Indolent peripheral T-cell lymphoma resembling Kimura's disease: a new variant of T-cell Lymphoma?

Abstract

Kimura's disease (KD) is a rare chronic inflammatory disorder of unknown etiology prevalent in middle-aged Asian males. Kimura's disease transforming to T-cell lymphoma or coexisting with T-cell lymphoma have not been reported in the scientific literature except two cases of Kimura's disease resembling peripheral T-cell lymphoma morphologically. There was no corresponding entity included in the current WHO classification (5th ed., 2022). It might be a new variant of peripheral T-cell lymphoma. Here, we present the first reported case of coexisting KD and indolent peripheral T-cell lymphoma in a 55-year-old Chinese man.

1. Introduction

Kimura’s disease (KD) is a rare lymphoproliferative fibroinflammatory disorder that commonly affects the subcutaneous tissue and lymph nodes of the head and neck. This condition was first reported by Kim and Szeto [1] in 1937 and further characterized in 1948 by Kimura [2]. Young Asian men (especially East Asians) are most commonly affected with peak age of onset in their 30 s [3]. The most common laboratory findings are elevated serum immunoglobulin E (IgE) and eosinophilia [3,4].

Kimura's disease is regarded as an inflammatory disorder closely related to immune dysregulation. Its exact etiology remains unclear, with genetic factors possibly playing a role in susceptibility rather than being direct causative agents. Studies have shown that the frequency of certain human leukocyte antigen (HLA) alleles is significantly increased in patients, suggesting a genetic predisposition that may influence the immune response to unknown antigens. In terms of immune mechanisms, a key feature of Kimura's disease is a marked Th2-type immune response bias. This is manifested by a large number of infiltrating eosinophils in the affected tissues, along with increased eosinophils in the peripheral blood and extremely elevated serum IgE levels. Th2 cells and the key cytokines they secrete (such as IL-4, IL-5, and IL-13) drive B cells to produce IgE, promoting the activation, recruitment, and survival of eosinophils. At the same time, there is often significant lymphoid follicle formation (especially B cells), plasma cell infiltration, and varying degrees of fibrosis in the lesion tissues [[10], [11], [12]]. Currently, it is widely believed that this abnormal Th2 dominance and eosinophil activation are the core immunopathological basis for the chronic inflammation, tissue hyperplasia, and mass formation in Kimura's disease. However, the triggering factors (such as underlying infections, autoantigens, or environmental factors) still need further exploration [16,[19], [20], [21]].

The benign nature of Kimura's disease is well-established, although it exhibits a high recurrence rate. Recent reports have indicated a potential association between Kimura's disease and the development of T-cell lymphoma [13,14]. Here, we report a case of indolent peripheral T-cell lymphoma resembling Kimura's disease. According to the current WHO classification, this entity does not fit several common variants of peripheral T-cell lymphoma, such as lymphoepithelioid variant, T-zone variant, and follicular variant. This case may represent a new variant of peripheral T-cell lymphoma or an unknown mature T-cell lymphoma. During our follow-up, the patient was also diagnosed with KD.

2. Case report

A 55-year-old Chinese male came to the Affiliated Hospital of Nantong University for treatment of bilateral elbow masses. The patient was found to have bilateral elbow masses in 2019, since then the masses had been slowly growing, and the elbow masses were removed in October 2021. Otherwise, the patient’s past medical and personal histories were unremarkable. He had no family history of allergies or lymphoid neoplasms. At the time of presentation, there were no systemic symptoms (fever, night sweat, or weight loss). His physical examination revealed a 4.5c m mass on left elbow. Laboratory work showed prolonged elevated eosinophils for 4 years, up to 17.3 % in the peripheral blood (reference range: 0 %–5 %) with absolute eosinophil count up to 1 × 10^9/L (reference range: 0.05–0.5 × 10^9/L). Ultrasound demonstrates a hypoechoic mass in the elbow, which is irregular in shape and shows blood flow signals within (Fig. 1).

Fig. 1.

(A-B) B-ultrasound shows a hypoechoic mass with irregular shape and blood flow signals inside.

