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CASE HISTORY

  1. Top of page
  2. CASE HISTORY
  3. FLOW CYTOMETRIC STUDIES
  4. DISCUSSION
  5. LITERATURE CITED
  6. Supporting Information

This patient is a 54-year-old man who was referred to the hematology/oncology service with a recent onset of fevers, cervical lymphadenopathy, absolute lymphocytosis, and mild splenomegaly. His past medical history was significant for seizures, which had been well controlled on Dilantin for the past 8 years. Laboratory data were significant for a mildly increased WBC of 11.9 K/cumm (normal: 4.5–11) showing absolute lymphocytosis (Fig. 1), a thrombocytopenia of 104 K/cumm (normal: 140–400), increased liver function tests of alanine transaminase of 64 IntUnits/L (normal: 17–63) and aspartate transaminase of 65 (normal: 15–41), and an erythrocyte sedimentation rate (ESR) of 14 mm/h (normal: 0–10). The phenytoin level was 5.8 mcg/mL (therapeutic range: 10–20). Peripheral blood was sent for flow cytometric analysis to assess the absolute lymphocytosis.

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Figure 1. Wright-Giemsa stained peripheral blood smear showing two mature lymphocytes with mildly irregular nuclear contours and mature chromatin (1000×).

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FLOW CYTOMETRIC STUDIES

  1. Top of page
  2. CASE HISTORY
  3. FLOW CYTOMETRIC STUDIES
  4. DISCUSSION
  5. LITERATURE CITED
  6. Supporting Information

Flow cytometry was performed for CD1, sCD3, CD4, CD5, CD7, CD8, TCRαβ, and TCRγδ. List mode files for the following tubes are available for download from the website: CD3-FL (FITC)/CD8-PC5/CD4-ECD; CD7-FL (FITC)/CD1-PE; CD3-PE/CD10-FL (FITC); TCRαβ-FL (FITC)/CD3-PE; TCRγδ-FL/CD3-PE; CD5-PE/CD2-FL (FITC). All antibodies, except for TCRαβ and TCRγδ were obtained form Beckman Coulter (Brea, CA). TCRαβ and TCRγδ were obtained form BD Biosciences (San Jose, CA).

Files were collected on a FC500 Beckman Coulter (CXP2.0), and the software used was CXP analysis software.

DISCUSSION

  1. Top of page
  2. CASE HISTORY
  3. FLOW CYTOMETRIC STUDIES
  4. DISCUSSION
  5. LITERATURE CITED
  6. Supporting Information

Flow cytometry analysis revealed a peripheral expansion of sCD3+, CD4–, CD8–, TCRγδ+ T-lymphocytes (Figs. 2 and 3; see additional analysis as Supporting Information, web only). Given the clinical presentation of lymphadenopathy, fevers, and abnormal liver function tests that fully resolved after cessation of Dilantin, overall features are best characterized as a phenytoin-induced “pseudolymphoma.” The term “pseudolymphoma” refers to a benign, drug-induced lymphocytic infiltrate in lymph nodes, skin, or peripheral blood that mimics lymphoma histologically or cytologically (1, 2). In our case, nearly 70% of the patient's peripheral blood T-lymphocytes represented γδ T-lymphocytes that showed partial loss of CD7 and normal expression of CD2 and CD5. In healthy individuals, peripheral αβ T-lymphocytes predominate with γδ T-lymphocytes accounting for only 1–5% of the total T-lymphocyte pool. γδ T-lymphocytes are preferably found in spleen and epithelial-rich tissues, such as skin, intestine, and the reproductive tract, serving as a first line of defense against bacterial peptides without the need of major histocompatibility complex-restricted function (3, 4). Roden et al. (5) describe the largest series of immunophenotypic characteristics of benign peripheral blood γδ T cells and conditions associated with their increase. Flow cytometric T-cell immunophenotyping was performed on 352 consecutive peripheral blood specimens and of these 62 cases (18%) showed an increase of γδ T cells of either more than 5% of the total lymphocytes or more than 200 cells per μL (5). Clinical data was available from 36 of the 62 cases. The most commonly encountered immunophenotypic alteration of T-cell-associated antigens was noted for CD5 with 16 of the 62 cases (26%) showing either complete loss, partial loss, or diminished intensity of this marker. Diminished CD7 intensity was observed in only 3 of 62 cases (5%), whereas none of the cases demonstrated loss or diminished expression for CD2 or CD3. When assessed for clinical conditions associated with immune system activation or prior splenectomy, 28 of 36 cases (78%) had an associated clinical condition with 18 of 28 cases (64%) demonstrating an infection/inflammatory disorder and 9 of 36 (32%) an autoimmune disorder (5).

