Sezary Syndrome

Background

This is a variant of a cutaneous T-cell lymphoma. It likely represents the leukemic phase of mycosis fungoides. The typical patient is an older adult with generalized erythroderma, pruritis (itching), and Sezary cells circulating in the peripheral blood. This Sezary cell is the malignant pleomorphic T cell seen in mycosis fungoides and has a convoluted nucleus. In the peripheral smear, these cells number greater than 1.0x10*9/l. Prior to sophisticated molecular techniques such as flow cytometry, a Sezary prep was performed by concentrating the white blood cells and doing a morphologic count. However, there are many inflammatory conditions which may elicit Sezary-like cells in the peripheral smear. In addition, a morphological appraisal of a peripheral smear slide is not a very sensitive technique.

A recent proposal for the minimum criteria for the diagnosis includes:

>5% circulating atypical mononuclear cells
AND
Evidence of peripheral blood T-cell clone by means of at least one of the following tests:

Very large Sezary cells (>14 microns)
Cytogenetic evidence of an abnormal clone
Loss of pan T-cell antigens by immunophenotyping
T-cell clone by Southern blot or PCR SSCP (Single strand conformational polyorphism) analysis

The Sezary syndrome is a late and ominous development in mycosis fungoides and may progress to extensive organ involvement. In general, the higher the Sezary count, the poorer the prognosis.

Since this is a later stage in the development of mycosis fungoides, the histopathological features are variable. There is usually irregular epidermal hyperplasia with spongiosis. Epidermotropism and Pautrier microabscesses may be present but up to one third of cases may have non-specific findings. In these cases, the pathologist must correlate the histopathologic findings with the clinical and molecular studies.

OUTLINE

Pathogenesis

Laboratory/Radiologic/Other Diagnostic Testing

Gross Appearance and Clinical Variants

Histopathological Features and Variants

Special Stains/
Immunohistochemistry/
Electron Microscopy

Differential Diagnosis

Prognosis

Treatment

Commonly Used Terms

Internet Links

PATHOGENESIS CHARACTERIZATION

BACTERIAL SUPERANTIGENS

Cutaneous colonization with staphylococci influences the disease activity of Sezary syndrome: a potential role for bacterial superantigens.

Tokura Y, Yagi H, Ohshima A, Kurokawa S, Wakita H, Yokote R, Shirahama S, Furukawa F, Takigawa M.

Department of Dermatology, Hamamatsu University School of Medicine, Japan.

Br J Dermatol 1995 Jul;133(1):6-12 Abstract quote

It has previously been shown that circulating Sezary cells respond in vitro to superantigenic staphylococcal exotoxins in a manner that is restricted by their V beta usage.

This study was conducted to examine whether cutaneous colonization with Staphylococcus aureus influences the activity of the skin lesions of Sezary syndrome, and whether S. aureus isolated from patients with Sezary syndrome stimulates circulating Sezary cells in vitro. Two patients with Sezary syndrome, whose skin was colonized with S. aureus, were treated with antibacterial agents, and the relation between the severity of the skin disease and the degree of S. aureus colonization was assessed. In addition, the patients' peripheral blood mononuclear cells were cultured in the presence of mitomycin C-treated S. aureus or superantigenic staphylococcal toxins.

The antibacterial treatment improved the skin disease, and eliminated S. aureus in both patients. In one patient, 98% of the peripheral blood mononuclear cells bore V alpha 2V beta 17 of the T-cell receptor, indicative of the presence of an extremely high percentage of circulating Sezary cells. The peripheral blood lymphocytes from this patient responded well in vitro to superantigenic staphylococcal enterotoxin (SE), but not to SEA or toxic shock syndrome toxin-1, or to mitomycin-treated S. aureus isolated from the same patient.

Cutaneous colonization by S. aureus influences the disease activity of CTCL, possibly by activation of Sezary cells by bacterial superantigenic exoproteins.

Association of erythrodermic cutaneous T-cell lymphoma, superantigen-positive Staphylococcus aureus, and oligoclonal T-cell receptor V beta gene expansion.

Jackow CM, Cather JC, Hearne V, Asano AT, Musser JM, Duvic M.

Department of Dermatology, University of Texas Medical School, Houston, USA.

Blood 1997 Jan 1;89(1):32-40 Abstract quote

Forty-two patients with cutaneous T-cell lymphoma, including 31 with exfoliative erythroderma or Sezary syndrome and 11 with mycosis fungoides, were studied for the occurrence of staphylococcal infection.

Thirty-two of 42 (76%) had a positive staphylococcal culture from skin or blood. One half of the patients with positive cultures grew Staphylococcus aureus. This group included 11 with Sezary syndrome and 5 with rapidly enlarging mycosis fungoides plaques or tumors. All of the S aureus carried enterotoxin genes. Surprisingly, 6 of 16 strains were the same toxic shock toxin-1 (TSST-1)-positive clone, designated electrophoretic type (ET)-41. Analysis of the T-cell receptor V beta repertoire in 14 CTCL patients found that only 4 had the expected monoclonal expansion of a specific V beta gene, whereas 10 had oligoclonal or polyclonal expansion of several V beta families. All patients with TSST-1+ S aureus had overexpansion of V beta Z in blood and/or skin lesions.

These studies show that S aureus containing superantigen enterotoxins are commonly found in patients with CTCL especially individuals with erythroderma where they could exacerbate and/or perpetuate stimulate chronic T-cell expansion and cutaneous inflammation. Attention to toxigenic S aureus in CTCL patients would be expected to improve the quality of care and outcome of this patient population.

CLINICAL VARIANTS/GROSS DISEASE CHARACTERIZATION

LYMPH NODES

Histologic assessment of lymph nodes in mycosis fungoides/Sezary syndrome (cutaneous T-cell lymphoma): clinical correlations and prognostic import of a new classification system.

Sausville EA, Worsham GF, Matthews MJ, Makuch RW, Fischmann AB, Schechter GP, Gazdar AF, Bunn PA Jr.

Hum Pathol 1985 Nov;16(11):1098-109 Abstract quote

Mycosis fungoides and the Sezary syndrome share common cutaneous histopathologic features, and this spectrum of malignant disease is referred to here as cutaneous T-cell lymphoma (CTCL).

A method (LN classification) for describing the histopathologic features of lymph nodes in CTCL is presented.

In this system, lymph node biopsy specimens are scored according to the number of atypical lymphoid cells in T-cell-dependent paracortical zones and the preservation or distortion of the lymph node architecture. Lymph node architecture is preserved in lymph nodes scored LN1 to LN3, and these nodes may have coexistent dermatopathic change. LN1 nodes have single infrequent atypical lymphocytes in paracortical T-cell regions. LN2 nodes have small clusters of paracortical atypical cells. LN3 nodes have large clusters of atypical cells. LN4 nodes are partially or totally effaced by atypical cells. This system was used to classify 96 lymph node biopsy specimens obtained within six months of the initial diagnosis of CTCL; no LN1 nodes, 37 LN2, 44 LN3, and 15 LN4 nodes were found. The LN class was significantly correlated with the extent of skin, blood, and visceral involvement, as well as with survival. Patients with LN2 lymph nodes have an estimated five-year survival of 70 per cent, while patients with LN3 and LN4 nodes have estimated five-year survivals of 30 and 15 per cent, respectively. The survival differences between the LN subgroups were all significant (P less than 0.05).

