Plasmacytosis mimicking multiple myeloma in angioimmunoblastic T-cell lymphoma: A case report and review of literature

Abstract

BACKGROUND

Angioimmunoblastic T-cell lymphoma (AITL) is a common subtype of peripheral T-cell lymphoma. Approximately half of patients with AITL may concurrently present with hypergammaglobulinemia. Increased numbers of plasma cells in the bone marrow are commonly observed at diagnosis. These tumors mimic plasma cell myelomas, hindering a conundrum of clinical diagnoses and potentially delaying appropriate treatment.

CASE SUMMARY

A 78-year-old woman experienced poor appetite, weight loss of 5 kg, fatigue 2 months before presentation, and shortness of breath 2 d before presentation, but no fever or night sweats. Physical examination revealed splenomegaly and many palpable masses over the bilateral axillary regions, approximately > 2 cm in size, with rubbery consistency and no tenderness. Blood tests revealed anemia and thrombocytopenia, lactate dehydrogenase level of 153 U/L, total protein level of 10.9 g/dL, albumin to globulin ratio of 0.2, and immunoglobulin G level more than the upper limit of 3000 mg/dL. The free kappa and lambda light chain concentrations were 451 and 614 mg/L, respectively. A pathological examination confirmed the diagnosis of AITL. The initial treatment was the cyclophosphamide, epirubicin, vincristine, and prednisolone regimen. Following this treatment, pleural effusion was controlled, and the patient was discharged in a stable condition and followed up in our outpatient department.

CONCLUSION

This report highlights the importance of differentiating reactive plasmacytosis from plasma cell myeloma in patients with hypergammaglobulinemia. A precise diagnosis of AITL requires a comprehensive evaluation, involving clinical, immunophenotypic, and histological findings conducted by a multidisciplinary team to ensure appropriate treatment.

Key Words: Angioimmunoblastic T-cell lymphoma; Plasmacytosis; Multiple myeloma; Lymphoma, Hypergammaglobulinemia; Case report

Core Tip: Angioimmunoblastic T-cell lymphoma (AITL) is a common subtype of peripheral T-cell lymphoma. These tumors mimic plasma cell myelomas, hindering a conundrum of clinical diagnoses and potentially delaying appropriate treatment. A precise diagnosis of AITL requires a comprehensive evaluation, involving clinical, immunophenotypic, and histological findings conducted by a multidisciplinary team to ensure appropriate treatment. This report highlights the importance of differentiating reactive plasmacytosis from plasma cell myeloma in patients with hypergammaglobulinemia.

INTRODUCTION

Angioimmunoblastic T-cell lymphoma (AITL) is a common subtype of peripheral T-cell lymphoma (PTCL), accounting for approximately 25%-30% of all PTCL cases in Europe and 18%-28% in Asia[1,2]. Patients diagnosed with AITL are usually aged 50 to 60 years, and there are slightly more males than females[3]. Clinical features of AITL include B symptoms (fever, weight loss, and chills), skin rashes, pruritus, lymphadenopathy, hepatosplenomegaly, anemia, thrombocytopenia, and hyper-gammaglobulinemia. The clinical course may be aggressive, and approximately 81%-98% of patients are diagnosed with Ann Arbor stage III/IV disease, which may be due to the difficulty in diagnosis[4]. For accurate diagnosis, pathological confirmation of biopsy specimens is critical. Histopathological analyses of AITL revealed that the tissue was infiltrated by reactive inflammatory cells, including lymphocytes, eosinophils, plasma cells, and histiocytes[1]. Irregular proliferation of follicular dendritic cells and proliferative high endothelial venules are the pathological characteristics of AITL[5]. However, approximately half of patients with AITL may concurrently present with hypergammaglobulinemia[6]. Plasma cells present in AITL are usually polyclonal; monoclonal plasma cell proliferation is less common[1,5]. Moreover, increased numbers of plasma cells in the bone marrow are commonly observed at the time of diagnosis. These mimic plasma cell myelomas result in a problem of clinical diagnoses that could potentially mislead appropriate treatment. We report a case of AITL with plasmacytosis mimicking multiple myeloma. This report highlights the importance of an accurate diagnosis and appropriate treatment initiation for AITL.

