Sézary syndrome presenting with leonine facies ajd_560

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1 Australasian Journal of Dermatology (2009) 50, doi: /j x CASE REPORT Sézary syndrome presenting with leonine facies ajd_560 Shano Nassem, 1 Rajesh Kashyap, 1 Namrata P Awasthi, 1 Narendra Krishnani 2 and Neeraj Kumari 2 Departments of 1 Hematology and 2 Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India ABSTRACT A 71-year-old man presented with erythroderma and multiple nodular skin lesions over the face, scalp, upper limbs and trunk. The facial skin was thickened, producing the rare leonine facies appearance. Investigations revealed the presence of atypical lymphoid cells in the peripheral blood, bone marrow and skin. The atypical lymphoid cells in the peripheral blood and bone marrow were positive for helper T-cell antigens (CD4, CD2, CD5 and CD7) on immunophenotyping by flow cytometry. The histopathology of skin showed dermal infiltration by atypical small lymphocytes with epidermotropism. These cells were positive for helper T-lymphocyte antigens on immunohistochemistry. A diagnosis of Sézary syndrome was made based on clinical, peripheral blood and immunophenotypical findings. Key words: cutaneous T-cell lymphoma, erythroderma, skin nodules. INTRODUCTION Correspondence: Dr Rajesh Kashyap, Department of Hematology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Rae Bareily Road, Lucknow, Uttar Pradesh , India. rajkashyapmd@yahoo.co.in Shano Nassem, MD. Rajesh Kashyap, MD. Namrata P Awasthi, MD. Narendra Krishnani, MD. Neeraj Kumari, MD. Submitted 4 July 2008; accepted 21 January SS is an aggressive primary CTCL and is characterized by the classical triad of erythroderma, generalized lymphadenopathy and neoplastic T-lymphocytes (Sézary cells) in skin, lymph nodes and peripheral blood. 1,2 It is considered by some authors to be an erythrodermic leukaemic variant of MF, but is classified as a separate entity in the new World Health Organization European Organisation for Research and Treatment of Cancer classification of cutaneous lymphomas. 2 The ISCL has described three subgroups of erythrodermic CTCL: SS, erythrodermic MF (secondary erythroderma developing in patients with pre-existent MF) and erythrodermic CTCL not otherwise defined. 3 It is sometimes difficult to distinguish between these three conditions and, to overcome this problem, the ISCL has proposed the presence of one or more of the following criteria for diagnosis of SS: an absolute Sézary cell count of at least 1000/ml; an expanded CD4 + T-cell population resulting in a CD4 : CD8 ratio greater than 10; and demonstration of T-cell clone in the peripheral blood by molecular or cytogenetic methods. 3 CASE REPORT A 71-year-old man presented with complaints of redcoloured skin associated with itching and multiple nodules (tumours) over the body for the last 4 months. On physical examination, generalized erythema with fine scaling was present. The facial skin was thickened, giving the leonine facies appearance. There was no diffuse thickening of the skin over the rest of the body. Nodular lesions were present on the trunk, upper limbs and scalp (Fig. 1). The lesions were firm to hard and non-tender. The cervical, axillary and inguinal groups of lymph nodes were enlarged. Both the liver and spleen were increased in size. There was no preceding history of eczematous skin lesions. Laboratory investigations showed a haemoglobin level of 12.0 g/dl, total leukocyte count of /L and platelet count of /L. The peripheral blood smear examination revealed the presence of atypical lymphoid cells (42% on differential leukocyte count) twice the size of small lymphocytes with increased nuclear cytoplasmic ratio. The nucleus was convoluted with grooves in the surface of the nuclear membrane, chromatin was condensed and Abbreviations: ALCL ATL CD CTCL ISCL MF PCFCL PCMZL SPTCL SS TNMB anaplastic large-cell lymphoma adult T-cell leukaemia cluster of differentiation cutaneous T-cell lymphoma International Society for Cutaneous Lymphoma mycosis fungoides primary cutaneous follicle-centre lymphoma primary cutaneous marginal-zone lymphoma subcutaneous panniculitis-like T-cell lymphoma Sézary syndrome tumour, node, metastasis, and blood

