungoides (MF) was first used by Alibert, a French dermatologist, when he described a severe disorder in which large necrotic tumors resembling mushrooms presented on a patient's skin. Mycosis fungoides is the most common type of cutaneous T-cell lymphoma (CTCL), which was coined at an international workshop sponsored by the National Cancer Institute in 1979. Cutaneous T-cell lymphoma was used to describe a heterogeneous group of malignant T-cell lymphomas with primary manifestations in the skin.

Sézary syndrome (SS) is a variant of mycosis fungoides, occurring in about 5% of all cases of mycosis fungoides. The patient with Sézary syndrome has generalized exfoliative erythroderma, lymphadenopathy, and more than 1000 per mm3 of atypical T lymphocytes with cerebriform nuclei circulating in the peripheral blood or other evidence of a significant malignant T-cell clone in the blood such as clonal T-cell gene rearrangement (identical to that found in the skin).

The T-cell gene rearrangement is demonstrated by molecular or cytogenetic techniques and/or an expansion of cells with a malignant T-cell immunophenotype (an increase of CD4+ cells such that the CD4/CD8 ratio is >10, and/or an expansion of T cells with a loss of 1 or more of the normal T-cell antigens [eg, CD2, CD3, CD5]). The circulating malignant cells tend to be CD7 and CD26–.

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Cutaneous T-Cell Lymphoma [in the Dermatology section]

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Mycosis Fungoides

Pegylated Liposomal Doxorubicin Effective in Hard-To-Treat Cutaneous T-Cell Lymphoma

The Usefulness of CD26 in Flow Cytometric Analysis of Peripheral Blood in Sezary Syndrome

Pathophysiology

Mycosis fungoides is a malignant lymphoma characterized by the expansion of a clone of CD4+ (or helper) memory T cells (CD45RO+) that normally patrol and home to the skin.2 The malignant clone frequently lacks normal T-cell antigens such as CD2, CD5, or CD7. The normal and malignant cutaneous T cell homes to skin by virtue of interactions with dermal capillary endothelial cells. Cutaneous T cells express cutaneous lymphocyte antigen (CLA), an adhesion molecule that mediates tethering of the T lymphocyte to endothelial cells in cutaneous postcapillary venules via its interaction with E selectin.

Further promoting the proclivity of the cutaneous T cell to home in to the skin is the release by keratinocytes of cytokines, which infuse the dermis, coat the luminal surface of the dermal endothelial cells, and upregulate the adhesion molecules in the dermal capillary endothelial lumen, which react to CCR4 found on cutaneous T cells.

Extravasating into the dermis, the cells show an affinity for the epidermis, clustering around Langerhans cells as seen microscopically as Pautrier microabscesses. However, the malignant cells that adhere to the skin retain the ability to exit the skin via afferent lymphatics. They travel to lymph nodes and then through efferent lymphatics back to the blood to join the circulating population of CLA-positive T cells. Then, mycosis fungoides is fundamentally a systemic disease, even when the disease appears to be in an early stage and clinically limited to the skin.

Frequency United States

Approximately 1000 new cases of mycosis fungoides occur per year (ie, 0.36 cases per 100,000 population).

Mortality/Morbidity

• An analysis of 20-year trends reporting on incidence and associated mortality of those with mycosis fungoides shows a decline in the mortality rate in the United States, perhaps related to an increased recognition and earlier diagnosis of the disease.7 The overall mortality rate is 0.064 per 100,000 persons; however, the mortality rate widely varies depending on the stage of disease at diagnosis.
• Late-stage mycosis fungoides or Sézary syndrome is associated with declining immunocompetence. Death most often results from systemic infection, especially with Staphylococcus aureus, Pseudomonas aeruginosa, and other organisms. Secondary malignancies, such as higher-grade non-Hodgkin lymphoma, Hodgkin disease, colon cancer, and cardiopulmonary complications (eg, high output failure, comorbid cardiopulmonary disease) also contribute to mortality.