CASE PRESENTATION

Chief complaints

The patient was a 78-year-old woman and present to our hospital due to dyspnea.

History of present illness

Two months before the presentation, the patient experienced poor ap-petite, weight loss of 5 kg, and fatigue. Two days before the presentation, the patient experienced shortness of breath but no fever or night sweats. In the emergency room, chest radiography revealed ground-glass opacity over the left lung, and ultrasonography confirmed pleural effusion. After the patient underwent thoracentesis using a pigtail catheter and the symptoms were relieved, the patient was admitted to our hospital in 2023.

History of past illness

The patient had a history of hypertension.

Personal and family history

The patient had no remarkable personal or family history.

Physical examination

After admission, a physical examination revealed splenomegaly and many palpable masses over the bilateral axillary regions, approximately > 2 cm in size, with rubbery consistency and no tenderness. No remarkable abnormal findings were observed in the other organs.

Laboratory examinations

Blood tests revealed mild anemia (hemoglobin level of 10.6 g/dL) and thrombocytopenia (platelet count of 137000 cells/mm³), lactate dehydrogenase level of 153 U/L, total protein level of 10.9 g/dL, albumin level of 3.9 g/dL, albumin to globulin ratio of 0.2. Due to the abnormal albumin-to-globulin ratio, other blood tests were performed on the 2^nd day of hospitalization. They revealed an IgA level of 358.2 mg/dL, an IgM level of 196.0 mg/dL, and an IgG level of more than the upper limit of 3000 mg/dL. The free kappa and lambda light chain concentrations were 451 and 614 mg/L, respectively. The kappa-to-lambda ratio was 0.73. Serum protein electrophoresis (SPEP) revealed an albumin fraction of 4.1%, alpha-1 globulin fraction of 3.8%, alpha-2 globulin fraction of 5.6%, beta globulin fraction of 36.6%, and gamma globulin fraction of 49.9%, and serum immunofixation electrophoresis did not reveal M-peak. A peripheral blood smear revealed plasma cells and a Rouleaux formation (Figure 1A).

Figure 1 Positron-emission tomography-computed tomography scan. Initial positron-emission tomography-computed tomography showed malignant lymphoma activity disseminated in the Waldeyer's ring, bilateral nuchal, bilateral submental and submandibular, bilateral neck, bilateral supraclavicular, bilateral mediastinal, bilateral pulmonary hilar, bilateral axillary, splenic, celiac, paraaortic, bilateral iliac, and bilateral inguinal lymph nodes.

Imaging examinations

On the 12^th day of hospitalization, positron emission tomography-computed tomography (PET-CT) was performed to exclude the presence of other primitive unknown tumors and confirm the stage of the lymphoma, which revealed malignant lymphoma activity disseminated in many regions, as shown in Figure 1.