2 286 S Nassem et al. Figure 1 facies. Photograph of the patient showing the classical leonine Figure 3 Photomicrograph of the skin shows diffuse infiltration of the dermis by atypical lymphocytes with epidermotropism (H&E, 4). Figure 2 Photomicrograph of the peripheral blood smear film showing Sézary cells (Leishman stain, 100). hyperchromatic with the nucleoli not being seen. The cytoplasm was scant to moderate in amount with a few cells showing vacuolations (Fig. 2). Fine-needle aspirate examination of the skin nodules showed similar cells. In the bonemarrow biopsy there was interstitial infiltration by the atypical lymphocytes. Immunophenotyping by flow cytometry showed atypical lymphoid cells present in the peripheral blood, and bone marrow positive for helper T-cell antigens (CD7, CD3, CD5, CD2 and CD4) and negative for the B-cell antigens (CD19, CD20, CD23, CD10, CD43 and CD25). Electron microscopy analysis of lymphocytes revealed them to have serpentine nucleus with multiple nuclear indentations. Biopsy of the nodular skin lesions showed sheets of atypical cells in the superficial dermis, large to medium-sized with round to oval irregular nuclei, dispersed chromatin, occasional prominent nucleoli and scant cytoplasm (Fig. 3). On immunohistochemistry these cells were leukocyte common antigen and CD3 positive, and negative for CD20 and CD30. A diagnosis of SS was made based on clinical, peripheral and immunophenotypical findings. The disease was advanced (stage IV-B2) and it was decided to treat the patient with systemic combination chemotherapy, the CHOP regimen (cyclophosphamide 750 mg/m 2 i.v. on day 1, doxorubicin 50 mg/m 2 i.v. on day 1, vincritine 1.5 mg/m 2 i.v. on day 1 and prednisolone 100 mg per oral on days 1 5), given at 3-week intervals. After three cycles of chemotherapy the patient had symptomatic improvement with decrease in the intensity of pruritus and erthyroderma, and there was regression in the size of the enlarged lymph nodes. The patient subsequently refused further chemotherapy. DISCUSSION Primary CTCL is a heterogeneous group of disorders characterized by localization of neoplastic lymphocytes to the skin. More than two-thirds of these lymphomas are of T-cell origin. MF and SS occur due to malignant clonal proliferation of helper T-lymphocytes that comprise the skin-