The LN classification system was clearly shown to be reproducible among experienced pathologists. The LN system for the histopathologic classification of lymph nodes in CTCL is of prognostic value and should be used to assess lymph node biopsies in patients with CTCL.

SKIN

Primary Sézary Syndrome Commonly Shows Low-Grade Cytologic Atypia and an Absence of Epidermotropism

A. Hafeez Diwan, MD, PhD, Victor G. Prieto, Marco Herling, MD, Madeleine Duvic, and Dan Jones, MD, PhD

Am J Clin Pathol 2005;123:510-515 Abstract quote

The dermatopathologic findings in cases of Sézary syndrome (SS) that arise in patients without a previous diagnosis of mycosis fungoides have not been well characterized. We evaluated the histologic findings in skin biopsy specimens from 31 patients with such primary SS and correlated them with clinical and hematologic parameters at the time of biopsy.

The most characteristic histologic finding was the presence of a dermal perivascular lymphoid infiltrate, usually with mild to moderate cytologic atypia and variable numbers of eosinophils; epidermotropism was absent or minimal in 19 cases (61%). Reactive epidermal changes such as spongiosis, parakeratosis, and acanthosis also were present frequently (27 [87%], 17 [55%], 19 [61%] cases, respectively). The number of eosinophils present in skin biopsy specimens correlated with the level of peripheral blood lymphocytosis.

In erythrodermic patients or patients with persistent xerosis and pruritus, it is important to carefully evaluate the degree of lymphocyte atypia in the dermal perivascular infiltrate and correlate with blood flow cytometric findings to diagnose primary SS. Many cases will lack the epidermotropism usually seen in mycosis fungoides.

SPECIAL STAINS/
IMMUNOPEROXIDASE/
OTHER CHARACTERIZATION

FLOW CYTOMETRY

The usefulness of CD26 in flow cytometric analysis of peripheral blood in Sézary syndrome.

Kelemen K, Guitart J, Kuzel TM, Goolsby CL, Peterson LC.

Department of Pathology, Northwestern Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Am J Clin Pathol. 2008 Jan;129(1):146-56. Abstract quote

The loss of CD26 expression was proposed to be a constant feature of circulating Sézary cells by flow cytometric immunophenotyping (FCIP), but the experience with CD26 is limited.

To establish its usefulness, CD26 results were correlated with morphologic, molecular, and immunophenotypic findings. Based on FCIP of 179 samples of peripheral blood, CD26 negativity was found in 59.3% of cases with Sézary syndrome (SS), 33.3% of mycosis fungoides (MF), 14.2% of benign dermatosis (BD), and no control cases.

In diagnostic subgroups of SS based on morphologic, molecular, and immunophenotypic criteria, the percentage of CD26- cases varied from 41.1% to 63.6%.

The specificity of a CD26- result was inferior to that of T-cell antigen loss in differentiating SS from MF and BD. CD26 offers lower diagnostic performance than previously suggested; however, in addition to the findings of major T-cell antigen loss, it could improve sensitivity of FCIP in patients with SS.

Association of change in clinical status and change in the percentage of the CD4+CD26- lymphocyte population in patients with Sezary syndrome.

Introcaso CE, Hess SD, Kamoun M, Ubriani R, Gelfand JM, Rook AH.

Department of Dermatology, The University of Pennsylvania, Philadelphia, Pennsylvania, USA.

J Am Acad Dermatol. 2005 Sep;53(3):428-34. Abstract quote

BACKGROUND: Because there are currently many effective therapies available for Sezary syndrome, close monitoring of disease progression is required in order for a clinician to know when to institute or change an intervention. It has been our clinical experience that changes in patients' CD4+CD26- T-cell populations of peripheral blood lymphocytes herald changes in their clinical status.

OBJECTIVE: Our purpose was to evaluate whether a change in patients' CD4+CD26- population of T cells presages a change in their clinical status. We also sought to investigate the association between a change in T-cell populations that are CD4+CD7-, CD8+, CD56+, and the CD4+/CD8+ T-cell ratio and a change in the patient's clinical status.

METHODS: We conducted a retrospective chart review analysis of 21 patients with Sezary syndrome who had flow cytometry, usually including levels of CD4+CD26-, CD4+CD7-, CD8+, CD56+, and CD4+/CD8+ ratios measured at two time periods, 12 weeks apart.

RESULTS: We report two cases in which changes in patients' clinical status were preceded by several weeks by a change in their CD4+CD26- level. We report weak associations between a decreasing CD4+CD26- T-cell population, a decreasing CD4+CD7- population, an increasing CD56+ population, and an improving clinical status. We also report stronger associations between both a decreasing CD8+ population and an increasing CD4+/CD8+ ratio and a worsening clinical status.

LIMITATIONS: The study was limited by the number of patients and the time period over which the study was conducted. In addition, varying configurations of CD4+CD26- T-cell populations were observed that may have limited the utility of this measurement.

CONCLUSIONS: Flow cytometry assays of patients' blood and, in particular, measurement of the CD4+CD26- population of lymphocytes over time may be a valuable tool for monitoring patients with Sezary syndrome. There exist varying configurations of CD26 T lymphocytes that may cause differences in standards for what is considered positive and negative between observers. Further prospective analysis involving larger groups of patients is recommended.

Flow cytometric DNA ploidy analysis of peripheral blood from patients with sezary syndrome: detection of aneuploid neoplastic T cells in the blood is associated with large cell transformation in tissue.

Wang S, Li N, Heald P, Fisk JM, Fadare O, Howe JG, McNiff JM, Smith BR.

Department of Laboratory Medicine and Pathology Yale University School of Medicine, Yale New Haven Hospital, New Haven, CT.

Am J Clin Pathol. 2004 Nov;122(5):774-82. Abstract quote

We reviewed and screened 219 cutaneous T-cell lymphoma (CTCL) cases for Sezary syndrome (SS); 63 met the criteria for SS. Of these, 17 (27%) demonstrated circulating aneuploid cells and 46 (73%) showed only euploid cells in blood samples.

Of 17 aneuploid cases, DNA ploidy study was essential for initial blood-based diagnosis of SS in 4 (24%) and important in monitoring minimal residual disease after treatment in 9 (53%) in which neoplastic T cells showed otherwise unremarkable or nonspecific flow cytometric immunophenotypic findings. Tissue biopsy slides (predominantly skin and lymph node) at the time of DNA ploidy studies were available for 47 of 63 cases. Of 14 cases with circulating aneuploid cells, 11 (79%) showed large cell transformation (LCT; 6 [43%]) or markedly increased large cells (ILC; 5 [36%]) in tissue, whereas only 10 (30%) of 33 euploid cases showed LCT (4 [12%]) or ILC (6 [18%]) (P < .01).

There was no significant difference in blood tumor burden, immunophenotype, or proliferation index between euploid and aneuploid groups or histologic high- and low-grade groups. DNA ploidy study by flow cytometry is important for blood-based diagnosis of SS and detection of minimal residual disease in aneuploid SS after treatment.

