Atypical presentation of Sézary Syndrome with CD4+/CD7+/CD26- T-cells and marked epidermotropism: A case report and literature review

Gabriela Maloney, DO,* Sujata Gaitode, MD,** Igor Altman, MD,*** Marylee Braniecki, MD**

*Traditional Rotating Intern, Largo Medical Center, Largo, FL **University of Illinois Hospital & Health Sciences System, Wound Care, Chicago, IL ***University of Illinois Hospital & Health Sciences System, Dermatology Department, Chicago, IL

Abstract We present an atypical case of Sézary syndrome in a 46-year-old African American female who presented with tenderness, pruritus, hyperpigmented lesions and lymphadenopathy. Her condition was characterized by the retention of T-cell CD7 expression, significant atypical lymphocytic epidermotropism that histologically mimicked , and circulating Sézary cells ( CD4+/CD7+/CD26-) of fewer than 1000/uL. It is important to recognize this unique presentation and be able to differentiate it from mycosis fungoides (MF), as this can significantly alter the prognosis and treatment while having an impact on the patient’s life. Introduction Mycosis fungoides (MF) is the most common type of cutaneous T-cell , accounting for approximately 50% of cases. It has three main clinical stages, including patch, plaque, and tumor, all with epidermotropic infiltrates of small- to medium-sized neoplastic T cells. Early MF tends to have neoplastic with an immunohistochemical profile positive for CD3, CD4 and CD45, and negative for CD7 and CD8.1Sézary syndrome (SS) is a rare, leukemic variant of cutaneous T-cell lymphoma characterized by cerebriform cells (Sézary cells), erythroderma and pruritus along with circulating, mature neoplastic T cells. Symptoms often Figure 1. Multiple breast erosions. develop insidiously, making the diagnosis very severe pruritic cutaneous lesions in both breasts Figure 2. Atypical lymphocytic infiltrates in difficult, often taking up to an average of 20.5 2 that started as bruises and progressed to erosions epidermis and dermis associated with erosion months from symptom onset to diagnosis. and sloughing of skin (Figure 1). She also had on breast skin (50x). Loss of CD7 expression has been reported small, erythematous, crusted papules on her as the most commonly used method for bilateral temples that extended down to the sides detection of cutaneous T-cell . of her neck and were accompanied by a severe However, CD7 expressivity has been reported burning sensation. The patient then progressed to to be highly variable.3-6 Studies have found that develop erythroderma covering 70% of her body some patients that were CD4+/CD7+ in early surface area. studies demonstrated loss of CD7 expressivity Skin biopsies of the breast were performed and over time, therefore making it a less reliable revealed a CD4-positive T-cell lymphoma with marker to separate normal from neoplastic cell foci of atypical cell aggregates within the epidermis populations.3,5 (epidermotropism and Pautrier microabscesses) associated with extensive papillary dermal involvement by atypical lymphoid infiltrate Case Report composed of small- to medium-sized cells Figure 3. Scalp with prominent epidermal and A 46-year-old African American female presented (Figure 2). The atypical lymphoid infiltrate was follicular involvement by atypical lymphocytes with tenderness, pruritus and hyperpigmented positive for CD4 and CD7, and negative for (50x). lesions on both breasts shortly after completing CD8. Direct immunofluorescence study for IgG, two months of radiation for breast cancer on the did not meet the criteria for Sézary syndrome. IgA, IgM, C3, and fibrinogen were all negative. left breast. She was staged T2N0M0, ER+, PR-, The neoplastic T-cells did not express CD56 or Because of the CD7 positivity, the patient was CD26. The clonal T-cell receptor gamma HER-2/neu- and Ki-67 30% and underwent tested for HTLV, which was negative. a lumpectomy, five months of chemotherapy rearrangement was detected, and the CD4:CD8 with doxorubicin and cyclophosphamide, and Biopsies of the scalp vertex and occipital scalp ratio was approximately 15:1 (Figure 6, p. 50). demonstrated similar morphologic findings with radiation. The patient also had breast tenderness, The patient was diagnosed with an atypical case a periadnexal and folliculotropic distribution