An Erythrodermic Patient with Associated Leucoderma – An Unusual Presentation of Sezary Syndrome

BULLETIN FOR MEDICAL PRACTITIONERS

Dr Mark Tang, Registrar
Dr Tan Suat Hoon, Consultant
National Skin Centre

Introduction

Sezary syndrome is a rare leukaemic variant of erythrodermic mycosis fungoides. We describe a patient with Sezary syndrome presenting with both generalized erythroderma and extensive well-demarcated vitiligo-like leucoderma of his lower limbs. Apart from the absence of melanocytes in the leucodermic skin, histopathological features of both areas were identical, showing an inflitrate of atypical lymphocytes with epidermotropism.

Case Report

A 42-year old Malay man, of skin type IV, presented with a 3-year history of pruritic erythematous rashes over his trunk and arms. The erythematous rash had gradually progressed and had become generalized over the past 1 year. However, he had also noted progressive depigmented patches over his lower limbs over the same duration. There were no other systemic complaints such as fever, night sweats or weight loss. Apart from intermittent oral anti-histamines and oral steroids prescribed by his general practitioner, there was no recent ingestion or topical application of any other medication. There was no history of exposure to any toxic chemicals.

Physical examination revealed generalized erythroderma of his face, scalp and body. There was extensive well-demarcated vitiligo-like depigmented patches over both his lower limbs, mainly over his shins and thighs, distributed in a fairly symmetrical manner (Fig 1). In addition, there were some smaller depigmented patches scattered over his chest and abdomen as well. Enlarged inguinal lymph nodes measuring 2cm x 2 cm were found bilaterally but no axillary or cervical lymphadenopathy was found. There was no associated hepatosplenomegaly.

Histological examination of both the erythrodermic (Fig 2) and leucodermic skin specimens showed infiltrates of atypical lymphocytes with epidermotropism. In addition, the leucodermic skin specimen revealed a loss of melanocytes in the epidermis. Immunohistochemical studies showed that these atypical lymphocytes were CD3, CD4, CD5 positive and CD8 negative, consistent with epidermotropic CTCL involving CD4+ T-helper cells. Other investigations done showed a markedly raised white cell count of 58,900 cells/mm 3 with 90% lymphocytes, 8% neutrophils and 2% monocytes. Peripheral blood examination detected 60% involvement of atypical lymphocytes with cerebriform nuclei. Flow cytometry of his blood demonstrated that the majority of lymphocytes were CD3+, CD4+, CD5+, CD7+, CD8-, CD20-, CD19-, Tdt- cells, suggestive of a T-cell lymphoproliferative disorder. T-cell gamma gene receptor analysis of the peripheral blood by multiplex polymerase chain reaction (PCR)-agarose gel electrophoresis detected the presence of gamma gene rearrangement in the V-J region.

A complete biochemical evaluation, including hepatic and renal function tests, HIV serology and serum immunoglobulins revealed no abnormalities. Chest X-ray examination was normal. Computerised tomography of the
abdomen and pelvis revealed only bilateral inguinal lymphadenopathy without concomitant enlargement of the liver, spleen and other intra-abdominal lymph nodes. Lymph node biopsy and bone marrow studies were not performed because the patient did not consent to these investigations.

The diagnosis of Sezary syndrome with clinical lymph node involvement was made. As the patient refused systemic chemotherapy, he underwent total skin electron beam therapy (TSEB) as palliative therapy, after his pruritus had become unbearable. The patient received a total dose of 29 Gys over a 12-week period with good control of his symptoms. The complete blood count done subsequently showed a marked reduction of the white cell count to 15,000 cells/mm 3 with 47% lymphocytes. Although he remained relatively symptom-free, there was no evidence of re-pigmentation of the leucoderma of his lower limbs and body.

Discussion

Sezary syndrome is a rare neoplasia of malignant T-lymphocytes and a leukaemic variant of mycosis fungoides. The diagnosis of Sezary syndrome in this patient was based on the findings of erythroderma, lymphadenopathy, compatible skin histology and the presence of >5% circulating atypical lymphocytes (Sezary cells) in the peripheral blood. This was further confirmed with peripheral blood TCR gene analysis which detected a monoclonal T-cell rearrangement. TCR gene analysis by PCR method is currently the most sensitive method available to distinguish patients with a genuine T-cell leukemia such as Sezary syndrome from those with reactive forms of erythroderma. This method has a reported sensitivity of 90-100%1 . It is also interesting to note that in this case, flow cytometry of the patient’s blood revealed predominant CD7+ lymphocytes. While loss of the pan-T cell CD7 antigen has been proposed as a marker for circulating Sezary cells, some cases of CD7+ Sezary syndrome have been reported previously.2 Recently, loss of CD26 has been reported to be possibly superior to the loss of other markers, including CD7, in Sezary syndrome. It has been suggested that the lack of CD26 is a constant feature in Sezary syndrome and that the levels of CD4+CD26- subpopulation correlate with the extent of peripheral blood involvement 3 .

