International Journal of Hematology

, Volume 98, Issue 3, pp 366–374

Clinical manifestation of angioimmunoblastic T-cell lymphoma with exuberant plasmacytosis

Authors

  • Hisao Nagoshi
    • Division of Hematology and Oncology, Department of MedicineKyoto Prefectural University of Medicine
    • Division of Hematology and Oncology, Department of MedicineKyoto Prefectural University of Medicine
  • Tsutomu Kobayashi
    • Division of Hematology and Oncology, Department of MedicineKyoto Prefectural University of Medicine
  • Saori Maegawa
    • Division of Hematology and Oncology, Department of MedicineKyoto Prefectural University of Medicine
  • Yoshiaki Chinen
    • Division of Hematology and Oncology, Department of MedicineKyoto Prefectural University of Medicine
  • Miki Kiyota
    • Division of Hematology and Oncology, Department of MedicineKyoto Prefectural University of Medicine
  • Ryuko Nakayama
    • Division of Hematology and Oncology, Department of MedicineKyoto Prefectural University of Medicine
  • Shinsuke Mizutani
    • Division of Hematology and Oncology, Department of MedicineKyoto Prefectural University of Medicine
  • Yuji Shimura
    • Division of Hematology and Oncology, Department of MedicineKyoto Prefectural University of Medicine
  • Mio Yamamoto-Sugitani
    • Division of Hematology and Oncology, Department of MedicineKyoto Prefectural University of Medicine
  • Yosuke Matsumoto
    • Division of Hematology and Oncology, Department of MedicineKyoto Prefectural University of Medicine
  • Shigeo Horiike
    • Division of Hematology and Oncology, Department of MedicineKyoto Prefectural University of Medicine
  • Masafumi Taniwaki
    • Division of Hematology and Oncology, Department of MedicineKyoto Prefectural University of Medicine
Case Report

DOI: 10.1007/s12185-013-1411-z

Cite this article as:
Nagoshi, H., Kuroda, J., Kobayashi, T. et al. Int J Hematol (2013) 98: 366. doi:10.1007/s12185-013-1411-z

Abstract

Angioimmunoblastic T-cell lymphoma (AITL) is a rare subtype of non-Hodgkin lymphoma characterized by aggressive symptoms and various abnormal laboratory test results. One of the rare immunologic abnormalities in AITL is exuberant polyclonal plasmacytosis, but its clinical significance has not been evaluated. This report concerns three AITL cases with exuberant polyclonal plasmacytosis and investigates its clinical impact by comparison with 12 patients without plasmacytosis. Our study found that the performance status (PS) of the former was significantly worse and their serum immunoglobulin levels were significantly higher. All other parameters, including B symptoms, various prognostic scores, blood cell counts other than plasmacyte, and serum levels of lactate dehydrogenase, C-reactive protein and soluble interleukin-2 receptor, showed no significant differences. More importantly, although the diagnosis of AITL with plasmacytosis was not straightforward in our series, outcomes of treatment with conventional chemotherapy or immunosuppressive therapy with cyclosporine A were favorable. To conclude, AITL should be considered a candidate underlying disease of exuberant polyclonal plasmacytosis. Provided a correct diagnosis is made early and is followed by adequate treatment, the prognosis for AITL with plasmacytosis may not be worse than that for those without plasmacytosis despite the severe exhaustion at first presentation.

Keywords

Angioimmunoblastic T-cell lymphomaPlasmacytosisPolyclonal hyperglobulinemiaPrognosis