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Figure 2. Dot plot for CD4 and CD8 expression on gated sCD3 positive T-lymphocytes.

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Figure 3. Dot plot for TCR γδ and CD3 expression on gated sCD3 positive T-lymphocytes.

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Aberrant CD5 expression on γδ T cells has been described as one of the more consistent immunophenotypic alterations of γδ T-cell malignancies (6). Descriptions of γδ T-cell lymphomas began to appear in the literature after the characterization of this T-cell subset in the 1980s. γδ T-cell lymphomas tend to occur in those organs where their normal counterparts normally reside, namely in skin (primary cutaneous γδ T-cell lymphoma), spleen (hepatosplenic T-cell lymphoma), GI tract (enteropathy-associated T-cell lymphoma), and rarely, peripheral blood (γδ T-cell large granular lymphocytic leukemia). Ahmad et al. (7) report on flow cytometric immunophenotypic findings of peripheral blood or bone marrow involvement by these γδ T-cell lymphomas in a series of nine patients. In their analysis including a comprehensive literature review, expressions of CD5, CD8, CD16, and CD57 differed in γδ T-cell large granular lymphocytic leukemia compared to hepatosplenic T-cell lymphoma and cutaneous γδ T-cell lymphoma. Whereas CD5 expression was commonly retained on malignant cells in γδ T-cell large granular lymphocytic leukemia (60% of cases), this marker was lost in all hepatosplenic lymphoma cases and 80% of cutaneous γδ T-cell lymphoma cases (7). Coexpression of CD8 and CD57 appeared to be more common on malignant T-cells of γδ T-cell large granular lymphocytic leukemia than cutaneous γδ T-cell lymphoma or hepatosplenic T-cell lymphoma with the conclusion that CD57 may be useful for the subclassification of γδ T-cell lymphomas. Furthermore, results of this study indicate that CD5 expression appears to be retained in the more indolent γδ T-cell lymphomas, such as γδ T-cell large granular lymphocytic leukemia, compared to the aggressive forms of hepatosplenic T-cell lymphoma or cutaneous γδ T-cell lymphoma (7).

In summary, this case is an example of a benign peripheral expansion of γδ T-cells in a patient with drug-induced “pseudolymphoma.” A sCD3+, CD4−, CD8− T-cell population should prompt analysis for TCR γδ, as these T-cells typically lack CD4 and CD8. Differential diagnostic considerations should also include a T-lymphoblastic leukemia/lymphoma, which usually will express immature markers, such as CD1, CD34 and terminal deoxynucleotidyl transferase (TdT) or autoimmune lymphoproliferative syndrome (ALPS), a disorder associated with splenomegaly, lymphadenopathy, and marked expansion of αβ t-cells lacking expression of CD4 and CD8.

CASE 1 DIAGNOSIS: Phenytoin-induced “pseudolymphoma”

LITERATURE CITED

  1. Top of page
  2. CASE HISTORY
  3. FLOW CYTOMETRIC STUDIES
  4. DISCUSSION
  5. LITERATURE CITED
  6. Supporting Information

Supporting Information

  1. Top of page
  2. CASE HISTORY
  3. FLOW CYTOMETRIC STUDIES
  4. DISCUSSION
  5. LITERATURE CITED
  6. Supporting Information

Additional Supporting Information may be found in the online version of this article.

FilenameFormatSizeDescription
CYTO_25097_sm_suppinfo1.fcs303KSupporting Information 1
CYTO_25097_sm_suppinfo2.fcs291KSupporting Information 2
CYTO_25097_sm_suppinfo3.fcs266KSupporting Information 3
CYTO_25097_sm_suppinfo4.fcs267KSupporting Information 4
CYTO_25097_sm_suppinfo5.fcs286KSupporting Information 5
CYTO_25097_sm_suppinfo6.fcs283KSupporting Information 6
CYTO_20597_sm_suppinfoCase1.pdf1687KFigure Legend: Dot plots for T-cell markers used to further characterize the peripheral T-cell lymphocytosis. 55% of all CD3+ events represent gamma/delta T-cells (I) lacking expression of CD4 or CD8 (F) and co-expressing CD2 and CD5 (B). CD7 expression is diminished on these T-cells (D).

Please note: Wiley Blackwell is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.