This patient further illustrates the interesting but uncommon association of Sezary syndrome with leucoderma. The features of epidermotropic cutaneous T-cell lymphoma (CTCL) involving CD4+ T-helper cells was demonstrated histologically from both the erythrodermic and leucodermic sites.

The association of leucoderma and CTCL is uncommon. A recent paper by investigators for the French Study Group on Cutaneous Lymphomas reported only 4 patients with extensive leucoderma out of 82 patients followed by their group for erythrodermic CTCL since 1994. Of the 4 cases, 2 had Sezary syndrome and 2 had erythrodermic CTCL with equal sex distribution and a mean age of 65 years (range 60-78). 3 of them were fair skinned Causacians and 1 was a dark-skinned African. The leucoderma occurred together with a flare of the CTCL 1-5 years after the onset of erythroderma and regressed with treatment of the disease. The clinical features of the lesions were similar in all cases, with depigmented patches located over the trunk and the limbs.4 Other isolated case reports were of a 62 year old Yemenite Jew with a 2 year history of idiopathic erythroderma that was subsequently diagnosed as Sezary syndrome 5 and another case of vitiligo associated with Sezary syndrome mentioned in a review article on vitiligo.6

Other important causes of leucoderma in a patient with CTCL include toxic chemical leucoderma 7 and
previous PUVA treatment 8 ; but there was no history of such exposure in this patient.

Leucoderma associated with Sezary syndrome must be clearly differentiated from hypopigmented mycosis fungoides (MF). Hypopigmented MF is a common variant of MF in Asians, predominantly presenting in dark-skinned individuals with a younger age of onset.9 It is noteworthy that our patient developed both generalized erythroderma and leucoderma of his lower limbs at around the same time. This clearly differs from hypopigmented MF where hypopigmented patches, rather than depigmented lesions, are the sole manifestation of the disease and there is no associated erythroderma or leukaemic involvement. The lesions in hypopigemented MF show a good response (including repigmentation) to therapy.10,11

Apart from the lack of melanin and pigmentation of the leucodermic skin, the histological picture of both the
erythrodermic and leucodermic skin showed identical pathological features of an epidermotropic infiltrate of
atypical lymphocytes. The absence of melanin and melanocytes in the leucodermic skin suggest that melanocyte destruction had resulted in the depigmentation. Possible mechanisms include cell-mediated destruction by tumour or reactional lymphocytes or the production of anti-melanocyte autoantibodies which were formed secondary to the release of antigens from previously damaged melanocytes. Both these theories are consistent with the T-cell mediated autoimmune basis of vitiligo.12 Other less likely mechanisms include altered melanocyte function and disordered melanogenesis which have been found to play a role in hypopigmented MF lesions 13 or the role of post-inflammatory hypopigmentation secondary to the inflammatory process in Sezary syndrome 7 .

Based on the TMN staging criteria 14, our patient has Stage IIIb (T4,N1,M0 B1) erythrodermic cutaneous T-cell lymphoma. This portends a poor prognosis as the the most important prognostic factor is the stage of skin disease at presentation.15 Other poor prognostic factors in this case include the presence of lymphadenopathy and the detection of a peripheral blood clone which has now been shown to be an independent prognostic factor since it reflects a higher tumour burden in these patients 16. The erythrodermic stage of the disease is associated with a median survival time of less than 30 months. The prognostic significance of leucoderma in Sezary syndrome is not certain although it has been reported to be associated with disease flares in Sezary syndrome.

Despite the availability of numerous therapeutic options, the treatment of cutaneous T-cell lymphoma remains challenging. No curative treatment exists for Stage III disease and therapy is considered palliative for most
patients, as in our case. Our patient underwent total skin electron beam therapy (TSEB) which managed to relieve him of his intractable pruritus with a concomitant fall in his total white cell count. However, results from TSEB alone are often not sustained and should ideally be combined with other modalities such as systemic chemotherapy or extra-corporeal photochemotherapy. The emergence of new FDA-approved agents such as targretin, a new synthetic retinoid, and Ontak, a novel interleukin-2- diptheria toxin fusion protein, may have an important role to play in the future management of such cases of advanced CTCL.17

Acknowledgements

We acknowledge the help of Dr Lim Lay Cheng, Consultant Haematologist, Singapore General Hospital, who was involved in the co-management of the patient.

References

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