3 Sézary syndrome with leonine facies 287 associated lymphoid tissue. 1 They together comprise 45% of all lymphomas that arise in skin. SS is very rare in Asians and it typically affects middle-aged adults, with peak age at presentation of 55 years. There is a 2 : 1 male predominance and it occurs twice as often in black persons as in white persons. Environmental and occupational exposure to solvents, chemicals and toxins, as well as a role of human T-lymphotropic virus type 1, have been suggested but not proven. 2,4 The skin involvement in SS is most commonly in the form of plaque formation or erythroderma. Erythroderma is the first manifestation of disease in approximately 30% of cases. Eczematous lesions and non-specific chronic dermatitis may precede erythroderma in up to 27% of patients. 5 Generalized dermal thickening due to infiltrative disease may produce the rare leonine facies appearance. 6 Other major clinical manifestations include alopecia, onychodystrophy and keratoderma. Laboratory findings include elevated white cell count (> /L), hyperuricaemia and elevated lactic dehydrogenase level. 2,5 Sézary cells in the peripheral blood are seen in most patients with erythroderma, in 25% of patients with cutaneous tumours and in 10% of patients with generalized plaques. The TNMB classification is used for clinical staging of MF/SS. As per this system, SS patients are classified as T4 (erythrodermic) with their B status as B2 (Sézary cells >1000/mL). SS patients can have variable N and M (with or without visceral involvement; bone marrow involvement is judged as M1). 7 SS presenting with cutaneous nodules or tumours needs to be differentiated from other CTLC such as ALCL, ATL and SPTCL. PCFCL and PCMZL are B-cell lymphomas that involve the skin and need to be differentiated from MF/SS. In cutaneous ALCL, patients usually present with rapidly growing solitary or localized nodules or tumours, often with ulceration. Histopathologically, the cutaneous ALCL is composed of anaplastic cells located in the dermis. These cells are strongly positive for CD30 antigen and may be of T-cell or null cell lineage. Fifty per cent of ATL patients have skin lesion, most commonly tumours or nodules. The presence of hypercalcaemia with punched out bone lesions is the clinical hallmark of disease and distinguishes it from MF/SS. The skin lesions show a superficial or more diffuse infiltration by medium to large-sized T-lymphocytes, which often display epidermotropism, mimicking MM/SS. The lymphocytes characteristically express the T-cell markers CD3 and CD4, with a B-cell marker, CD25. In SPTCL, subcutaneous nodules or plaques involving mainly the legs is the common presenting feature. Histopathologically, the tumour is confined mainly to the subcutis and there is infiltration of fat lobules by variably sized pleomorphic cells in a lace-like pattern, and resembles a lobular panniculitis. The presence of karyorrhexis is a characteristic feature. PCFCL presents clinically as non-scaling solitary or grouped plaques, papules or tumours located on the scalp, forehead, trunk or legs. The tumours may be surrounded by erythematous papules and indurated plaques. The tumour is characterized by nodular to diffuse infiltration by neoplastic cells, with almost constant sparing of the epidermis. In patients with PCZML, red to violaceous papules, plaques or nodules are present preferentially on the trunk or extremities. The skin biopsy shows patchy, nodular or diffuse infiltration of the entire dermis and superficial subcutaneous fat tissue by small lymphocytes, lymphoplasmacytoid cells and plasma cells. 1,8 The skin histology in up to one-third of cases of SS may be non-specific. In others it may be similar to MF, but the infiltrate is characterized by a dense monomorphic proliferation of atypical small lymphocytes and epidermotropism may be absent. Immunophenotyping of the skin specimen shows the atypical cells to be CD4 positive with a variable loss of CD5, CD2 and CD7. The lack of expression of CD26 has been found to be a constant feature in SS and helps to distinguish it from other inflammatory conditions and cutaneous lymphomas. In SS, systemic chemotherapy has been recommended for those patients who are refractory or who present with extensive adenopathy and/or visceral involvement and require immediate palliation. Combination chemotherapy: the CHOP regimen, the EPOCH regimen (etoposide, vincristine, doxorubicin and cyclophosphamide/prednisolone bolus) and ESHAP (etoposide, methylprednisolone, highdose cytarabine and cisplatin) have shown better response rates and duration of remission compared with single chemotherapy agents such as purine analogues, methotrexate and liposomal doxorubicin. However, the risk of infection and myelosuppression are the main drawbacks of combination chemotherapy. Alemtuzumab (campath) an anti-cd52 monoclonal antibody and denileukin defitox (ONTAK), an interleukin-2 and diphtheria toxin chimerical monoclonal antibody represent the new class of therapeutic options in patients with advanced/relapsed disease. Vorinostat is a histone deactylase inhibitor being evaluated in CTCL patients. It probably acts by restoring the expression of tumour suppressor or cell cycle regulatory genes by increasing the acetylation of histones. 9,10 In conclusion, SS is a rare aggressive CTCL. It should be suspected in any patient presenting with erythroderma with or without associated skin lesions. Clinical presentation with a combination of complete blood counts and peripheral smear examination (for Sézary cells), histopathology, immunophenotyping and molecular genetic studies are required to confirm the diagnosis. Most patients present with advanced-stage disease and treatment is palliative. REFERENCES 1. Willemze R, Jaffe ES, Burg G, Cerroni L, Berti E, Swerdlow SH et al. WHO-EORTC classification for cutaneous lymphoma. Blood 2005; 105: Hwang ST, Janik JE, Jaffe ES, Wilson WH. Mycosis fungoides and Sézary syndrome. Lancet 2008; 371: Vonderheid EC, Bernengo MG, Burg G, Duvic M, Heald P, Laroche L et al. Update on erythrodermic cutaneous T-cell lymphoma: report of the International Society of Cutaneous Lymphoma. Am. Acad. Dermatol. 2002; 46: Bazarbachi A, Soriano V, Pawson R, Vallejo A, Moudgil T, Matutes E et al. Mycosis fungoides and Sézary syndrome are not associated with HTLV-1 infection: an international study. Br. J. Hematol. 1997; 9b:

4 288 S Nassem et al. 5. Bernengo MG. Sézary syndrome. In: Orphanet Encyclopedia. Available from URL: (accessed 27 April 2008). 6. Waterhouse DR, Shetty S, Gathercole JS, Seely CJ. Sézary syndrome and otitis externa. Med. J. Aust. 2007; 186: Olsen E, Vonderheid E, Pimpinelli N, Willemze R, Kim Y, Knobler R et al. Revision to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphoma (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood 2007; 110: Demirre M, Kerl H, Willemze R. Primary cutaneous B-cell lymphomas: a practical approach. Hematol. Oncol. Clin. N. Am. 2003; 17: Whittaker SJ, Foss FM. Efficacy and tolerability of currently available therapies for mycosis fungoides and Sézary syndrome variants of cutaneous lymphomas. Cancer Treat. Rev. 2007; 33: Zinzani PL, Ferreri AJ, Cerroni L. Mycosis fungoides. Crit. Rev. Oncol. Hematol. 2008; 65:

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