Further diagnostic work-up

On the 3^rd day of hospitalization, an excisional biopsy of the right axillary lymph node was performed. On the 4^th day of hospitalization, bone marrow aspiration and biopsy were performed. A peripheral blood smear revealed plasma cells and a Rouleaux formation (Figure 2A). A smear of the bone marrow aspiration revealed numerous atypical plasma cells (Figure 2B), accounting for 23.6% of the nucleated cells, and immature plasma cells with prominent nucleoli were also observed. Moreover, the smear revealed an aggregation of small-to-medium-sized lymphoma cells. Immunohistochemical analysis showed plasma cells expressing both kappa (Figure 2C) and lambda (Figure 2D). On the 11^th day of hospitalization, pathological examination revealed a destroyed architecture of the lymph nodes with follicular dendritic cells and small-to-medium-sized atypical infiltrating lymphocytes with frequent mitoses and clear cytoplasm (Figure 2E). The stroma was rich in capillaries with enlarged endothelial cells. Lymphocytes clustered around endothelial cells. Morphological findings were similar to those of AITL. Immunohistochemical analysis showed that the atypical lymphocytes were T cells expressing CD3, CD4, PD-1, ICOS, and BCL-6 (Figure 2F) but not CD8, CD10, or CD20. Pan-T-cell markers include CD2, CD3, and CD5. Neoplastic T cells typically express CD4. Therefore, the atypical lymphocytes were T cells. Follicular T helper cells (TFH) markers included CD10, CXCL13, ICOS, BCL6, and PD1. The original AITL cells are associated with TFH, so AITL cells may also express some TFH markers. CD30 was positive in approximately 20%-30% of cells in the entire specimen (Figure 2G). In situ hybridization for Epstein-Barr virus (EBV)-encoded mRNA (EBER) was positive in approximately 10%-15% of cells in the specimen. The Ki67 proliferation index was approximately 50% (Figure 2H).

Figure 2 Microscopic evaluation of the lesion. A: A plasma cell and rouleaux formation in peripheral blood smear (magnification, 1000 ×); B: Plasmacytosis with atypical and immature plasma cells in bone marrow smear (magnification, 1000 ×); C: Immunohistochemistry (IHC) results for kappa show positivity in bone marrow (magnification, 200 ×); D: IHC results for lambda show positivity in bone marrow (magnification, 200 ×); E: Small- to medium-sized atypical lymphocytes and follicular dendritic cells with clear cytoplasm and capillaries with enlarged endothelial cells are observed using hematoxylin and eosin staining (magnification, 400 ×); F: IHC results for BCL-6 show positivity (magnification, 100 ×); G: IHC results for CD30 show positivity (magnification, 100 ×); H: IHC results for Ki-67 show positivity (magnification, 100 ×).

FINAL DIAGNOSIS

Based on these findings, we concluded the diagnosis of AITL.

TREATMENT

In terms of treatment, we decided to use six cycles of chemotherapy using the cyclophosphamide, epirubicin, vincristine, and prednisolone (CHOP) regimen on the 13^th day of hospitalization. Brentuximab vedotin (BV) is an expensive drug and the Taiwan Health Insurance Authority allows access in strict situations; therefore, the use of this combination is limited in resource-constrained settings. Therefore, BV was not administered to the patient.

OUTCOME AND FOLLOW-UP

After the first cycle of chemotherapy, pleural effusion was controlled, and the pig-tail catheter was removed. The patient was discharged in a stable condition on the 20^th day of hospitalization and followed up in our outpatient department. Thus, chemotherapy with the CHOP regimen was administered every 3 wk in a cyclic manner. To date, six cycles of the CHOP regimen have been completed, and no dose adjustment is required. Follow-up PET-CT revealed a partial response, with residual lymphoma still observed in the mediastinum and bilateral pulmonary hila compared to the previous scan (Figure 3). We will discuss initiating second-line therapy with BV for the patient.

Figure 3 Positron-emission tomography-computed tomography scan. Follow-up positron-emission tomography-computed tomography revealed residual lymphoma in the mediastinum and bilateral pulmonary hila.

DISCUSSION

We present a case of AITL with plasmacytosis mimicking multiple myeloma. Symp-toms of anemia, elevated serum IgG levels, and bone marrow involvement with numerous plasma cells led to a differential diagnosis of plasma cell disorder (monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and multiple myeloma). This presentation posed a considerable challenge regarding the initial diagnostic considerations before pathological confirmation.