Introduction

Angioimmunoblastic T-cell lymphoma (AITL) is a rare subtype of non-Hodgkin lymphoma (NHL), accounting for about 1–2 % of all NHLs and for 15–27 % of peripheral T-cell lymphomas (PTCLs) [15]. Most AITL patients present with advanced-disease stage, which is frequently accompanied by aggressive systemic symptoms, such as systemic lymphadenopathy, high fever, body weight loss, night sweating, skin rash, or abnormal immunological symptoms. In addition, AITL is frequently characterized by various abnormal laboratory test findings, such as anemia including hemolytic anemia or anemia of chronic inflammation, thrombocytopenia, polyclonal hypergammaglobulinemia, elevated serum lactate dehydrogenase (LDH) and C-reactive protein (CRP), or the emergence of various types of autoimmune antibodies [68]. The etiology and underlying pathophysiologic mechanism of this disease remain unclear, but it has been postulated that functionally activated lymphoma cells of AITL generate various cytokines, such as interleukin-6 (IL-6), IL-10, IL-21, platelet-derived growth factor, or chemokines, such as CXCL13, which further promote lymphoma cell proliferation in an autocrine and a paracrine manner and thereby promote tumor progression and enhance systemic symptoms [913]. Because of poor prognosis with a median survival of <3 years and a 5-year survival rate of approximately 10–30 % [2, 68], it is critically important to evaluate risk factors as quickly as possible for the treatment of AITL, even though the diagnosis of AITL is not always straightforward [1, 14].

Of the various symptoms and abnormal laboratory test results associated with AITL, circulating plasma cells have been occasionally detected in approximately one-third of AITL patients, but occurrence of exuberant polyclonal plasmacytosis has only rarely been reported in association with AITL [1518]. Perhaps due to its rare occurrence, the clinical significance of plasmacytosis in AITL has not been assessed in detail. This report concerns three cases of AITL accompanied by exuberant polyclonal plasmacytosis and assesses the clinical significance of plasmacytosis in AITL by comparing clinical outcomes, symptoms and laboratory test results for the three cases with those for 12 patients with AITL without plasmacytosis consecutively treated at our institute.

Materials and methods

Evaluation of patients and various factors

This study was conducted in accordance with the ethical principles of the Declaration of Helsinki. We retrospectively analyzed clinical data and treatment outcomes for 15 AITL patients, including two previously reported patients [19, 20], who were consecutively treated at our institute between January 1990 and December 2012. Factors analyzed include patients’ background (age and gender), symptoms [performance status (PS), respiratory malfunction, skin lesions], disease status (disease stage according to the Ann Arbor Staging System, International Prognostic Index (IPI) [21], Prognostic Index for T-cell lymphomas (PIT) [22], AITL Prognostic Index (ATPI) [7], Prognostic Index for AITL (PIAI) [6]), and laboratory test results (peripheral blood plasma cell ratio and count, white blood cell count (WBC), hemoglobin level (Hb), platelet count (Plt), serum levels of LDH, CRP, total protein (TP), albumin (Alb), immunoglobulin (Ig) G, IgA, IgM, ferritin and soluble IL-2 receptor (sIL2R), and degree of bone marrow tumor cell infiltration). Biopsied specimens were used to investigate the presence of Epstein–Barr virus (EBV) in 13 patients by means of either immunohistochemical staining for EBER (EBER-ISH) or polymerase chain reaction (PCR) for EBV-DNA, and that of chromosome abnormalities in 11 patients by means of G-banding. In the absence of established definition, in this article, we tentatively defined the condition of exuberant polyclonal plasmacytosis with polyclonal hypergammoglobulinemia in AITL as the presence of more than 20 % plasma cells in peripheral blood and an absolute plasma cell count greater than 2 × 109/L along with the definition of plasma cell leukemia [23]. The clonality of plasma cells was evaluated by the light chain restriction of surface immunolgobulin by flow cytometric analyses. Polyclonal hypergammoglobulinemia was diagnosed by the conventional immunoelectrophoresis.

Statistical analysis

For the comparison of AITL with and without plasmacytosis, the Chi-square test was utilized for age, sex, skin lesion and bone marrow invasion, and the Mann–Whitney U test for assessing differences in PS, disease stage, prognostic indexes and laboratory tests. The confidence interval was 95 % for all analyses and P < 0.05 was considered statistically significant. Survival of patients was assessed by means of Kaplan–Meier’s analysis.

