A Report on 18 Cases of Children with Kimura Disease in China and Literature Review

doi:10.21203/rs.3.rs-1829412/v1

Background: Kimura’s disease (KD), also known as Eosinophilic Granuloma, is a benign, rare and chronic inflammatory disorder of unknown etiology and it affects subcutaneous tissues, lymph nodes, and salivary glands. Unusual presentations of KD might cause diagnostic difficulty or be misdiagnosed as malignancy if clinical suspicion is insufficiently high. Here, we aimed to explore the clinical characteristics, diagnosis and the therapeutic effect of children’s KD in China, in order to improve pediatricians’ knowledge of children’s KD.

Methods: The Clinical data of 18 cases of KD diagnosed at Shenzhen Children's Hospital from January 2015 to January 2022 were analyzed retrospectively through case record review.

Results: Of 18 cases, 17 were male and one is female. The masses appear as focal, painless, and immovable with an unclear boundary. The most common predilection is head-neck region (n=8, 44.4%). 12 patients showed cutaneous pruritus, 3 patients with nephrotic syndrome and 2 with simple hematuria. 16 patients showed peripheral blood eosinophilia. 12 of 13 patients presented with increased serum Immunoglobulin E (IgE) level. The prominent pathological characteristic is marked lymphoid hyperplasia accompanied by various degrees of vascular hyperplasia and eosinophil infiltration. Among the 18 patients followed for more than 6 months, 9 experienced recurrence of disease after treatment (surgical resection alone: 6/12; oral corticosteroids combined with immunosuppressants: 3/3; surgical resection followed by oral corticosteroids combined with immunosuppressants: 0/3). Through comparison with the clinical features of adult kimura disease, it showed that there was no significant difference between children and adults.

Conclusion: KD is characterized by subcutaneous masses but it is also a systemic disease. The diagnosis should be confirmed by pathology. Surgical resection, radiotherapy, hormone or chemotherapy has definite therapeutic effects, but the rate of recurrence in children is high. Given the high rate of recurrence and reported association with lymphoma, patients require careful long-term follow-up.

Kimura disease

Child

Eosinophilia

immunoglobulin E

treatment

pathology

Kimura Disease (KD) is also known as eosinophilic lymphogranuloma, and the cause of the disease is not yet clear. It displays a long-term soft painless mass, associated with eosinophilic hyperplasia in the peripheral blood and elevated IgE levels. Chronic inflammatory diseases such as renal lesion and cutaneous pruritus are found in some patients. The rate of incidence in KD is low. Although KD is often found in male teenagers and young adults, it has been reported in different ages. At present, there are over 400 reported cases. Children are seldom affected by KD therefore, the characteristics and treatment of KD of childhood have not been well illustrated [1]. This study retrospectively analyzed the clinical data of 18 children with KD diagnosed in Shenzhen Children's Hospital from 2015 to 2022 and reviewed the literature, in order to improve pediatricians’ knowledge of children KD.

The 18 children confirmed from January 2015 to January 2022 in Shenzhen Children's Hospital have been vindicated to conform to the typical pathological changes of kimura disease through lymph node biopsy. And 3 Chinese journal search engines (http://www.cqvip.com/, http://www.wanfangdata.com.cn/, and http://www.cnki.net/) were used to search for reported cases of Chinese children with kimura disease from 2000 to 2022. Clinical features, lab findings, pathological features, treatment process, outcome and other clinical data were retrospectively analyzed and summarized.

Lesion sites

Of the 18 cases, lesion sites were located in the head, neck, upper arms, groin and armpit. Some patients had multiple lesions. The most common lesions occurred in the scalp in 4 cases (28.6%), 4 (20%) in the neck, 3 (13.3%) in the postauricular part, 1 (6.7%) in the eye socket, 3 (20%) in the groin and 3 (13.3%) in the armpits.

Clinical characteristics

All the 18 cases showed enlarged lymph nodes or painless soft tissue masses. The masses were mainly distributed under the skin, tenacious and fixed, with poor mobility or different levels of adhesion, without local manifestations such as local congestion or red, swelling, heat or pain, diameter scope 0.5-10cm. Most can be associated with cutaneous and cutaneous pruritus and some associated with pigmentation; or associated with nephrotic syndrome or simple hematuria. In our center, 12 cases (66.7%) were complicated with cutaneous pruritus, 3 cases (16.7%) with nephrotic syndrome and 2 (11.1%) with simple hematuria.

