Characteristics of ¹⁸F-FDG PET/CT in patients with Kimura’s disease from China

Abstract

Background

‘Kimura’s disease (KD) is a rare chronic inflammatory disorder of unknown etiology and is difficult to diagnose due to poor clinical presentation and imaging features. Few studies on characteristics of ¹⁸F-FDG PET/CT of KD have been reported. This study aimed to observe the reliable characteristics and usefulness of ¹⁸F-FDG PET/CT for the evaluation of consecutive patients with KD.

Methods

The clinical data and ¹⁸F-FDG PET/CT imaging findings of 8 patients with pathologically confirmed KD were reviewed retrospectively.¹⁸F-FDG PET/CT images were evaluated visually and semiquantitatively by measuring the maximum standardized uptake value (SUV_max). The correlations between clinical data and ¹⁸F-FDG PET/CT features were analyzed by simple linear regression.

Results

This study included 7 males and one female ranging in age from 17 to 79 years. The longest diameter of lesions ranged from 0.8 cm to 4.8 cm, and regional or generalized lymphadenopathy was found in all 8 patients with eosinophilia, while subcutaneous masses and salivary gland involvement concurrently were found in 4 patients. ¹⁸F-FDG PET/CT revealed that these involved lesions had high ¹⁸F-FDG uptake with SUV_max > 2.5 (2.6 to 6.3). Moreover, the margin of the lesions was well defined in 6 cases and ill defined in 2 cases, and homogeneous density and ¹⁸F-FDG uptake were both found in all these lesions. There was negative correlation between eosinophils and SUV_max (R² = 0.538).

Conclusions

Kimura’s disease should be considered when ¹⁸F-FDG PET/CT is characterized by homogeneous lesions of regional or generalized lymphadenopathy, accompanied with subcutaneous masses and salivary gland involvement concurrently, especially in patients with eosinophilia.

Background

Kimura’s disease (KD) is a rare chronic inflammatory disorder of unknown etiology that was first described by Kim and Szeto [1] in 1937 and recognized as a distinct clinicopathologic entity after the report of Kimura, et al. in 1948 [2], which is an unusual granulation combined with hyperplastic changes in of lymphatic tissue.

The gold standard for diagnosing KD is pathological examination, characterized as lympho-follicular hyperplasia with inflammatory cell infiltration, eosinophilic infiltrates and eosinophilic microabscesses in the lymphocyte area, proliferation and fibrosis of capillaries [3]. It mainly occurs in young Asian males, and usually presents as subcutaneous soft tissue masses and drainage area lymphadenopathy, predominantly in the head-neck region, and may involve the salivary gland, generally accompanied by eosinophilia and increased IgE in serological examination [4, 5].

Radiologic imaging (such as CT and MRI) is limited in diagnosing KD [6,7,8]. The differential diagnosis necessitates the arduous exclusion of potential mimicking diseases, such as inflammatory lymph nodes, metastatic lymph nodes, lymphoma, and neoplasms. Recently, ¹⁸F-fluorodeoxyglucose positron emission tomography/ computed tomography (¹⁸F-FDG PET/CT) has become useful for diagnosing tumors and inflammation. However, to the best of our knowledge, only 4 case reports on KD patients on ¹⁸F-FDG PET/CT were misdiagnosed as lymphoma [9, 10] or lung cancer [11] or malignant lesions [12]. The study aimed to analyze ¹⁸F-FDG PET/CT imaging findings of KD, with a view to improving the knowledge and diagnosis of KD.

Methods

Clinical data

This retrospective study was approved (approval number: (2023) 0525F), and the requirement to obtain informed written consent was waived by Clinical Research Ethics Committee of the First Affiliated Hospital of Zhejiang University School of Medicine. The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. A total of 8 patients with suspected lymphoma who underwent ¹⁸F-FDG PET/CT imaging at our hospital between May 2015 and August 2022 were retrospectively analyzed. All of them were finally diagnosed as KD by pathological examination via biopsy or resection. Their disease duration ranged from 0.5 months to 108 months (median 4 months). Of these 8 patients, 4 patients had a history of KD that recurred after treatment with surgical resection (n = 2) and oral corticosteroids (n = 2) during follow-up of 6 to 108 months (median 48 months). Their clinical data were collected by electronic medical records, including patient gender, age, clinical presentations, laboratory and imaging results, therapy and follow-up results. GraphPad Prism and simple linear regression were used to analyze the relationship between SUV_max and eosinophils.