Results

Clinical and biologic manifestation of AITL patients at presentation

Fifteen patients with AITL, including three with plasmacytosis, were retrospectively investigated. As seen in Table 1, the median age of all patients was 65 years (range 38–84). All showed signs of systemic lymphadenopathy and eight (53.3 %) presented with skin rash at diagnosis. The disease stage of all but one was advanced (III and IV), 12 (80 %) presented with B symptoms, and 86.7 % of patients with unfavorable PS (PS ≥ 2). All patients with plasmacytosis had PS ≥ 3. Most patients showed high-risk prognostic indexes for IPI, PIT, ATPI and PIAI. All these features, except for female preponderance in our study, are concordant with the findings reported for other larger-scale investigations of AITL [68]. Frequently observed abnormal laboratory test results were anemia (73.3 % of all patients), elevated LDH (86.7 %), polyclonal hyperimmunoglobulinemia (80 %), elevated CRP (93.3 %) and elevated sIL2R (93.3 %). Bone marrow invasion of tumor cells was identified in one patient and three patients (20 %) showed exuberant polyclonal plasmacytosis in their peripheral blood. Peripheral plasmacyte counts of three patients with plasmacytosis were 14.5 × 109/L, 5.0 × 109/L, and 2.0 × 109/L (Tables 1, 2, 3), while the remaining 12 patients showed no abnormal plasmacytosis in their peripheral blood. Chromosomal analysis by means of G-banding using tumor biopsy samples identified karyotypic abnormalities in six of the 11 patients analyzed, but we found no recurrent abnormality in our series (Supplementary Table). The presence of EBV infection was detected in nine of 13 patients either by PCR for EBV-DNA or EBER-ISH.
Table 1

Background, clinical manifestation and prognostic indices of 15 AITL patients

Subject

Total

Plasmacytosis (+)

Plasmacytosis (−)

P

Mourad [8]

Tokunaga [7]

Patient number

15

3

12

 

157

207

Age (median, range)

65 (38–84)

63 (57–69)

66.5 (38–84)

NS

62 (20–89)

67 (34–91)

Male:female

5:10

2:1

3:9

NS

95:62

132:75

Performance status 0/1/2/3/4

0/2/10/2/1

0/0/0/2/1

0/2/10/0/0

0.01

PS ≥ 2 50 %

PS ≥ 2 36 %

Ann Arbor disease stage I/II/III/IV

1/0/8/6

0/0/2/1

1/0/6/5

NS

Stage ≥ III 81 %

Stage ≥ III 90 %

LDH, median (range) (IU/L) (normal range; 114–243)

346

414 (346–477)

327 (141–1650)

NS

>ULN, 66 %

>ULN, 75 %

Skin rash, +/−

8/7

3/0

5/7

NS

44 %

NA

Respiratory involvement, +/−

5/10

2/1

3/9

NS

10 %

7 %

B symptoms, +/−

12/3

3/0

9/3

NS

72 %

60 %

Bone marrow invasion, +/−

1/14

0/3

1/11

NS

47 %

29 %

Risk factor number in IPI 0/1/2/3/4/5

0/0/3/0/10/2

0/0/0/0/2/1

0/0/3/0/8/1

NS

0–1/2–3/4–5 11 %/51 %/38 %

0–1/2/3/4–5 11 %/20 %/39 %/36 %

Risk factor number in PIT 0/1/2/3

0/2/2/11

0/0/0/3

0/2/2/8

NS

0–1/2/3–4 26 %/35 %/39 %

0/1/2/3–4 4 %/19 %/43 %/34 %

Risk factor number in PIAI 0/1/2/3/4/5

0/2/1/8/3/1

0/0/0/1/2/0

0/2/1/7/1/1

NS

NA

NA

Risk factor number in ATPI 0/1/2/3/4/5

0/1/6/3/3/2

0/0/0/0/1/2

0/1/6/3/2/0

0.01

NA

0–1/2/3/4–6 15 %/19 %/26 %/15 %

Data from previous larger studies of AITL are also shown for reference

IPI International prognostic index, PIT Prognostic Index for PTCL-U, PIAI Prognostic Index for AITL, ATPI AITL Prognostic Index, PS performance status, ULN upper limit of normal, NS no significant difference, NA not available