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Mycosis fungoides is more common in black than in white patients (incidence ratio = 1.6).

Mycosis fungoides occurs more frequently in men than in women (male-to-female ratio of 2:1).

The most common age at presentation is 50 years; however, mycosis fungoides can also be diagnosed in children and adolescents with apparently similar outcomes.

Clinical History

• Skin rash
  • This may consist of flat patches, plaques, or tumors, which may have a long natural history.
  • The median duration from the onset of skin symptoms to diagnosis is 6 years. Early in the course of mycosis fungoides, as well as in erythrodermic cases, skin lesions may be nonspecific, with a nondiagnostic biopsy result, so that confusion with benign conditions is common.
  • Obtain repeated biopsies in those patients who have progressive chronic dermatosis or whose condition is refractory to topical treatments.
• Pruritus, erythroderma: Often, the diagnosis of mycosis fungoides is made possible through the examination of a noncutaneous site (eg, blood, lymph nodes).

Physical

• Flat skin patch, plaque, and tumors
  • The patch phase of mycosis fungoides is characterized by flat, usually erythematous, macules that may have a fine scale, may be single or multiple, and may be pruritic. In dark-skinned individuals, the patches may appear as hypopigmented or hyperpigmented areas. As the patches become more infiltrative, they evolve into palpable plaques.
  • The plaques tend to be raised, demonstrating fine-scale, well-demarcated, erythematous shapes with irregular borders. Annular or serpiginous patterns with central clearing and pruritus are common.
  • Patches and plaques may affect any area of the skin, but they are often distributed asymmetrically in the areas that a bathing suit would cover (ie, hips, buttocks, groin, lower trunk, axillae, breasts). When mycosis fungoides affects the scalp, it is often accompanied by alopecia.
  • Despite the fact that mycosis fungoides and Sézary syndrome are types of non-Hodgkin lymphoma, an entirely different staging system is used that is based on the particular skin findings and findings of extracutaneous disease that are observed in affected patients.
    • Stage IA disease (as defined by the tumor, node, metastases, blood [TNMB] system) is defined as patchy or plaquelike skin disease involving less than 10% of the skin surface area (T1 skin disease).
    • Stage IB disease is defined as patchy or plaquelike skin disease involving greater than or equal to 10% of the skin surface area (T2 skin disease).
• Skin tumors
  • Patients with evidence or a history of patchy or plaquelike skin lesions can also have tumors.
  • The tumors are red-violet nodules that may be dome-shaped, exophytic, or ulcerated.
  • Stage IIB disease is defined by the presence of tumors (T3 skin lesions).
• Skin erythroderma
  • Generalized erythroderma is often intensely symptomatic, with pruritus and scaling that can be profound. The patients experience thickening of the skin folds in the face (leonine facies), hyperkeratosis and fissuring of the palms and soles, onychodystrophy, ectropion of the eyelids, alopecia, and edema. Sun exposure may be painful as well as pruritic.
  • Stage III disease is defined by the presence of generalized erythroderma.
  • Patients with erythroderma and significant blood involvement are now considered to have stage IVA1 disease.2
• Lymph nodes
  • Extracutaneous involvement is more clinically evident as the stage and extent of mycosis fungoides increases.
  • Peripheral lymphadenopathy is the most frequent site of extracutaneous involvement in mycosis fungoides.
  • Evaluate palpable lymphadenopathy by obtaining a biopsy, because the result influences the patient's stage, prognosis, and treatment.
  • Stage IVA2 disease is defined by a lymph node biopsy result showing total effacement by atypical cells (LN4 node).2
• Liver and lung: Stage IVB disease is defined by the presence of visceral involvement (eg, liver, lung, bone marrow).

Causes

Various theories implicate occupational or environmental exposures (eg, Agent Orange), other forms of chronic antigenic stimulation, or viral exposures; however, the etiology of mycosis fungoides remains unknown.

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