Detection of aneuploid neoplastic T cells in peripheral blood samples of patients with CTCL is associated with LCT in skin, lymph node, or other tissues.

Immunoperoxidase
J Am Acad Dermatol 1998;39:554-9.
J Invest Dermatol 1994;102:328-32.

Large expansion of CD4+ CD7- T cells but this can also be found in the peripheral blood of benign dermatoses

Furthermore, in patients with CD7 expression, the median 5 year survival was 67% versus 20% in CD7- patients.

Sezary syndrome: cutaneous immunoperoxidase double-labeling technique demonstrates CD4/CD8 ratio non-specificity.

Balfour EM, Glusac EJ, Heald P, Talley LL, Smoller BR.

Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, Department of Dermatology, Department of Pathology, Yale University, New Haven, CT, and Department of Dermatology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
J Cutan Pathol. 2003 Aug;30(7):437-442 Abstract quote
BACKGROUND: Sezary syndrome (SS) is an erythrodermic cutaneous T-cell lymphoma with a leukemic component. Biopsies from these patients may suggest erythrodermic mycosis fungoides or SS but most often are not diagnostic. Additional methods are therefore usually needed to diagnose SS. These include a peripheral blood morphological assessment, flow cytometry, and gene rearrangement studies. The Cutaneous Lymphoma Study Group of the European Organization for Research and Treatment of Cancer has proposed criteria for the diagnosis of SS based on peripheral blood analysis. These include an increased T-cell count with a CD4/CD8 ratio of >/=10, in conjunction with evidence of a T-cell clone in the blood (Willemze et al., Blood 1997; 90: 354-371).

METHODS: We have conducted a study designed to obtain CD4/CD8 ratios by immunoperoxidase staining of skin biopsies, as opposed to flow cytometry. Fourteen biopsies from eight patients with SS and 14 control biopsies were evaluated for CD4/CD8 ratio via double immunostaining.

RESULTS: A CD4/CD8 ratio of >10 : 1 was seen in 85% of SS biopsies and 43% of controls with horseradish peroxidase used as the CD4 antibody. With alkaline phosphotase used as the CD4 antibody, 54% of SS biopsies and 21% of control biopsies exhibited a >10 : 1 ratio. We demonstrate that double-labeling immunoperoxidase staining with antibodies to CD4 and CD8 on skin biopsies is not specific for SS. By comparing the CD4/CD8 ratios from skin biopsies in Sezary cases with those from biopsies in inflammatory dermatoses cases, we conclude that flow cytometry remains the most specific method for determining the CD4/CD8 ratios in patients with cutaneous eruptions. Although immunohistochemistry would be useful for laboratories with limited access to flow cytometry, we dismiss such a use, as CD4/CD8 ratios >/=10 were also found in 21-43% of non-Sezary cases examined.

CONCLUSIONS: We conclude that a CD4/CD8 ratio >10 : 1 on skin biopsy is not sufficiently specific to support a diagnosis of SS.

CD4+CD7� T cells compose the dominant T-cell clone in the peripheral blood of patients with S�zary syndrome

J Am Acad Dermatol 2001;44:456-61

Peripheral blood lymphocytes of patients with SS were analyzed by two-color flow cytometry using antibodies to the V region of the T cell receptor (TCR) in combination with an antibody to CD7. In addition, T cells were analyzed for TCR- gene rearrangement by polymerase chain reaction (PCR) techniques.

Results: Clonal T-cell expansion was detected in 7 patients with SS by immunostaining of the TCR V regions. PCR analysis confirmed the presence of dominant T cell clones. Double-immunostaining revealed that in each case cells of the clonal V TCR rearrangement homogeneously express the CD4+CD7� phenotype. Furthermore, CD4+CD7� cells express the CD15s antigen but lack expression of CD26 and CD49d.

Conclusion: Expansion of clonal T cells strongly correlates with the expansion of CD4+CD7� T cells in 7 tested patients with SS. This supports our model that a subset of late differentiated, normal CD4+CD7� memory T cells may represent the physiologic counterpart of S�zary cells. Monitoring of circulating T cells with the CD4+CD7�CD15s+CD26�CD49d� phenotype proved to be useful for the identification of clonal T cells in patients with SS.

Absence of CD26 Expression Is a Useful Marker for Diagnosis of T-Cell Lymphoma in Peripheral Blood

Dan Jones, MD, PhD, Nam H. Dang, MD, PhD, Madeleine Duvic, MD, LaBaron T. Washington, MD, and Yang O. Huh, MD

Am J Clin Pathol 2001;115:885-892 Abstract quote

We report flow cytometric characterization of surface CD26 expression in 271 peripheral blood samples from 154 patients evaluated for the presence of a T-cell lymphoproliferative disorder, primarily mycosis fungoides/S�zary syndrome (MF/SS). The presence of morphologically identifiable tumor cells on peripheral blood smears was the criterion for lymphomatous involvement.

In 66 of 69 samples from 28 patients, we identified an abnormal CD26�/dim T-cell population that was distinct from the variable CD26 expression seen in normal peripheral blood T cells. This population was CD26� in 23 patients and weakly CD26+ in 5 patients. CD7 was more variably expressed in MF/SS tumor cells, allowing recognition of a distinct, quantifiable abnormal T-cell population in only 34 of 69 involved samples. An increased CD4/CD8 ratio and lower surface expression of CD4 in tumor cells also helped separate the CD26�/dim atypical population for quantification. In 35 blood samples from other types of T-cell tumors, tumor cells in 10 of 11 morphologically involved cases showed absent/dim CD26.

Although capable of detecting abnormalities in most cases of MF/SS, CD7 expression does not provide as clear a separation of the neoplastic population and can be replaced by CD26 staining in routine peripheral blood flow cytometric screening of MF/SS patients.

PROGNOSIS AND TREATMENT CHARACTERIZATION

PROGNOSIS

Long-term outcome of 525 patients with mycosis fungoides and Sezary syndrome: clinical prognostic factors and risk for disease progression.

Kim YH, Liu HL, Mraz-Gernhard S, Varghese A, Hoppe RT.

Department of Dermatology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Arch Dermatol. 2003 Jul;139(7):857-66 Abstract quote
OBJECTIVES: To study and update the clinical characteristics and long-term outcome of our patients with mycosis fungoides (MF) and Sezary syndrome (SS), and to identify important clinical factors predictive of survival and disease progression.

DESIGN: A single-center, retrospective cohort analysis.

SETTING: Academic referral center for cutaneous lymphoma.

PATIENTS: Five hundred twenty-five patients with MF and SS evaluated and managed at Stanford University Cutaneous Lymphoma Clinic, Stanford, Calif, from 1958 through 1999.

