Clinical manifestation of angioimmunoblastic T-cell lymphoma with exuberant plasmacytosis
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- Nagoshi, H., Kuroda, J., Kobayashi, T. et al. Int J Hematol (2013) 98: 366. doi:10.1007/s12185-013-1411-z
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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.
KeywordsAngioimmunoblastic T-cell lymphomaPlasmacytosisPolyclonal hyperglobulinemiaPrognosis
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) [1–5]. 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 [6–8]. 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 [9–13]. Because of poor prognosis with a median survival of <3 years and a 5-year survival rate of approximately 10–30 % [2, 6–8], 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 [15–18]. 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) , Prognostic Index for T-cell lymphomas (PIT) , AITL Prognostic Index (ATPI) , Prognostic Index for AITL (PIAI) ), 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 . 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.
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.
Clinical and biologic manifestation of AITL patients at presentation
Background, clinical manifestation and prognostic indices of 15 AITL patients
Age (median, range)
Performance status 0/1/2/3/4
PS ≥ 2 50 %
PS ≥ 2 36 %
Ann Arbor disease stage I/II/III/IV
Stage ≥ III 81 %
Stage ≥ III 90 %
LDH, median (range) (IU/L) (normal range; 114–243)
>ULN, 66 %
>ULN, 75 %
Skin rash, +/−
Respiratory involvement, +/−
B symptoms, +/−
Bone marrow invasion, +/−
Risk factor number in IPI 0/1/2/3/4/5
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
0–1/2/3–4 26 %/35 %/39 %
0/1/2/3–4 4 %/19 %/43 %/34 %
Risk factor number in PIAI 0/1/2/3/4/5
Risk factor number in ATPI 0/1/2/3/4/5
0–1/2/3/4–6 15 %/19 %/26 %/15 %
Laboratory data of 15 AITL patients
Plasmacytosis (+) median (range)
Plasmacytosis (−) Median (range)
Complete blood count
White blood cell (×109/L)
>10, 28 %
<12, 65 %
<13 (male) and < 11 (female), 61 %
<150, 20 %
<150, 34 %
Total protein (g/dL)
<6.5, 24 %
<3.5, 50 %
<3.5, 53 %
>1700, 54 %
Total Ig > 1200, 50 %
>400, 37 %
C-reactive protein (mg/dL)
>2.0, 46 %
Soluble IL-2 receptor (U/mL)
>4000, 64 %
Laboratory data at diagnosis of three AITL patients with plasmacytosis
Complete blood count
White blood cell (×109/L)
Bone marrow analysis
All nucleated cell count (×109/L)
Lymphoma cell (%)
Total bilirubin (mg/dL)
Total protein (g/dL)
C-reactive protein (mg/dL)
Soluble IL-2 receptor (U/mL)
Other immunologic tests
Brief case reports for three AITL patients with plasmacytosis
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).
Treatment and prognosis of 15 AITL patients
First-line treatment/best response
Second-line treatment/best response
Third-line treatment/best response
Fourth-line treatment/best response
Overall survival (months)
CsA + Dexa/PR
HDCT with Auto-PBSCT/PR
CsA + Dexa/CR
HDCT with Auto-PBSCT/PR
VP-16 + PSL/PR
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 . 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 [15–18]. 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 [15–18], 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 [1–8]. 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.
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.