Laboratory results

At laboratory investigations, peripheral blood eosinophilia was detected in 16 of the 18 patients, as high as 60.3% (reference value 0.5%-5%). Whereas an elevated IgE level was documented in all the 12 of the 13 patients tested. Immunoglobulin A, G, M, Erythrocyte sedimentation rate (ESR), C-reactive protein were all in the normal range. Urinary protein was positive in 3 cases and hematuria in 2 cases. Of these three patients, one received ultrasound-guided kidney biopsy, which showed minimal change disease with a small amount of Immunoglobulin A deposition. Bone marrow aspiration was carried out in six patients, all showing increased eosino-phils.

Imaging examinations

17 of the 18 cases were examined with local ultrasonography. Main findings of ultrasonography: Solid mass was founded under the skin, with medium echo or low echo mass, uneven inner echo, irregular and unclear edges. Findings of Color Doppler: Rich blood flow signals were seen inside as well as multiple enlarged lymph nodes.

Pathological examination

All patients were performed with surgery or ultrasonographic-guided lymph node puncture biopsy. KD was diagnosed in all postoperative pathological results. The irregular shape of masses in KD pathological tissues was visible to naked eyes, without capsules. The section was grey brown and tough. Of the 18 cases, 17 had solid masses (93.3%) and 1 had cystic solid masses (6.7%) accompanied with bleeding. The max volume of masses was in the temporal part. Microscopically, irregular nodular lesions were found in subcutaneous soft tissues and most affected lymph nodes; lymphoid hyperplasia, lymphofollicular hyperplasia accompanied with inflammatory cell infiltration were observed; a large number of eosinophils infiltrated to focal aggregation, forming eosinophilic microabscess; proliferation of microvessels and interstitial collagen fibers were also seen; those with gland affected showed acinar atrophy and gland destruction, and infiltration of lymphocytes and a large number of eosinophils in interstitial tissues (Fig. 1).

Characteristics of immunophenotype

In this study, 17 cases were detected by immunohistochemistry. Among them: 5 were diffuse and strong expression of CD3/CD20, 9 were expression of CD21, 7 were expression of CD34, 9 were expression of CD68, 4 were expression of CD38, 6 were expression of pax-5 (+), 7 were expression of s-100+ and 3 were expression of CD1a. See Table 1 for detailed immunohistochemical results.

Treatment and outcome

Among the 18 patients, 1 experienced recurrence after taking glucocorticoid orally for around one year. Combined with vincristine chemotherapy, the curative effect was satisfactory without recurrence. 3 were treated with surgical resection plus taking glucocorticoid orally. The curative effect was satisfactory, but recurrence occurred after drug withdrawal. 3 were complicated with nephrotic syndrome. In the years when nephrotic syndrome was treated with glucocorticoid, the disease was well controlled. Once the medicine stopped, the hormone mass enlarged obviously. Surgical resection was operated on the remaining 12 cases and 3 had recurrence. One patient received glucocorticoid combined with omalizumab for six months without relapse. One case was treated with methylprednisolone, cyclosporine and baricitinib with poor efficacy and repeated recurrence. The main treatment methods of kimura disease include surgery, glucocorticoids and chemotherapy, with good curative effects. Of which, 9 had recurrence and the recurrence rate was 50%. See Table 1 for clinical data of children when admitted to hospital.