MAIN OUTCOME MEASURES: We calculated long-term actuarial overall and disease-specific survivals and disease progression by the Kaplan-Meier method, and relative risk (RR) for survival calculated from expected survivals in control populations. RESULTS: The majority of our patients presented with T1 (30%) or T2 (37%) disease; 18% presented with T3 and 15% with T4 skin involvement. Forty-three percent of deaths were attributable to MF, primarily in patients with T3 or T4 disease. The patients with a more advanced T classification and clinical stage had a worse survival outcome. Except for patients with T1 or stage IA disease, the RR for death is greater in patients with MF than in a control population (RR, 2.2 in stage IB/IIA disease, 3.9 in stage IIB/III disease, and 12.8 in stage IV disease). Despite similar overall survival in patients with stage IB or IIA disease, their disease-specific survivals were significantly different (P =.006). The most significant clinical prognostic factors in the univariate analysis were patient age, TNM and B classifications, overall clinical stage groupings, and the presence or absence of extracutaneous disease. In the multivariate analysis, patient age, T classification, and the presence of extracutaneous disease were the most important independent factors. The risk for disease progression to a more advanced TNM or B classification, worse clinical stage, or death due to MF correlated with the severity of the initial T classification. The risk for development of extracutaneous disease also correlated with T classification; none of these patients had T1 disease when their extracutaneous disease was detected.

CONCLUSIONS: Patients with MF and SS have varying risks for disease progression or death. The most important clinical predictive factors for survival include patient age, T classification, and the presence of extracutaneous disease. The significant disease-specific survival differences between different clinical stages validate the usefulness of the present MF clinical staging system of the National Cancer Institute.

DIABETES MELLITUS

Effect of insulin-dependent diabetes mellitus on response to extracorporeal photopheresis in patients with Sezary syndrome.

Bouwhuis SA, el-Azhary RA, Gibson LE, McEvoy MT, Pittelkow MR.

Department of Dermatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
J Am Acad Dermatol 2002 Jul;47(1):63-7 Abstract quote
BACKGROUND: Extracorporeal photopheresis (ECP) has become a primary therapy for selected forms of cutaneous T-cell lymphoma, especially Sezary syndrome. Variability in response of patients with Sezary syndrome to ECP has been reported.

OBJECTIVE: Our purpose was to determine whether underlying medical conditions influence the efficacy of ECP in patients with Sezary syndrome.

METHODS: We retrospectively reviewed the medical records of 55 patients with Sezary syndrome who received ECP between 1987 and 2000. Efficacy criteria included decrease in Sezary cell count, erythroderma, lymphadenopathy, organomegaly, and pruritus.

RESULTS: Thirty-four patients responded well and 10 patients responded partially to ECP; 11 patients had no response. Nine patients with no response to ECP had insulin-dependent diabetes mellitus (IDDM). IDDM was documented in only 2 patients with a good response and in no patients with a partial response to ECP.

CONCLUSION: Patients with Sezary syndrome and IDDM typically respond poorly to the standard ECP treatment regimen.

TUMOR BURDEN

Prognostic significance of tumor burden in the blood of patients with erythrodermic primary cutaneous T-cell lymphoma.

Scarisbrick JJ, Whittaker S, Evans AV, Fraser-Andrews EA, Child FJ, Dean A, Russell-Jones R.

Skin Tumour Unit, St John's Institute of Dermatology, St Thomas' Hospital, London, England.

Blood 2001 Feb 1;97(3):624-30 Abstract quote

Erythrodermic cutaneous T-cell lymphoma (CTCL) includes patients with erythrodermic mycosis fungoides who may or may not exhibit blood involvement and Sezary syndrome and in whom hematological involvement is, by definition, present at diagnosis.

These patients were stratified into 5 hematologic stages (H0-H4) by measuring blood tumor burden, and these data were correlated with survival. The study identified 57 patients: 3 had no evidence of hematologic involvement (H0), 8 had a peripheral blood T-cell clone detected by polymerase chain reaction (PCR) analysis of the T-cell receptor gene and less than 5% Sezary cells on peripheral blood smear (H1), and 14 had either a T-cell clone detected by Southern blot analysis or PCR positivity with more than 5% circulating Sezary cells (H2).

Twenty-four patients had absolute Sezary counts of more than 1 x 10(9) cells per liter (H3), and 8 patients had counts in excess of 10 x 10(9) cells per liter (H4). The disease-specific death rate was higher with increasing hematologic stage, after correcting for age at diagnosis. A univariate analysis of 30 patients with defined lymph node stage found hematologic stage (P =.045) and lymph node stage (P =.013) but not age (P =.136) to be poor prognostic indicators of survival. Multivariate analysis identified only lymph node stage to be prognostically important, although likelihood ratio tests indicated that hematologic stage provides additional information (P =.035). Increasing tumor burden in blood and lymph nodes of patients with erythrodermic CTCL was associated with a worse prognosis.

The data imply that a hematologic staging system could complement existing tumor-node-metastasis staging criteria in erythrodermic CTCL.

TREATMENT

EXTRACORPOREAL PHOTOPHERESIS

Sezary syndrome and seronegative polyarthritis: treatment with extracorporeal photochemotherapy.
Macheiner W, Jantschitsch C, Graninger W, Paloczy K, Balint G, Marschalko M, Kainberger F, Breier F, Knobler RM.

Department of Dermatology, Division of Special and Environmental Dermatology, University of Vienna Medical School, Wahringer Gurtel 18-20, A-1090 Vienna, Austria.

J Am Acad Dermatol 2003 Feb;48(2):220-6 Abstract quote
We describe a patient with therapy-resistant cutaneous T-cell lymphoma, Sezary syndrome variant, in association with concurrent polyarthritis and vitiligo, who was successfully treated with extracorporeal photochemotherapy (ECP).

The combination of Sezary syndrome with seronegative rheumatoid arthritis is rare. In our patient the T-cell lymphoma was refractory to standard treatments that included psoralen-UVA, lymph node irradiation, and polychemotherapy. ECP has been shown to be effective in the treatment of selected cases of Sezary syndrome. There is a strong suggestion that ECP as a monotherapy can provide a significant benefit for other T-cell-mediated diseases including rheumatoid arthritis.

In spite of a disease duration of 10 years, a very low CD8 cell count (2% of lymphocytes), a very high CD4 cell count (94%), and multiple unsuccessful chemotherapeutic trials before initiation of ECP, our patient achieved a long-lasting complete remission of both diseases with normalization of the CD4+ and CD8+ T-lymphocyte subsets. Concurrent developing vitiligo was unaffected by ECP.

Circulating CD4+CD7- Lymphocyte Burden and Rapidity of Response: Predictors of Outcome in the Treatment of Sezary Syndrome and Erythrodermic Mycosis Fungoides With Extracorporeal Photopheresis.

Stevens SR, Baron ED, Masten S, Cooper KD.

Department of Dermatology, Case Western Reserve University, 11100 Euclid Ave, Cleveland, OH 44106.

Arch Dermatol 2002 Oct;138(10):1347-50 Abstract quote
BACKGROUND: Extracorporeal photopheresis (ECP) is an effective treatment for cutaneous T-cell lymphoma. Controversy has arisen regarding its ability to improve survival rates in Sezary syndrome (SS). We describe our experience with ECP in the treatment of SS and erythrodermic mycosis fungoides, with particular emphasis on early predictors of long-term outcome.

