Monoclonal T-Cell Dyscrasia of Undetermined Significance Associated with Recalcitrant Erythroderma

OBSERVATION Monoclonal T-Cell Dyscrasia of Undetermined Significance Associated With Recalcitrant Erythroderma

Robert Gniadecki, MD, PhD, DSc; Ansgar Lukowsky, PhD

Background: Erythroderma is a diffuse, inflammatory the proportion of CD3+CD4+CD7−CD26− cells. Cell deple- skin reaction that, in rare instances, is associated with tion studies indicated that the monoclonal T cells were hematologic maligancies such as cutaneous T-cell lym- present within the CD4+CD7− cell population. Clini- phoma (erythrodermic mycosis fungoides) or T-cell leu- cally, all patients had chronic, recalcitrant erythro- kemia (Se´zary syndrome or adult T-cell leukemia/ derma but none developed any hematological malig- lymphoma). nancy during their lifetimes or fulfilled the criteria for cutaneous lymphoma or Se´zary syndrome. Observations: We screened 30 patients with erythroderma (20 patients with erythroderma of known etiol- Conclusions: A proportion of patients with chronic eryth- ogy and 10 patients with idiopathic erythroderma) for roderma present with the monoclonal expansion of the presence of circulating monoclonal T-lymphocyte CD4+CD7−CD26− lymphocytes in their blood. This con- populations using T-cell receptor (TCR)–␥ gene– dition represents a probably benign T-cell dyscrasia, or specific polymerase chain reaction and automated cap- one of very low malignancy. Alongside monoclonal gam- illary DNA electrophoresis. Moreover, the phenotypic mapathy of undetermined significance (MGUS) and analysis of peripheral blood CD4+ lymphocytes was per- monoclonal (B-cell) lymphocytosis of undetermined sig- formed using the following surface markers: CD3, CD7, nificance (MLUS), we propose using monoclonal T-cell CD8, CD25, CD26, CD27, CD28, CD29, CD30, CD45RO, dyscrasia of undetermined significance (MTUS) to under- CD45RA, CD56, CD134, HLA-DR, TCR␣␤, TCR␥␦, and line a conceptual similarity between this disorder and the cutaneous lymphocyte antigen (CLA ). In 5 patients with more common types of lymphocytic dyscrasia. idiopathic erythroderma we detected T-cell clones in peripheral blood (in 1 case, associated with the presence of the same clone in the skin) and a 2-fold increase in Arch Dermatol. 2005;141:361-367

RYTHRODERMA IS AN EXTEN- goides or Se´zary syndrome.1,3-5 However, sive inflammatory skin re- some researchers believe that chronic eryth- action affecting more than roderma, eg, erythrodermic atopic derma- 90% of the body surface. The titis, is a preneoplastic condition.6-9 This condition is rare, with an in- concept has been promoted by Winkel- cidence of approximately 1 per 100000 mann and coworkers6,10,11 who coined the E1 polulation, and its etiology is variable. Ec- term pre-Se´zary syndrome. This syndrome zemas, psoriasis, and drug reactions are the is defined as chronic erythroderma resem- most frequent causes of erythroderma. In bling that seen in Se´zary syndrome, a Se´- 15% to 30% of cases the cause cannot be 9 1,2 zary cell count less than 10 /mL, and a high found (idiopathic erythroderma), and up risk of progression into frank leukemia (Se´- to 40% of these run a chronic course not zary syndrome). Other features are palmo- manageable by local or systemic thera- plantar keratoderma, alopecia, onychodys- pies (chronic idiopathic erythroderma or “red man” syndrome).3,4 trophy, lymphadenopathy, and an increased level of circulating IgE. However, because none of these symptoms has been found See also pages 305, 325, consistently in all patients, pre-Se´zary syn- 353, 382, and 395 drome is difficult to separate from pseudo– Author Affiliations: CTCL erythrodermas such as adult-onset Departments of Dermatology, The possible association between atopic dermatitis or Ofuji papuloerythro- Bispebjerg Hospital, University derma.5 For this reason the concept of pre- of Copenhagen, Denmark chronic erythroderma and cutaneous T- (Dr Gniadecki) and Charité cell lymphoma (CTCL) has long been rec- Se´zary syndrome has not been universally Hospital, Berlin, Germany ognized. Only a small proportion (5%- accepted. (Dr Lukowsky). 10%) of patients with chronic erythroderma Molecular biology and flow cytometry Financial Disclosure: None. develop clinically unequivocal mycosis fun- techniques that enable sensitive detec-

