Summary
Background
The early diagnosis of Sézary syndrome (SS) is challenging. Loss of CD7 and CD26 expression on CD4+ T cells is the currently used criterion in the initial diagnosis and staging of ...patients with SS.
Objectives
Our aim was to evaluate the respective value of CD26, CD7 and KIR3DL2 expression on CD4+ T cells and total lymphocytes at initial diagnosis of SS.
Methods
This prospective study included 254 patients with clinical features consistent with cutaneous T‐cell lymphoma seen at our institution between March 2014 and February 2019. Peripheral blood analysis by flow cytometry was performed for each patient at the time of diagnosis and during follow‐up. The diagnosis of SS was based on ISCL/EORTC criteria.
Results
The presence of KIR3DL2+ Sézary cells (SCs) ≥ 200 μL−1 correlated with the diagnosis of SS, with sensitivity of 88·6% and specificity of 96·3%. All 154 patients with either inflammatory skin disease or other haematological disease had KIR3DL2+ cells < 200 μL−1, while eight of them had CD4+ CD26− T cells ≥ 1000 μL−1. Of five patients with SS and lymphopenia, four had CD4+ CD7− T cells < 1000 μL−1 and three had CD4+ CD26− T cells < 1000 μL−1. However, all of them had KIR3DL2+ CD4+ T cells ≥ 200 μL−1. Among patients with available samples during evolution, all B1‐staged patients with ≥ 200 μL−1 KIR3DL2+ SCs at diagnosis evolved to B2 stage within 7 months.
Conclusions
KIR3DL2 expression on T cells is highly specific and helps the early diagnosis of SS, especially in those patients with lymphopenia.
What's already known about this topic?
In the ISCL/EORTC cutaneous T‐cell lymphoma (CTCL) categorization of blood involvement (B0–B2), B2 is defined as a T‐cell receptor clonal rearrangement in blood, associated with high blood‐smear Sézary cell (SC) count.
Flow cytometry was developed to circumvent interobserver variability of SC manual counts; however, it mostly relies on detection of cells lacking CD7 and/or CD26 expression.
We previously reported the reliability of KIR3DL2 as the first positive SC marker.
What does this study add?
Based on our analysis of 254 patients, we propose that KIR3DL2 be added to the ISCL/EORTC criteria for initial diagnosis of Sézary syndrome (SS) and B2 staging.
This marker improved sensitivity of SS B2‐stage CTCL diagnosis with a specificity > 95%, especially for patients with lymphopenia.
We found KIR3DL2 helped early diagnosis of SS and was more reliable than CD26 in assessing blood tumour burden during therapy.
What is the translational message?
SC quantification is the major means of staging at initial diagnosis and monitoring blood tumour burden in a clinical trials setting.
We recommend using a threshold value of KIR3DL2+ SCs ≥ 200 μL−1 or KIR3DL2+ SCs/lymphocytes ≥ 10% in the diagnostic criteria of SS and propose a novel algorithm for CTCL B2 blood staging.
Linked Comment: Sun and Wang. Br J Dermatol 2020; 182:1325–1326.
Summary
Background
Clinical and histological diagnosis of Sézary syndrome (SS) and mycosis fungoides (MF) is challenging in clinical routine.
Objectives
We investigated five blood markers previously ...described for SS (T‐plastin, Twist, KIR3DL2, NKp46 and Tox) in a prospective validation cohort of patients.
Methods
We included 447 patients in this study and 107 patients were followed up for prognosis. The markers were analysed by reverse transcriptase quantitative real‐time polymerase chain reaction (RT‐qPCR) on peripheral blood leucocytes and CD4+ T cells in a cohort of consecutive patients with early MF, erythrodermic MF and SS and compared with patients presenting with benign inflammatory dermatoses (BID) and erythrodermic BID. The markers were assessed in parallel to gold standard values such as CD4/CD8 ratio, loss of CD7 and CD26 membrane expression and CD4 absolute values. Sensitivity and specificity were analysed by receiver operator characteristic curves. The prognostic value of selected markers was analysed on a subset of patients. This study was conducted in one centre.
Results
We defined cut‐off values for each marker. T‐plastin, Twist and KIR3DL2 had the best validity. SS may be overrepresented. The combination of T‐plastin and Twist was able to differentiate between erythrodermic MF or BID and SS. The additional analysis of KIR3DL2 may be useful to predict the prognosis.
Conclusions
We propose T‐plastin, Twist and KIR3DL2 measured by RT‐qPCR as new diagnostic markers for Sézary syndrome.
What is already known about this topic?
T‐plastin, Twist, KIR3DL2, NKp46 and Tox have been described as blood markers for Sézary syndrome (SS).
What does this study add?