OBSERVATIONS: We included 17 patients (15 with SS and 2 with erythrodermic mycosis fungoides) who received ECP as initial treatment. Four of these patients were moribund on presentation (Eastern Cooperative Oncology Group Performance Status score, 4) and underwent only 1 to 2 cycles of ECP. The median survival was 56 months for the 11 patients with SS and an Eastern Cooperative Oncology Group Performance Status score of less than 4. If all 15 patients with SS are considered, median survival was 34 months. Response after 5 months of ECP correlated with long-term survival. A low number (<6.0 x10(3)/ micro L) of circulating CD4(+)CD7(-) lymphocytes correlated with response after 5 months of ECP.

CONCLUSIONS: Extracorporeal photopheresis is a safe, effective, and well-tolerated treatment for erythrodermic mycosis fungoides and SS. Low numbers of CD4(+)CD7(-) cells in the circulation and a positive response after 5 months of therapy predicted long-term survival. Moribund patients are much less likely to benefit from ECP.

Complete molecular remission during biologic response modifier therapy for S�zary syndrome is associated with enhanced helper T type 1 cytokine production and natural killer cell activity

Elisa K. Yoo, MD Maureen Cassin, MD Stuart R. Lessin, MD Alain H. Rook, MD

J Am Acad Dermatol 2001;45:208-16 Abstract quote

Background: Cutaneous T-cell lymphoma (CTCL) is a clonally derived, skin-invasive malignancy of CD4+ T lymphocytes with the phenotype of mature helper T cells. Advancing stages of CTCL are associated with depressed cell-mediated immunity, increased production of T helper type 2 cytokines and decreased levels of T helper type 1 cytokines.

Objective: Our purpose was to evaluate the cytokine secretion pattern and cell-mediated cytotoxicity in peripheral blood mononuclear cells of patients with S�zary syndrome in relation to the presence of the malignant clone.

Methods: Serial polymerase chain reaction for the T-cell receptor- or T-cell receptor- gene rearrangement was used to determine the presence of the malignant clone. Enzyme-linked immunosorbent assays were used to determine the levels of interleukin 4 and interferon gamma produced by the peripheral blood mononuclear cells from the patients with S�zary syndrome.

Results: We demonstrate 3 cases of S�zary syndrome with typically suppressed cell-mediated cytotoxicity, elevated production of interleukin 4, and depressed production of interferon gamma by their peripheral blood mononuclear cells before institution of therapy with biologic response modifier therapy. In all 3 cases after clinical and molecular remission, we observed striking immunologic changes, including an increase in levels of natural killer cell activity and interferon gamma production and decreased production of interleukin 4.

Conclusions: The observation that the cytokine secretion pattern by peripheral blood mononuclear cells from 3 patients with S�zary syndrome normalized with the disappearance of the malignant clone from the peripheral blood suggests that the malignant T cells account for the aberrant cytokine production. Moreover, the aberrant cytokine production may be the cause for suppression of cell-mediated immunity seen in advancing stages of CTCL.

Combination treatment with extracorporeal photopheresis, interferon alfa and interleukin-2 in a patient with the Sezary syndrome.

Fritz TM, Kleinhans M, Nestle FO, Burg G, Dummer R.

Department of Dermatology, University Hospital Zurich, Gloriastrasse 31, 8091 Zurich, Switzerland.

Br J Dermatol 1999 Jun;140(6):1144-7 Abstract quote

Extracorporeal photopheresis is generally accepted as standard therapy for the leukaemic and erythrodermic variant of cutaneous T-cell lymphoma, the Sezary syndrome (SS). Because of the limited efficacy in some patients with SS, combination therapy is often necessary.

We report a new combination therapy for an intensively treated 62-year-old woman with advanced SS (T4N1BM1, stage IVb). Previous treatment with PUVA, retinoids alone and in combination with photopheresis, chlorambucil, and chemotherapy using cyclophosphamide, doxorubicin, vincristine and prednisone failed and were associated with significant side-effects. Six cycles of combination therapy with extracorporeal photopheresis, low-dose interferon alfa and interleukin-2 resulted in fading of the erythroderma and in a decrease of Sezary cells in the white blood cell count. The CD4/CD8 ratio decreased from 66 to 6 and the proportion of CD4 + CD7 - cells from 47% to 11%. Only mild side-effects such as influenza-like symptoms, fever and nausea were observed. Two months after this therapy, the patient developed enlarged lymph nodes without erythroderma, and died 1 year later from the lymphoma.

Combination therapy with extracorporeal photopheresis, interferon alfa and interleukin-2 might be useful in selected patients with SS.

2-CdA

Treatment of late-stage Sezary syndrome with 2-Chlorodeoxyadenosine.

Bouwhuis SA, El-Azhary RA, McEvoy MT, Gibson LE, Habermann TM, Witzig TE, Pittelkow MR.

Department of Dermatology and the Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN, USA.
Int J Dermatol 2002 Jun;41(6):352-6 Abstract quote
BACKGROUND: 2-Chlorodeoxyadenosine (2-CdA), a purine adenosine analog, is safe and effective chemotherapy for patients with hairy cell leukemia and low-grade lymphomas. Adverse effects include neutropenia, lymphocytopenia, and infectious complications. Our objective was to evaluate the efficacy of 2-CdA (2-6 seven-day cycles) in the treatment of late-stage, recalcitrant Sezary syndrome.

METHODS: Retrospective review of medical records of six patients with Sezary syndrome who had received 2-CdA cycles at Mayo Clinic, Rochester between March 1995 and March 2000. Variables assessed from the records included improvement in global appearance, extent of erythroderma, size of lymph nodes, pruritus, and leukocyte, lymphocyte, and absolute Sezary cell counts.

RESULTS: Two patients, both with stage III Sezary syndrome, whose previous treatment consisted of only two modalities, responded well to the treatment, with moderate to total clearing of erythroderma and pruritus associated with a significant decrease in Sezary cell counts. The other four patients had only a partial response (one patient) or no response (three patients) to 2-CdA. The mortality rate was 50%. All three patients died of Staphylococcus aureus sepsis. However, only one patient was receiving 2-CdA treatment when he died. The other two patients died 8 and 9 weeks after the last 2-CdA cycle. This high mortality rate is attributed to infectious complications after 2-CdA treatment in patients with recalcitrant disease.

CONCLUSION: 2-Chlorodeoxyadenosine shows efficacy in stage III Sezary syndrome, but it also carries a substantial risk of septic complications and mortality. It can be used if no other suitable alternatives are available. Caution should be exercised in all these patients regarding skin care and avoidance of infections or sepsis.

