Misdiagnosed recurrent multiple Kimura's disease: A case report and review of the literature

Introduction

Kimura's disease (KD) was first reported in China by Kim in 1937 as eosinophilic hyperplastic lymphogranuloma (1). Until 1948, the disease was widely recognized in Japan and systematically described by Professor Kimura as ‘unusual granulations combined with hyperplastic changes in lymphoid tissue’ (2,3). KD is a chronic disease and its etiology has not been fully elucidated to date. Patients suffering from this condition mainly present with solitary or multiple painless masses in the maxillofacial and other regions, which often recur after treatment (4,5). Clinically, KD is always accompanied by enlarged regional lymph nodes, eosinophilia and markedly elevated serum IgE levels (2,5). This disease has been most commonly diagnosed in middle-aged individuals in the Far East, for example China and Japan (6–8). Thus far, only 200 cases have been reported worldwide. We herein report a rare case of KD in a 48-year-old man and review the relevant literature to help improve the level of clinicians' knowledge regarding the diagnosis and treatment of this disease.

Case report

A 48-year-old man was admitted to the Hainan Branch of Chinese People's Liberation Army General Hospital (Sanya, China) in December 2017, with recurrent masses in the right parotid gland and neck region for ~15 years. The patient was in good overall condition and had no other complaints, such as pain, swelling, local numbness or xerostomia. There were no reported allergies or other systemic manifestations. The patient had undergone surgical resection of the masses twice (1997 and 2000), but the masses recurred both times after ~6 months. Both postoperative pathological diagnoses were lymphadenitis.

Physical examination revealed maxillofacial asymmetry. Hard, mobile masses were identified in the region of the right parotid gland and neck, arranged longitudinally. On palpation, the borders of the masses were clear, without adhesions to the surrounding tissue; the total size was 15×10×3 cm. Masses were also identified in the left supraclavicular fossa, the right forearm near the wrist joint and the left medial upper arm, sized 5×5×2, 4×3×2 and 4×3×1 cm, respectively (Fig. 1). In addition, multiple enlarged lymph nodes were palpated in the submandibular area and the neck region.

Figure 1. The patient who presented with painless masses (arrows) in the region of the right parotid gland and neck, the left supraclavicular fossa, the right forearm near the wrist joint and the left medial upper arm.

Reviewing the results of the laboratory tests, with an increased eosinophil percentage (0.55%; normal, 0.01–0.05%), markedly elevated serum IgE levels (27,100 IU/ml; normal, 0–100 IU/ml) and leukocyte count (21.78×109/l; normal, 3.5×109/l), and decreased neutrophil percentage (0.28%; normal, 0.50–0.70%). The results of other investigations, including routine urinalysis, liver and kidney function tests, were within normal limits. Chest radiography was also normal.

Ultrasound examination of the right parotid gland region revealed uneven echogenicity, consistent with a high likelihood of a benign tumor (Fig. 2); a low-echogenicity nodule was identified in the right submaxillary region, which was considered to be a reactive hyperplastic lymph node. On magnetic resonance imaging (MRI) examination, a widespread abnormal signal was detected in the right parotid gland and submaxillary region, and a contrast-enhanced scan revealed inhomogeneous enhancement; the right side of the sternocleidomastoid muscle and the parotid gland were partially involved, with half of the lesions wrapped around the carotid sheath (Fig. 3); multiple enlarged lymph nodes were also identified displaying obvious enhancement.

Figure 2. Ultrasound of the right parotid gland region showing uneven echogenicity.

Figure 3. Magnetic resonance imaging examination showing widespread abnormal signal was detected. Administration of contrast material revealed uneven enhancement.

A detailed surgical plan was formulated and, following a full preoperative preparation, the right parotid gland and neck masses were resected under general anesthesia, together with the right superficial parotid lobe (Fig. 4).

Figure 4. Intraoperative view (left panel) and resected specimens (right panel).

Postoperative pathological examination established the diagnosis of eosinophilic hyperplastic lymphogranuloma, also referred to as KD (Fig. 5), with lesions involving the parotid gland and lymph node tissue.

Figure 5. Diffuse infiltration of the parotid gland by eosinophil granulocytes and lymphocytes (hematoxylin and eosin staining; magnification, ×40).