Imaging technique

All patients underwent ¹⁸F-FDG PET/CT imaging using a PET/CT scanner (Biograph16, Siemens, Germany) after fasting for at least 6 h, and blood glucose levels were controlled at 3.0–11.0 mmol/L. Images were acquired approximately 1 h after an intravenous injection of 3.7–4.44 MBq/kg ¹⁸F-FDG, from the base of the skull to the mid-thigh in the supine position. PET scan was performed for 2 min per bed position and reconstructed with noncontrast CT images, with the standardized protocol of 120 kV, 150 mA, and a slice thickness of 5 mm.¹⁸F-FDG was synthesized in the FDG4 synthesis module (Siemens, Germany) in our PET center. The radiochemical purity of ¹⁸F-FDG was > 98%.

Image analysis

All ¹⁸F-FDG PET/CT imaging was independently interpreted by two experienced nuclear physicians blinded to the clinical data and pathologic findings using volume viewer software on a dedicated workstation (MedEx, Beijing, China). Any different opinions between the two physicians were discussed to reach an agreement. Imaging features included uptake of FDG, density, size, shape and boundary. Avid uptake of lesions was semiquantified by maximum standardized uptake values (SUV_max), and the size of lesions included the longest diameter and its corresponding vertical diameter.

Results

Clinical characteristics

The 8 KD patients were enrolled in this study, including 7 males ranging in age from 17 to 39 years with a mean age of 27 years and one female with 79 years. Their clinical characteristics are summarized in Table 1. In these 8 KD patients, the initial manifestations were lymphadenopathy with rash (n = 2), lymphadenopathy (n = 2), painless subcutaneous mass (n = 2), and rash (n = 2). Increased eosinophils in blood and bone marrow were identified in the all patients (100%), ranging from 30% to 61.6%, and compared to the normal range of 0.5–5% and < 5%, respectively. Elevated IgE levels in blood were observed in 6 cases (75.0%). No patient had renal injury. They underwent ¹⁸F-FDG PET/CT because of suspected lymphoma, and were finally diagnosed as KD by pathological examination via biopsy or resection. After ¹⁸F-FDG-PET/CT and diagnosis of KD, they all received oral corticosteroids for 2 to 3 months and recovered, and the blood eosinophils were decreased to normal levels within one week except in one patient. However, 4 patients relapsed during 5–86 months (median 23.5 months) after clinical follow-up (Table 1).

Table 1 Clinical characteristics of 8 Kimura’s disease patients

Features of ¹⁸F-FDG imaging

The findings of ¹⁸F-FDG PET/CT in the 8 KD patients are shown in Table 2. On ¹⁸F-FDG PET/CT (Figs. 1, 2, 3 and 4), multiple homogenous nodes or masses with increased FDG uptake (SUV_max ranging from 2.6 to 6.3) were indicated to involve regional enlarged lymph nodes (n = 3), and generalized enlarged lymph nodes (n = 5). Bilateral involvement was more common than unilateral disease, a total of 5 patients (62.5%) presented bilateral multiple lesions, and 3 patients (37.5%) had unilateral multiple lesions (Table 2), 6 (75%) patients had clear boundary lesions, 2 (25%) patients had ill defined lesions (Fig. 4), and 2 patients had fused lesions (Fig. 4). Moreover, ¹⁸F-FDG PET/CT revealed that 4 patients had subcutaneous masses and salivary gland involvement concurrently (Figs. 1, 2 and 3). A negative correlation between eosinophils and SUV_max (R² = 0.538) was found by the simple linear regression (Fig. 5), and no relationship was found between SUV_max and disease duration, IgE, lesion size and lesion distribution, however, SUV_max and eosinophils were not significant influencing factors for recurrence.

Table 2 ¹⁸F-FDG PET/CT imaging characteristics of 8 Kimura’s disease patients

Fig. 1

A 79-years-old female patient admitted to hospital because of gradually swollen facial lumps with a history of lymphadenopathy for 2 years without therapy. In laboratory tests, an elevated number of eosinophils [2.53 (34.7%)] and normal IgE (6.1) were found in the peripheral blood. A On ¹⁸F-FDG PET/CT MIP (maximum intensity projection), multiple masses with FDG-avid (red arrows, SUV_max ranging from 3.0 to 6.3) were found in head-neck region, mediastinum, and abdomen. B, C On CT transverse slice (B) and ¹⁸F-FDG PET/CT transverse slice (C), these multiple masses were homogeneous density and clear boundary in bilateral parotid gland, nasal cavity, right lower eyelid (B, green arrows) with homogeneous increased FDG uptakes (C, yellow arrows). D, E On CT transverse slice (D) and ¹⁸F-FDG PET/CT transverse slice (E), there were homogeneous density and clear boundary enlarged lymph node (D, green arrows) with homogeneous increased FDG uptake (E, yellow arrows) in hepatic hilar region and retroperitoneum