Table 2

Laboratory data of 15 AITL patients

 

Normal range

All median

Plasmacytosis (+) median (range)

Plasmacytosis (−) Median (range)

P

Mourad [8]

Tokunaga [7]

Complete blood count

  

 White blood cell (×109/L)

3.4–7.3

8.7

19.3 (16.9–20.4)

8.3 (4.0–32.9)

NS

NA

>10, 28 %

 Plasmacyte (%)

0

0

26 (12–70)

0 (0–1)

NA

NA

 Hemoglobin (g/dL)

11.7–15.1

10.3

9 (8.4–9.3)

10.9 (4.4–14.5)

NS

<12, 65 %

<13 (male) and < 11 (female), 61 %

 Platelet (×109/L)

160–327

191

116 (96–269)

192 (30–358)

NS

<150, 20 %

<150, 34 %

Serological data

  

 Total protein (g/dL)

6.4–8.4

7.3

10.2 (9.6–12.5)

7.2 (5.7–7.9)

0.01

NA

<6.5, 24 %

 Albumin (g/dL)

3.9–5.2

3.1

2.4 (2.1–2.4)

3.2 (2.0–4.9)

0.03

<3.5, 50 %

<3.5, 53 %

 IgG (mg/dL)

803–1785

2317

4445 (3747–6198)

2185 (1196–2377)

0.01

 

>1700, 54 %

 IgA (mg/dL)

102–411

373

950 (476–1378)

348 (70–659)

0.01

Total Ig > 1200, 50 %

>400, 37 %

 IgM (mg/dL)

30–207

278

460 (278–1387)

256 (24–1055)

NS

 

NA

 C-reactive protein (mg/dL)

<0.3

3.1

2.4 (2.2–11.1)

4.1 (0.1–23.7)

NS

NA

>2.0, 46 %

 Soluble IL-2 receptor (U/mL)

122–496

7660

5730 (4720–15500)

9290 (531–43188)

NS

NA

>4000, 64 %

Data from previous larger studies of AITL are also shown for reference

Ig immunoglobulin, ULN upper limit of normal, NS no significant difference, NA not available

Table 3

Laboratory data at diagnosis of three AITL patients with plasmacytosis

 

Normal range

Patient #1

Patient #2

Patient #3

Complete blood count

 White blood cell (×109/L)

3.4–7.3

19.3

16.9

20.7

 Plasmacyte (%)

0

26

12

70

 Hemoglobin (g/dL)

11.7–15.1

8.5

9.3

9.0

 Platelet (×109/L)

160–327

43.0

269.0

116.0

Bone marrow analysis

 All nucleated cell count (×109/L)

100–250

163

97

24

 Plasmacyte (%)

 

22.2

16.0

24.4

 Lymphoma cell (%)

 

0

0

0

Serological data

 LDH (IU/L)

114–243

264

414

238

 AST (IU/L)

12–35

16

18

17

 ALT (IU/L)

6–33

18

10

17

 Total bilirubin (mg/dL)

0.2–1.0

1.11

0.46

0.87

 BUN (mg/dL)

7.0–20.0

40.5

15.7

10.1

 Creatinine (mg/dL)

0.3–1.1

1.11

1.42

1.08

 Total protein (g/dL)

6.4–8.4

10.6

9.6

9.4

 Albumin (g/dL)

3.9–5.2

2.1

2.4

3.0

 IgG (mg/dL)

803–1785

6198

4445

3747

 IgA (mg/dL)

102–411

950

476

1378

 IgM (mg/dL)

30–207

278

1387

461

 C-reactive protein (mg/dL)

<0.3

20.97

11.13

0.81

 Beta-2-microglobulin (mg/dL)