The diagnosis of AITL is difficult and requires clinical features, morphology, immunophenotype, and molecular findings for any conclusion. The pathological analysis of biopsy specimens is critical for diagnosis. Pathological examination of soft tissues based on hematoxylin and eosin staining may reveal the infiltration of small- to medium-sized lymphocytes, and other histiocytes, plasma cells, and eosinophils composed of arborizing high endothelial venules[7]. In the present case, the morphological findings were similar to those observed in AITL. As the original AITL cells are TFH, immunohistochemical examination of neoplastic cells is typically positive for T cell markers (CD4, CD5, and CD2), as well as TFH markers (CD10, CXCL13, ICOS, BCL6, and PD1). According to the 2016 World Health Organization classification, atypical cells ex-pressing at least two (ideally three) TFH markers are recognized diagnoses of PTCL with TFH phenotype[7]. Recently, recurrent mutations in IDH2, TET2, DNMT3A, and RHOA have been characterized in AITL. In the present case, the pathological examination revealed infiltrating lymphocytes and elevated endothelial venule levels. Immunohistochemical results were positive for BCL-6, ICOS, and PD-1, indicating the presence of TFH. However, we did not check for mutations because the test was unavailable at our hospital. Based on the morphologic features and three of five TFH immunohistochemical features, a diagnosis of AITL can be established.

AITL may present with hypergammaglobulinemia, in which polyclonal plasma cell proliferation has been reported more frequently than monoclonal[1,8]. Hypergammaglobulinemia and plasmacytosis in the bone marrow may obscure an underlying malignancy. Reactive plasmacytosis and the coexistence of myeloma and AITL remain unclear and should be distinguished. Reactive plasmacytosis may occur in underlying malignancies, chronic infections (EBV, parvovirus B19, and hepatitis), and autoimmune diseases (rheumatoid arthritis and systemic lupus erythematosus)[9].

Many studies have revealed the relationship between AITL and plasma cell proliferation (Table 1). Awareness of this relationship is important as it may aid in making more accurate and effective differential diagnoses. Of the total 18 reported cases, 15 were diagnosed with reactive plasmacytosis, with the majority exhibiting polyclonal proliferation. Polyclonal proliferation is more likely than monoclonal proliferation to result in reactive plasmacytosis. Faisal et al[10] reported a case of monoclonal IgG kappa, using SPEP and immunofixation. However, flow cytometry of peripheral blood indicated polyclonal plasma cell proliferation, along with elevated levels of both kappa and lambda free light chains, ultimately leading to reactive plasmacytosis. Jawad et al[11] reported four cases of pseudo-monoclonal gammopathy in which both serum free light chains (kappa and lambda) were abnormally elevated, and reactive plasmacytosis was later confirmed via mass spectrometry. Jang et al[12] and Xu et al[13] reported two concurrent AITL and plasma cell disorder cases, which were confirmed using flow cytometry. Kishimoto et al[1] reported a case of concurrent AITL and plasma cell myeloma confirmed by multiplex polymerase chain reaction with DNA extracted from both the lymph node and bone mar-row to provide evidence supporting the possibility of different origins.

Table 1 Reported cases of angioimmunoblastic T-cell lymphoma with plasma cell proliferation.