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 roderma (n=2) or relapsing disease between periods with no or All Known Patients With minimal skin symptoms (n=2). For control purposes (control of Erythroderma, 1997-2000 ␥ N = 34 CD7 antibody and TCR- rearrangement sensitivity) blood from 6 patients with Se´zary syndrome were included (the samples were provided by Mark Pittelkow, MD, Mayo Clinic, Rochester, Minn). Immunophenotyping of For all patients, a minimum workup included hematologic and Peripheral Blood Performed n = 30 blood chemistry studies, 4-mm skin punch biopsy specimens for histologic studies, a chest radiograph, and abdominal ultrasono- graphic screening for occult tumors.

Idiopathic Erythroderma Erythroderma of Known Cause n = 10 n = 20 PERIPHERAL BLOOD IMMUNOPHENOTYPING Chronic, Recalcitrant, n = 6 Eczemas, n = 5 Acute or Relapsing, n = 4 Atopic Dermatitis, n = 5 Psoriasis, n = 3 Venous blood was collected in EDTA Vacutainer tubes (Becton, Viral, n = 2 Dickinson and Co, Franklin Lakes, NJ) and processed immedi- Pityriasis Rubra Pilaris, n = 1 ately. One milliliter of blood was lysed for 5 minutes at 37°C with Drug Induced, n = 1 Papuloerythroderma, n = 1 50 mL of lysis buffer (0.83% ammonium chloride, 0.1% kalium Hypereosinophilic Syndrome, n = 1 bicarbonate, and 0.004% EDTA) and the leukocytes were washed Sézary Syndrome, n = 1 once in phosphate-buffered saline (PBS) solution. The cells were counted manually and resuspended in PBS solution for a con- 6 Figure 1. Characteristics of the patients with erythroderma included centration of 2.4ϫ10 /mL. Antibody staining for immunophe- in this study. notyping by laser scanning cytometry was performed according to the method published by Clatch and colleagues,19-22 with slight tion and characterization of clonal expansion of T cells modifications. Briefly, 3 µL of the fluorescein isothiocyanate have been used for more than a decade for the diagnosis (FITC)–, phycoerythrin (PE)-, and phycoerythrin cyanogen 5 (PECy5)–labeled antibodies (Table 1) was added to 20 µL of of leukemias and lymphomas, including cutaneous lym- 12 cell suspension and the mixture was gently pipetted onto custom- phomas. A T-cell population with monoclonally rear- made chamber slides assembled on standard microscope glass ranged T-cell receptor (TCR) genes is readily detectable slides. The following antibody-labeling reactions were per- in peripheral blood in Se´zary syndrome. Patients with Se´- formed: (1) CD45,CD4,CD8; (2) CD3,CD4, CLA; (3) CD4, HLA- zary syndrome also have an increased proportion of cir- DR, CD134; (4) CD4, CD45RO, CD45RA; (5) CD4, CD25, CD56; culating CD4+CD7− and CD26− cells,5 but it is still un- (6) CD4, CD7, CD26; (7) CD4, CD7, CD27; (8) CD4, CD7, clear whether these represent a malignant population or CD28; (9) CD4, CD7, CD29; (10) CD4, CD7, CD30; (11) CD4, merely reactive lymphocytes.13-16 CD4+7− are also detect- TCR␣␤, TCR␥␦; and (12) isotype controls. After a 30-minute able in late stages of mycosis fungoides with or without incubation at 4°C the cells were washed with PBS and scanned erythroderma, and they might be used for monitoring re- in a laser scanning cytometer (CompuCyte, Cambridge, Mass) 17,18 using the 488-nm line of argon laser as an excitation source. In- sponse to therapy. tegrated fluorescence in the green (FITC), orange (RPE) and far In view of these reports suggesting the diagnostic value red (PC5) channels were collected on a cell-to-cell basis and pre- of flow cytometry and TCR gene rearrangement for CTCL sented as dot-plot diagrams following off-line fluorescence com- we have included these studies in the standard diagnos- pensation with the CompuCyte software. After scanning, the tic workup of patients with erythroderma since 1999. We chamber slides were disassembled and the cells adhering to the were able to identify a group of patients with chronic, bottom slide were fixed briefly in methanol, air-dried, and stained recalcitrant erythroderma accompanied by a monoclo- with Wright-Giemsa. The slides with stained cells were reposi- nal expansion of CD4+7−26−29+ T lymphocytes. These pa- tioned in the laser scanning cytometer and the cells with the re- tients fulfilled the criteria for pre-Se´zary syndrome but quired characteristics were re-found for visual inspection. none developed CTCL during the 4-year observation period. We propose that the clinical syndrome described TCR-␥ GENE REARRANGEMENT STUDIES herein represents a T-cell variant within the group of monoclonal hematologic dyscrasias with a yet undeter- Skin biopsy specimens (4-mm punch) and mononuclear blood mined risk of progression to malignancy. cells purified on Ficoll were analyzed by means of a polymerase chain reaction with fluorescence fragment product analysis using an automated capillary electrophoresis DNA sequencer METHODS (GeneScan; Applied Biosystems, Foster City, Calif), as described elsewhere in detail.23-25 For lymphocyte depletion/ PATIENTS enrichment the peripheral leukocytes were prepared by ammonium chloride lysis, as described above, and washed twice in PBS. A total of 30 patients, 7 women and 23 men aged between 29 CD4+ cells were positively isolated or selectively depleted using and 90 years seen in our department during a 3-year period were a Dynabeads M-450 CD4 kit (Dynal Biotech, Oslo, Norway) ac- included. Of 5 more patients with erythroderma, 3 died or were cording to the protocol supplied by the manufacturer. For CD7 lost to follow-up before immunophenotyping and 2 did not re- depletion, 150 µL of CD7 antibody (Dako Corp, Glostrup, Den- ceive peripheral blood immunophenotyping because the at- mark) was added to 107 peripheral leukocytes (total volume, 1 tending physician did not order the study. Patient distribution mL) and the cells were incubated at 4°C for 30 minutes. After and diagnoses are shown in Figure 1. Six of the 10 patients washing, the cells were resuspended in 80 µL of PBS solution with idiopathic erythroderma had chronic, recalcitrant dis- and 20 µL of goat anti-mouse antibodies linked to Dynabeads ease defined as symptoms persisting for more than 6 months M-450 magnetic beads (Dynal Biotech) was added. After a 20- without any response to local and systemic glucocorticoid treat- minute incubation at 4°C the cells were washed and resus- ment. The other 4 patients experienced a single episode of eryth- pended in 500 µL of PBS in an Eppendorf tube and mounted on