0.8–2.0

14.94

8.69

NA

 Soluble IL-2 receptor (U/mL)

122–496

5730

4720

15500

Other immunologic tests

 Anti-nuclear antibody

<×40

×40

<×40

×40

 Coombs test

Negative

Positive

Positive

Positive

LDH lactate dehydrogenase, AST aspartate aminotransferase, ALT alanine aminotransferase

Brief case reports for three AITL patients with plasmacytosis

Case #1

A 75-year-old female initially admitted to a local hospital with complaints of severe malaise and continuous high grade fever >38 °C of unknown cause which had lasted for a month, was transferred to our hospital for the treatment of subsequent respiratory failure which was suspected to be due to unspecified immunologic pneumonitis and was not responsive to antibacterial agents. Her PS was 4 at presentation. Computed tomography (CT) identified bilateral massive pulmonary infiltration (Fig. 1a) as well as systemic lymphadenopathy and splenomegaly (Fig. 1b). As shown in Table 3, laboratory tests identified various abnormalities, including elevated WBC count with 26.0 % accounted for by polyclonal plasmacytes, which were morphologically diverse and positive for CD19, CD38 and CD138, but negative for CD20, CD56, or light chain restriction of immunoglobulin (Fig. 1c). Anemia, thrombocytopenia, polyclonal hyperimmunoglobulinemia, elevated CRP and sIL2R were also detected. Anti-nuclear antibody (ANA) and direct Coombs test results were positive, and PCR showed EBV-DNA in peripheral blood was positive (7.8 × 104 copies/106 cells). Bone marrow analysis showed that plasmacytes accounted for 22.2 %, but that there were no abnormal lymphoid cells. Based on the findings of the histologic examination of a lymph node biopsy specimen (Fig. 1d) the patient was diagnosed with AITL, Stage IIIB. Scores for IPI, PIT, PIAI and ATPI at diagnosis were 4, 3, 4 and 5, respectively. Although artificial respiration was required due to acute respiratory failure for the first week, methyl-predonisolone pulse therapy successfully resolved her respiratory failure, after which the patient attained complete remission (CR) as a result of systemic chemotherapy consisting of 8 courses of conventional CHOP. Currently, this patient has maintained CR for 23 months.
https://static-content.springer.com/image/art%3A10.1007%2Fs12185-013-1411-z/MediaObjects/12185_2013_1411_Fig1_HTML.gif
Fig. 1

Clinical findings of patient #1. a Chest computed tomography (CT) scan showed massive infiltrative shadow on bilateral lungs. b Abdominal CT scan showed marked splenomegaly. c Plasmacytes with variable morphology were identified in peripheral blood smear (Wright–Giemsa staining) as well as grape cells with cytoplasmic vacuoles (arrow). d Histologic view of lymph node biopsy specimen (H&E) showing partial effacement of the lymph node architecture resulting from diffuse infiltration of numerous small- to medium-sized immunoblasts and medium- to large-sized abnormal lymphoid cells in inter-follicular lesion. Proliferation of high endothelial venules (HEVs) is also visible (arrowheads). Electrophoresis of serum protein (e) and immunoelectrophoresis (f) showed a polyclonal hypergammaglobulinemia

