Clinical presentation, pathologic features, and diagnosis of Sézary syndrome

INTRODUCTION — Sézary syndrome (SS) and mycosis fungoides (MF) are the most common subtypes of cutaneous T cell lymphoma (CTCL) [1].

●Mycosis fungoides – MF is a mature T cell non-Hodgkin lymphoma that presents with localized or widespread skin lesions, including erythroderma, patches, plaques, or tumors; lymph nodes, blood, and viscera may also be involved.

●Sézary syndrome – SS is a distinctive erythrodermic CTCL with leukemic involvement by malignant T cells that typically bear the same T cell receptor rearrangement as the clone in the skin; occasionally, skin and blood clones do not match, but this should not dissuade one from considering the diagnosis. SS may present de novo with typical skin, blood, and nodal involvement or it may evolve from patch/plaque or erythrodermic MF.

MF and SS share certain pathologic and clinical features, and the same histologic criteria are used to diagnose and stage SS and all stages and types of MF [2]. However, patients with SS are generally more symptomatic, have lower rates of remission, and have inferior survival compared with patients with MF.

This topic discusses the clinical presentation, pathologic features, diagnosis, and differential diagnosis of SS.

Treatment of SS is discussed separately. (See "Treatment of Sézary syndrome".)

Diagnosis and management of MF are discussed separately.

●(See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides".)

●(See "Treatment of early stage (IA to IIA) mycosis fungoides".)

●(See "Treatment of advanced stage (IIB to IV) mycosis fungoides".)

PATHOPHYSIOLOGY — The cause of most cases of SS remains unclear [3]. Numerous gene mutations and deletions have been associated with SS, but their roles as oncogenic drivers are uncertain. A small percentage of cases are associated with human T-lymphotropic viruses type 1 and 2 (HTLV-I/II).

●Cellular origin – Tumor cells in SS appear to be derived from skin-homing CD4-positive (CD4+) T cells or central memory T cells. Expression of cutaneous lymphocyte antigen (CLA) and high levels of the chemokine receptors CCR4 and CCR7 provide the T cells with the capacity to traffic bi-directionally into and out of the skin in response to the appropriate chemokines [4,5].

●Immunosuppression – Increased production of type 2 T helper cell (Th2) cytokines has been implicated in some of the characteristic immune abnormalities associated with SS [6]. Among the associated immune deficits are:

•Decreased T cell responses to antigens and mitogens

•Impaired cell-mediated cytotoxicity, including natural killer (NK) cell activity

•Increased levels of serum immunoglobulin E (IgE)

•Peripheral eosinophilia

•Impaired dendritic cell functions

Impaired immunity in patients with SS has been attributed, at least partially, to the increased production of Th2 cytokines by the malignant clone; these cytokines antagonize Th1 immunity and lead to decreased production of interleukin (IL)-12 and interferon (IFN) gamma, which are critical for anti-tumor immunity [7,8]. Activated T cells of patients with SS may also produce increased IL-10 and transforming growth factor (TGF)-beta, which can further impair cell-mediated immunity. In some cases, the malignant T cells can behave like regulatory T cells by manifesting FOXP3, increased CTLA4 expression, and enhanced production of IL-10 or TGF-beta, leading to suppression of normal T cell function [9,10]. Increased production of IL-31 by the malignant T cells has been associated with worsening pruritus among patients with SS [11].

Abnormalities of immune checkpoint molecules also contribute to depressed Th1 immunity and impaired cell-mediated immunity. Increased expression of programmed death domain 1 (PD-1) and other immune checkpoint molecules inhibit cytotoxic T cell function; anti-PD-1 monoclonal antibodies have been used to treat SS and mycosis fungoides (MF) [12]. TIGIT (T cell immunoreceptor with immunoglobulin and ITIM domain) is another checkpoint molecule that can suppress cellular immune functions in this setting [13]; TIGIT may be highly expressed by the malignant T cells and on CD8 T cells in the setting of SS, and high levels of TIGIT expression are associated with poor prognosis. The malignant T cells fail to normally upregulate CD40 ligand expression during activation, which may lead to impaired activation and differentiation of dendritic cells (DCs), which constitutively express CD40. A decline in the number and function of DCs parallels an increase in the circulating burden of malignant T cells.

●Apoptosis – Defects in apoptosis are thought to lead to accumulation of the malignant T cells in vivo. Defects of proapoptotic pathways have been identified, including decreased expression of Fas (CD95), which may be due to hypermethylation of the FAS promoter [14,15]; treatment with methotrexate, IFN alpha, or IFN gamma can upregulate CD95 expression, thereby rendering cells more susceptible to Fas ligand-mediated death. Other apoptotic defects include increased expression of the apoptosis inhibitor cFLIP and tumor cell loss of TRAIL-receptor 2, leading to resistance to TRAIL.

●Cytogenetic/molecular abnormalities – Molecular abnormalities among individuals with SS/MF are heterogeneous. However, the pathophysiology appears to involve an intricate network of aberrant signaling through the T cell receptor, NFkB, CCR4/MAPK, and JAK/STAT pathways; aberrant tumor microenvironment, altered cell migration; and abnormal DNA damage response and chromatin structure [16]. Cytogenetic studies have revealed translocations and deletions in SS (eg, 1p, 10q, 14q, 15q) in conjunction with clonal evolution and chromosomal instability [17,18].

Upregulation of GATA3 and decreased expression of STAT4 transcription factors may account for the Th2 phenotype in many cases of SS [10]. TP53 alterations appear to be the most common molecular abnormality in SS, but mutations and/or deletions in ZEB1, RB1, PTEN, DNMT3A, and CDKN1B and gain-of-function mutations in the JAK-STAT pathway are often found [19-21]. T-plastin, an actin-bundling protein that is not normally expressed in hematopoietic cells, is expressed by malignant T cells of SS; this feature can facilitate identification of the lymphoma cells [22]. Somatically acquired single-nucleotide variants observed in cases of MF/SS most frequently involve C > T transitions [19,23-25]; this mutational signature at CpG sites, which is uncommon in other hematological cancers, is associated with exposure to ultraviolet (UV) light.