The resected masses had a pale fish-like cut surface on gross examination. Microscopically, the lesion consisted of exuberantly hyperplastic lymphoid follicles, abundant T cell infiltrates, prominent vascular proliferation, and marked eosinophilic infiltrates and fibrotic changes between the follicles (Fig. 2). The T cells in the follicles were diffusely positive for CD3 and CD5, with a significant decrease of CD7, negative EBER, and a low Ki-67 proliferative rate (∼ 10 %) (Fig. 3). TCRβand TCRγ showed clonal proliferation (Fig. 4). The presence of eosinophils infiltrating the interfollicular zone, coupled with the absence of CD7 expression, our final diagnosis was indolent T-cell lymphoma with features of Kimura disease. The low proliferation index of Ki67 suggested it was an inert lymphoma, and follow-up was recommended without any systemic treatment.

Fig. 2.

(A) There was diffuse infiltration of lymphoid tissue between fibrous and adipose tissue (H&E, × 40), (B) marked proliferation of small blood vessels and infiltration of T cells in lymphoid tissue(H&E, × 100), (C-D) marked eosinophilic infiltrates and fibrotic changes between the follicles (H&E, × 200).

Fig. 3.

(A) The tumor cells showing diffuse CD3 positivity (CD3 immunostaining, × 100), (B)the tumor cells showing diffuse positivity with CD5 (CD5 immunostaining, × 100), (C)the T cells showing a significant decrease of CD7 (CD7 immunostaining, × 100), (D)the tumor cells showing a low Ki-67 proliferative rate (Ki67 immunostaining, × 100), (E)the tumor cells showing negativity with EBER (EBER immunostaining, × 100).

Fig. 4.

TCRβand TCRγ showed clonal proliferation with left elbow mass.

After 5 months, a new 4 cm mass appeared at the right submaxillary and left posterior ear. The mass from the left posterior ear showed similar microscopic morphology, immunohistochemical profile, EBER status, and Ki-67 proliferative rate to those of the prior elbow mass. TCRβand TCRγ again indicated clonal proliferation (Fig. 5). The right submaxillary mass showed similar findings except for a more severe eosinophilic infiltrate and diffuse CD7 positivity of the T cells (Fig. 6). Whole-body PET-CT found increased FDG uptake in the right submaxillary and lymphoid tissue from the left posterior ear, left elbow, and left hand. Lymph node enlargement and FDG avid were found in bilateral neck, axilla, groin and other parts. The largest one was located at the left posterior ear, with a size of 3.2 × 1.2 cm and standard uptake value (SUV) max of 3.4 (Fig. 7). Bone marrow biopsy specimen showed that the hematopoietic cells of three lineages were basically normal, and eosinophilia was increased, accounting for about 20 %. Bone marrow aspiration showed clonal proliferation of the T cells. Our final diagnosis was Kimura disease on the right submaxilla and indolent peripheral T-cell lymphoma with morphologic features of Kimura disease in the retroauricular area. The patient was then treated with local radiotherapy for the left retroauricular lesion. Subcutaneous nodules reappeared after one and a half years later on the right upper arm. The microscopic morphology exhibited similarities to that of the lymphoid tissue located retroauricularly on the left side, and once again, TCRβand TCRγ again indicated clonal proliferation. The patient did not receive any subsequent treatment apart from undergoing B-ultrasound follow-up of the lymph nodes. However, two weeks ago, there was a recurrence of abnormally enlarged lymph nodes in the submental and left upper arm.

Fig. 5.

The mass from the left posterior ear was detected TCRβand TCRγ clonal proliferation.

Fig. 6.

(A-B)The right submaxillary mass showed severe eosinophilic infiltrate (C-E)the tumor cells showing diffuse positivity with CD3, CD5 and CD7 (CD3, CD5 and CD7 immunostaining, × 100), (F)the tumor cells showing negativity with EBER (EBER immunostaining, × 100).

Fig. 7.

(A)3D Maximum Intensity Projection (3D-MIP) , (B)the group of images are, in order, axial PET, CT, PET/CT fusion, and CT. Arrow shows the right submaxillary (1.1 cm * 1.5 cm, SUVmax: 3.2). (C) Arrow shows the left postauricular region (1.2 cm * 3.2 cm, SUVmax: 3.4). (D) shows multiple enlarged lymph nodes in the bilateral carotid spaces, bilateral posterior cervical spaces, mesentery, paraabdominal aorta, bilateral paraexternal iliac arteries, and bilateral inguinal regions.