Case #2

A 60-year-old male was initially admitted to a local hospital and later transferred to our hospital for further examination of high grade fever >39 °C, systemic skin rash and systemic lymphadenopathy of unknown cause which had lasted for 2 months (Fig. 2a). His PS was 3 at presentation. Laboratory tests identified various abnormalities, including elevated WBC count with 12.0 % accounted for by polyclonal plasmacytes positive for CD19, CD38 and CD138, but negative for CD20, CD56, as well as light chain restriction of immunoglobulin (Fig. 2b). Anemia, polyclonal hyperimmunoglobulinemia, elevated LDH, CRP and sIL2R were also identified. Serum IL-6 was elevated to 13.1 pg/ml (normal range <4.0 pg/ml). Findings for both direct and indirect Coombs tests and cold agglutination test were positive, and PCR demonstrated that EBV-DNA in peripheral blood was positive (7.5 × 10 copies/106 cells). Bone marrow analysis showed that 16.0 % of the cells were plasmacytes and no abnormal lymphoid cells (Table 3). Based on the histologic examination findings of a lymph node biopsy specimen (Fig. 2c), the patient was diagnosed with AITL, Stage IVB. Scores for IPI, PIT, PIAI and ATPI at diagnosis were 5, 3, 3 and 5, respectively. Although the first course of CHOP therapy induced transient and partial improvement of systemic symptoms, the disease rapidly progressed again before the initiation of the second course. Salvage therapy with a combination of cyclosporine A (CsA) and dexamethasone improved his systemic symptoms, normalized laboratory findings and eventually induced PR within 3 weeks. Since then, the patient has maintained PR for 10 months with CsA maintenance therapy.
https://static-content.springer.com/image/art%3A10.1007%2Fs12185-013-1411-z/MediaObjects/12185_2013_1411_Fig2_HTML.gif
Fig. 2

Clinical findings of patient #2. a18F-fluorodeoxyglucose (FDG)-positron emission tomography image before treatment showed systemic lymphadenopathy and hepatosplenomegaly with strong uptake of 18FDG. b Plasmacytes with variable morphology were identified in peripheral blood smear (Wright–Giemsa staining) as well as immature plasma cell precursor cells (arrows). c Diffuse infiltration of numerous small- to medium-sized immunoblasts and abnormal lymphoid cells with a background of polymorphic immunoblasts, plasma cells, eosinophils and proliferation of HEVs (arrowheads). Electrophoresis of serum protein (d) and immunoelectrophoresis (e) showed a polyclonal hypergammaglobulinemia

Case #3

A 68-year-old male was initially admitted to another department of our hospital with complaints of chest pain, dyspnea, high grade fever >39 °C, skin rash, pleural effusion, delirium and systemic lymphadenopathy. Because symptoms progressed for 2 months without establishment of a definite diagnosis, he was transferred to the hematology/oncology division for further examination. His PS was 3 at presentation. Laboratory tests identified various abnormalities, including elevated WBC count with 70.0 % accounted for by polyclonal plasmacytes which were positive for CD19, CD38 and CD138, but negative for CD20, CD56, as well as light chain restriction of immunoglobulin. Anemia, polyclonal hyperimmunoglobulinemia, elevated LDH and sIL2R were identified and ANA and direct Coombs test results were positive. Bone marrow analysis identified 24.4 % of the cells as plasmacytes (Table 3). Based on the histologic examination findings of a lymph node biopsy specimen, this patient was diagnosed with AITL, Stage IIIB. Scores for IPI, PIT, PIAI and ATPI at diagnosis were 4, 3, 4 and 5, respectively. Three course of CHOP and a single course of CHASE induced CR, and, since then, the patient has maintained CR for 102 months.

Comparison of clinical/biologic manifestations and treatment outcomes of AITL with and without plasmacytosis

The three patients with plasmacytosis described above were admitted to our division with markedly unfavorable PS at their initial presentation, which was significantly worse than that of patients without plasmacytosis. Nevertheless, other variables such as age, disease stage, or various symptoms, were not significantly different. For prognostic indices as well, except for ATPI, no significant differences were found between patients with and without plasmacytosis (Table 1). As for laboratory data, the quantities of various serum protein components were significantly different, but those of LDH, CRP and sIL2R were not (Table 2).