Gene expression profiles, microRNA profiling, and cell marker studies suggest that MF and SS may be distinct entities with differing pathogenesis [5,26-28]. Comparative genomic hybridization has identified chromosomal abnormalities that occur in both MF and SS and abnormalities that are present in either MF or SS, but not both [29-32]. Malignant T cells of SS express CD27, CCR7, L-selectin, and CCR4, which are markers of central memory T cells; by contrast, the malignant T cells of MF fail to express CCR7, L-selectin, and CD27, but do express high levels of CCR4 and CLA, which is typical of skin-resident effector T cells [5]. Hypotheses regarding the pathogenesis of MF are discussed separately. (See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides", section on 'Pathogenesis'.)

A small percentage of cases is associated with human T-lymphotropic viruses type 1 and 2 (HTLV-I/II) [33-35], which are endemic in southern Japan, Caribbean islands, the Middle East, and other locations. (See "Clinical manifestations, pathologic features, and diagnosis of adult T cell leukemia-lymphoma".)

EPIDEMIOLOGY — The incidence of SS is not well-defined. SS is an acquired disorder; it is not reported in family clusters.

In the United States, analysis of the Surveillance, Epidemiology and End Results (SEER) data from 2001 to 2005 estimated the incidence of cutaneous T cell lymphomas at 0.8 cases per million persons per year, with a male:female ratio of 2.11 [36]. Similarly, the Cancer Registry of Norway from 2000 to 2003 estimated the incidence at approximately 0.9 cases per million persons per year [37].

SS is a disease of older adults with very few cases reported among patients <30 years old [38]. In the United States, the incidence appears higher among White Americans (0.36 cases per million persons per year) than among Black Americans (0.04 cases per million persons per year). However, a retrospective single-center study of 393 patients with SS from Georgia (a state in which nearly one-third of residents self-identify as African American) reported that 55 percent of patients were White American and 43 percent were African American [39].

SS is not inherited, and siblings and children of patients with SS do not have an increased risk of developing SS. A relationship of chemical exposure with mycosis fungoides (MF)/SS has been reported [40], and a study of MF/SS in Canada reported geographic clustering of cases in industrial areas [41].

CLINICAL MANIFESTATIONS — Patients with SS generally present with diffuse skin involvement, rather than evolving through patches and plaques to erythroderma. Adenopathy and pruritus are common and can profoundly affect quality of life [42]. Patients who evolve from typical mycosis fungoides (MF) lesions to erythroderma and a leukemic phase of blood involvement (eMF), may show the same manifestations as SS.  

Skin

●Cutaneous lesions – Patients with SS commonly present with widespread erythema (picture 1), which can be finely scaly, indurated, or even resemble livedo reticularis. The severity of erythema and the body surface area (BSA) involved may wax and wane, but at some point in the disease course, the skin involvement should cover >80 percent BSA to meet the definition of erythroderma from the International Society for Cutaneous Lymphoma (ISCL), United States Cutaneous Lymphoma Consortium (USCLC), and European Organization of Research and Treatment of Cancer (EORTC) [43]. (See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides", section on 'Skin lesions'.)

Other skin lesions that may be present with SS include:

•Keratosis pilaris-like lesions – Inflamed follicular-based papules or scale may signal follicular involvement (picture 1).

•Alopecia – Alopecia is common and can present as reduced hair density diffusely over the scalp and body or as patches of alopecia (picture 2A-B).

•Ectropion – An outward turning of the lower eyelid with increased exposure of the ocular surface and sensitive mucous membranes of the inner lid can develop because of the tautness and induration in the skin and may be associated with disruption of normal tear drainage patterns.

•Keratoderma – Thickened retention of keratin on the palms and soles (keratoderma) is a common finding and can help to distinguish SS from other causes of erythroderma, but it can occasionally make the distinction between SS and pityriasis rubra pilaris difficult (picture 3).

•Hypertrophic nails – Nails may become hypertrophic due to posterior nail fold involvement.

•Leonine facies – Infiltration (thickening) of the facial skin leading to prominent convexities and furrowed creases.

•Erosions and superinfection – Patients are often colonized with Staphylococcus aureus, and erosions and superinfection from constant scratching are common.

•Focal areas of scaling – Tinea corporis is common; a potassium hydroxide preparation performed where scaly patches predominate can aid in diagnosis. (See "Approach to the patient with annular skin lesions", section on 'Diagnostic tests'.)

•Lichenification – Diffuse lichenification, characterized as thickened skin with increased skin lines, may occur with long-standing disease, chronic pruritus, and scratching. Fissures are common.

●Pruritus – Pruritus is the most common and debilitating symptom of patients with SS [44]. Pruritus may exacerbate sleep dysfunction, anxiety, and depression. The degree of pruritus is not necessarily related to the degree of blood involvement or the extent and depth of erythema. Pruritus may be triggered by a variety of mediators related to the tumor microenvironment including interleukins (IL) characteristic of the Th2 cytokine profile or IL-31 [11,45]. Therapy that ameliorates the extent and severity of both skin and blood involvement improves pruritus.

Management of pruritus in MF or SS with skin-directed and systemic antipruritic agents is described separately. (See "Treatment of early stage (IA to IIA) mycosis fungoides".)

Extracutaneous

●Lymphadenopathy – Peripheral lymphadenopathy is common in SS, but it may go undetected by physical examination, especially in patients with obesity. Imaging is required to determine enlargement of both peripheral and central nodes. Lymph nodes >1.5 cm in long diameter (LDi) are considered abnormal [46].

●Viscera – The incidence of visceral involvement in patients with MF and SS is poorly defined.

At present, solid organ involvement in SS is defined by imaging and is only infrequently reported. However, early studies that performed liver and bone marrow biopsies at initial staging found a high incidence (6/18) of visceral involvement in patients with erythroderma; blood involvement was not specified [47].

The incidence of bone marrow involvement is largely unknown, since bone marrow biopsies are not routinely performed unless there are unexplained abnormal hematologic parameters.

Associated conditions

●Infections – Patients with SS are at increased risk for infection due to an underlying immune dysfunction and physical factors.

Patients with SS have impaired cellular and humoral immunity and increased severity of viral (eg, herpes), dermatophyte, and bacterial infections, especially S. aureus [48]. In one study, most patients with SS had colonization of skin or nares with S. aureus [49]. With concomitant pruritus, there are frequent excoriations and potential for bacteremia.