warmth, peau d’orange appearance, and axillary of Sézary syndrome associated with a prominent (Figure 3). Immunophenotyping demonstrated lymphadenopathy, which raised a concern for CD4+/CD7+, “mycosis fungoides-like” cutaneous CD4, CD5 and CD7 positivity, with a marked mastitis. The patient did not respond to two histology. The presence of epidermotropism, increase of CD4:CD8 of approximately 10:1 courses of antibiotics. Breast biopsies showed atypical T-cell morphology and clonal T-cell (Figures 4 and 5, p. 50). Testing was negative for mild acute and chronic inflammation, with no rearrangement helped distinguish this case from CD8, CD10, CD30, CD56, and BCL6. signs of malignancy. Left axillary lymph-node reactive benign dermatoses. biopsy with flow cytometry demonstrated a Peripheral blood flow cytometry indicated The patient was staged IVA1. She was started peripheral T-cell lymphoma. atypical circulating T-cell lymphocytes that on bexarotene, prednisone, photophoresis and appeared Sézary by morphology, but the Sézary A few months later, the patient developed more topical pimecrolimus. cell count was only 800 cells/uL and therefore MALONEY, GAITODE, ALTMAN, BRANIECKI Page 49 plaque stage is very similar but with elevation Epidermotropism is often absent or minimal Discussion and induration present, typically presenting in in SS; therefore, only approximately 60% of In the case presented here, the patient’s 2 initial cutaneous patches and the histological continuity with the patches. Tumors develop skin biopsies are diagnostic for SS. An atypical within the patches or plaques, but not all patients infiltrate at the dermoepidermal evaluation showing epidermotropism of atypical 1 lymphocytes lead to a possible diagnosis of progress to this stage. Histologically, neoplastic junction, eosinophilia, parakeratosis, acanthosis, mycosis fungoides. However, the patient’s rapid T-cell infiltrates appear within the superficial and spongiosis are the most common progression of skin involvement along with dermis accompanied by sparse epidermotropism histopathological features of SS. However, those and no spongiosis in the early stages of the findings are also commonly seen in many benign persistent CD7 expression on the lymphocytes 9 and presence of circulating atypical (CD4+/ disease. As the lesions progress, intraepidermal inflammatory conditions. CD7+/CD26-) lymphocytes in the blood collections of lymphocytes (Pautrier Sézary syndrome typically is diagnosed based supported the diagnosis of Sézary syndrome. microabscesses) and well-developed, band-like on evidence of molecular clonality of T-cell 1Early Mycosis fungoides (MF) is the most common lichenoid lymphocytic infiltrates are seen. gene rearrangement, absolute Sézary cell count MF tends to have neoplastic lymphocytes with an 3 type of cutaneous T-cell lymphoma, accounting greater than or equal to 1,000 cells/mm, a for approximately 50% of the cases. It has three immunohistochemical profile positive for CD3, CD4:CD8 ratio greater than or equal to 10 by primary, distinct clinical stages: patch, plaque, CD4 and CD45, and negative for CD7 and flow cytometry, >40% loss of CD7, >36% loss of and tumor. All stages are characterized by CD8. Even though the immunohistochemical CD26, and presence of CD25.9 epidermotropic infiltrates of small- to medium- profile of our patient was CD7+, there have been The differential diagnosis for Sézary syndrome sized neoplastic T cells. MF has a median age of reports of CD7+ MF reported in the literature. includes (but is not limited to) generalized atopic presentation of 57 years, affecting men more often T-cell clones are identified in anywhere from dermatitis, pityriasis rubra pilaris, erythrodermic than women with a 2:1 ratio. It is commonly seen 57% to 70% of cases. Loss of pan-T-cell antigens hypersensitivity reactions, parapsoriasis, DRESS in photoprotected areas, especially the buttocks, (CD2, CD5, and CD7) has also been reported 1 syndrome, dermatomyositis, graft-versus-host- groin, upper thighs, breasts, and axilla. The in early patch stages of MF, which can be useful disease, generalized anaphylaxis, erythrodermic patch stage is characterized by 5 cm to 10 cm, to distinguish it from psoriasis and spongiotic dermatitis.3 Detection of the same clones from MF, acute or chronic leukemias, CTCL