The patient was administered 25 mg prednisone twice daily for 2 weeks after the definitive diagnosis. On repeat blood tests, the eosinophil count returned to normal levels, and the masses of the left supraclavicular fossa, right forearm and left medial upper arm notably decreased in size. Therefore, the initial treatment was successful in controlling the disease. Next, the patient will be advised to undergo radiotherapy (total dose, 20–50 Gy; 1.8–2.0 Gy per day, five days a week, over the course of 2–5 weeks).

Discussion

KD is a rare condition, with <300 reported cases to date. Based on these cases, KD is rarely observed in Europe and America (9,10), but frequently occurs in East Asian and Southeast Asian populations (11–14), with China and Japan being the most common. The pathogeny of KD remains unknown. The minimum age reported is 5 years, but it mostly occurs in middle-aged men (15–17). Women only account for a small proportion of the patients, with a male:female ratio of ~3:1 (18). Clinically, KD has a specific predilection for the head, neck (5,10) and limbs, with the lesions most commonly developing in the soft tissue, whereas maxillofacial salivary glands and lymph nodes may also be affected. Patients with KD disease often have a long course, manifesting solitary or multiple soft tissue masses. KD is usually associated with peripheral blood eosinophilia and markedly elevated IgE levels.

The etiology of KD remains unknown (4,5,10,13). It has been confirmed that there is no correlation with tuberculosis, bacterial, fungal or viral infections, poisoning or syphilis (19). Most scholars tend to consider KD as an IgE-mediated type I allergy and inflammatory disease (20), and this hypothesis is supported by the increased eosinophil count and IgE levels in the peripheral blood (21,22). Googe et al reported increased IgE levels in KD patients with renal involvement, which supports the theory that KD is an immune response (23); moreover, clinical application of steroid therapy appears to be effective, further supporting this theory. In recent years, Ohta et al measured Th1/Th2 and Tc1/Tc2 lymphocyte subsets by flow cytometry in KD patients, and interestingly observed that Th2 and Tc1 cell numbers increased significantly in patients with KD compared with the healthy control group; therefore, they reported that Th2 and Tc1 cells appear to play an important role in the pathogenesis of KD (24). Other studies demonstrated that the release of cytokines in patients with KD can increase the permeability of the glomerular basement membrane, causing proteinuria, which may ultimately cause renal damage (25,26). Chim et al considered a clonal T-cell lymphoproliferative disorder as the possible cause of KD; however, this result was from a single case study, and the etiological analysis remains speculative (27).

KD patients are typically men in their 30s and the highest incidence of this disease worldwide is observed in the Asian population. Although Asian and non-Asian patients have certain characteristics in common, it has been reported that non-Asian patients do not generally exhibit involvement of the salivary glands (10); by contrast, in Asian patients KD has a predilection for pre-auricular, parotid and submandibular salivary glands, the neck and the maxillofacial region. The majority of the patients present with firm, painless, single or multiple subcutaneous masses, progressively increasing in size. Mass size may vary greatly, ranging from 1 to 7 cm (28). In addition, multiple regional lymph nodes are involved, manifesting as a single or multiple fused nodules. Although KD mostly involves the maxillofacial region, involvement of other sites has also been reported, including the axilla, trunk, kidney, arm, nerves, orbit, spermatic cord and groin (6,29). In the case presented herein, the patient had a right parotid swelling, along with multiple supraclavicular fossa and arm masses for 15 years. The skin overlying the KD lesions was not inflamed, although mild itching was occasionally reported. With disease progression, skin pigmentation, thickening, local erosion and ulceration may develop, sometimes affecting the whole body in severe cases. Some scholars report that renal involvement is a common systemic manifestation that may affect up to 60% of the patients (5,25,30,31). In addition, the disease may be complicated by asthma, fatigue, fever, allergic rhinitis, atopic dermatitis, urticaria and other allergic symptoms (20). KD is generally benign and self-limited, with a prolonged course. On long-term follow-up, malignant transformation has not been reported. The overall prognosis is good, but recurrence is common.