It is important to remember that body temperature can be normal in the face of bacteremia, due to the loss of body heat through dilated skin vasculature and a disrupted skin barrier. There should be a low threshold to check blood cultures in patients with new constitutional symptoms, particularly if they have either a high white blood cell count or low neutrophil count or if the patient has a port, indwelling line, or is undergoing photopheresis and to consider use of antibiotics while awaiting blood culture results. Patients treated with antibiotics to cover staphylococci may also show improvement in their skin lesions.

Patients taking alemtuzumab, a particularly effective treatment for SS, are prone to bacterial, fungal, and viral skin infections, especially cytomegalovirus (CMV) [50]. There have also been reports of progressive multifocal leukoencephalopathy (PML) due to polyomavirus in patients with SS in the absence of immunosuppressive therapy [51] and at least one therapy for MF/SS (brentuximab) has been associated with PML [52].

Management of infections in patients with SS is discussed separately. (See "Treatment of Sézary syndrome", section on 'Prevention of infections'.)

●Second malignancies – There is an increased incidence of second cancers (especially other lymphomas) in patients with MF or SS [53-55]. Whether this is related to an inherent impairment of immune surveillance or prior treatments is not clear. There is also an increased incidence of melanoma and squamous cell carcinoma.

As an example, an analysis of the US Surveillance, Epidemiology, and End Results Program (SEER) registry reported 197 second malignancies among 1798 patients with an initial diagnosis of MF or SS [53]. When compared with age-, sex-, and race-matched persons from the general population, patients with MF or SS had a significantly higher rate of the following (as expressed using the standardized incidence ratio [SIR]):

•Hodgkin lymphoma (SIR 17.1 [95% CI 6.3-37.3])

•Non-Hodgkin lymphoma (SIR 5.1 [95% CI 3.3-7.4])

•Melanoma (SIR 2.6 [95% CI 1.3-4.8])

•Urinary cancer (SIR 1.7 [95% CI 1.1-2.7])

EVALUATION — SS should be considered in any patient presenting with erythroderma, regardless of underlying or preceding skin conditions that can cause erythroderma. It should also be considered in any patient with a persistent erythematous skin rash unresponsive to topical steroids and accompanied by pronounced pruritus.

Routine blood work — Complete blood count (CBC) with differential, complete metabolic panel, liver function tests, lactate dehydrogenase (LDH). All patients with mycosis fungoides (MF) or SS should be tested for human T-lymphotrophic virus (HTLV)-I/II to evaluate for adult T cell leukemia-lymphoma (ATLL) [43]; this is especially important in patients with CD8+ or CD25+ infiltrates or from endemic areas [4,56].

In circumstances where immunosuppressive therapy is indicated, testing for human immuno deficiency virus (HIV), hepatitis B and C, and tuberculosis should be performed.

Skin biopsy — The initial evaluation should include a biopsy of involved skin with assessment of the morphology, immunophenotype, and TCR (T cell receptor gene) clonality of cellular infiltrates.

It is always best to biopsy the most indurated area of skin. If more than one type of lesion (eg, confluent patchy erythema, follicular-based papules, alopecia, or livedo-like erythema) is present, a biopsy of each representative type of lesion should be performed. This helps to determine both the extent of involvement and identifies certain prognostic factors, such as folliculotropism. A punch biopsy should be ≥4 mm. Clonality studies can be performed on formalin-fixed tissue, but the yield is greater when the tissue is collected on saline and immediately submitted for preparation/assessment.

Because the skin infiltrate in SS is generally much less dense than that of plaque stage MF, it is important to minimize interventions that could affect the infiltrate prior to taking the biopsy, including topical or systemic corticosteroids and any other immunosuppressive medication. In general, these agents, especially topical steroids, should be discontinued for at least 14 days prior to skin biopsy to help maximize the potential for a firm diagnosis.

Lymph node assessment

●Imaging – Positron emission tomography/computed tomography (PET/CT) or CT of neck, chest, abdomen, and pelvis is recommended to determine whether there are any abnormal peripheral or central nodes.

Both imaging methods allow tracking the size and number of lymph nodes judged to be of concern (ie, long diameter [LDi] >1.5 cm) [43], but PET/CT offers additional information through metabolic scoring.

●Biopsy of representative lymph node

•Choice of lymph node for biopsy – The choice of lymph node for biopsy is of great importance as the pathologic assessment will be applied to all abnormal lymph nodes. The preferred lymph node for biopsy is the largest accessible peripheral node draining an area of involved skin, the one with the most concerning morphological features on imaging, and if PET data are available, the one that shows the highest standardized uptake value (SUV) [43].

•Choice of type of lymph node biopsy – An excisional biopsy is preferred since lymph node staging in MF and SS is dependent on pathologic architectural changes. A core biopsy may suffice if sufficient tissue is available for all standard and ancillary assessments [43]. Biopsy permits not only staging but evaluation for other causes of node enlargement.

•Methods of assessment of lymph node – Evaluation by light microscopy and immunophenotyping, the latter by either immunohistochemistry or by flow cytometry, is necessary. TCR gene rearrangement clonality is not required but, if performed, is expected to match that of skin.

Viscera assessment — As with lymph node assessment, imaging is key to determining visceral involvement and should be based on Lugano criteria [46].

Either PET/CT or contrast-enhanced CT of neck, chest, abdomen, and pelvis should be performed. Biopsy of potential visceral involvement would be indicated if using CT scan for assessment, but if using PET/CT, one could use metabolic assessment per Lugano guidelines.  

Bone marrow (BM) examination is currently only required for unexplained hematologic abnormalities. If performed to assess SS, involvement should be based on core biopsy, not by imaging [43].

Blood assessment — There are many ways to assess blood involvement by lymphoma in SS. The methods depend on what is available at the institution/practice and the most recent advances in this area. There is no current algorithm for using all methods collectively.