Conventional CHOP therapy was performed as the first-line chemotherapy for 12 of the 15 patients and the overall response rate for CHOP was 50.0 % including 25.0 % complete response (CR). One patient was treated with CHOP-like regimen, and another with CsA as the first-line therapy. Two patients died due to disease progression during the first-line therapy course, and 10 patients required salvage therapy. One patient showed spontaneous tumor regression and eventually attained CR without therapy. At the end of the median observation period of 28 months, the estimated 2-year and 5-year overall survival (OS) rates were 85.6 and 71.3 %, respectively. At the time of writing, all three patients with plasmacytosis are alive, while eight of the patients without plasmacytosis are alive and four have died (Table 4). Due to the small scale of this study, it was not possible to compare OS for patients with and without plasmacytosis.
Table 4

Treatment and prognosis of 15 AITL patients

 

Plasmacytosis

First-line treatment/best response

Second-line treatment/best response

Third-line treatment/best response

Fourth-line treatment/best response

Latest status

Overall survival (months)

1

+

CHOP/CR

CR

23, alive

2

CHOP/SD

CsA + Dexa/PR

PR

10, alive

3

CHOP/SD

CHASE/CR

CR

102, alive

4

CHOP/PR

HDCT with Auto-PBSCT/PR

→PD

CsA/CR

RIST/CR

CR

34, alive

5

CHOP/SD

CHASE/SD

CsA + Dexa/CR

CR

40, alive

6

CHOP/PD

PD

4, died

7

CHOP/CR

CR

20, alive

8

CsA/SD

CHASE-PD

PD

16, died

9

Spontaneous regression

CR

28, alive

10

CHOP/PR

VP-16/CR

→relapsed

DeVIC/PD

PD

37, died

11

CHOP/PR

ESHAP/PR

HDCT with Auto-PBSCT/PR

→PD

CBT/CR

CR

77, alive

12

CHOP/PR

CsA/CR

CR

42, alive

13

CHOP/PD

PD

5, alive

14

CHOP/CR

→relapsed

VP-16 + PSL/PR

PR

11, alive

15

CHOP-like/PR

VP-16/CR

→relapsed

CHOP/PD

ESHAP/PD

PD

179, died

CR complete response, PR partial response, SD stable disease PD progressive disease, Auto-PBSCT autologous peripheral blood stem cell transplantation, CBT cord blood transplantation with myeloablative conditioning, CHASE cyclophosphamide, cytosine arabinoside, etoposide and dexamethasone; CHOP cyclophosphamide, adriamycin, vincristine and predonisolone; CsA cyclosporine A, DeVIC dexamethasone, etoposide, ifosfamide and carboplatin; Dexa dexamethasone, ESHAP etoposide, methylprednisolone, cytosine arabinoside and cisplatin; HDCT myeloablative high-dose chemotherapy, PSL predonisolone, RIST reduced-intensity allogeneic stem cell transplantation, VP-16 etoposide

Discussion

In the latest WHO classification established in 2008, lymphoid neoplasms have been categorized into more than 60 disease subtypes on the basis of their respective normal counterparts, cytogenetic and molecular features, underlying pathogenetic conditions and clinical manifestation, and accrued clinical experience has made it possible to establish prognostic models for individual subcategories. Because the prognosis of AITL is unfavorable, the prediction of prognosis is critically important for planning well-designed therapeutic strategy. Indeed, it has been shown that AITL-specific prognostic models, such as ATPI or PIAI, are more suitable for the prediction of outcomes of AITL than IPI, which is commonly utilized for the majority of NHL cases, and PIT, which is utilized for a broad range of T-cell NHLs [6, 7]. For the establishment of ATPI and PIAI, a range of variables including B symptoms, mediastinal lymphadenopathy, peripheral blood cell counts, or serum levels of total protein, albumin, Ig, β2-microglobulin, CRP and sIL2R were investigated for their prognostic relevance in addition to variables already included in IPI and PIT. B symptoms, blood cell counts, IgA level and mediastinal lymphadenopathy were found to be viable prognostic variables for either AITL-specific ATPI or PIAI [6, 7]. However, plasmacytosis has not been assessed for its prognostic significance for AITL.