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Antibody Conjugate Source, Catalogue No.* Target CD3-RPE Dako, R0810 20-kDa ε-chain of the TCR/␨/CD3 complex on T cells CD4-RPE Diatec, 3022 59-kDa CD4 protein is a receptor for MHC class II molecules and CD4-PC5 Coulter, M2636 is present on T-helper/inducer lymphocytes CD7-RPE Pharmingen, 30305X 40-kDa glycoprotein present on thymocytes and most mature T lymphocytes CD8-FITC Diatec, 3031 32-kDa receptor for class I MHC molecules present predominantly on human suppressor/cytotoxic T cells CD25-FITC Dako, F0801 ␣ subunit of the interleukin 2 receptor expressed on activated T cells and B cells CD26-FITC Dako, F7175 110-kDa dipeptidyl peptidase IV required for T-cell activation CD27-FITC Pharmingen, 30824X 110-kDa polypeptide dimer from the tumor necrosis factor receptor superfamily involved in T-cell activation CD28-FITC Dako, F7163 44-kDa surface immunoglobulinlike protein present on most CD4+ T cells and involved in cell-cell adhesion via CD80 and CD86 CD29-FITC Dako, F7068 130-kDa integrin ␤1-chain forming the very late antigen (VLA) expressed ubiquitously and detected on approximately 40% of human T cells, preferentially on memory CD4+ cells CD30-FITC Dako, F0849 120-kDa protein of the tumor necrosis factor receptor superfamily present on a small subset of activated lymphocytes and malignant cells, mainly in lymphomatoid papulosis, Hodgkin lymphoma, and adult T-cell leukemia/lymphoma CD45RO-RPE Pharmingen, 31305X 180-kDa isoform of the human leukocyte common antigen found predominantly on memory T cells CD45RA-FITC Pharmingen, 31264X 220-kDa isoform of the human leukocyte common antigen found predominantly on naive T cells CD45-PC5 Diatec, 3096 Panleukocyte marker CD56-RPE Dako, R7127 140-kDa neural cell adhesion molecule present on NK cells and activated T cells and B cells CD134-FITC Pharmingen, 34464X 50-kDa costimulatory protein (OX-40) from the tumor necrosis factor family expressed on small subpopulations of T cells and B cells and in lymphomatoid papulosis HLA-DR-RPE Pharmingen, 34235X 35-kDa HLA-DR ␣-chain expressed on activated T cells CLA-FITC Pharmingen, 35824X Cutaneous lymphocyte antigen, a carbohydrate domain shared by sialyl Lewis antigens, serves as a ligand for selectins CD62E and CD62L and is involved in the migration of activated leukocytes and lymphoma cells to the skin TCR␣␤-FITC Pharmingen, 32254X T-cell antigen receptor ␣␤ TCR␥␦-RPE Pharmingen, 33685A T-cell antigen receptor ␥␦

