A rare case of Sézary syndrome - A diagnostic challenge

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A 67-year-old lady presented with skin rashes for 6-years associated with severe pruritus, progressing to erythroderma requiring hospitalisation. Physical examination revealed cervical lymph node enlargement, goitre, sparse hair, erythematous plaques on the preauricular area [Figure 1a], and several infiltrating papulonodular lesions on bilateral temporal areas along with swelling of both eyelids on an erythematous scaly background. [Figure 1b]. Examination revealed palmoplantar keratoderma, fissures, and nail dystrophy. Additionally, she reported a weight loss of about 15 kg over the past four months. She had a 30-year history of hyperthyroidism and thyroid nodules, with regular outpatient follow-up but no active treatment. Histopathology of the lesion on the preauricular area showed epidermotropism of lymphocytes, with diffuse infiltration of lymphocytes surrounding blood vessels in the superficial dermis, and some of these lymphocytes exhibited increased size and mitotic features [Figure 2]. Immunohistochemical analysis was positive for CD3, CD4, CD5 and CD7, negative for CD8, CD2 and CD30 and approximately 50% positivity for Ki-67 [Figure 3]. Clonal rearrangement observed in tissue sections indicated monoclonal rearrangement of T-cell receptors (TCR). Laboratory examinations revealed the presence of Sézary cells in the blood smear. Flow cytometry analysis of peripheral blood indicated that CD3⁺CD4⁺CD26^- mature T-lymphocytes constituted 22.4% of the samples, accompanied by immunophenotypic abnormalities, suggesting the origin of Sézary syndrome (SS) tumour cells. Positron emission tomography (PET) and computed tomography (CT) scans revealed abnormal radioactive concentrations in multiple locations, including the skin, nodules, and thyroid, consistent with malignant lymphoma. A diagnosis of Sézary syndrome (SS) was made and the patient was referred to a cancer hospital. Patient was treated with intermittently with programmed cell death protein1(PD-1) blockade immunotherapy combined with cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisolone (CHOP) chemotherapy as well as PD-1 blockade immunotherapy combined with dexamethasone, ifosfamide, cisplatin, and etoposide (DICE) chemotherapy. Although there was a brief period of improvement, the overall treatment response was poor, leading to the decision to discontinue therapy. The patient was assessed quarterly for one year before discontinuing treatment and was subsequently lost to follow-up.

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Figure 1a:

Cervical lymph node enlargement, goitre enlargement, sparse hair, and a plaque on the preauricular area.

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Figure 1b:

Diffuse erythema and scaling on the back.

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Figure 2:

Biopsy from the plaque on the preauricular area showing epidermotropism with diffuse perivascular lymphocytic infiltration in the superficial dermis. Few lymphocytes exhibited increased size and mitotic features (Haematoxylin and eosin 40×).

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Figure 3:

Immunohistochemistry positive for CD3, CD4, CD5 and CD7, negative for CD8, CD20, CD30 and approximately 50% positivity for Ki-67. 100×.

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In the latest world health organisation classification of diseases, mycosis fungoides (MF) and SS are identified as two separate forms of cutaneous T cell lymphoma (CTCL).¹ Research findings by Carly M Harro et al;² revealed that tumour cells in SS and MF display different phenotypes and differentiation pathways. At times, it can be challenging to differentiate between erythrodermic MF and SS. Numerous studies suggest that circulating cells in MF and SS exhibit comparable naïve/memory maturation phenotypic heterogeneity and could indicate a continuum of the same disease process. Additionally, cases labelled as “MF transformation to SS” or “secondary SS” cannot be accurately separated from “de novo” SS solely through phenotypic analysis.³ Recent findings regarding phenotypic diversity among malignant cells in both forms of CTCL have led to a shift in perspective. The current consensus suggests that it is the various functional states and the extent of genetic changes, rather than the distinct origins of the cells, that dictate the presentation of CTCL in either the form of MF or SS.² A recent agreement from the European organization for research and treatment of cancer (EORTC) has proposed defining blood involvement considering phenotypic criteria instead of morphological ones, particularly when more than 1000/mm³ of CD4⁺CD26⁻ or CD4⁺CD7⁻ cells are present.⁴ The presence of a notable group of CD4₊ cells that do not express CD2, CD5, and/or CD7 is highly indicative (with specificity exceeding 90%) for MF in the majority of documented studies. Additionally, the absence of CD7 (≥40%) and/or CD26 (≥80%) shows high sensitivity (over 80%) and total specificity (100%) for SS.⁵ The constellation of characteristic erythroderma, circulating Sézary cells, and CD4⁺/CD7^- immunophenotype definitively fulfils the international society for cutaneous lymphomas (ISCL) or EORTC criteria for SS diagnosis. Most patients with CTCL exhibit patch/plaque stage MF and tend to have a favourable prognosis. Those with advanced-stage MF/SS necessitate a collaborative treatment strategy. While systemic chemotherapy can yield high response rates, these are often transient and accompanied by considerable side effects. Given that the treatment of advanced-stage MF/SS primarily focuses on palliative care, a strategy that involves stage-based sequential therapies in an escalated manner is recommended.⁵ Patients with SS are especially vulnerable to sepsis and the risk of death resulting from bacterial and viral infections.⁶ Our patient was in an advanced stage of disease with poor response to multiple lines of therapy. Given the treatment-refractory status and socioeconomic constraints, the prognosis remains unfavourable.

In conclusion, in cases of diagnostically challenging erythematous papulosquamous eruptions, we recommend a stepwise algorithm incorporating histopathology, immunohistochemical profiling, rearrangement studies for the gene for TCR and flow cytometric analysis to achieve timely diagnosis, which profoundly influences therapeutic outcomes.