●Cytological evaluation/Sezary cells – The peripheral blood of patients with SS is characterized by a large number of atypical mononuclear cells with moderately to highly grooved (ie, cerebriform) nuclei and a high nuclear to cytoplasmic ratio, termed Sézary cells (picture 4 and picture 5). Sézary cells are best demonstrated on a buffy coat preparation of the peripheral blood, also called a "Sézary cell" prep. Typical Sézary cells are larger than a normal resting lymphocyte, and approximate the size of a normal monocyte [57]. However, a subset of patients demonstrates a smaller variant of Sézary cells that are approximately the size of a resting lymphocyte.

The cerebriform nuclear morphology that characterizes Sézary cells is not specific for neoplastic T cells [57]. Small numbers of Sézary-like cells can be observed in the peripheral blood of healthy individuals or those with other benign or malignant diseases [2].

Sézary cell counts are subjective and there is considerable inter-observer variability. However, they may be useful in clinical practice to help track blood involvement in patients who are CD8+ or negative for both CD4 and CD8 in the skin or blood. Reliability is increased if the assessment is performed by the same cytopathologist(s) each time. Sézary cell counts are usually reported as a percentage of lymphocytes examined; the absolute count is determined by multiplying the percentage by the absolute lymphocyte count of the CBC.

●Flow cytometry – Flow cytometry is objective, quantifiable, and reproducible and the preferred method for the determination of blood involvement, staging, monitoring of patients on therapy, and determining response in clinical trials of MF and SS [43,58,59].

Although there are no current specific guidelines, a single effective, validated and universally accepted method and biomarker set to identify and track the blood tumor burden by flow cytometry is needed for MF and SS. One group of international experts in hematopathology has recommended a set of gating principles to standardize the methodology of flow cytometry and a set of at least 6 standard markers [60]. The EuroFlow consortium has developed a sensitive and standardized multiparameter flow cytometry with a gating strategy based on whole phenotypic parameters [61]. Many new markers have been suggested but in the absence of a standardized and uniformly accepted approach, the determination of blood tumor involvement by absolute counts of CD4+, CD26- and/or CD4+, CD7- subsets remains [43].

●TCR gene rearrangement clonality – TCR gene rearrangement to assess clonality of circulating lymphocytes is important to confirm the relationship of abnormal cells in peripheral blood to the skin lymphoma. The TCR clone should generally match that in the skin, recognizing that more than one clonal rearrangement may be found. Due to plasticity of the neoplastic cells over time or with treatment, different clones may be selected as the major component in blood, or a new clone may emerge over the course of the patient’s illness. An international study observed that clonality-discordance between skin and blood appeared to be associated with improved survival [62].

PATHOLOGY

Skin pathology — A diagnostic skin biopsy may be difficult to make in patients with SS, potentially requiring multiple biopsies and even the added input of blood flow cytometry and lymph node biopsy to confirm the diagnosis of SS.

●Light microscopic findings – A biopsy of representative erythrodermic skin with routine hematoxylin and eosin staining technique is rarely sufficient to diagnose mycosis fungoides (MF).

Generally, there are atypical lymphocytes in a sparse dermal infiltrate along with epidermotropism (movement of the atypical lymphocytes into the epidermis), which is suggestive, but not diagnostic, of MF; epidermotropism may be completely absent in biopsies from SS patients. The more diagnostic intra-epidermal aggregates of atypical cells (ie, Pautrier microabscesses) may or may not be present. Significant edema and a nonspecific infiltrate of inflammatory T cells may predominate, making diagnosis more difficult [57].

Histologic findings in affected skin in SS and MF are described in more detail separately. (See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides", section on 'Skin biopsy'.)

●Immunophenotyping – The immunophenotype of the tumor cells (typically CD3+, CD4+) is usually established by immunohistochemistry using formalin-fixed tissue. The panel of markers typically includes at least CD3, CD5, CD4, CD8, CD7, CD30, and a B cell marker (eg, CD20), but it would be expanded depending on the differential suggested by the light microscopic findings.

●Clonality – Clonality of TCR (T cell receptor gene) is consistent with, but not diagnostic of MF and SS, because T cell clones may be present in skin in many nonmalignant skin disorders [63-65].

Polymerase chain reaction (PCR) is sensitive for detecting clonality in MF/SS, but its utility depends on the specific technique (Biomed-2 primer sets/protocols are the preferred methods [43]) and the presence of enough tumor cells in the tissue submitted for testing. Thus, the size and type of skin lesion(s) selected for biopsy is key. Initial clonality testing typically addresses potential TCR gamma/delta rearrangements. However, if these studies are negative, they should be followed by testing for TCR alpha/beta rearrangement.

Next-generation sequencing (NGS)/high-throughput sequencing (HTS) of TCR beta and gamma third complementarity determining regions is more sensitive than PCR for detecting clones within skin and blood and can better discriminate between MF/SS and a benign inflammatory process [66].

If a clonality study is negative or indeterminate using formalin-fixed tissue, another skin biopsy collected on saline may have greater yield. It is not unusual to identify more than one clone in tissue and/or blood, which may reflect the plasticity of the aberrant lymphocytes and/or clonal evolution in an individual.

In situations where the diagnosis by skin biopsy is still equivocal, the diagnosis of SS may be made by blood studies or nodal biopsy, described below. (See 'Additional methods to establish diagnosis of SS' below.)

Lymph node pathology — In contrast to other types of primary cutaneous lymphoma, enlarged lymph nodes in MF and SS may demonstrate reactive changes, dermatopathic features, or frank lymphoma.

The amount and/or size of the abnormal lymphocytes and the degree of effacement of the normal lymph node architecture are used to give a grade of involvement, using either of the two different scoring systems (NCI and Dutch) [2]. An NCI grade LN4 and a Dutch grade 3/4 are both indicative of nodal lymphoma (N3 involvement). TCR clonality testing would be expected to find a positive clone that matches that in skin lesions. Further details of grading are discussed separately. (See "Staging and prognosis of mycosis fungoides and Sézary syndrome".)

The importance of the choice of node for biopsy cannot be overstated. In one report of 22 patients with SS and a node >1.5 cm in diameter by CT, all 12 node biopsies that met criteria for N3 were of the largest node (or equivalent in size to the largest node); the majority of biopsies of smaller nodes had N1 or N2 characterization [67]. The importance of biopsying abnormal nodes is illustrated by the finding that 3 of 22 patients with SS had findings of tuberculosis, adenocarcinoma, or diffuse large B cell lymphoma.