Macpherson and Pincus. Clinical Diagnosis and Management by Laboratory Methods. Twentyfirst Edition. WB Saunders. 2006.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fifth Edition. Mosby Elesevier 2008

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PATHOGENESIS	CHARACTERIZATION
BACTERIAL SUPERANTIGENS
Cutaneous colonization with staphylococci influences the disease activity of Sezary syndrome: a potential role for bacterial superantigens. Tokura Y, Yagi H, Ohshima A, Kurokawa S, Wakita H, Yokote R, Shirahama S, Furukawa F, Takigawa M. Department of Dermatology, Hamamatsu University School of Medicine, Japan.	Br J Dermatol 1995 Jul;133(1):6-12 Abstract quote It has previously been shown that circulating Sezary cells respond in vitro to superantigenic staphylococcal exotoxins in a manner that is restricted by their V beta usage. This study was conducted to examine whether cutaneous colonization with Staphylococcus aureus influences the activity of the skin lesions of Sezary syndrome, and whether S. aureus isolated from patients with Sezary syndrome stimulates circulating Sezary cells in vitro. Two patients with Sezary syndrome, whose skin was colonized with S. aureus, were treated with antibacterial agents, and the relation between the severity of the skin disease and the degree of S. aureus colonization was assessed. In addition, the patients' peripheral blood mononuclear cells were cultured in the presence of mitomycin C-treated S. aureus or superantigenic staphylococcal toxins. The antibacterial treatment improved the skin disease, and eliminated S. aureus in both patients. In one patient, 98% of the peripheral blood mononuclear cells bore V alpha 2V beta 17 of the T-cell receptor, indicative of the presence of an extremely high percentage of circulating Sezary cells. The peripheral blood lymphocytes from this patient responded well in vitro to superantigenic staphylococcal enterotoxin (SE), but not to SEA or toxic shock syndrome toxin-1, or to mitomycin-treated S. aureus isolated from the same patient. Cutaneous colonization by S. aureus influences the disease activity of CTCL, possibly by activation of Sezary cells by bacterial superantigenic exoproteins.
Association of erythrodermic cutaneous T-cell lymphoma, superantigen-positive Staphylococcus aureus, and oligoclonal T-cell receptor V beta gene expansion. Jackow CM, Cather JC, Hearne V, Asano AT, Musser JM, Duvic M. Department of Dermatology, University of Texas Medical School, Houston, USA.	Blood 1997 Jan 1;89(1):32-40 Abstract quote Forty-two patients with cutaneous T-cell lymphoma, including 31 with exfoliative erythroderma or Sezary syndrome and 11 with mycosis fungoides, were studied for the occurrence of staphylococcal infection. Thirty-two of 42 (76%) had a positive staphylococcal culture from skin or blood. One half of the patients with positive cultures grew Staphylococcus aureus. This group included 11 with Sezary syndrome and 5 with rapidly enlarging mycosis fungoides plaques or tumors. All of the S aureus carried enterotoxin genes. Surprisingly, 6 of 16 strains were the same toxic shock toxin-1 (TSST-1)-positive clone, designated electrophoretic type (ET)-41. Analysis of the T-cell receptor V beta repertoire in 14 CTCL patients found that only 4 had the expected monoclonal expansion of a specific V beta gene, whereas 10 had oligoclonal or polyclonal expansion of several V beta families. All patients with TSST-1+ S aureus had overexpansion of V beta Z in blood and/or skin lesions. These studies show that S aureus containing superantigen enterotoxins are commonly found in patients with CTCL especially individuals with erythroderma where they could exacerbate and/or perpetuate stimulate chronic T-cell expansion and cutaneous inflammation. Attention to toxigenic S aureus in CTCL patients would be expected to improve the quality of care and outcome of this patient population.

