Double-positive CD4 and CD8 Sézary syndrome.

Sézary syndrome (SS) is a malignancy of CD4+ central memory T-lymphocytes, characterized by the triad of erythroderma, lymphadenopathy, and involvement of peripheral blood by neoplastic cells. We describe a rare case of double-positive CD4 and CD8 SS.

Case report

An 83-year-old man presented to our clinic with pruritic skin lesions of 7 months' duration. The physical examination revealed erythroderma, nonscarring diffuse alopecia, palmoplantar keratoderma, onychodystrophy, edema of the lower limbs, and ectropion, without lymphadenopathy or weight loss (Fig 1). His medical history included hypertension and diabetes mellitus. He denied previous skin diseases, exposure to new medications, or possible allergens.

Fig 1

Diffuse erythema and scaling.

Three simultaneous skin biopsy specimens obtained for pathologic examination revealed psoriasiform dermatitis with mild spongiosis and exocytosis of small lymphocytes and, in one of the biopsy specimens obtained, there were groups of 3 or 4 atypical lymphocytes with clear halos infiltrating the epidermis (Pautrier microabscesses). Immunohistochemical staining showed positivity for CD3, CD4, and CD8, without significant loss of CD7 in dermal and epidermal lymphocytes (Fig 2, Fig 3).

Fig 2

Immunohistochemistry showing exocytosis of small lymphocytes positive for CD4. (Original magnification: ×100.)

Fig 3

Immunohistochemistry showing exocytosis of small lymphocytes positive for CD8. (Original magnification: ×100.)

T-cell receptor (TCR) gene rearrangement analysis detected monoclonal proliferation, with the same clone of lymphocytes present in peripheral blood and infiltrating the skin. Sézary cell count was 2192 cells/mm3; immunophenotyping of lymphocytes showed 68.5% of lymphocytes with double positivity for CD4 and CD8 (Fig 4, A), 30% of these cells did not express CD7, and 100% did not express CD26. Human T cell lymphotropic virus serology was negative. The total lymphocyte count was 2610 cells/mm3 (normal range, 900-3400 cells/mm3) and lactate dehydrogenase was 333 U/L (normal range, 135-225 U/L). General laboratory tests showed no significant abnormalities.

Fig 4

A, Immunophenotyping of lymphocytes. Sixty-eight percent of CD4+ and CD8+ malignant cells. B, CD107a and interferon gamma production after stimulation with phorbol miristate acetate in TCD4+CD8+ neoplastic cells, TCD4+CD8–, and TCD4–CD8+ cells. Peripheral blood mononuclear cells were cultured with phorbol miristate acetate (50 ng/mL) and ionomycin (1 μg/mL) for 20 hours. T cells were assessed for interferon production and activation markers expression by flow cytometry.

Imaging studies showed axillary lymph node enlargement up to 3 cm bilaterally, without other significant findings, but a biopsy specimen was not obtained because the patient was lost to follow-up.

A diagnosis of double-positive CD4 and CD8 SS was made.

We evaluated the production of activation/inhibition molecules (CD69 and PD-1) and effector molecules (interferon gamma and CD107a), on TCD4+CD8+, TCD4+CD8–, and TCD4–CD8+ cells unstimulated and after stimulation with phorbol myristate acetate (Fig 4, B and Table I). Expression of CD69 and PD-1 were similar between the groups, but CD4+CD8+ T cells were less responsive to the production of interferon gamma. Also, expression of CD107a, an indicator of cytotoxicity, were 5 times lower in CD4+CD8+ cells than in CD4+CD8– cells.

Table I

PD-1, CD107a, CD69, and interferon gamma before and after stimulation with phorbol myristate acetate

	TCD4+CD8+ (68.5%)		TCD4+CD8– (21.3%)		TCD4–CD8+ (10.3%)
	UNS	PMA	UNS	PMA	UNS	PMA
PD-1+	0.02%	0.38%	0.01%	0.29%	0.09%	72.1%
	142 (MFI)	182 (MFI)	82 (MFI)	107 (MFI)	65 (MFI)	1246 (MFI)
CD107a+	0.18%	1.07%	0.08%	5.84%	0.29%	87.1%
	882 (MFI)	447 (MFI)	416 (MFI)	297 (MFI)	437 (MFI)	11409 (MFI)
CD69+	0.28%	85.1%	0.04%	53.3%	5.80%	95.9%
	608 (MFI)	5676 (MFI)	297 (MFI)	3126 (MFI)	1010 (MFI)	9491 (MFI)
Interferon gamma–positive	0.02%	1.42%	0%	2.21%	0.15%	0.49%

MFI, Mean fluorescence intensity; PMA, phorbol myristate acetate; UNS, unstimulated.

Discussion

SS is a cutaneous T-cell lymphoma with peripheral blood involvement by malignant cells (Sézary cells). Clinically, it presents with erythroderma and varying degrees of skin infiltration, nonscarring diffuse alopecia, palmoplantar keratoderma, nail involvement, lymphadenopathy, intense pruritus, and weight loss. One to 10% of erythroderma, or exfoliative dermatitis, is caused by SS.

Diagnostic criteria include T-cell receptor (TCR) gene rearrangement analysis with a monoclonal population of T-lymphocytes in the blood and matching clone infiltrating the skin. Sézary cell count in peripheral blood smear should be ≥1000 cells/μL or should have 1 of 2 immunophenotypic criteria, which are a CD4/CD8 ratio ≥10 or increase in CD4 cells with abnormal phenotype (CD4+CD7– ≥40% or CD4+CD26– ≥30%).

Formerly thought to be a leukemic variant of mycosis fungoides, there are now different opinions if SS may be considered another disease, with different immunophenotypes of malignant cells and different genetic mutations.4, 5 Occasionally, with the improvement of erythroderma, classic lesions of mycosis fungoides become evident, contrary to the hypothesis that they may be different diseases.

Classically, SS is a CD4+ T-cell neoplasm, with the lymphocytes expressing the pan-T CD3 cell marker, CD4 phenotype, CCR4 (skin homing adressin), CCR7, and L-selectin (lymph node homing adressins), the immunophenotype of central memory T-lymphocytes. By contrast, mycosis fungoides malignant cells express CCR4 and cutaneous lymphocyte antigen but lack lymph node homing adressins.

There are few reports of CD8+ cutaneous T-cell lymphomas, with different clinical presentations and outcomes. Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma is a provisional entity with aggressive clinical course. There are few reports of other cutaneous T-cell lymphomas expressing the CD8 phenotype, such as pagetoid reticulosis, mycosis fungoides, lymphomatoid papulosis, cutaneous anaplastic large cell lymphoma, and SS.6, 7

Double-positive CD4 and CD8 lymphoproliferative diseases are extremely rare, with anecdotal reports in the literature. Most cases had adult T-cell leukemia/lymphoma and large granular lymphocytic leukemia. There was 1 report of CD4+CD8+ mycosis fungoides and 1 report of double-positive SS.

A previous study from our group showed a deficient immune response in patients with SS. The data suggest that double-positive CD4+CD8+ neoplastic T-cells shows a lower cytotoxic potential compared to CD4+CD8– cells.

Conclusions

We report an unusual case of double-positive SS in an erythrodermic patient. We emphasize the need for comprehensive and detailed clinical and laboratory investigation of every patient who presents with erythroderma. Careful evaluation should be made to detect any infectious or tumoral progression in patients with double-positive CD4 and CD8 SS because of their immunosuppressive state.