Viscera pathology — Patients with imaging abnormalities suggestive of MF/SS should have pathologic documentation, or they should be judged as Mx. If abnormalities were discovered on PET/CT, metabolic scoring can be used to suggest involvement and a means of tracking treatment response, as per Lugano guidelines [46].

Patients with SS in whom a bone marrow (BM) core biopsy shows nodular, diffuse, or interstitial involvement (>5 percent of BM cellularity) and where the immunophenotype and molecular findings are consistent with those of the skin biopsy are considered to have marrow involvement and are classified as M1A [43].

DIAGNOSIS — The diagnosis of SS is based upon the extent and type of skin involvement (erythroderma), a pathologic evaluation of the skin, and peripheral blood findings, interpreted within the clinical context.

●Skin – The skin biopsy may be only suggestive of MF/SS on light microscopic examination, but the pertinent immunophenotyping studies and a positive TCR rearrangement demonstrating clonality can be used to confirm the diagnosis. (See 'Skin pathology' above.)

In situations where the diagnosis by skin biopsy is still equivocal, the diagnosis may be made by blood studies or nodal biopsy. Immunophenotype, molecular biomarkers, mutations in DNA epigenetic enzymes, and cytogenetics may be useful for differentiating SS from other erythrodermic conditions.

For patients in whom the skin biopsy is not diagnostic for mycosis fungoides (MF)/SS, alternative diagnostic methods are described below. (See 'Additional methods to establish diagnosis of SS' below.)

●Blood – A diagnosis of SS requires a significant level of blood involvement that should reach the B2 staging characterization and a positive TCR clone in the blood that matches the skin. (See 'Staging' below.)

There are several methods to quantitate blood involvement:

•The ISCL/USCLC/EORTC consortium currently recommends using absolute counts of CD4+CD7- and CD4+CD26 lymphocytes to determine B staging and for tracking purposes in MF/SS [43]. The absolute number may be calculated from the percentage of the aberrant lymphocytes (from flow cytometry) x the absolute lymphocyte count (from the complete blood count [CBC]).

•Sézary cell counts may also be used, with the calculation based on percentage of Sézary cells x absolute lymphocyte count (from the CBC).

Diagnostic criteria — Consensus criteria for the classification as SS requires each of the following three criteria [2,43]:

●Skin – One of the following:

Biopsy is diagnostic of MF/SS

or

Skin biopsy is compatible/suggestive of MF/SS plus:

•Biopsy of enlarged lymph node confirming MF/SS

or

•Significant aberrant lymphocyte population in blood with positive TCR clone matching that in skin

●Erythroderma – Erythema covering ≥80 percent of body surface area.

●Leukemic blood tumor burden – Both of the following:

•B2 blood involvement – To characterize blood involvement in SS, it is important to define the levels of aberrant lymphocytes integral to B staging [43]. B0 is currently defined as <250/microL Sézary cell count, or CD4+CD26- or CD4+CD7- lymphocytes. B2 blood involvement, typically seen with untreated SS, is currently defined as >1000/microL of Sézary cells or CD4+CD26- or CD4+CD7- lymphocytes. B1 is defined as not meeting the criteria for B0 or B2.

For patients with lymphopenia (<1000 lymphocytes/microL), it is difficult to use absolute counts of aberrant lymphocyte subsets to establish B2 without underestimating the severity of the blood tumor burden. In the face of lymphopenia, the percentage of the aberrant lymphocyte subsets may have greater relevance [43]. The ISCL previously reported on B2 assignment based on 40 percent CD4+CD7- and 30 percent of CD4+CD26- cells [59], but the specificity of the latter percentages for lymphoma has come into question. In one report, >40 percent CD4+CD7- cells were found in 54 percent of patients with SS but in none with erythrodermic inflammatory dermatoses (EID; sensitivity 54 percent, specificity 100 percent), and >30 percent CD4+CD26- cells were found in 86 percent of patients with SS but in 53 percent of patients with EID (sensitivity 86 percent, specificity 47 percent). If the CD4+CD26- threshold was raised to >80 percent, then this was seen in 66 percent of SS patients and none of the EID patients [60].

•TCR clonality – A clonal TCR rearrangement in blood that matches that in skin. Abnormal TCR clones in blood that do not match skin can be considered unrelated to the process in the skin and may be related to age.

Designation as T4 (erythroderma) plus B2 designation in the tumor-node-metastasis-blood (TNMB) classification system fulfills the criteria for SS. There may also be cases where a large population of abnormal lymphocytes in the blood are not represented by these specific CD4+CD7- and CD4+CD26- subsets and that could also represent B2 involvement of SS.  

If the work-up is inconclusive, but the diagnosis of SS is still suspected, the patient should continue to be re-evaluated over time, as those originally presenting with MF may evolve to SS. In one study with a median follow-up of 1.6 years (range, 0.5 to 9 years), 6 of 31 erythrodermic MF patients (eMF) with B1 blood staging evolved toward SS in a median of 1.2 years (range, 0.5 to 2.5 years), all of them expressing blood biomarkers [68].

Additional methods to establish diagnosis of SS — Biopsies of patch lesions, like erythroderma, may not meet the pathologic diagnostic criteria for MF based on microscopy, immunophenotyping, and molecular studies. When the skin biopsy does not provide a firm diagnosis, alternative methods may be used to aid the diagnosis of SS/MF; alternate methods include a diagnostic algorithm, evaluation of other involved tissues, and/or adjunctive studies to differentiate SS from other erythrodermic conditions, as follows.

●Pathologic algorithm – An algorithm developed for the diagnosis of early MF may also be useful in SS [69]. Key pathological findings of this algorithm include the following criteria; four points are needed for a diagnosis of MF/SS:

•Clinical – Persistent and/or progressive patches/thin plaques with one of the following (1 point) or two of the following (2 points):

-Variation in size/shape of lesions

-Non-sun exposed areas

-Poikiloderma

•Histopathological – Superficial lymphoid infiltrate with 1 point for one criterion and 2 points for both criteria:

-Epidermotropism without spongiosis

-Lymphoid atypia

•Molecular/biological – Clonal TCR gene rearrangement (1 point).