Literature review

3 Chinese journal search engines (http://www.cqvip.com/, http://www.wanfangdata.com.cn/, and http://www.cnki.net/) were used to search for reported cases of Chinese children with kimura disease from 2000 to 2022 and totally 50 cases of Chinese children with kimura disease were collected. Among them, 46 were boys and 4 were girls; sex ratio 23:2; age of onset was ranging from half a month to 18 years old, and the median age was 11 years old. 8 were from 0 to 5 years old, 15 from 5 to 10 years old, 20 from 10 to 15 years old and 7 from 15 to 18 years old; the course of disease was from 1 week to 10 years. All the 50 cases were characterized by superficial lymphadenopathy or subcutaneous mass, mainly distributed in the parotid gland, head and neck, ears, eyes, armpit and submaxillary. The neck, postauricular part and parotid gland were often affected. Kimura disease was associated with a high incidence rate of nephrotic syndrome, urticaria and chronic eczema. Of the 50 patients, 14 had nephrotic syndrome and 22 had cutaneous pruritus or allergy-related symptoms. In the lab examination, 43 cases were examined for percentage of peripheral blood eosinophils and 38 (88.4%) had peripheral blood eosinophilia; 24 cases were detected for serum IgE and 24 (100%) had elevation. In the clinical manifestations of KD, we found that there was no obvious difference between children and adults. The treatment methods of kimura disease in Chinese children include surgical resection, hormone therapy, chemotherapy and radiotherapy. Of the 50 cases, 3 were treated by operation combined with radiotherapy, 3 treated by operation combined with hormone therapy, 12 treated by hormone combined with chemotherapy (cytotoxic drugs include cyclophosphamide, cellcept, tacrolimus and cyclosporine), 1 treated by hormone combined with cetirizine and 3 treated by Chinese patent drugs including tripterygium wilfordii. All had different levels of improvements but also had a high recurrence rate. 39 patients had follow-up data and 21 relapsed, with a relapse rate of around 53.8%, which was much higher than the reports of adults. See Table 2 for clinical characteristics and treatment summary of 50 cases of kimura disease in children. The clinical characteristics and outcome comparison of kimura disease in children and adults are listed in Table 3.

Table 3

Clinical features of 65 cases of kimura disease in Chinese children compared with those of reports of adult kimura disease in multiple centers in China

	This study	Sun et. al	Li et. al	Zou et. al	Liu et. al	Wang et. al	Wang et. al
Number of cases	65	37	26	43	45	59	43
Gender (male: female)	12:1	1.8:1	6.7:1	6.17:1	2.46:1	4.9:1	2.3:1
Age (median age)	10 years old	44 years old	33 years old	40 years old	ND	ND	35 years old
Time interval between onset and diagnosis	1 week to 12 years	1 month to 20 years	5 months to 10 years	0.5 months to 30 years	1 week to 21 years	ND	2 months to 35 years
Head and neck	47 (72.3%)	28 (75.7%)	22 (95.7%)	36 (83.7%)	34 (75.6%)	5 (84.7%)	31 (72.1%)
Armpit	10 (15.4%)	3 (8.1%)	2 (8.7%)	5 (11.6%)	3 (6.7%)	0	ND
Upper arms	6 (9.2%)	2 (5.4%)	0	2 (4.7%)	ND	1 (1.7%)	ND
Eosinophils	51 (89.5%)	29 (96.7%)	23 (100%)	41 (95.4%)	16 (51.6%)	49 (83.1%)	33 (76.7%)
IgE elevated	33 (97.1%)	6 (100%)	ND	11 (91.67%)	2 (67.7%)	4 (100%)	31 (72.1%)
Nephrotic syndrome	16 (24.6%)	3 (8.1%)	ND	2 (4.7%)	0	ND	ND
Measles and eczema	31 (47.7%)	22 (59.5%)	12 (52.2%)	5 (11.6%)	5 (11.1%)	33 (55.9%)	25 (58.1%)
Surgery	26 (40%)	37 (100%)	3 (13%)	27 (62.8%)	41 (91.1%)	38 (64.4%)	26 (60.5%)
Drug treatment	35 (53.8%)	8 (21.6%)	2 (8.7%)	9 (20.9%)	3 (6.7%)	6 (10.2%)	3 (7.0%)
Radiotherapy + surgery	3 (4.6%)	1 (2.7%)	18 (78.3%)	4 (9.3%)	1 (2.2%)	12 (20.3%)	12 (27.9%)
Recurrence	28 (43.1%)	18 (48.7%)	4 (17.4%)	16 (37.2%)	3 (6.7%)	ND	10(23.3%)

KD is a rare chronic inflammatory disease and usually seen in young and middle-aged men in Asia. The sex ratio of the incidence is around 3-14:1. The reported cases of kimura disease in children are rare and the sex ratio is as high as 28:1. It was first reported by Professor Jin Xianzhai in 1937 in China, which was originally called eosinophilic lymphogranuloma. In 1948, Kimura, a Japanese scholar systematically described the disease. [2,4]. Afterwards, the name kimura disease was used around the world. In this group of data, 14 cases with kimura disease are boys and 1 is girl. The sex ratio of the incidence is similar to that in the literature report. The age of onset is relatively concentrated and the median age is 6.37 years old. In the literature review, the onset median age is 11 years old. This might be related to the small number of samples in our center. Next, the progression KD is slow, thus easily leading to misdiagnosis or missed diagnosis. Different centers need different time periods to confirm KD. Therefore, different centers are different in the median age of diagnosis.