Abbreviations: FITC, fluorescein isothiocyanate; MHC, major histocompatability complex; NK, natural killer; PC5, phycoerythrin cyanogen 5; RPE, phycoerythrin. *Places of manufacture are the following: Coulter, Miami, Fla; Dako, Glostrup, Denmark; Diatec, Oslo, Norway; BD Pharmingen, Franklin Lakes, NJ.

a magnetic device (Dynal). The supernatant was collected as the nal population of lymphocytes by detecting a clonally re- negative fraction. The next two 500-µL washes were discarded, arranged TCR-␥ receptor chain. In the other 4 patients and the remaining cells constituted the positive fraction. To check only a blood sample gave this result, but in patient 5 both for the purity of the separated fractions the CD4- and CD7- blood and skin samples showed identical rearrange- depleted cells were stained for tricolor laser scanning cytometry with the following: (1) CD3-RPE + CD4-PECy5 + CD8- ments. None of these patients, however, showed blood FITC; (2) CD3-RPE + CD4-PECy5 + CD7-FITC; and (3) CD3- or bone marrow characteristics of leukemic involve- RPE + CD4-PECy5 + CD26-FITC. In 2 of 4 cases it was technically ment (summary characteristics are provided in Table 2). feasible to deplete more than 95% of CD4+ or CD7+ cells. They did not have palpable lymph nodes except patient 3, in whom findings from excisional biopsy of the left RESULTS inguinal node showed reactive dermopathic changes. A slight eosinophilia and an increase in total IgE concen- PATIENTS WITH ERYTHRODERMA, PERIPHERAL tration were noted in most patients. Peripheral blood CD3+CD4+CD7–CD26– CELL EXPANSION, AND smears showed normal numbers of Se´zary cells. Biopsy MONOCLONAL T-CELL DYSCRASIA specimens from all patients showed predominantly lymphocytic, superficial perivascular infiltrates without exo- Peripheral blood immunophenotypic studies were per- cytosis or epidermotropism, with slight to moderate para- formed using a broad panel of antibodies (Table 1) to de- keratosis and spongiosis. Their clinical course was termine the CD4/CD8 cell ratio and subpopulations of protracted, as they were resistant to treatments that in- CD3+4+ lymphocytes according to the expression of dif- cluded topical and systemic glucocorticoids, systemic reti- ferent surface markers. Among the 30 patients included noids (acitretin), psoralen–UV-A, and methotrexate. In in this study, we found 5 patients (apart from 1 patient the case of patient 1, however, a temporary improve- with clinically obvious Se´zary syndrome) who pre- ment was noted after he received a weekly dose of 25 mg sented with a more than 2-fold enrichment in the ratio of methotrexate, and the clinical response correlated with of CD3+CD4+CD7−CD26−/CD3+CD4+ lymphocyte sub- a decrease in the proportion of CD4+CD7− cells from 69% populations (Table 2, Figure 2, and Figure 3). Since to 31%. However, his erythroderma relapsed 4 months the presence of CD4+CD7− lymphocytes could signify the later despite the treatment, and his CD4+CD7− cell count development of Se´zary syndrome, we performed the TCR increased to 71%. None of these 5 patients developed un- clonality studies. In all 5 patients we found a monoclo- equivocal Se´zary syndrome as defined by the clinical or