•Immunopathologic – Loss of mature T cell antigens (<10 percent CD7+ T cells or <50 percent CD2+CD3+ and/or CD5+ T cells) or epidermal/dermal discordance of CD2, CD3, CD5, or CD7 (1 point maximum).

●Analysis of other involved tissues – If the findings on skin biopsy are only suggestive or inadequate for the diagnosis of MF or SS, evaluation of the peripheral blood with flow cytometry and clonality studies (with or without Sézary cell prep) can help to confirm the diagnosis. If imaging demonstrates nodal enlargement, diagnosis may also be forthcoming by biopsy of a representative abnormal lymph node.

●Additional studies to differentiate erythrodermic inflammatory dermatoses from SS

•Studies have reported that the level of KIR3DL2, which is not present on normal CD4+ cells, represents the most sensitive diagnostic criterion of SS when compared with all other available biological criteria, and that an eosinophil cell count >700/microL and >85 percent CD3+KIR3DL2+ T cells at diagnosis were associated with a significantly reduced disease-specific survival [68]. KIR3DL2 immunostaining allowed the assessment of treatment efficiency and specificity toward tumor cells, detection of residual disease following treatment, and occurrence of relapse. High throughput sequencing may also be utilized to assess minimal residual disease.

•Altered expression of STAT4, TWIST1, and either DNM3 or PLS3 was reported to distinguish 98 percent of patients with SS from patients with EID with 100 percent specificity [17].

•Another study reported a progressive increase in the expression of the biomarkers KIR3DL2, TWIST, PLS3 (T-plastin), and NKp46 from B0 to B1 through B2, suggesting a spectrum of eMF up to SS [68].

•TP53 alterations appear to be the most common genetic mutation in SS [21]. Cytogenetic studies have revealed translocations and deletions in SS, especially 1p, 10q, 14q, and 15q, in conjunction with clonal evolution and chromosomal instability [17,18].

STAGING — Staging of MF/SS includes the nature, size, and amount of skin lesions; the extent and type of nodal and visceral involvement; and the blood tumor burden [43].

Although all patients with SS will likely have erythroderma (T4) at some point, the T stage may change to T2 as the skin involvement waxes and wanes; this would not change the designation of SS. Enlarged lymph nodes without a biopsy documentation of lymphomatous involvement should be classified as Nx. Abnormalities of viscera in which neither imaging nor biopsy have established involvement with lymphoma should be defined as Mx for staging purposes. A separate classification of visceral disease in SS and MF has been developed specifically with SS in mind with M1A indicating BM involvement alone and M1B indicating other visceral organs involved.

Determination of blood involvement is described above. (See 'Diagnostic criteria' above.)

Details of staging are discussed separately. (See "Staging and prognosis of mycosis fungoides and Sézary syndrome".)

DIFFERENTIAL DIAGNOSIS — SS typically presents with generalized erythroderma and blood involvement by the malignant T cells (Sézary cells). Other cutaneous findings may be present that help to distinguish SS from benign inflammatory dermatoses and secondary lymphomas. (See 'Additional methods to establish diagnosis of SS' above.)

The differential diagnosis includes erythrodermic mycosis fungoides (eMF), other primary cutaneous disorders that present with erythroderma, drug eruptions, and other lymphoproliferative or hematologic malignancies that have circulating malignant T cells.

Mycosis fungoides — Mycosis fungoides (MF) and SS share many pathophysiologic and clinical features and therapeutic approaches.

Patients with eMF have varying degrees of blood involvement. The diagnosis of SS specifically requires that patients either meet the criteria of MF/SS in the skin or that the skin biopsy is suggestive of MF/SS and other parameters (ie, blood or nodal involvement) cement the diagnosis. (See 'Diagnostic criteria' above.)

For SS, patients should also meet the criteria of B2 involvement. (See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides".)

Primary skin disorders — Non-malignant dermatoses can resemble SS clinically and pathologically, but cytogenetic/molecular features can be helpful to distinguish them. (See 'Pathophysiology' above.)

Psoriasis — Although less common since the advent of biologic agents, psoriatic erythroderma still occurs and given the common nature of psoriasis, erythrodermic MF/SS may also occur in patients with psoriasis.

Clinical clues that may help to distinguish psoriasis from SS/MF include:

●Nails may show the typical pitting or oil spots (not seen in MF/SS)

●Relative sparing of the face

●Scattered pustules and distribution of plaques over joints or in areas of trauma

Histologically, psoriasis will typically show psoriasiform epidermal hyperplasia characterized by acanthosis with elongation of the rete ridges and a reactive, primarily perivascular CD4+ lymphocytic dermal infiltrate [70], all of which can be seen in MF/SS. However, typical neutrophil collections in the upper epidermis are not seen in MF/SS, unless there is impetiginization. The absence of both CD7 and CD5 expression on atypical-appearing lymphocytes and presence of folliculotropism are features of MF/SS and not typical of psoriasis.

TCR clonality can be seen with either psoriasis or MF/SS, and it is not diagnostic of MF/SS in the absence of other typical histological findings. Blood of patients with psoriasis will typically not have a significant population of abnormal lymphocytes. (See "Psoriasis: Epidemiology, clinical manifestations, and diagnosis", section on 'Erythrodermic psoriasis'.)

Pityriasis rubra pilaris — Like erythrodermic MF/SS, pityriasis rubra pilaris (PRP) can demonstrate widespread areas of erythema and scale, including the scalp; however, in PRP there are usually "islands" of sparing [71,72].

Follicular hyperkeratosis with a "nutmeg grater"-like texture can mimic follicular MF/SS but is in an atypical distribution (ie, over the dorsum of the hands, knees, and elbows) with PRP. Nails may be thickened and dystrophic as with SS. Keratoderma may occur, but it is often a waxy orange-red color that is distinct from the keratoderma of MF/SS. Pruritus and burning are common symptoms. The histology of PRP typically displays a psoriasiform dermatitis with irregular hyperkeratosis, perivascular lymphohistiocytic infiltrate, alternating vertical and horizontal ortho and parakeratosis, and follicular plugging with shoulder parakeratosis. The biopsy would not be expected to show all the immunophenotypic features of MF, nor would the blood involvement typical of SS be present unless the entire picture is in fact representative of PRP-like MF/SS. (See "Pityriasis rubra pilaris: Pathogenesis, clinical manifestations, and diagnosis".)