The most common manifestation of the disease is a single or multiple painless soft tissue masses in the head and neck. This group of data have revealed that the proportion of lesions involving the head and neck is 44.4%. The main reason is that KD easily affects lymphatic tissues and the lymphatic tissues are mainly located in the head and neck. Some patients with KD also have symptoms like cutaneous pruritus, which may be related to the infiltration of nerve fiber by inflammatory lymphocytes and eosinophils [5]. In this center, 12 cases (66.7%) have symptoms like cutaneous pruritus. Besides, kimura disease is a systemic disease, which may affect multiple organs. Kidney is an internal organ which is most frequently affected. Kidney damage may be related to elevated IgE and damage of mediation of immune complexes. About 12%-16% of kimura disease patients may have kidney affected, of which 59%-78% show nephrotic syndrome. At present, the main reason of death of KD patients is nephrotic syndrome complicated with infection. Therefore, we must pay attention to the early diagnosis and treatment of nephrotic syndrome in KD patients [6]. In this group, 3 childrens have nephrotic syndrome, the diagnosis of nephrotic syndrome was earlier in 2 cases than kimura's disease. They have accepted treatment of glucocorticoid. In the process of glucocorticoid decreasing and withdrawing, the masses increase slowly and thus is confirmed. Therefore, kimura disease doesn't necessarily present mass or soft tissue swelling as the initial symptom. We should guard against the possibility of kimura disease for patients with nephrotic syndrome as the initial symptom and complicated with other manifestations. In the literature report, the proportion of children KD complicated with nephrotic syndrome is higher than the adults, which suggests that children with KD are more likely to have kidney damage.

KD is a rare chronic inflammatory disease of unknown etiology. At present, the cause of disease is still unclear. In the lab examination, the main characteristics are specific eosinophils counts and percentage in the peripheral blood and elevated serum total IgE value, which may be related to T cell immune regulation disorder and IgE mediated type I immune response or may be related to bacteria, fungi, parasitic infection and working environment [7]. 14 cases have been examined with percentage of peripheral blood eosinophils in our center. The percentage of peripheral blood eosinophils in 16 (88.9%) is higher than the normal value. Meantime, immunoglobulin examination has been performed in 13; 12 (92.3%) have higher IgE quantitative determination than the normal value. The image findings of kimura disease are also characterized by involvement of parotid gland and subcutaneous multiple lesions, accompanied with multiple enlarged lymph nodes, uniform density or signals, no necrosis or fusion, vague boundary between the lesions and the surrounding tissues and no capsules. Local ultrasound examination of all 17 patients in our center suggested hypoechoic masses. Histopathological examination is the gold standard for the diagnosis of the disease. Under light microscopy, typical pathological changes are caused by hyperplasia lymph follicle and massive eosinophilic granulocyte infiltration and eosinophilic microabscess. For patients with atypical pathological manifestations in skin biopsy, space-occupying lesions should be identified when the disease is diagnosed, such as Hodgkin lymphoma, Kaposi's sarcoma, lymphatic tumor metastasis and other malignant diseases; benign tumor, skin inflammation, pyogenic granuloma and other infectious lymphadenopathy, especially angiolymphoid hyperplasia with eosinophilia [8,9]. In this study, 18 cases have typical KD pathological changes. Under the microscope, the lesions have affected salivary glands and lymph nodes, forming lymphoid follicles and microabscesses. 17 have been examined with immunocytochemistry. Immunohistochemical associated antibodies also have relevant characteristics. 5 are strongly and diffusely expressive for CD3/CD20, 9 are expression of CD21, suggesting that T cells, B cells and dendritic cells are positive and multiple cells in lymphoid tissues are present, which usually indicate benign lesions. 7 are expression of CD34, 9 are expression of CD68, 4 are expression of CD38, 6 are expression of pax-5 (+), 7 are expression of s-100+ and 3 are expression of CD1a. While the expression of CD1a on the surface of immature dendritic cells can mediate the presentation of tumor-derived lipid and glycolid antigens to tumor-specific T cells so as to promote the antitumor immune response of these cytolytic cells [10].