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 Table 2. Characteristics of the Patients With Monoclonal T-Cell Dyscrasia of Undetermined Significance (MTUS)

Feature Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Sex/age, y M/90 M/72 F/78 F/73 M/75 Total duration of 48 4 137 erythroderma, y Clinical features Skin surface involved, % 100 100 100 90 90 Scaling Slight Slight Severe Moderate Severe Itch Moderate Moderate Severe Slight Moderate Added surface involvement None None Onycholysis of both index None None fingernails; scalp alopecia Lymph node involvement None None Left inguinal (reactive) None None Laboratory results Bone marrow biopsy Normal Reactive changes Reactive changes Normal Normal Skin biopsy Superficial perivascular Superficial perivascular Superficial perivascular Superficial perivascular Superficial lymphocytic infiltrate lymphocytic infiltrate lymphocytic infiltrate lymphocytic infiltrate perivascular lymphocytic infiltrate Blood chemistry and Total IgE, 853 IU/L Total IgE, 655 IU/L Total IgE, 408 IU/L Normal Eosinophilia, hematology* Eosinophilia, 0.9 ϫ 109/L 1.1 ϫ 109/L Creatinine, 2.57 mg/dL (196 µmol/L) Flow cytometry of peripheral blood CD4/CD8 ratio 1.22 1.50 1.77 1.04 1.52 Percentage of lymphocytes CD4+CD7−† 6987597348 CD4+CD26−† 6793676586 CD4+CD7−CD26−†5586464137 CD4+CD28−‡ 7963485960 Monoclonal TCR␥ chain rearrangement§ Blood + + + + + Skin − − − − +

*Values for hemoglobin, creatinine, liver enzymes, lactate dehydrogenase, immunoglobulins, total IgE, and M−component levels were obtained as well as total and differential white blood cell counts. Normal values are 0 to 0.45 ϫ109/L for eosinophil count, 60 to 130 µmol/L for creatinine, and less than150 IU/L for total IgE. †Expressed as proportion of CD3+CD4+ cells. Values from this laboratory are as follows for healthy individuals: CD4/CD8 ratio, 0.44 to 6.17; CD3+CD4+CD7−,5%to 47% (age−dependent); CD3+CD4+CD26−, 41% to 89%; and CD3+CD4+CD7−CD26−, 3% to 35% (age−dependent). For patients with erythroderma values were as follows: CD4/CD8 ratio, 0.31−7.75; CD3+CD4+CD7−, 15% to 59%; CD3+CD4+CD26−, 30% to 84%; and CD3+CD4+CD7−CD26−, 9% to 47% (age dependent). ‡Expressed as proportion of CD3+CD4+CD7− cells. §Plus and minus signs indicate presence or absence of the monoclonal TCR␥ chain rearrangement.

