Sezary Syndrome

Sezary syndrome is one of several closely related clinicopatho-logical entities referred to as cutaneous T-cell lymphoma (CTCL).238-242 The most commonly occurring entity, mycosis fungoides, is characterized by chronic, slowly progressive cutaneous lesions (plaques and nodules) with eventual adenopathy, bone marrow involvement, and systemic disease.243,244 These disorders are caused by the proliferation of mature T cells (CD4 or helper cell phenotype positive) that have a high affinity for the skin.245 Sezary syndrome refers to one phase of CTCL characterized by intense erythroderma, extreme pruritus, adenopathy, splenomegaly, and a leukemic blood picture.239,240 Clonal cytogenetic abnormalities and rearrangements of the T-cell antigen receptor gene have confirmed the monoclonal proliferation of these disorders.

Morphologically, Sezary cells are either small (approximately 8 |m) or larger (approximately 15 to 20 |im), the latter reportedly reflecting a block in the cell cycle between G1 and S phase.239 Sezary cells contain a hyperchromatic convoluted or cerebriform nucleus, which is more serpentine than the convoluted nuclei in T-cell lymphoblastic lymphoma (Plate 3-2Q). Similar-appearing peripheral T cells with cerebriform nuclear contours may rarely be found in patients with non-Hodgkin's lymphoma of the diffuse mixed cell type,246 although they generally are pathognomonic for CTCL. Sezary cells have also been observed in the skin and blood of patients with a number of benign dermatoses, including erythrodermic eczema, psoriasis, lichen planus, and actinic reticuloid.247 However, while Sezary cells are CD4+, in chronic actinic dermatitis the cells are immunophenotypically suppressor cells (CD8+). A case of pseudo-Sezary syndrome has been reported in a patient with the acquired immunodeficiency syndrome.248 Intense erythroid skin infiltration developed as a result of skin infiltration by large atypical lymphoid cells, although Sezary-like cells appeared in the blood. CD8+ and T-cell receptor gene rearrangements were not present, suggesting that this was a polyclonal reaction.248

The marked nuclear irregularity of Sezary cells is well seen on ultrastructural analysis.239,249 Cytogenetic studies have shown serial changes over time from hypo- or pseudodiploidy to hyperdiploidy, near-tetraploidy that correlates with the appearance of large Sezary cells, poor prognosis, and short sur-vival.250 The WBC count in patients with Sezary syndrome may range from 8.0 to several hundred X 109/L with all the cells being neoplastic T cells.239 Higher leukocyte counts occur in patients with nodal and visceral involvement, but do not bear a relationship to the stage of cutaneous disease. The proliferation of hairy cells may involve constitutive interleukin (IL)-2 receptor alpha expression on the basis of STAT3 (intracellular signaling enzyme) activation.251 Moreover, sensitive detection techniques can delineate small numbers of Sezary-type cells in the peripheral blood of some patients with early stage mycosis fun-goides.240,252

Histopathologically, patients with CTCL typically display epidermal involvement with T lymphocytes that may form small clusters of neoplastic and reactive cells called Pautrier's microabscesses.239,242 Patients whose cutaneous lesions display a predominance of immature cells appear to have a worse prognosis than those with more well-differentiated cells,253 although clinical stage (e.g., nodal or visceral involvement) is probably a more important factor.

Lymph node biopsy may reveal dermatopathic lymphadenopathy or a variable degree of involvement by malignant convoluted T cells.254,255 The T-cell zones (paracortical areas) are preferentially infiltrated, but early involvement is not associated with destruction of lymph node architecture.255 Infiltration of the spleen is also typical and involves the periarteriolar sheets and red pulp.242 Although not often recognized during life, autopsy studies document the involvement of visceral organs in most patients with CTCL.256 Pulmonary involvement has been reported, even when the skin eruption has improved.257 The cellular composition of such involvement closely resembles the cutaneous lesions, although there is a preservation of parenchymal tissue, despite heavy infiltration with the neoplastic T cells.244 Portal areas may be involved, as in Hodgkin's disease, or the hepatic parenchyma may be infiltrated, as in myeloid leukemia and malignant histiocytosis. The extensive lesions found in autopsy studies are not surprising, in view of prospective staging studies indicating a high frequency of generally asymptomatic extracutaneous dissemination occurring early in the course of disease.243,244

Transition of patients with Sezary syndrome into a more aggressive phase of the disease, including a change in morphology (transformation to a large cell lymphoma) of the malignant cells has been reported.258,259 The large cells express helper T-cell markers suggesting direct evolution from the preceding Sezary cells. This transformation event is more likely in patients with advanced CTCL and carries with it a poor prognosis.260 The development of a malignant B-cell disorder (plasma cell myeloma) has been reported in a patient with long-standing CTCL.261 In this case it was postulated that sustained helper cell T-cell activity caused polyclonal plasma cell proliferation with eventual emergence of a monoclonal plasma cell population. There is also a slight increased risk of other malignancies, particularly lung and colon cancer, in patients with long-standing CTCL.262,263

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