Atopic dermatitis — Both atopic dermatitis and MF/SS can present with erythroderma. Given the frequency of atopic dermatitis in the general population, it is not uncommon for patients with MF/SS to have both disorders.

Lichenification, prurigo nodularis, and eyelid involvement are common in long-standing atopic dermatitis, but otherwise, there are no typical skin-associated findings that can help to distinguish atopic dermatitis versus MF/SS short of the presence of concomitant thick plaques, tumors, and/or keratoderma in MF/SS. Both eczema and MF/SS can be accompanied by eosinophilia in the blood and tissue, although it would be unlikely that patients with atopic dermatitis would meet the criteria for B2 staging of MF/SS in the blood. Lymphadenopathy may be seen in MF/SS and in patients with atopy and hyperIgE. On skin biopsy, atopic dermatitis has spongiosis as a primary finding, and this can be a helpful clue. Although spongiosis should not exclude MF/SS from consideration, the algorithm for patch stage MF specifically excludes significant spongiosis for point scoring of pathology [69]. (See 'Additional methods to establish diagnosis of SS' above.)

Finding a CD4+ infiltrate and a clonal TCR rearrangement does not exclude atopic dermatitis as a cause of the erythroderma. (See "Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis".)

One study suggested that specific immunoglobulin E (IgE) reactivity to common allergens is common in SS [73]. Conversely, another study reported that zero of nine patients with SS had any IgE reactivity to the >103 environmental and food allergens tested in a microarray analysis, but four of nine patients with SS and elevated IgE showed low reactivity to staphylococcal enterotoxins. All four patients with "pre-SS" (erythroderma, elevated total IgE and CD4+ skin infiltrate, but not otherwise meeting criteria for SS) and three of three of the atopic dermatitis controls had both high reactivity towards staphylococcal enterotoxin and multiple environmental and/or food allergens [74].

Skin reactions to various agents

●Contact dermatitis – Chronic contact dermatitis can mimic erythrodermic MF/SS. This can be a reaction to a topical application (eg, fragrance), exposure to an allergen that is in contact with widespread body areas (eg, fabric softener), systemic exposure to chemicals that are cross reactive with another agent of which the patient has prior contact allergy (eg, ingestion of cashews in someone with allergic reaction to poison ivy), or a generalized photoallergic dermatitis (eg, compositae).

Clinically, the distribution of the rash may help to direct one to a particular type of reaction. These patients do not typically have alopecia, nail changes, or keratoderma, such as can be seen with some cases of MF/SS. Histologic changes may be similar to those seen with eczema. Patch testing, which could help reveal the inciting agent, is impossible when the patient is erythrodermic. Systemic steroids may be needed to quiet the rash to a point that patch testing is possible. (See "Clinical features and diagnosis of allergic contact dermatitis".)

●Chronic actinic dermatitis – Chronic actinic dermatitis (formerly called persistent light reaction or actinic reticuloid) can present with erythroderma. To make this diagnosis, three criteria must be fulfilled [75]:

•Persistent eczematous eruption +/- papules and plaques, predominantly on exposed skin.

•Histologic findings compatible with chronic eczema, although changes suggestive of MF may be present.

•Reduction in minimal erythema dose to ultraviolet B on normal skin and possibly a change to longer wavelength ultraviolet light as well.

Chronic actinic dermatitis may follow photoallergy to topical agents, which then becomes more generalized and persistent. There may be some clinical clues as to the UV light relationship, such as sparing of finger webs, upper eyelids, behind the ears, and inside skin creases. Histologically, this can be very difficult to distinguish from MF and SS, although there is a tendency for the infiltrate to be more CD8+ than CD4+ [76]. In addition, there have been reports of up to 20 percent CD8+ Sézary cells in affected patients [77]. UVB phototesting is mandatory, as is patch and photopatch testing, all of which can be difficult in the face of an erythrodermic reaction. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Chronic actinic dermatitis'.)

●Scabies – Diffuse crusted scabies (formerly called "Norwegian" scabies) can mimic erythrodermic MF/SS clinically in its skin presentation, including the presence of dystrophic nails and intense pruritus. Histologic changes can be similar to eczema, except where one is fortunate enough to find signs of the mite, including the mite itself, eggs, or scybala (feces).

A scabies prep in multiple areas of the body is usually diagnostic, and a trial of antiscabietic medications can differentiate the two conditions. (See "Scabies: Epidemiology, clinical features, and diagnosis", section on 'Diagnosis'.)

●Drug eruption – Two types of drug eruptions can mimic SS:

•An erythrodermic reaction to a drug that may mimic SS clinically, but on histology typically shows a perivascular lymphohistiocytic infiltrate with eosinophils and a lichenoid vacuolar degeneration that is different from MF/SS.

•An MF/SS mimicker, both clinically and histologically.

Drugs should always be considered in the differential diagnosis of MF/SS, and an attempt should be made to stop potentially offending drugs and to avoid substitution with a similar class of drugs for at least two months to see if the rash will improve or resolve without other treatment. In addition, the biologic agents or immunosuppressive agents that are used to treat psoriasis, atopic dermatitis, and a variety of autoimmune disorders can induce a lymphoma, including one that mimics MF/SS. A trial off of the potential offending drug should be performed before initiating directed therapy for the lymphoma. (See "Drug eruptions".)

●Graft-versus-host disease (GVHD) – GVHD typically occurs in patients who have undergone an allogeneic hematopoietic cell transplantation, where immune competent cells from an allogeneic donor participate in an immune attack on the skin and other host tissues. GVHD rarely occurs after solid organ transplantation or in other settings where an immune-incompetent person receives an infusion of immune competent cells that result in a T cell targeted attack. Acute GVHD may be associated with a widespread erythematous rash or erythroderma. The skin biopsy may reveal dermal lymphocytes with varying degrees of dyskeratosis of epidermal cells. The clinical setting and the associated findings of lung, liver, ocular, and GI disease can usually help distinguish this condition from SS. (See "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease".)