hematologic criteria,5 or any other kind of malignancy still detectable after CD7 depletion or in positively se- during their lifetime. All died within 4 years after diag- lected CD4+ cells. nosis of causes unrelated to erythroderma (2 of ische- We were also interested in investigating the morpho- mic heart disease, 1 of stroke, and 1 of unknown cause). logic characteristics of CD4+CD7− cells. To accomplish this task we took advantage of the laser scanning cytometry FURTHER CHARACTERISTICS OF technique, which provides the possibility of finding cells CD3+CD4+CD7−CD26− CELLS with specific characteristics and observing their morpho- logic features under a light microscope. In each of the 4 The phenotypic characteristics of CD4+CD7−CD26− cells described patients we observed 100 to 150 Wright-Giemsa– were the following: CD3+, CD8−, CD25−, CD27+/−, CD28+, stained CD4+CD7− cells and found that only 6 to 17 cells CD29+, CD30−, CD45RO+, CD45RA−, CD56−, CD134−, could be classified as having Se´zary cell morphology. Oth- HLA-DR−, CLA−, TCR␣␤+, and TCR␥␦−, ie, they corre- erwise, the cells were small lymphocytes. This was not dif- sponded to the phenotype of resting memory CD4+ cells. ferent from what can be found in the peripheral blood of To investigate the possibility that the subpopulation healthy volunteers. In conclusion, our findings indicate of monoclonal T cells resided within the expanded that some of the CD4+CD7− cells are monoclonal but re- CD4+CD7−CD26− compartment, we repeated the TCR␥ tain normal lymphocytic morphology. rearrangement studies on peripheral blood cells depleted of monoclonal CD4 and CD7 antibodies. In 2 cases (patients 1 and 3) we succeeded in obtaining pure popu- COMMENT lations containing less than 4% of CD4+ cells (CD4 antibody depletion) or CD7− cells (CD7 antibody deple- Monoclonal expansions of lymphocytes occur occasion- tion). In both patients the monoclonal TCR␥ ally in elderly individuals and comprise B-cell, T-cell, or rearrangement was absent in the CD4-depleted cells but plasma-cell dyscrasias. B-cell and plasma-cell dyscrasias

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 clonal T−cell dyscrasia could correspond to the pre−Se´zary A syndrome.10 Some support to this speculative notion is provided by an obvious similarity with the known surface phenotype of the cells in Se´zary syndrome or advanced mycosis fungoides. A lack of CD7 and CD26 expression is by no means specific to Se´zary cells. Reactive−memory T cells in benign inflammatory skin conditions, such as atopic dermatitis, psoriasis, or infections, often have the CD7−CD26−CD45RO+ phenotype.34-36 According to this concept monoclonal T−cell populations represent reactive cells that were not eliminated by immunoregulatory processes. It is important to stress in this context that T−cell rearrangement studies do not al- low differentiating whether the detected clone is a result B of malignant tranformation or, rather, due to selection of reactive T lymphocytes. None of our patients with erythroderma and monoclonal T−cell dyscrasia fulfilled the criteria of Se´zary syndrome; they all had Se´zary cell counts be- low 5% or 1000/µL, did not develop lymphadenopathy, and their CD4/CD8 ratio was much lower than that normally seeninSe´zarysyndrome.TheCD7expressionismuchlower in Se´zary syndrome than in MTUS (Figure 3B). Moreover, the CD4+CD7− cells in our patients did not have the Se´zary cell morphology but mostly resembled normal small lymphocytes. None of the patients developed lymphoma or another malignancy during the period of observation. Taken together, we cannot eliminate the possibility that observed monoclonal cells are non−neoplastic or alternatively rep- Figure 2. Typical erythroderma (bright red with slight scaling) in a patient with resent an “abortive” dead−end transformation event. monoclonal T−cell dyscrasia of undetermined significance (MTUS) (patient 1). Monoclonal CD4 and CD8 cells have repeatedly been found in different autoimmune and inflammatory dis- are most common and can be detected in approximately eases such as rheumatoid arthritis, atherosclerosis, chronic 10% of healthy adults older than 80 years by the pres- viral infections, and multiple sclerosis.37-41 At least in pa- ence of a monoclonal immunoglobulin peak on serum tients with rheumatoid arthritis, there is ample evidence electrophoresis. This condition, named monoclonal gam- suggesting that monoclonal circulating CD4+CD7−CD45RO+ mapathy of undetermined significance (MGUS) is con- cells escaped from peripheral tolerance and are autoreac- sidered to be preneoplastic since patients with MGUS have tive.40,42 The maintenance of these clones is supported by a severely increased risk for developing multiple my- some cytokines43 and further enhanced by their resistance eloma and macroglobulinemia.26 Another type of B−cell to apoptosis.44 It is conceivable that the monoclonal T−cell dyscrasia is monoclonal B lymphocytosis of undeter- population in patients with erythroderma results from a mined significance (MLUS), which is a clinically benign chronic stimulation of the immune system with a yet uni- variant of chronic B−cell leukemia.27 dentified cutaneous autoantigen. However, in contrast to Here we describe a subpopulation of elderly patients the clones detected in rheumatoid arthritis40 and in healthy with idiopathic, chronic erythroderma with associated aging individuals,41,44-47 which are approximately en- monoclonal dyscrasia of T cells (an abbreviation, MTUS, riched 5−fold in CD28− cells, we did not find any differ- is proposed to be analogous with MGUS and MLUS). ences in the proportion of CD4+28− cells between patients Monoclonal expansions of T cells are much less com- with monoclonal T−cell dyscrasia and those with a known mon that B−cell dyscrasias and their clinical relevance is cause of erythroderma (Table 2). This seems to be an im- poorly understood. CD8+ and CD4+ lymphocyte clones portant point since it has been argued that the loss of CD28 have been detected in elderly individuals28,29 and even in expression occurs specifically in senescent T cells,47 de- old mice.30 These monoclonal T cells have a variable pends on the cytokine balance,48 and, most importantly, phenotype; however, the most consistent finding is the CD4+28− cells may represent a functionally distinct cell CD7−CD45RO+, which resembles the phenotype seen in type resembling the natural killer lymphocytes.48,49 If the our patients with erythroderma. T−cell clones detected by us in patients with erythroder- Very little is known about the pathogenesis and clini- mia represent inflammatory, possibly autoreactive T cells, cal importance of monoclonal T−cell dyscrasias in elderly their nature is probably different from that of CD4+CD7− people. Some authors have suggested that they occur be- CD28− cells. cause of a transformational event analogous to the situa- In summary, we describe an association between tion seen in MGUS, and it seems that at least in some cases chronic idiopathic erythroderma with monoclonal T− (albeit rarely) clinically silent monoclonal T−cell dyscra- cell dyscrasia in elderly patients (MTUS−E syndrome). sia progresses into malignancy.31-33 If the same pathogenic It is likely that the presence of T−cell monoclonality and scenario was true for our patients, erythroderma with mono- erythroderma are related since their association by chance