So far, there has been no effective treatment to KD. The purpose of treatment is to retain function and aesthetic effects and prevent recurrence and sequelae. In asymptomatic cases, as lesions sometimes regress spontaneously, conservative observation is suggested. At present, KD treatment methods in the literature reports include surgery, glucocorticoid therapy, chemotherapy, radiotherapy, cryotherapy, photodynamic therapy, anti-IgE antibody biotherapy, etc. Because KD lesion sites are shallow, surgery is the preferred treatment. However, due to the characteristics of infiltration, no capsule and unclear boundary, complete surgical resection is difficult to realize and the postoperative recurrence rate is high. The recurrence rate in our center is as high as 50%, which is close to the recurrence rate in the literature review. For cases with the lesions difficult to be completely excised by surgery or of easy recurrence, glucocorticoid or local radiotherapy can be adopted in the meantime. Local radiotherapy is suitable for patients with multiple or recurrent and refractory KD and not for children. Hormone therapy is suitable for patients with multiple nephrotic syndromes or associated with nephrotic syndrome. But in case of hormone reduction or withdrawal, it is easy to recur. For patients of recurrence or steroid resistance, cytotoxic drugs and immunosuppressive therapy should be considered. It has been reported in the literature that leflunomide, cyclosporine, mycophenolate mofetil have certain therapeutic effects. Few literatures have reported that montelukast sodium and cetirizine hydrochloride could treat hormone resistant kimura disease. Although the therapeutic methods are not unified at present, the prognosis of KD is good and the disease has no malignant potential. It is hereby reported to increase pediatricians' better knowledge of the disease. Although the disease is rare, the therapeutic effect is good. Most do not need excessive drug intervention [11,12]. In this study, most patients are treated with surgical resection. However, as the disease is rare, it needs further study with larger sample data.

The clinical manifestations and lab findings of children kimura disease are similar to those of adults. The definitive diagnosis can only be confirmed with histopathological examination of the excised swelling. KD has a better prognosis. Surgical adjuvant drugs and radiotherapy have certain effects, but the recurrence rate is high, so follow-up should be strengthened. Kimura disease in children lacks reports of large sample cases, so there are few new developments. Clinical pediatrician should increase their knowledge of the disease to reduce misdiagnosis and missed diagnosis and improve the diagnostic rate of the first visit.

KD Kimura’s disease

IgE Immunoglobulin E

ESR Erythrocyte sedimentation rate

Ethics approval and consent to participate

This study protocol has been approved by the Ethics Committee of Shenzhen Children's Hospital. The ethics committee waived the requirement for informed consent because anonymous data were analyzed retrospectively.

Consent for publication

All authors listed approved it for publication.

Availability of data and materials

Clinical data were collected from the electronic database of the Shenzhen Children’s Hospital, including disease onset, disease course, previous treatments, laboratory data and so on.All data generated or analysed during this study are included in this published article.

Competing interests

All the authors declare that they have no conflict of interest.

Funding

There are no funding sources.

Authors' contributions

All authors listed have made a substantial, direct, and intellectual contribution to the work.

Acknowledgements

The author thanks Prof. Yu Xia and Jun Yang, for their guidance.

Authors' information (optional)

The first author: Qingfang Zhou, Shenzhen Children's Hospital of China Medical University, Shenzhen, Guangdong Province, 518000, China. E-mail address: [email protected].

Co-first author：Ruohang Weng, Department of Rheumatology and Immunology, Shenzhen Children's Hospital, Shenzhen, Guangdong Province, 518000, China. E-mail address: [email protected].

The second author: Linlin Wang, Department of Rheumatology and Immunology, Shenzhen Children's Hospital, Shenzhen, Guangdong Province, 518000, China. E-mail address: [email protected].

The third author: Ying Luo, Department of Rheumatology and Immunology, Shenzhen Children's Hospital, Shenzhen, Guangdong Province, 518000, China. E-mail address: [email protected].

The fourth author: Tingyan He, Department of Rheumatology and Immunology, Shenzhen Children's Hospital, Shenzhen, Guangdong Province, 518000, China. E-mail address: [email protected].

The fifth author: Jun Yang, Department of Rheumatology and Immunology, Shenzhen Children's Hospital, Shenzhen, Guangdong Province, 518000, China. E-mail address: [email protected].

Corresponding author:Yu Xia, Department of Rheumatology and Immunology, Shenzhen Children's Hospital, Shenzhen, Guangdong Province, 518000, China. E-mail address: [email protected].

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Tables 1 and 2 are available in the Supplementary Files section

A Report on 18 Cases of Children with Kimura Disease in China and Literature Review

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Abstract

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Methods

Results

Discussion

Conclusion

Abbreviations

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Supplementary Files

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