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSIS
Long-term outcome of 525 patients with mycosis fungoides and Sezary syndrome: clinical prognostic factors and risk for disease progression. Kim YH, Liu HL, Mraz-Gernhard S, Varghese A, Hoppe RT. Department of Dermatology, Stanford University School of Medicine, Stanford, CA 94305, USA.	Arch Dermatol. 2003 Jul;139(7):857-66 Abstract quote OBJECTIVES: To study and update the clinical characteristics and long-term outcome of our patients with mycosis fungoides (MF) and Sezary syndrome (SS), and to identify important clinical factors predictive of survival and disease progression. DESIGN: A single-center, retrospective cohort analysis. SETTING: Academic referral center for cutaneous lymphoma. PATIENTS: Five hundred twenty-five patients with MF and SS evaluated and managed at Stanford University Cutaneous Lymphoma Clinic, Stanford, Calif, from 1958 through 1999. MAIN OUTCOME MEASURES: We calculated long-term actuarial overall and disease-specific survivals and disease progression by the Kaplan-Meier method, and relative risk (RR) for survival calculated from expected survivals in control populations. RESULTS: The majority of our patients presented with T1 (30%) or T2 (37%) disease; 18% presented with T3 and 15% with T4 skin involvement. Forty-three percent of deaths were attributable to MF, primarily in patients with T3 or T4 disease. The patients with a more advanced T classification and clinical stage had a worse survival outcome. Except for patients with T1 or stage IA disease, the RR for death is greater in patients with MF than in a control population (RR, 2.2 in stage IB/IIA disease, 3.9 in stage IIB/III disease, and 12.8 in stage IV disease). Despite similar overall survival in patients with stage IB or IIA disease, their disease-specific survivals were significantly different (P =.006). The most significant clinical prognostic factors in the univariate analysis were patient age, TNM and B classifications, overall clinical stage groupings, and the presence or absence of extracutaneous disease. In the multivariate analysis, patient age, T classification, and the presence of extracutaneous disease were the most important independent factors. The risk for disease progression to a more advanced TNM or B classification, worse clinical stage, or death due to MF correlated with the severity of the initial T classification. The risk for development of extracutaneous disease also correlated with T classification; none of these patients had T1 disease when their extracutaneous disease was detected. CONCLUSIONS: Patients with MF and SS have varying risks for disease progression or death. The most important clinical predictive factors for survival include patient age, T classification, and the presence of extracutaneous disease. The significant disease-specific survival differences between different clinical stages validate the usefulness of the present MF clinical staging system of the National Cancer Institute.
DIABETES MELLITUS
Effect of insulin-dependent diabetes mellitus on response to extracorporeal photopheresis in patients with Sezary syndrome. Bouwhuis SA, el-Azhary RA, Gibson LE, McEvoy MT, Pittelkow MR. Department of Dermatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.	J Am Acad Dermatol 2002 Jul;47(1):63-7 Abstract quote BACKGROUND: Extracorporeal photopheresis (ECP) has become a primary therapy for selected forms of cutaneous T-cell lymphoma, especially Sezary syndrome. Variability in response of patients with Sezary syndrome to ECP has been reported. OBJECTIVE: Our purpose was to determine whether underlying medical conditions influence the efficacy of ECP in patients with Sezary syndrome. METHODS: We retrospectively reviewed the medical records of 55 patients with Sezary syndrome who received ECP between 1987 and 2000. Efficacy criteria included decrease in Sezary cell count, erythroderma, lymphadenopathy, organomegaly, and pruritus. RESULTS: Thirty-four patients responded well and 10 patients responded partially to ECP; 11 patients had no response. Nine patients with no response to ECP had insulin-dependent diabetes mellitus (IDDM). IDDM was documented in only 2 patients with a good response and in no patients with a partial response to ECP. CONCLUSION: Patients with Sezary syndrome and IDDM typically respond poorly to the standard ECP treatment regimen.
TUMOR BURDEN
Prognostic significance of tumor burden in the blood of patients with erythrodermic primary cutaneous T-cell lymphoma. Scarisbrick JJ, Whittaker S, Evans AV, Fraser-Andrews EA, Child FJ, Dean A, Russell-Jones R. Skin Tumour Unit, St John's Institute of Dermatology, St Thomas' Hospital, London, England.	Blood 2001 Feb 1;97(3):624-30 Abstract quote Erythrodermic cutaneous T-cell lymphoma (CTCL) includes patients with erythrodermic mycosis fungoides who may or may not exhibit blood involvement and Sezary syndrome and in whom hematological involvement is, by definition, present at diagnosis. These patients were stratified into 5 hematologic stages (H0-H4) by measuring blood tumor burden, and these data were correlated with survival. The study identified 57 patients: 3 had no evidence of hematologic involvement (H0), 8 had a peripheral blood T-cell clone detected by polymerase chain reaction (PCR) analysis of the T-cell receptor gene and less than 5% Sezary cells on peripheral blood smear (H1), and 14 had either a T-cell clone detected by Southern blot analysis or PCR positivity with more than 5% circulating Sezary cells (H2). Twenty-four patients had absolute Sezary counts of more than 1 x 10(9) cells per liter (H3), and 8 patients had counts in excess of 10 x 10(9) cells per liter (H4). The disease-specific death rate was higher with increasing hematologic stage, after correcting for age at diagnosis. A univariate analysis of 30 patients with defined lymph node stage found hematologic stage (P =.045) and lymph node stage (P =.013) but not age (P =.136) to be poor prognostic indicators of survival. Multivariate analysis identified only lymph node stage to be prognostically important, although likelihood ratio tests indicated that hematologic stage provides additional information (P =.035). Increasing tumor burden in blood and lymph nodes of patients with erythrodermic CTCL was associated with a worse prognosis. The data imply that a hematologic staging system could complement existing tumor-node-metastasis staging criteria in erythrodermic CTCL.
TREATMENT
EXTRACORPOREAL PHOTOPHERESIS
Sezary syndrome and seronegative polyarthritis: treatment with extracorporeal photochemotherapy. Macheiner W, Jantschitsch C, Graninger W, Paloczy K, Balint G, Marschalko M, Kainberger F, Breier F, Knobler RM. Department of Dermatology, Division of Special and Environmental Dermatology, University of Vienna Medical School, Wahringer Gurtel 18-20, A-1090 Vienna, Austria.	J Am Acad Dermatol 2003 Feb;48(2):220-6 Abstract quote We describe a patient with therapy-resistant cutaneous T-cell lymphoma, Sezary syndrome variant, in association with concurrent polyarthritis and vitiligo, who was successfully treated with extracorporeal photochemotherapy (ECP). The combination of Sezary syndrome with seronegative rheumatoid arthritis is rare. In our patient the T-cell lymphoma was refractory to standard treatments that included psoralen-UVA, lymph node irradiation, and polychemotherapy. ECP has been shown to be effective in the treatment of selected cases of Sezary syndrome. There is a strong suggestion that ECP as a monotherapy can provide a significant benefit for other T-cell-mediated diseases including rheumatoid arthritis. In spite of a disease duration of 10 years, a very low CD8 cell count (2% of lymphocytes), a very high CD4 cell count (94%), and multiple unsuccessful chemotherapeutic trials before initiation of ECP, our patient achieved a long-lasting complete remission of both diseases with normalization of the CD4+ and CD8+ T-lymphocyte subsets. Concurrent developing vitiligo was unaffected by ECP.
Circulating CD4+CD7- Lymphocyte Burden and Rapidity of Response: Predictors of Outcome in the Treatment of Sezary Syndrome and Erythrodermic Mycosis Fungoides With Extracorporeal Photopheresis. Stevens SR, Baron ED, Masten S, Cooper KD. Department of Dermatology, Case Western Reserve University, 11100 Euclid Ave, Cleveland, OH 44106.	Arch Dermatol 2002 Oct;138(10):1347-50 Abstract quote BACKGROUND: Extracorporeal photopheresis (ECP) is an effective treatment for cutaneous T-cell lymphoma. Controversy has arisen regarding its ability to improve survival rates in Sezary syndrome (SS). We describe our experience with ECP in the treatment of SS and erythrodermic mycosis fungoides, with particular emphasis on early predictors of long-term outcome. OBSERVATIONS: We included 17 patients (15 with SS and 2 with erythrodermic mycosis fungoides) who received ECP as initial treatment. Four of these patients were moribund on presentation (Eastern Cooperative Oncology Group Performance Status score, 4) and underwent only 1 to 2 cycles of ECP. The median survival was 56 months for the 11 patients with SS and an Eastern Cooperative Oncology Group Performance Status score of less than 4. If all 15 patients with SS are considered, median survival was 34 months. Response after 5 months of ECP correlated with long-term survival. A low number (<6.0 x10(3)/ micro L) of circulating CD4(+)CD7(-) lymphocytes correlated with response after 5 months of ECP. CONCLUSIONS: Extracorporeal photopheresis is a safe, effective, and well-tolerated treatment for erythrodermic mycosis fungoides and SS. Low numbers of CD4(+)CD7(-) cells in the circulation and a positive response after 5 months of therapy predicted long-term survival. Moribund patients are much less likely to benefit from ECP.
Complete molecular remission during biologic response modifier therapy for S�zary syndrome is associated with enhanced helper T type 1 cytokine production and natural killer cell activity Elisa K. Yoo, MD Maureen Cassin, MD Stuart R. Lessin, MD Alain H. Rook, MD	J Am Acad Dermatol 2001;45:208-16 Abstract quote Background: Cutaneous T-cell lymphoma (CTCL) is a clonally derived, skin-invasive malignancy of CD4+ T lymphocytes with the phenotype of mature helper T cells. Advancing stages of CTCL are associated with depressed cell-mediated immunity, increased production of T helper type 2 cytokines and decreased levels of T helper type 1 cytokines. Objective: Our purpose was to evaluate the cytokine secretion pattern and cell-mediated cytotoxicity in peripheral blood mononuclear cells of patients with S�zary syndrome in relation to the presence of the malignant clone. Methods: Serial polymerase chain reaction for the T-cell receptor- or T-cell receptor- gene rearrangement was used to determine the presence of the malignant clone. Enzyme-linked immunosorbent assays were used to determine the levels of interleukin 4 and interferon gamma produced by the peripheral blood mononuclear cells from the patients with S�zary syndrome. Results: We demonstrate 3 cases of S�zary syndrome with typically suppressed cell-mediated cytotoxicity, elevated production of interleukin 4, and depressed production of interferon gamma by their peripheral blood mononuclear cells before institution of therapy with biologic response modifier therapy. In all 3 cases after clinical and molecular remission, we observed striking immunologic changes, including an increase in levels of natural killer cell activity and interferon gamma production and decreased production of interleukin 4. Conclusions: The observation that the cytokine secretion pattern by peripheral blood mononuclear cells from 3 patients with S�zary syndrome normalized with the disappearance of the malignant clone from the peripheral blood suggests that the malignant T cells account for the aberrant cytokine production. Moreover, the aberrant cytokine production may be the cause for suppression of cell-mediated immunity seen in advancing stages of CTCL.
Combination treatment with extracorporeal photopheresis, interferon alfa and interleukin-2 in a patient with the Sezary syndrome. Fritz TM, Kleinhans M, Nestle FO, Burg G, Dummer R. Department of Dermatology, University Hospital Zurich, Gloriastrasse 31, 8091 Zurich, Switzerland.	Br J Dermatol 1999 Jun;140(6):1144-7 Abstract quote Extracorporeal photopheresis is generally accepted as standard therapy for the leukaemic and erythrodermic variant of cutaneous T-cell lymphoma, the Sezary syndrome (SS). Because of the limited efficacy in some patients with SS, combination therapy is often necessary. We report a new combination therapy for an intensively treated 62-year-old woman with advanced SS (T4N1BM1, stage IVb). Previous treatment with PUVA, retinoids alone and in combination with photopheresis, chlorambucil, and chemotherapy using cyclophosphamide, doxorubicin, vincristine and prednisone failed and were associated with significant side-effects. Six cycles of combination therapy with extracorporeal photopheresis, low-dose interferon alfa and interleukin-2 resulted in fading of the erythroderma and in a decrease of Sezary cells in the white blood cell count. The CD4/CD8 ratio decreased from 66 to 6 and the proportion of CD4 + CD7 - cells from 47% to 11%. Only mild side-effects such as influenza-like symptoms, fever and nausea were observed. Two months after this therapy, the patient developed enlarged lymph nodes without erythroderma, and died 1 year later from the lymphoma. Combination therapy with extracorporeal photopheresis, interferon alfa and interleukin-2 might be useful in selected patients with SS.
2-CdA
Treatment of late-stage Sezary syndrome with 2-Chlorodeoxyadenosine. Bouwhuis SA, El-Azhary RA, McEvoy MT, Gibson LE, Habermann TM, Witzig TE, Pittelkow MR. Department of Dermatology and the Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN, USA.	Int J Dermatol 2002 Jun;41(6):352-6 Abstract quote BACKGROUND: 2-Chlorodeoxyadenosine (2-CdA), a purine adenosine analog, is safe and effective chemotherapy for patients with hairy cell leukemia and low-grade lymphomas. Adverse effects include neutropenia, lymphocytopenia, and infectious complications. Our objective was to evaluate the efficacy of 2-CdA (2-6 seven-day cycles) in the treatment of late-stage, recalcitrant Sezary syndrome. METHODS: Retrospective review of medical records of six patients with Sezary syndrome who had received 2-CdA cycles at Mayo Clinic, Rochester between March 1995 and March 2000. Variables assessed from the records included improvement in global appearance, extent of erythroderma, size of lymph nodes, pruritus, and leukocyte, lymphocyte, and absolute Sezary cell counts. RESULTS: Two patients, both with stage III Sezary syndrome, whose previous treatment consisted of only two modalities, responded well to the treatment, with moderate to total clearing of erythroderma and pruritus associated with a significant decrease in Sezary cell counts. The other four patients had only a partial response (one patient) or no response (three patients) to 2-CdA. The mortality rate was 50%. All three patients died of Staphylococcus aureus sepsis. However, only one patient was receiving 2-CdA treatment when he died. The other two patients died 8 and 9 weeks after the last 2-CdA cycle. This high mortality rate is attributed to infectious complications after 2-CdA treatment in patients with recalcitrant disease. CONCLUSION: 2-Chlorodeoxyadenosine shows efficacy in stage III Sezary syndrome, but it also carries a substantial risk of septic complications and mortality. It can be used if no other suitable alternatives are available. Caution should be exercised in all these patients regarding skin care and avoidance of infections or sepsis.