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60 Cells – 7 +

30 Proportion of CD4 Healthy Controls 15 Patients With Erythroderma Patients With Erythroderma and Monoclonal T-Cell Dyscrasia 0 15 3045 60 75 90 Age, y

B CD8-FITC

CD4-PE CD4-PE CD4-PE CD26-FITC

CD7-PE CD7-PE CD7-PE CD28-FITC

CD7-PE CD7-PE CD7-PE

Controls Patients With MTUS Patients With Sézary Syndrome

Figure 3. Phenotypic characteristics of peripheral blood CD3+CD4+ lymphocytes in healthy individuals, patients with monoclonal T−cell dyscrasia of undetermined significance (MTUS), and patients with erythroderma of other etiology. A, Proportion of CD4+CD7− cells as a function of age, with regression line and 95% prediction interval. B, Examples of laser scanning cytometry results of peripheral blood lymphocytes in a patient with erythroderma (control), patient 1 with MTUS, and a patient with Se´zary syndrome. In Se´zary syndrome CD4+CD7− cells have a 2− to 3−fold reduced CD7 expression compared with CD4+CD7− cells in patients with MTUS. FITC indicates fluorescein isothiocyanate.

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 is extremely improbable (approximately10−8, as the prob- 19. Clatch RJ, Walloch JL, Zutter MM, Kamentsky LA. Immunophenotypic analysis −5 of hematologic malignancy by laser scanning cytometry. Am J Clin Pathol. 1996; ability of having erythroderma is 10 and the probability 105:744-755. of having T−cell dyscrasia is 10−3). Moreover, the case of 20. Clatch RJ, Foreman JR, Walloch JL. Simplified immunophenotypic analysis by patient 1, in whom the use of methotrexate provided a tem- laser scanning cytometry. Cytometry. 1998;34:3-16. 21. Clatch RJ, Foreman JR. Five−color immunophenotyping plus DNA content analy- porary alleviation of symptoms, with an associated de- sis by laser scanning cytometry. Cytometry. 1998;34:36-38. crease in the proportion of CD4+CD7−CD26− cells, further 22. Clatch RJ. Immunophenotyping of hematological malignancies by laser scanning cytometry. 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