Fig. 2

A 39-year-old male had lymphadenopathy with elevated eosinophils [3.98 (43.7)] and IgE (> 2000) in peripheral blood for half month. A On ¹⁸F-FDG PET/CT MIP, a subcutaneous mass in the left head and neck region had FDG-avid (red arrows, SUV_max = 3.5). B On CT transverse slice, there were enlarged lymph nodes of submaxillary involved submandibular gland, with homogeneous density and clear boundary. (green arrows). C On.¹⁸F-FDG PET/CT transverse slice, the increased FDG uptakes of enlarged submaxillary lymph nodes involved submandibular gland was homogeneous (yellow arrows)

Fig. 3

A 17-year-old male with subcutaneous mass for 6 months was histologically proven Kimura disease (KD), and oral corticosteroids irregular. He had evaluated serum eosinophil [2.63 (29.7)] and IgE (355) in laboratory tests. A On ¹⁸F-FDG PET/CT MIP, subcutaneous masses with avid FDG uptake was found in the right head and neck region (red arrows, SUV_max ranging from 3.6 to 4.1). B, C On CT transverse slice (B) and ¹⁸F-FDG PET/CT transverse slice (C), there showed incrassated right eyelid (B, green arrows) with increased FDG uptakes (C, yellow arrows). D, E On CT transverse slice (D) and ¹⁸F-FDG PET/CT transverse slice (E), a homogeneous density mass (D, green arrows) with homogeneous increased FDG uptake (E, yellow arrows) was found in the right parotid gland

Fig. 4

A 19-year-old male with a history of KD for 9 years after surgery found enlarged painless lymph nodes during clinical follow-up, and evaluated serum eosinophil [5.76 (46.8%)] and IgE (856). A On ¹⁸F-FDG PET/CT MIP, regional enlarged lymph node with FDG-avid (red arrows, SUV_max ranging from 2.3 to 3.6) were found in retroperitoneum and right pelvic wall. B, C On CT transverse slice (B) and ¹⁸F-FDG PET/CT transverse slice (C), there was enlarged and homogeneous density lymph nodes of retroperitoneum (B, green arrows) with homogeneous increased FDG uptakes (C, yellow arrows). (D, E) On CT transverse slice (D) and ¹⁸F-FDG PET/CT transverse slice (E), there showed homogeneous of density, but ill-defined boundary and fused enlarged lymph nodes (D, green arrows) with homogeneous increased FDG uptake (E, yellow arrows) in right pelvic wall

Fig. 5

The correlation between SUV_max and serum eosinophil (%) before treatment

Discussion

KD is a rare, chronic lymphoproliferative disorder that mainly affects young and middle-aged Asian males [4, 5]. Our results demonstrated that KD was seen in 7 men (87.5%) and one female (12.5%) with ages ranging from 17–39 years except for one female aged 79 years, and it had a sluggish beginning and a long course from 0.5 months to 108 months (median 4 months). Clinically, KD mostly presents as painless subcutaneous masses involving the head and neck region, such as the salivary glands, orbit, and eyelid, and lymph nodes [4, 5]. In addition, it may also involve other sites, including the clavicular region, armpit, mediastinum, retroperitoneum, groin, and elbow joint [13]. This study indicated that the mass of KD mostly occurred in the bilateral multiple locations of enlarged lymph nodes (62.5%), unilateral regional enlarged lymph nodes (25.0%), and salivary glands (12.5%). It has been reported that the initial manifestation of KD is a soft mass that gradually becomes stiffer and tougher as it progresses, frequently accompanied by itching, eczema, and rash due to the infiltration of inflammatory lymphocytes and eosinophils [14, 15]. In laboratory tests, an elevated number of eosinophils and level of IgE may be found in the peripheral blood, particularly levels of eosinophils, which may rise to 10–20% [4, 5]. Moreover, KD often causes renal injuries, in up to 60% of KD patients [4, 5]. In this study, increased eosinophils in peripheral blood were identified in the all patients (100%), and elevated IgE levels in blood were observed in 6 patients (75.0%). No patient had renal injury.

