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September-October 2020, Volume 17, Issue 5

The Dreaded Other Category: What's Different in This Differential?

Moe Takeda, MD Hematopathology Fellow
University of Chicago, Chicago, IL

Girish Venkataraman, MD Editor in Chief, ASH Image Bank; Medical Director, Immunohistochemistry; Associate Professor, Department of Pathology
The University of Chicago Medicine, Chicago, IL

Published on: August 28, 2020

A 66-year-old man with extensive history of skin neoplasms including actinic keratosis, basal cell carcinoma, and low-stage melanoma presents to clinic with a persistent, pruritic, and irritated rash. He initially noticed redness on his head and face after he returned from a vacation in Florida, and it quickly spread throughout his torso, arms, and legs (Figure 1). He denies fevers, chills, fatigue, night sweats, or change in appetite or weight. He denies any new soaps, detergents, shampoos, or medications including over-the-counter supplements.

Positron emission tomography/computed tomography obtained four months after the first presentation demonstrated mild bilateral axillary and inguinal lymphadenopathy measuring up to 1.4 cm with maximal standardized uptake value of 2.9 cm. Complete blood counts are shown in the chart. Peripheral blood smear (Figure 2) showed circulating atypical cells. Additional flow cytometry was performed; the plots are depicted in Figure 3, with the population of interest marked in green. Although not shown, the cells of interest were negative for CD34 and TdT.

Test	Result	Reference Range
White blood cell count	31.5 × 10³/μL	3.5-11.0 × 10³/μL
Hemoglobin	11.8 g/dL	11.5-15.5 g/dL
Platelet count	233 × 10³/μL	150-450 × 10³/μL
Absolute neutrophil count	4.88 × 10³/μL	1.12-6.72 × 10³/μL
Absolute lymphocyte count	2.99 × 10³/μL	0.9-3.30 × 10³/μL
Manual Differential
Neutrophils	16%	39-75%
Lymphocytes	10%	16-47%
Monocytes	2%	4-12%
Eosinophils	3%	0-7%
Basophils	1%	0-2%
Myelocyte	1%	0%
Other cells	67%	0%

What is the diagnosis?

Correct!

The peripheral smear shows medium-sized atypical lymphoid cells with highly convoluted cerebriform and frequently hyperchromatic nuclei, consistent with Sézary syndrome (SS). Flow cytometry on peripheral blood demonstrated a CD4⁺ lymphoproliferative disorder (CD4/CD8 ratio 46:1) with aberrant loss of CD7 and CD26. The background normal CD8 T-cells (red population; Figure 3) do not show loss of CD7. Additionally, T-cell receptor gene rearrangement studies performed on the blood confirmed a monoclonal T-cell process.

According to the World Health Organization (WHO), SS is defined by the triad of erythroderma, generalized lymphadenopathy, and presence of clonal neoplastic T cells with cerebriform nuclei in the skin, lymph nodes, and peripheral blood.^1,2 Additionally, at least one of the following is required for diagnosis of SS: 1) a total Sézary cell count of 1,000/μL or higher, 2) an expanded CD4⁺ T-cell population with a CD4:CD8 ratio of of 10 or higher, or 3) an expanded CD4⁺ T-cell population with abnormal immunophenotype, including loss of CD7 or CD26.¹ In addition to erythroderma, lymphadenopathy, and presence of Sézary cells in the peripheral blood, our patient showed a markedly elevated CD4:CD8 ratio as observed in the flow plots with loss of CD7 expression in CD4 T cells that also showed concomitant loss of CD26, fulfilling the diagnostic criteria of Sézary syndrome.

Mycosis fungoides (MF) and SS are considered to be closely related but separate entities, per the WHO and the European Organization of Research and Treatment of Cancer (EORTC), as the cell of origin is considered to be different (mature skin-homing CD4⁺ T cell for MF and central memory CD4⁺ T-cells for Sezary cells).^1-3 The diagnostic criteria for quantifying CD4⁺/CD7^- or CD4⁺/CD26^- lymphocytes has been proposed by EORTC based on preliminary studies reporting some association of disease progression with loss of CD7 and/or CD26, although the cut-offs regarding exact CD7^- or CD26^- neoplastic cells have not been established.^4,5 Other studies have proposed enumerating immunophenotypically aberrant CD4⁺ T cells for diagnosis of MF/SS rather than quantifying the CD4⁺ T cells with aberrant CD7 or CD26 separately.⁶

After the diagnosis, our patient was started on extracorporeal photopheresis–and bexarotene but was transitioned to mogamulizumab after two months without improvement with the initial treatment regimen. He had a complete response in the blood to mogamulizumab but developed new cutaneous tumors that were biopsy-confirmed as a cutaneous T-cell lymphoma relapse. Treatment was changed to romidepsin with total skin electron beam; he has achieved a near complete response and is now awaiting bone marrow transplantation.

Follicular lymphoma (FL) is an incorrect choice. The cytomorphology of peripheral blood involvement by FL can show small- to medium-sized cells with occasional cleaved nuclei (“buttock cell”), inconspicuous nuclei, and scant pale cytoplasm. However, hyperchromatic cerebriform clefted nuclei is not typical. Likewise, the T-cell phenotype excludes the possibility of FL, which is a B-cell process.

Pertussis related lymphocytosis is also an incorrect choice. Pertussis can cause significant lymphocytosis, and the atypical lymphocytes of pertussis infection can have clefted nuclei. However, these are neither cerebriform nor have an abnormal T-cell phenotype, and the disease occurs in much younger pediatric age groups, typically without cutaneous manifestations.

T-lymphoblastic leukemia (T-ALL) is also an incorrect answer. Although T-ALL can occur in any age group and can have variable morphology including medium-sized cell with condensed nuclei and occasional blastoid cells as seen here. However, the flow phenotype with single CD4⁺ and CD7^– as well as lack of TdT and CD34 does not support T-ALL, which frequently exhibits CD4^–/CD8^- or CD4⁺/CD8⁺ phenotype with uniform CD7 and expression of TdT and CD34 (Figure 3).

References

Swerdlow SH, Campo E, Harris NL, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. World Health Organization: Intl Agency for Research on Cancer. 2017.
Pulitzer MP, Horna P, Almeida J. Sézary syndrome and mycosis fungoides: An overview, including the role of immunophenotyping. Cytometry B Clin Cytom. 2020; doi: 10.1002/cyto.b.21888.
Olsen E, Vonderheid E, Pimpinelli N, et al. Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood. 2007;110:1713-1722.
Scarisbrick JJ, Hodak E, Bagot M, et al. Developments in the understanding of blood involvement and stage in mycosis fungoides/Sezary syndrome. Eur J Cancer. 2018;101:278-280.
Scarisbrick JJ, Hodak E, Bagot M, et al. Blood classification and blood response criteria in mycosis fungoides and Sézary syndrome using flow cytometry: recommendations from the EORTC cutaneous lymphoma task force. Eur J Cancer. 2018;93:47-56.
Lyapichev KA, Bah I, Huen A, et al. Determination of immunophenotypic aberrancies provides better assessment of peripheral blood involvement by mycosis fungoides/Sézary syndrome than quantification of CD26- or CD7- CD4+ T-cells. Cytometry B Clin Cytom. 2020; doi: 10.1002/cyto.b.21933. [Epub ahead of print].

Dr. Takeda and Dr. Venkataraman indicated no relevant conflicts of interest.