3. Discussion

To the best of our knowledge, our report is the first documented case of concurrent KD and low-grade indolent T-cell lymphoma in the same patient. The pathological diagnosis of both lesions was clear and supported by the results of TCR clonality test.

The etiology and pathogenesis of Kimura's disease are not well understood and may be caused by immune dysregulation. The findings of increased eosinophils, mast cells, and increased levels of interleukin 5 and IgE suggest an abnormal T-cell hypersensitivity reaction [5]. Triggering factors, including allergies, infections, endocrine disorders, and autoimmunity, have been proposed in association with a phenotype involving both IgE-mediated type 1 hypersensitivity and Th2 cytokines [[6], [7], [8], [9]]. The levels of IL-4, IL-5 and IL-13 mRNA in peripheral blood mononuclear cells of KD patients were increased, indicating that KD had Th2 characteristic phenotype [10]. Local infiltration of IL-4+ and IL-5+ mast cells and T cells has also been demonstrated [11]. In 2022, Ryusuke et al. further revealed the possible pathogenesis of KD. Their study found that IL 13+ Tfh cells and type 2 immune cells were involved in the disease process of KD, and induced the proliferation of B cells and the occurrence of "allergic fibrosis" [12].

The above studies suggest that T cells are likely to be involved in the development and progression of KD, and the possibility of KD lesions progressing to peripheral T cell lymphoma has been described in earlier reports [13]. In 2006, Beyazit et al [13] reported a case of conversion to peripheral T-cell lymphoma during treatment for Kimura disease in a 35-year-old patient whose clinical presentation pattern changed over a follow-up period of more than 6 years. Eosinophilia was the first clinical manifestation of the patient. KD was diagnosed 4 years after hypereosinophilic syndrome (HES) treatment [13]. It eventually manifests as peripheral T-cell lymphoma of the parotid gland, preauricular, and skin. The parotid mass demonstrating diffuse effacement of the glandular architecture by an infiltrate composed of small to medium-sized lymphoid cells and eosinophils. The patient had systemic nodal hyperproliferation confirmed by PET-CT, and clonal T-cell proliferation was confirmed by TCR. The patient received CHOP regiment, after which his cutaneous lesions and preauricular swelling showed marked improvement. This unique pattern of presentation in this patient may represent a unique pathobiological progression in clonal neoplastic lymphoproliferative disorder. The above case [13] bears resemblance to the one we present here, due to the slight increase of eosinophils in blood and bone marrow, particularly in the bone marrow, eosinophil levels account for approximately 20 %, necessitating differentiation from HES. HES are defined by a blood hypereosinophilia (HE) more than 1.5 G/L on two examinations (and/or tissue HE), organ damage (and/or dysfunction attributable to tissue HE) and exclusion of other explanations for organ dysfunction. The lymphoid variant of HES (L-HES) is considered a reactive HES characterized by the presence of an abnormal circulating T-cell subset, with a Th2 profile and able to produce eosinophilopoietic cytokines such as interleukin-5. The current tally stands at 59 reported cases of l-HES [17,18], with a prevailing phenotypic characteristic of CD3-, CD4+. Additionally, patients with HES may exhibit positive T-lineage gene rearrangement. This case was diffusely positive for CD3 and CD5, and a slight increase in eosinophils is not sufficient for the diagnosis of HES.

Generally, Kimura's disease is a localized disorder with a benign clinical course, but recurrence is not uncommon. Approximately 12 % of patients have associated renal diseases, typically presenting as nephrotic syndrome. Renal biopsy shows IgE deposition in the glomerular basement membrane [22,23]. However, in the case we reported, neither renal dysfunction nor proteinuria was detected.