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CLINICAL VARIANTS/GROSS DISEASE	CHARACTERIZATION
LYMPH NODES
Histologic assessment of lymph nodes in mycosis fungoides/Sezary syndrome (cutaneous T-cell lymphoma): clinical correlations and prognostic import of a new classification system. Sausville EA, Worsham GF, Matthews MJ, Makuch RW, Fischmann AB, Schechter GP, Gazdar AF, Bunn PA Jr.	Hum Pathol 1985 Nov;16(11):1098-109 Abstract quote Mycosis fungoides and the Sezary syndrome share common cutaneous histopathologic features, and this spectrum of malignant disease is referred to here as cutaneous T-cell lymphoma (CTCL). A method (LN classification) for describing the histopathologic features of lymph nodes in CTCL is presented. In this system, lymph node biopsy specimens are scored according to the number of atypical lymphoid cells in T-cell-dependent paracortical zones and the preservation or distortion of the lymph node architecture. Lymph node architecture is preserved in lymph nodes scored LN1 to LN3, and these nodes may have coexistent dermatopathic change. LN1 nodes have single infrequent atypical lymphocytes in paracortical T-cell regions. LN2 nodes have small clusters of paracortical atypical cells. LN3 nodes have large clusters of atypical cells. LN4 nodes are partially or totally effaced by atypical cells. This system was used to classify 96 lymph node biopsy specimens obtained within six months of the initial diagnosis of CTCL; no LN1 nodes, 37 LN2, 44 LN3, and 15 LN4 nodes were found. The LN class was significantly correlated with the extent of skin, blood, and visceral involvement, as well as with survival. Patients with LN2 lymph nodes have an estimated five-year survival of 70 per cent, while patients with LN3 and LN4 nodes have estimated five-year survivals of 30 and 15 per cent, respectively. The survival differences between the LN subgroups were all significant (P less than 0.05). The LN classification system was clearly shown to be reproducible among experienced pathologists. The LN system for the histopathologic classification of lymph nodes in CTCL is of prognostic value and should be used to assess lymph node biopsies in patients with CTCL.
SKIN
Primary Sézary Syndrome Commonly Shows Low-Grade Cytologic Atypia and an Absence of Epidermotropism A. Hafeez Diwan, MD, PhD, Victor G. Prieto, Marco Herling, MD, Madeleine Duvic, and Dan Jones, MD, PhD	Am J Clin Pathol 2005;123:510-515 Abstract quote The dermatopathologic findings in cases of Sézary syndrome (SS) that arise in patients without a previous diagnosis of mycosis fungoides have not been well characterized. We evaluated the histologic findings in skin biopsy specimens from 31 patients with such primary SS and correlated them with clinical and hematologic parameters at the time of biopsy. The most characteristic histologic finding was the presence of a dermal perivascular lymphoid infiltrate, usually with mild to moderate cytologic atypia and variable numbers of eosinophils; epidermotropism was absent or minimal in 19 cases (61%). Reactive epidermal changes such as spongiosis, parakeratosis, and acanthosis also were present frequently (27 [87%], 17 [55%], 19 [61%] cases, respectively). The number of eosinophils present in skin biopsy specimens correlated with the level of peripheral blood lymphocytosis. In erythrodermic patients or patients with persistent xerosis and pruritus, it is important to carefully evaluate the degree of lymphocyte atypia in the dermal perivascular infiltrate and correlate with blood flow cytometric findings to diagnose primary SS. Many cases will lack the epidermotropism usually seen in mycosis fungoides.