Ref.	Year	Sex/age (yr)	Condition	IgH clonality	M protein	EBER	Treatment	Follow-up (month)
Sakai et al[27]	2006	M/73	AITL	Polyclonal	NA	NA	Steroids	DD (1)
Nagoshi et al[8]	2013	F/75	AITL	Polyclonal	NA	NA	CHOP	AIR (23)
		M/60	AITL	Polyclonal	NA	NA	CHOP	PD (NA)
		M/68	AITL	Polyclonal	NA	NA	CHOP + CHASE	AIR (102)
Huppmann et al[28]	2013	F/60	AITL	Polyclonal	NA	NA	ECHOP	NA
Jang et al[12]	2015	M/73	AITL	Monoclonal	IgM kappa	+	CHOP	NA
Adachi et al[29]	2015	M/78	AITL	Polyclonal	IgG and IgA	+	NA	DD (NA)
Xu et al[13]	2015	M/80	AITL	Monoclonal	IgA lambda	+	COP + Thalidomide	DD (6)
Jawad et al[11]	2017	F/30	RA	Polyclonal	NA	NA	Steroids + rituximab	Improvement of symptoms
		M/54	RA and SS	Polyclonal	NA	NA	rituximab	Improvement of symptoms
		M/24	IgG4RD	Polyclonal	NA	NA	rituximab	Improvement of symptoms
		F/51	MZL	Polyclonal	NA	NA	Steroid + rituximab	NA
Sachdev et al[30]	2018	M/69	AITL	Polyclonal	NA	+	CHOP	PD (24)
Kishimoto et al[1]	2019	F/87	AITL	Monoclonal	IgG Kappa	+	R-CHOP + lenalidomide	DD (12)
Sokol et al[31]	2019	M/62	AITL	Polyclonal	IgG and IgA	+	steroids	DD (NA)
Faisal et al [10]	2022	M/67	AITL	Monoclonal	IgG kappa	NA	CHOP	DD (NA)
Li et al[32]	2022	M/82	AITL	Polyclonal	IgG lambda, IgG Kappa	-	VP16+ lenalidomide	DD (2)
Mejia Saldarriaga et al[3]	2023	M/79	AITL	Polyclonal	IgG lambda, IgG Kappa	NA	BV-CHP	PD (2.5)

AITL: Angioimmunoblastic T-cell lymphoma; CHOP: Cyclophosphamide, doxorubicin, vincristine, prednisolone; R-CHOP: CHOP combined with rituximab; COP: Cyclophosphamide, vincristine, prednisolone; ECHOP: CHOP combined with etoposide; CHASE: Cyclophosphamide, cytosine arabinoside, etoposide and dexamethasone; VP-16: Etoposide; BV-CHP: Brentuximab vedotin, cyclophosphamide, doxorubicin, prednisolone; NA: Not available; DD: Die of disease; AIR: Alive in remission; RA: Rheumatoid arthritis; SS: Sjogren's syndrome; IgG4RD: IgG4-related disease.

When monoclonal hypergammaglobulinemia is present, flow cytometry and mass spectrometry are crucial to further confirm the occurrence reactive plasmacytosis. In addition, EBV infection of B cells in AITL may contribute to reactive plasma cell proliferation. EBER-positive cells can be detected using in situ hybridization in most patients with AITL. In the present case, the presence of polyclonal plasma cells (kappa and lambda) in the patient's peripheral blood and bone marrow suggested that plasma cell myeloma was un-likely. Moreover, the positivity for EBER in situ hybridization in our case tended to result in reactive plasmacytosis. However, the association between plasma cell proliferation and AITL remains unclear and requires further investigation.

Currently, CHOP-based chemotherapy regimens are widely accepted and are commonly used as frontline therapies for AITL[14]. However, long-term outcomes remain poor, with 5-year overall and event-free survival rates of 32%-41% and 18%-38%, respectively[4]. Additional agents, including etoposide, alemtuzumab, bortezomib, bevacizumab, and chidamide, have been incorporated into CHOP-based regimens. The rates of complete response, progression-free survival (PFS), and overall survival (OS) vary between 37%-65%, 30.3%-50%, and 32.8%-78.9%, respectively[15]. However, the efficacy of these therapies is unsatisfactory. Thus, CD30 has emerged as a potential therapeutic target. BV, cyclophosphamide, doxorubicin, and prednisolone (BV-CHP) may be a potential choice, as shown by the ECHELON-2 trial, where the 3-year PFS was 57.1% for the BV-CHP groups compared with 44.4% for the CHOP groups. Additionally, the median OS was not reached in either group[16]. However, it should be noted that AITL accounted for 12% of the patients in this trial. Feng et al[17] reported a real-world, retrospective study revealing that BV, in combination with chemotherapy, is an effective frontline treatment for patients with AITL. Although Yang et al[18] demonstrated that the efficiency of salvage therapy regimens for patients with relapsed/refractory AITL remains unclear, Horwitz et al[19] reported in a phase 2 study that BV exhibited impressive efficacy in treating relapsed/refractory AITL. However, the BV is not supported as a frontline or second-line treatment for AITL by the Taiwan Health Insurance Authority. Initially, we discussed the option of self-paid BV for our patient; how-ever, the patient preferred to consider self-paid BV as the disease progressed. Therefore, we initiated treatment with the CHOP regimen. Considering that BV is recommended for both frontline and second line in AITL treatments according to the national comprehensive cancer network guidelines[20], we believe that BV may offer potential benefits to the patient.