KD patients almost always have marked eosinophilia and elevated serum IgE levels. Some studies report that blood eosinophil counts are closely associated with the size of the lesion, i.e., the bigger the lesion, the higher the eosinophil count (32,33). Physical examination along with US, CT and MRI may help determine the characteristics, boundaries and blood supply of the mass, as well as the presence of lymph node involvement. On US, the mass may exhibit heterogeneous or homogeneous echogenicity (34), occasionally displaying increased vascularity. On CT scans, the lesions are strongly enhanced, reflecting their vascular nature; lymphadenopathy is reported among the typical findings. On MRI, the lesion exhibits intermediate to high signal intensity on T1-weighted images and hyperintense signals on T2-weighted images (35,36). Therefore, imaging may be a useful way of demonstrating the morphology and extent of the lesion, as well as its association with adjacent structures (8).

There are currently no uniform diagnostic criteria for KD. The following characteristics should raise suspicion of KD: i) Young male, with head and/or neck painless mass; ii) local enlarged lymph nodes; iii) long history; iv) parts of body other than the head and neck displaying multiple painless masses, accompanied by pruritus of the overlying skin; v) increased blood eosinophil count and serum IgE level (a high reference value is needed to make a correct diagnosis); and vi) CT and MRI showing a wide range of lesions and multiple enlarged lymph nodes. Based on these clinical manifestations and blood test results, the diagnosis of KD may be preliminarily considered, but the final diagnosis relies on pathological examination. The histopathological characteristics of KD include follicular hyperplasia, eosinophilic infiltrates and proliferation of postcapillary venules (2,10,12,23).

Clinically, the differential diagnosis of KD may include angiolymphoid hyperplasia with eosinophilia (ALHE), Hodgkin's lymphoma, angioimmunoblastic T-cell lymphoma, Langerhans cell histiocytosis, florid follicular hyperplasia, Castleman's disease, dermatopathic lymphadenopathy, sinonasal eosinophilic angiocentric fibrosis, drug reactions and parasitic infections. In the literature, the most common misdiagnosis is ALHE (10,37); however, patients with ALHE have normal IgE levels and no kidney damage (3,9,38,39).

In conclusion, the prognosis for KD is quite favorable, but may recur frequently in the original location (4), with a recurrence rate of up to 25% (40), posing a major challenge to the physician and patient. A standard treatment for KD has not yet been established. The goal of treatment currently is to maintain appearance and functionality, while preventing recurrence and long-term sequelae, including nephritis and myocarditis.

Although surgery is the most widely used treatment method and it can help reach a definite diagnosis (32,33,35,41,42), other options include radiotherapy, systemic corticosteroids, cytotoxic agents, cyclosporin and pentoxifylline (32,33,42). Oral corticosteroids are usually recommended in cases of symptomatic nephrotic syndrome (26) and, in order to prevent relapse and reduce the long-term side effects of steroid therapy, postoperative radiation therapy may be used (low-dose local irradiation, ~25–30 Gy) (43,44). Reportedly, the recurrence rate appears to be lower if two treatment modalities are combined (41). Recently, anti-IgE therapy has been introduced (45), and the size of lesion and peripheral blood eosinophil count of KD patients were reported to decrease following anti-IgE therapy.

In conclusion, KD is a chronic disorder of unknown etiology. In clinical practice, KD is easily misdiagnosed as other inflammatory lesions or benign tumors of the head and neck, so more thorough diagnostic workup is required. Only through a careful medical history and comprehensive clinical examination, combined with laboratory, imaging and histopathological examinations, can a definitive diagnosis be reached and individualized treatment administered.

Acknowledgements

Not applicable.

Funding

The present study was supported by the Hainan Key Research and Development Program (grant no. ZDYF2016170) and the Clinical Research Support Fund of PLA General Hospital (grant no. 2017FC-WJFWZX-22).

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

The patient provided consent for publication of the case details and associated images.

Availability of data and materials

Not applicable.

Authors' contributions

XL took care of the patient, wrote the medical records and wrote the manuscript. JW and HL collected relevant medical records and assisted with writing. MZ was responsible for surgical treatment and paper revision. All the authors have read and approved the final version of this manuscript.

Competing interests

The authors declare that they have no competing interests to disclose.

References