The most commonly used treatment for KD is surgical resection. Additionally, steroids are often used as a therapeutic strategy for multi-site involvement or to reduce or control lesion enlargement before surgical treatment [24,25]. Steroid is effective in reducing size of the mass, but the lesions may recur while reducing the dose of steroid [24,25]. Studies have also shown that radiotherapy can be beneficial, and it has been proven that the three main histological components of KD (cells, fibrous collagen, and blood vessels) respond well to radiation. Radiotherapy can be used as a single and adjuvant treatment modality. Studies have shown that the clinical remission rate achieved by radiotherapy is very high (92.2 %−100 %), and almost all cases have no adverse reactions, except for mild xerostomia in individual patients [26]. Regarding the optimal radiation dose, there is no consensus among different authors, which shows a wide range of reported doses. In particular, a study focusing on determining the threshold dose for local control found no association between the total dose and local control [26,27]. Recent studies have also shown that immunosuppressants have demonstrated great potential in the treatment of Kimura's disease. Traditional immunosuppressants such as cyclosporine [28] and azathioprine [29] have been clinically applied, and there is now a shift from traditional drugs to precision targeted therapy. Dupilumab, imatinib [25], etc., have shown significant efficacy in the treatment of eosinophilic syndromes and inhibition of TH2 inflammation, bringing new hope to patients. However, current studies have small sample sizes, and more large-scale, multi-center clinical trials are needed. In conclusion, the treatment of Kimura's disease requires multidisciplinary collaboration among pathology, oncology, radiation oncology, and hematology departments, which is a long and arduous task.

The case reported in this study involved an indolent T-cell lymphoma as the initial disease. During the follow-up without treatment, KD was re-diagnosed. However, both cases suggest that KD may serve as a risk factor for T-cell lymphoma. At the same time, malignant lymphoma, such as NK/T cell lymphoma and Hodgkin's lymphoma, has been reported during the follow-up of KD [14,15]. The subsequent lymphomas exhibited characteristic morphology and received definitive diagnoses, eliminating any possibility of misdiagnosis with KD.

This patient had KD and indolent T-cell lymphoma in sequence, and the morphology of T-cell lymphoma was very similar to KD, raising the question whether Kimura's disease was the driver of T-cell lymphoma, or could be transformed into T-cell lymphoma. The patient was found to have TCR rearrangements in both tumor resection specimens and bone marrow aspirates. We also showed that the same T cell clone was observed in biopsies at two different sites and marrow taken 1 year apart, demonstrating therefore that the primary and recurrent lesions were biologically related. In 2002, some scholars reported that there was clonal proliferation of T cells in KD, suggesting that T cells were indeed involved in the occurrence and development of KD. In this case, both typical KD histopathological morphology and indolent T-cell lymphoma were observed, which further suggested that KD may be the driver of T-cell lymphoma [16]. There are many similarities between the case report of Chim C et al [16] and our case. In conclusion, many previous reports have suggested that T-cell lymphoma may occur during the development of KD, whether it is low-grade indolent T-cell lymphoma or NK/ T-cell lymphoma, indicating that T cells are involved in the development of KD, or that KD is the driving factor of T-cell lymphoma. The specific mechanism needs to be further studied.

Indolent peripheral T-cell lymphoma similar to Kimura disease continued to recur with new lesions during the follow-up of our case, with biological behavior different from that of self-limited Kimura disease. There was no corresponding entity based on the current WHO classification. A new variant of peripheral T-cell lymphoma should be considered. The Ki-67 indices of the initial disease and three relapses were all around 10 %, indicating a relatively inert lesion. A low Ki-67 index may be a diagnostic feature of the disease, although more cases are needed for confirmation.

4. Conclusions

The purpose of this report is to present the clinical presentation, histological morphology, and immunophenotype of a case of indolent peripheral T-cell lymphoma resembling Kimura's disease in the Affiliated Hospital of Nantong University. Our findings suggest that this case might be a new variant of peripheral T-cell lymphoma. Presenting this case to a larger audience will help to avoid misdiagnosis or underdiagnosis of this uncommon variant.

CRediT authorship contribution statement

Hui Sun: Writing – original draft, Conceptualization. Jia Feng: Writing – review & editing, Conceptualization. Yaping Zhang: Writing – review & editing. Jianguo Zhang: Conceptualization. Shaolei Lu: Writing – review & editing. Yifei Liu: Writing – review & editing, Funding acquisition, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.