The evidence supporting the efficacy of immune checkpoint inhibitors remains inconclusive. In a phase 2 study investigating nivolumab in relapsed/refractory PTCL patients, rapid progression occurred in 4 out of 12 patients within one treatment cycle[21]. Another open-label phase 2 study assessing geptanolimab in relapsed/refractory PTCL patients demonstrated favorable activity and safety, with an overall response rate of 40.4%; however, patients with AILT were excluded from this study[22]. Furthermore, immune checkpoint inhibitors are not recommended by the NCCN guideline. Therefore, further investigation is warranted to determine the efficacy of immune checkpoint inhibitors. Moreover, the efficacy of chimeric antigen receptor T cell therapy remains uncertain, with several clinical trials evaluating its potential for patients with PTCL, including those with AITL[23].

Our study has some limitations. First, we did not assess the levels of interleukin (IL)-6 and IL-10, which are known to stimulate plasma cell proliferation and serve as possible contributing factors for plasmacytoma. The increased release of IL-6 or IL-10 is associated with the expansion of plasma cells in AITL[7]. Hence, elevated levels of IL-6 or IL-10 in patients with AITL may suggest a possible diagnosis of reactive plasmacytoma. The absence of IL data may weaken the persuasiveness of a reactive plasmacytoma diagnosis. Second, we could not check for mutations in IDH2, TET2, DNMT3A, or RHOA to confirm the diagnosis of AITL. The IDH2 mutation is detectable at a frequency of 20%-45% in AITL, whereas it is rare in other PTCLs exhibiting the TFH phenotype. In AITL, TET2 mutations are detectable in up to 80% of cases, DNMT3A mutations can be identified in 20%-30% of cases, and RHOA mutation are present in up to 70% of cases[24]. Moreover, RHOA and IDH2 mutations are primarily observed in neoplastic T cells[7]. Impairment of RHOA function, combined with TET2 loss of function, may contribute to the pathogenesis of AITL. In particular, mutations in RHOA are helpful in the early diagnosis of AITL[25]. In addition, these mutations may influence the development of mechanism-based treatment strategies. Diseases carrying TET2 mutations may respond effectively to hypo-methylating agents, such as 5-azacytidine and decitabine[4]. Nguyen et al[26] reported a phase 1 study revealing that patients with RHOA mutations may respond to dasatinib; further clinical trials are necessary to demonstrate its efficacy. Mutation data can as-sist in confirming the diagnosis of AITL and offer additional treatment options.

CONCLUSION

We report a rare case of AITL with plasmacytosis mimicking multiple myeloma. We also highlight the importance of differentiating reactive plasmacytosis from plasma cell myeloma in patients with hypergammaglobulinemia and plasmacytosis. Pathology, flow cytometry, gene mutations, abnormal polyclonal free light chains and elevated cytokine levels are useful tools for differential diagnosis. A precise diagnosis of AITL requires a comprehensive evaluation, involving clinical, immunophenotypic, and histological findings, conducted by a multidisciplinary team to ensure appropriate treatment. The CHOP-based chemotherapy regimen remains most used approach, and new therapies are continually being investigated in ongoing clinical trials.

ACKNOWLEDGEMENTS

This study received assistance of the Department of Medical Education and Research, Taichung Armed Forces General Hospital. This study was not funded.