Other lymphoproliferative or hematologic diseases — Erythroderma can be a nonspecific finding of an underlying systemic B or T cell lymphoma. The histologic findings are nonspecific. Imaging should be considered if the etiology is not clear, and if adenopathy is present, a representative lymph node should be biopsied. Any patient with erythroderma without a definitive diagnosis should be followed closely and repeat biopsies performed on skin or new, enlarged lymph nodes. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma".)

Adult T cell leukemia-lymphoma — Adult T cell leukemia-lymphoma (ATLL) can be difficult to distinguish from MF/SS. Both disorders share a similar skin and immunophenotypic picture, although ATLL has a more uniform, strong positivity for CD25. ATLL is much more likely to have disseminated extracutaneous disease with frequent lymphoma in the nodes, liver, bone, and central nervous system.

A key differentiating feature is the presence of HTLV-I/II in the malignant cells of ATLL, which can be determined by testing for the antibody in the blood. ATLL is common in Japan, the Caribbean, South America, and some areas of the Middle East. (See "Clinical manifestations, pathologic features, and diagnosis of adult T cell leukemia-lymphoma".)

T cell prolymphocytic leukemia — Both T cell prolymphocytic leukemia (T-PLL) and SS are T cell neoplasms that can involve the blood and skin. The morphology of the "cerebriform" (Sézary cell-like) variant seen in 5 percent of patients with T-PLL resembles the Sézary cells seen in SS. In such cases, SS can be distinguished from T-PLL by the immunophenotype; Sézary cells frequently lack expression for CD2, CD3, CD5, and/or CD7. In contrast, T-PLL cells have strong expression of CD52 and typically express CD2, CD3, and CD7. CD52 is also usually present on malignant T cells in SS and is the target for alemtuzumab. (See "Clinical manifestations, pathologic features, and diagnosis of T cell prolymphocytic leukemia".)

Hypereosinophilic syndrome — Erythroderma can be seen in patients with the idiopathic hypereosinophilic syndrome, some of whom have a clonal proliferation of T cells with increased production of Th2 cytokines, which may evolve into lymphoma [78-80]. Absence of CD4+CD26- subset and eosinophils >1500/microL in the blood of patients with lymphocytic-variant of hypereosinophilic syndrome (L-HES) is an important distinction between SS and L-HES [81]. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis".)

Idiopathic — A large percentage of erythrodermas may defy an exact diagnosis [82-85]. Many of these patients later turn out to have MF or SS, although at presentation they do not meet diagnostic criteria.

PROGNOSIS — Skin classification, stage of disease, elevated lactate dehydrogenase (LDH), advanced age and comorbidities, race, male sex, peripheral eosinophilia, large cell transformation, and folliculotropic MF have each been associated with poor prognosis and have been variably compiled into validated prognostic indices including the CTCL Severity Index (CTCL-SI), the Cutaneous Lymphoma International Prognostic Index (CLIPi), and the CLIC Prognostic Index [86]. (See "Staging and prognosis of mycosis fungoides and Sézary syndrome", section on 'Disease stage'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary cutaneous lymphoma".)

SUMMARY

●Description – Sézary syndrome (SS) and mycosis fungoides (MF) share pathologic findings, clinical features, and staging.

•SS presents de novo with erythroderma and a leukemic phase (circulating malignant T lymphocytes [Sézary cells]).

•A separate designation is given to those patients with MF that evolve into erythroderma with significant blood involvement (eMF).

●Pathogenesis – SS is thought to be derived from mature epidermotropic skin-homing CD4+ T cells or central memory T cells. Abnormalities of cell signaling, DNA repair, epigenetic regulators, apoptosis, and cell migration are prominent, but it is uncertain which are malignant drivers and/or secondary processes. Gene expression patterns may distinguish SS from MF. (See 'Pathophysiology' above.)

●Clinical presentation – Patients with SS commonly present with erythroderma (picture 1) with or without lymphadenopathy and pruritus. Other common clinical findings are alopecia, keratoderma, and less commonly involvement of other organs. (See 'Clinical manifestations' above.)

●Evaluation – SS should be suspected in a patient presenting with erythroderma or any patient with a persistent erythematous skin eruption and pruritus unresponsive to topical steroids.

The evaluation should include a biopsy(s) of involved skin; physical examination; imaging to evaluate potential extracutaneous disease and biopsy of suspected involvement; examination of blood with flow cytometry for an aberrant lymphocyte population; and analysis of T cell receptor (TCR) gene rearrangement in skin, blood, or other biopsy specimen to look for confluence of clonality. (See 'Evaluation' above.)

●Diagnosis

•Diagnostic criteria – SS is a clinicopathologic diagnosis that requires all of the following three criteria:

•Skin – One of the following:

Biopsy is diagnostic of MF/SS

or

Skin biopsy is compatible/suggestive of MF/SS plus:

-Biopsy of enlarged lymph node confirming MF/SS

or

-Significant aberrant lymphocyte population in blood with a TCR clone matching that in skin

•Erythroderma – Erythema covering ≥80 percent of body surface area.

•Leukemic blood tumor burden – Both of the following:

Abnormal lymphocytes in the blood sufficient to assign B2 classification, documented by at least one of the following:

-Increased CD4+ cells with an absolute count of >1000 cells/microL of CD4+CD26- or CD4+CD7- phenotype, by flow cytometry.

-Sézary cell count ≥1000 cells/microL.

-In the face of lymphopenia (<1000 lymphocytes/microL), increased CD4+CD7- cells ≥40 percent or CD4+CD26- cells ≥30 percent, by flow cytometry.

A clonal TCR rearrangement in the blood that matches that in skin.

•Additional diagnostic methods – Biopsies of patch lesions, like erythroderma, may not meet the diagnostic criteria for MF. When the skin biopsy does not provide a firm diagnosis, alternative methods may be used to aid the diagnosis of SS/MF, including a diagnostic pathologic algorithm, evaluation of other involved tissues, and/or adjunctive studies.

●Staging – Staging is discussed separately. (See "Staging and prognosis of mycosis fungoides and Sézary syndrome".)

●Differential diagnosis – The differential diagnosis includes erythrodermic MF, other primary cutaneous disorders that present with erythroderma, skin reactions to various agents, and other lymphoproliferative or hematologic malignancies that have circulating malignant T cells. (See 'Differential diagnosis' above.)