spectrum round, erythematous patches with a wrinkled 9 disease. Prognosis is generally poor, with a appearance and a fine overlying scale. The two different anatomical locations, as occurred in our case, has been shown to increase sensitivity median survival of four years from time of 10 and specificity when diagnosing MF.7Early diagnosis. Sézary syndrome has historically been MF can be very difficult to diagnose, often considered to arise from pre-existing MF, as an requiring years and many different biopsies. advanced systemic presentation. However, recent The differential diagnosis includes spongiotic lymphocyte studies suggest that SS and MF are dermatitis, psoriasis, dermatophytic infections, two distinct entities arising from two different 11 chronic actinic dermatitis, lymphomatoid contact subsets of atypical T-cells. CD26 is a dipeptidyl dermatitis, and lymphomatoid drug reactions. peptidase IV normally expressed in the majority Pagetoid reticulosis, primary cutaneous aggressive of T lymphocytes in the peripheral blood. It is epidermotropic CD8+ T-cell lymphoma, adult a surface proteolytic enzyme related to cellular T-cell leukemia/lymphoma (ATLL), and types activation, and its absence or decreased expression B and D lymphomatoid papulosis (LyP) are is highly characteristic of mycosis fungoides and Figure 4. Scalp showing atypical CD7+ lymphomas that may be nearly identical to MF Sézary syndrome. Jones et al. reported CD26 epidermotropic T cells (50x). histopathologically. Clinical presentation is most positivity ranging from 56% to 86% of CD4+ helpful in differentiating these cases, highlighting T-cells of healthy control subjects. They also the importance of good communication between reported loss of CD26 expressivity in 59 of 66 the dermatologist and dermatopathologist in this cases of MF or SS, with the remaining seven case.1 cases having only a dim expression of CD26. They concluded that absence of CD26 is a very useful A recent study demonstrated that only 9% of 4 marker when diagnosing MF or SS. CD7 is a the lesional lymphocytes are atypical and that glycoprotein belonging to the immunoglobulin reactive lymphocytes are also present in addition gene superfamily and is thought to be involved to the neoplastic cells, making architectural in signal transduction. It is expressed in almost all abnormalities more important than cytological CD8+ T cells and in approximately 90% of CD4+ 8,9Prognosis differences when diagnosing MF. T cells. CD7 expression in healthy subjects has varies according to the stage of the disease and been reported to be positive in 73% to 97% of the surface area involved. The risk of progression 4 Figure 5. Scalp with CD4+ uptake by non-neoplastic lymphocytes. The percentage of and visceral involvement tends to increase with lymphocytic infiltrate (30x). CD4+/CD7- T cells may correlate with Sézary- increasing surface area, presence of tumors cell counts in SS, but it is unknown whether and erythroderma. Subtypes of MF with no this is a result of neoplastic expansion of CD4+/ difference in prognosis include dyshidrotic MF, CD7- cells or aberrant loss of CD7 expressivity hypopigmented MF, and acanthosis-nigricans- in malignant T cells.5Loss of CD7 expression 1Sézary syndrome (SS) is a rare, leukemic like MF. has been reported to be the most commonly variant of cutaneous T-cell lymphoma. It is used method for detection of cutaneous T-cell characterized by cerebriform cells (Sézary cells), lymphomas. It is also believed that the size of the erythroderma, pruritus and circulating mature CD7- T cells correlates with disease progression neoplastic T-cells. Palmoplantar keratoderma, 12 in MF and SS. However, CD7 expressivity has subungual hyperkeratosis, yellow discoloration, been reported to be highly variable: Studies have nail thickening, onychomadesis, alopecia, and found up to 50% of MF or SS patients with a ectropion are also distinguishing features of SS. positive CD7 marker in their neoplastic T-cells.3-6 Symptoms often develop insidiously, making the Jones et al. speculated that CD7 expression may diagnosis very difficult, often taking an average of Figure 6. Scalp with very limited CD8 uptake 2 be vulnerable to reactive T-cell populations, 4 (30x). 20.5 months from symptom onset to diagnosis. concurrent illness, and effects of treatments.