We defined cut‐off values and tested the validity of these markers.
Our study suggests that a combination of these markers could be a useful, noninvasive tool for the early diagnosis of mycosis fungoides and SS.
Linked Comment: P.L. Ortiz Romero. Br J Dermatol 2021; 185:250–251.
Plain language summary available online
The early diagnosis of cutaneous T-cell lymphomas (CTCL) may be challenging and based on a combination of clinical, biological, histological, and molecular criteria (1).
Summary
The erythrodermic ulcerated form of mycosis fungoides (MF) is exceptional, and treatment of refractory cases is challenging. Brentuximab vedotin (BV) is a monoclonal antibody combined with ...monomethyl auristatin E, recently approved for the treatment of refractory CD30+ cutaneous T‐cell lymphoma. We report a case of refractory MF in a 56‐year‐old man with a long history of large‐plaque parapsoriasis, as revealed by psoriasiform erythroderma, treated initially with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) polychemotherapy, inducing a 2‐year complete response. After relapse, interferon and gemcitabine were unsuccessful. Finally, treatment with BV was decided upon, despite the absence of CD30 expression. After three infusions of BV 1·8 mg kg−1, we achieved a complete and stable response, allowing an allogeneic stem cell transplant. The patient is still in complete remission, 19 months after the graft. This case illustrates the possibility of using BV in refractory CD30– MF as a salvage therapy.
What's already known about this topic?
The efficiency of brentuximab vedotin in refractory CD30+ cutaneous T‐cell lymphoma is well established.
Erythrodermic forms of MF are challenging to treat, and allogeneic stem cell transplant is sometimes required.
What does this study add?
This psoriasiform, ulcerated and erythrodermic clinical presentation of MF is exceptional, and the response to brentuximab vedotin, despite the absence of CD30 expression on skin biopsy, allowed us to perform an allogeneic stem cell transplant, inducing long‐term complete remission.
Linked Comment: Sun and Wang. Br J Dermatol 2019; 180:1300–1301.
Summary
Background
The prognosis of Sézary syndrome (SS) and mycosis fungoides (MF) depends on lymph node (LN) involvement. The usefulness of LN image‐guided core‐needle biopsies (CNBs), instead of ...surgical sampling, has been poorly evaluated.
Objectives
To determine the prognostic value of LN CNB in MF/SS.
Methods
A retrospective search was conducted to identify all LN biopsy specimens of MF/SS between 2008 and 2019. Biopsies were staged according to the International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer (ISCL/EORTC) criteria. We performed immunolabelling and determined the tumour clone frequency (TCF) by high‐throughput sequencing of the T‐cell receptor beta locus.
Results
We included 119 consecutive biopsies from 100 patients, 45 with MF and 55 with SS. N1, N2 and N3 stages were diagnosed in 34 (29%), 26 (22%) and 59 (49%) cases, respectively. The TCF, Ki67 index, and percentage of cells positive for thymocyte selection‐associated high mobility group box protein (TOX), programmed cell death protein 1 (PD1), killer cell immunoglobulin‐like receptor 3DL2 (KIR3DL2) and cluster of differentiation (CD)30 were all positively correlated with the N stage. Median overall survival (OS) for N1/N2 vs. N3 patients was 42 months (range 26–not reached) vs. 14 months (range 5–30), respectively (P < 0·001). In univariate analyses, an age > 75 years, LN short‐axis diameter > 15 mm, N3 stage, presence of large‐cell transformation, TOX > 60%, PD1 > 25%, Ki67 > 30%, KIR3DL2 > 15%, CD30 > 10% and TCF > 25% were identified as adverse prognostic factors. In multivariate analyses, only an age > 75 years and Ki67 index > 30% were associated with reduced OS. We developed a new prognostic index associating the N stage and the Ki67 index, which better discriminates N3 patients with poor prognosis.
Conclusions
CNB allows an objective assessment of the LN involvement in MF/SS, relevant for staging and prognosis.
What is already known about this topic?
The prognosis of Sézary syndrome (SS) and mycosis fungoides (MF) depends on lymph node (LN) involvement.
The usefulness of LN core‐needle biopsies (CNBs) instead of surgical sampling in MF/SS has been poorly evaluated.
What does this study add?
LN image‐guided CNB allows objective assessment of LN involvement in MF/SS, relevant for staging and prognosis.
Expression of TOX, PD1, CD30 and KIR3DL2 is correlated with ISCL/EORTC N stage and with tumour clone frequency as assessed by next‐generation high‐throughput DNA sequencing of the T‐cell receptor beta locus.
Ki67 index > 30% appears as an independent factor associated with overall survival.
Linked Comment: E. Hodak. Br J Dermatol 2021; 185:251–252.
Plain language summary available online