In this study, we focused on plasmacytosis because three AITL patients with plasmacytosis showed several clinical characteristics distinct from those of AITL patients without plasmacytosis. First, they were severely exhausted with rather poor PS 3–4, which was significantly poorer than that of patients without plasmacytosis and required emergent admission at their first visit to our division. Second, for all three patients with plasmacytosis, more than a month was needed to establish the correct diagnosis, possibly because they displayed a wide array of clinical symptoms in addition to polyclonal plasmacytosis, which is rarely seen in general practice. Given the patients’ serious condition and the diagnostic delay, our first impression at their initial presentation was that their prognoses could be unfavorable, even lethal. However, once AITL was correctly diagnosed, all three patients with plasmacytosis responded well to either cytotoxic chemotherapy or immunosuppressants, and attained and maintained a favorable outcome throughout the follow-up period. Indeed, while the ATPI scores were worse for patients with than for those without plasmacytosis, prognostic scores along with IPI, PIT and PIAI were not significantly different for the two patient groups. The reason for the worse ATPI scores for patients with plasmacytosis might be that they had higher levels of IgA, which is one of the factors incorporated only in ATPI [7]. In addition, PS is one of the variables included in IPI and PIT, neither of which has proven to be always suitable for predicting prognosis of AITL.

The appearance of polyclonal plasmacytosis in peripheral blood is a worrisome issue which requires thoughtful diagnostic investigation. As was reported elsewhere [24, 25], circulating plasmacytes in our cases also proved to be a mixture of plasma cell progenitors, precursors and mature plasmacytes. Moreover, when our patients first visited the other clinics, the presence of polyclonal plasmacytosis was thought to be a reactive process to benign diseases, such as infection, serum sickness or autoimmune disease, rather than to malignant diseases, including AITL. The actual frequency of exuberant plasmacytosis has remained unclear, and only a handful of cases with AITL accompanied with exuberant plasmacytosis have been reported [1518]. The findings of our study indicate the importance of a differential diagnosis of AITL when polyclonal plasmacytosis is present. Tumor cells of AITL potentially generate various cytokines, such as IL-6 or IL-10, which promote proliferation and survival of plasma cell progenitors as well as various systemic abnormal signs, such as high fever, body weight loss, night sweating, lung complication, organomegaly, polyclonal hyperglobulinemia or autoantibodies. The involvement of inflammatory cytokines for polyclonal plasmacytosis is also the case with that accompanied with other underlying diseases, such as autoimmune disorders, chronic infection or malignancies [26, 27]. An even more important finding is that, while the clinical outcome of patients with plasmacytosis has not been clearly described in previous cases [1518], our study suggests that with an early and accurate diagnosis the presence of exuberant polyclonal plasmacytosis is not always a poor prognostic factor for AITL despite patients’ extremely poor condition at presentation.

Apart from plasmacytosis, the long-term outcomes of our cohort of 15 patients seemed to be more favorable than those previously reported for AITL [18]. A recent study found that CsA was highly efficacious for AITL patients, including those resistant to chemotherapy [19, 20, 28], and we speculate that the relatively favorable treatment outcomes of our cohort may be the result of the incorporation of CsA as salvage therapy. As shown in Table 4, only 2 of 13 patients attained a successful long-term outcome in response to the first-line cytotoxic chemotherapy, while 4 of the 5 patients who received CsA-containing therapy showed good disease control throughout the observation period. In contrast, 2 patients died during the first-line CHOP therapy due to disease progression, and 2 of the 6 patients who were treated only with cytotoxic salvage regimens maintained CR or PR, and remained alive throughout the observation period.

In conclusion, AITL, although rare, should be considered a candidate for underlying disease of exuberant polyclonal plasmacytosis. With the early and correct diagnosis of AITL and the use of conventional chemotherapy or immunosuppressive therapy, the prognosis of AITL with plasmacytosis may not be worse than that of AITL without plasmacytosis, although at first presentation the patients may be severely exhausted due to the poor PS.

Acknowledgments

This work was partly supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (M.T. and J.K.) and the Hoansha Foundation (J.K.).

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

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Supplementary material 1 (DOCX 20 kb)

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© The Japanese Society of Hematology 2013