Page 50 ATYPICAL PRESENTATION OF SÉZARY SYNDROME WITH CD4+/CD7+/CD26- T-CELLS AND MARKED EPIDERMOTROPISM: A CASE REPORT AND LITERATURE REVIEW Studies have also found that some patients who were CD4+/CD7+ in early studies demonstrated References 3,5 1. Pincus LB. Mycosis Fungoides. Surg Pathol loss of CD7 expressivity over time. This could Clin. 2014;7(2)143-167. explain the highly variable CD7 expression in MF and SS and makes it a less reliable marker to 2. Booken N, Nicolay JP, Weiss C, et al. Cutaneous separate normal from neoplastic cell populations. tumor cell load correlates with survival in patients with Sézary syndrome. J Dtsch Dermatol Ges. It is possible that our patient presented with a 2013;11:67-79. very early stage of Sézary syndrome in which there has not been enough CD7 loss, but the 3. Florell SR, Cessna M, Lundell RB, fact that the patient did not express CD26 is a et al. Usefulness (or lack thereof) of confirmatory marker for the presence of Sézary immunophenotyping in atypical cutaneous T-cell syndrome. Failure to meet the required criterion infiltrates. Am J Clin Pathol. 2006;125:727-36. of 1000 Sézary cells/uL can also be attributed to 4. Jones D, Dang NH, Duvic M, et al. Absence of early stages of the disease. CD26 expression is a useful marker for diagnosis Some sources define a Sézary cell count of >500 of T-cell lymphoma in peripheral blood. Am J cells/uL as diagnostic “substantial peripheral Clin Pathol. 2001;115(6):885-92. blood involvement” when erythroderma is also 5. Vonderheid EC, Bigler RD, Kotecha A, et 4 present. al. Variable CD7 expression on T cells in the leukemic phase of cutaneous lymphoma Conclusion (Sézary Syndrome). J Invest Dermatol. The overlapping features of mycosis fungoides 2001;117(3):654-62. and Sézary syndrome seen in this patient posed 6. Steinhoff M, Schopp S, Assaf C, et al. a diagnostic dilemma. The patient had severe Prevalence of genetically defined tumor cells pruritus and was initially diagnosed with a T-cell in CD7 as well as CD26 positive and negative lymphoma by axillary-node biopsy. Subsequent circulating T-cell subsets in Sézary Syndrome. skin biopsies showed significant atypical Leuk Res. 2009;33(1):88-99. lymphocytic epidermotropism and histologically appeared as mycosis fungoides, with a CD4:CD8 7. Thurber SE, Zhang B, Kim YH, et al. T-cell ratio of approximately 15:1 and T-cell clonal clonality analysis in biopsy specimens from two rearrangement. There was retention of T-cell different skin sites shows high specificity in the CD7 expression on the atypical lymphocytes, and diagnosis of patients suggested mycosis fungoides. the patient proceeded to develop erythroderma J Am Acad Dermatol. 2007;57:782-90. with evidence of circulating (CD4+/CD7+/ 8. Massone C, Kodama K, Kerl H, et al. CD26-) Sézary cells but did not fulfill the Histopathologic features of early (patch) lesions diagnostic criterion of a 1,000 cells/uL Sézary of mycosis fungoides: a morphologic study on cell count. 745 biopsy specimens from 427 patients. Am J This case was classified as “atypical” because the Surg Pathol. 2005;29:550-60. patient had clinical features of Sézary syndrome 9. Kubica AW, Pittelkow MR. Sézary Syndrome. with evidence of circulating (CD4+/CD7+/ Cutaneous Lymphomas. Surg Pathol Clin. CD26-) Sézary cells but also had significant 2014;7(2)191-202. epidermotropism, which is not typically seen 10. Kubica AW, Davis MD, Weaver AL, et al. with Sézary syndrome. Thus, a diagnosis of an Sézary syndrome: a study of 176 patients at Mayo atypical Sézary syndrome was favored, instead Clinic. J Am Acad Dermatol. 2012;67:1189-99. of erythrodermic MF, due to the advanced stage of disease at clinical presentation and rapid 11. Campbell JJ, Clark RA, Watanabe R, et al. progression of skin involvement. This case is Sézary syndrome and mycosis fungoides arise anticipated to undergo genotypic profiling to from distinct T-cell subsets: a biologic rationale better understand the complexity of the circulating for their distinct clinical behaviors. Blood. T cell (CD4+/CD7+/CD26-) subset seen in this 2010;116:767-71. patient with atypical Sézary syndrome. 12. Harmon CB, Witzig TE, Katzmann JA, et al. Detection of circulating T-cells with CD4+CD7- immunophenotype in patients with benign and malignant lymphoproliferative dermatoses. J Am Acad Dermatol. 1996;35:404-10.

Correspondence: Gabriela Maloney, DO; [email protected]

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