Conventional imaging techniques, such as ultrasonography (US), CT and MR, are commonly used in the detection of KD [6, 7]. Although they are useful for detecting the lesion morphology, anatomical distribution, enhancement pattern, and degree of intralesional vascularity, they are anatomical and local imaging, and it is difficult to find multiple or systemic lesions. ¹⁸F-FDG PET/CT (¹⁸F-fluorodeoxyglucose positron emission tomography/ computed tomography) has been widely used for diagnosing tumors, infection, fever of unknown origin and assessing therapy response due to a one-stop whole-body examination and changes in FDG metabolic parameters ahead of morphological changes by conventional imaging techniques (US, CT and MRI). On ¹⁸F-FDG PET/CT, KD presented remarkable increased uptake of FDG in the involved lymph node regions and was often misdiagnosed as inflammatory or neoplastic diseases, such as tuberculosis, lymphoma, or metastatic lymphadenopathy. In this study, ¹⁸F-FDG PET/CT revealed multiple isodense and homogenous nodes or masses with increased FDG uptake in regional (n = 3) or generalized lymphadenopathy (n = 5, 62.5%). In addition, ¹⁸F-FDG PET/CT revealed that 4 patients (50.0%) had subcutaneous masses and salivary gland involvement concurrently, and 6 patients (75.0%) were clear boundary lesions. In this study, the imaging features of ¹⁸F-FDG PET/CT in KD were summarized as homogeneous of density and high ¹⁸F-FDG uptake in the involved lesions of regional or generalized lymphadenopathy, with or without subcutaneous masses and salivary gland involvement concurrently. On 18F-FDG PET/CT, KD needs to be differentiated from lymphoma. Lymphoma usually presents as multiple well-defined homogeneous nodules with uniform enhancement on contrast-enhanced CT or MR [7]. Furthermore, peripheral blood eosinophilia, and elevated serum immunoglobulin E (IgE) levels are uncommon in lymphoma. Combined ¹⁸F-FDG PET/CT findings with peripheral blood eosinophilia, and elevated serum immunoglobulin E (IgE) levels will be help to differentiate KD from lymphoma. Although pathological examination remains the gold standard for diagnosing KD, KD should be considered when ¹⁸F-FDG PET/CT is characterized by FDG-valid, homogeneous lesions of regional or generalized lymphadenopathy, with or without subcutaneous masses and salivary gland involvement concurrently, especially in patients with increased eosinophilia.

The pathogenesis of KD are unknown, KD is classified as a benign reactive process, including allergic reactions, infections, and autoimmune reactions with an aberrant immune reaction, resulting in elevated serum immunoglobulin E (IgE) levels and peripheral blood eosinophilia. In addition, KD has a sluggish beginning and a long course, and increased small blood vessels, and prominent stromal fibrosis were found in the histologic findings with the progresses of KD. Previous study reported that on MRI, the mass show intermediate signal intensity on T₁WI, and high signal intensity on T₂WI. The degree of enhancement and the signal intensity on MR images may be related to different degrees of fibrosis and vascular proliferation [14,15,16]. ¹⁸F-FDG PET/CT is an imaging modality providing whole-body metabolic information, and its metabolic parameters, including SUV_max, are recognized as a valuable tool for diagnosis and monitoring of disease activity and treatment response in patients with systemic inflammatory disorders. Lin et al. [17] reported that higher blood eosinophil count is a predictive factor for the recurrence of KD. In addition, a study of Bai et al. [18] demonstrated that the SUV_max of main involved organ was positively correlated with serum eosinophils counts in patients with IgG4-related disease. However, in our study, there was a negative correlation between SUV_max and serum eosinophils counts. It may be because firstly, our sample is too small and there is may be some bias. Further studies with more samples from multi-center studies are required to determine the correlation between SUV_max and eosinophils. Second, these patients in our study have a long course and were in chronic stage with prominent stromal fibrosis, which hamper FDG uptake in the mass. Further studies will perform immunohistochemical analysis of mass and determine correlation between SUV_max and clinicopathology.

There is no gold standard treatment strategy for KD. The treatment options mainly include surgery, corticosteroids, and radiotherapy [5, 19]. Surgery is associated with increased recurrence (25–51.7%) due to its obscured margin [20, 21]. Radiotherapy may have a local control rate of 64%, but it is only used in recurrent or refractory cases due to concerns regarding secondary malignancies from high doses of radiation [20]. Medication therapy (steroid) has been effective in some patients, however, steroid withdrawal could often cause lesion recurrence [5, 22]. Although currently, combined corticosteroids and surgery or radiotherapy has been widely used treatment, followed by steroid alone, the outcomes are variable and lesion relapses are common [18]. In the study, combined oral corticosteroids and surgical resection were used in 3 patients, and only oral corticosteroids were used in 5 patients. Moreover, 4 patients relapsed during 5–86 months (median 23.5 months) of clinical follow-up.

There are several limitations in this study. First, it only enrolled 8 patients with KD, and 8 patients is a sample too small to perform any statistical analysis. Further studies with more samples from multi-center studies are required to determine the role of ¹⁸F-FDG PET/CT in clinical assessing of patients with KD. Second, the study was retrospective and only described the imaging features of ¹⁸F-FDG PET/CT in KD. Further studies will perform immunohistochemical analysis of mass and determine correlation between SUV_max and clinicopathology. Third, in our study, most of patients did not underwent ¹⁸F-FDG PECT/CT post-therapy. In the future, large-scale prospective investigations are needed to validate the clinical value of PET/CT in KD.

Conclusions

Kimura’s disease should be considered when ¹⁸F-FDG PET/CT is characterized by homogeneous lesions of regional or generalized lymphadenopathy, with or without subcutaneous masses and salivary gland involvement concurrently, especially in patients with increased eosinophilia. Pathological examination remains the gold standard for diagnosing KD.