Kimura Disease 

Updated: Apr 27, 2017
Author: Alan Snyder; Chief Editor: William D James, MD 

Overview

Background

Kimura disease is a chronic inflammatory disorder of unknown etiology that most commonly presents as painless lymphadenopathy or subcutaneous masses in the head and neck region. The first report of Kimura disease was from China in 1937, in which Kimm and Szeto[1] described seven cases of a condition they termed "eosinophilic hyperplastic lymphogranuloma." The disorder received its current name in 1948, when Kimura et al[2] noted the vascular component and referred to it as an "unusual granulation combined with hyperplastic changes in lymphoid tissue."

Controversy has existed in the literature regarding whether Kimura disease and angiolymphoid hyperplasia with eosinophilia (ALHE) are the same entity. Some authors believe that Kimura disease represents a chronic, deeper form of ALHE; however, most papers distinguish the two on the basis of clinical and histopathologic characteristics.[3, 4] ALHE appears to represent an arteriovenous malformation with secondary inflammation. Kimura disease may represent a primary inflammatory process with secondary vascular proliferation.[5, 6] Reports have described both diseases presenting simultaneously.[7]

Pathophysiology

The pathophysiology of Kimura disease remains unknown. It has been hypothesized that an infection or toxin may trigger an autoimmune phenomenon or lead to a type I (immunoglobulin E [IgE]–mediated) hypersensitivity reaction. Some evidence has suggested a predominance of TH 2 cells in patients with Kimura disease.[8] Additional studies have shown elevated granulocyte-macrophage stimulating-factor (GM-CSF), tumor necrosis factor-α (TNF-α), soluble interleukin (IL)–2 receptor (sIL-2R), IL-4, IL-5, IL-10, and IL-13.[9, 10] Another study indicated that the activation of the IL-21/pERK1/2 pathway is a component of Kimura disease immunopathogenesis and that pERK1/2 could be a potential prognostic indicator of the disease.[11] These findings may help lay the groundwork for elucidating the underlying pathophysiology of Kimura disease.

Epidemiology

Frequency

United States

Kimura disease has rarely been reported in the United States.

International

The exact prevalence of Kimura disease is not known. Most cases of this rare disease are reported in East and Southeast Asia, with a small number of cases reported in Europe and the Middle East.[12, 13]

Race

Most cases of Kimura disease have been reported in Asians, and the prevalence among persons of other races is thought to be low. A retrospective review of 21 histopathologic specimens diagnosed as Kimura disease at the US Armed Forces Institute of Pathology found the following racial distribution: 7 whites, 6 African Americans, 6 Asians, 1 Hispanic, and 1 Arab.[14] This illustrates that if clinically suspected, Kimura disease should be included on the differential diagnosis for persons of any racial group.[15]

Sex

Males are affected by Kimura disease more commonly than females, with a 3.5:1 to 9:1 male-to-female ratio in most series reported, with the exception of one series in which the male-to-female ratio was 19:1.[15, 16]

Age

Kimura disease is usually seen in young adults during the third decade of life, with the median age being 28-32 years.[14, 17, 18] Although more rare, pediatric populations can develop Kimura disease, and cases have been reported in persons aged as young as 15 months.[13]

Prognosis

The course of Kimura disease is chronic, with lesions frequently persisting or recurring despite treatment. Kimura disease can lead to disfigurement secondary to the growth of untreated lesions, particularly given the predilection for the head and neck. Additionally, recurrence after treatment is well described. Smoking habits and a history of systemic disease also have been associated with poor prognosis of the disease.[19] To date, malignant transformation of Kimura disease has not been described in the literature.

 

Presentation

History

Kimura disease typically presents as a painless mass or masses in the head and neck region, with occasional pruritus of the overlying skin. Renal disease, nephrotic syndrome in particular, is present in up to 20% of patients with Kimura disease.[20] An estimated 12-16% of patients with Kimura disease exhibit proteinuria upon examination, of which 59-78% have nephrotic syndrome.[21] Less commonly, several reports in the literature have linked Kimura disease with a hypercoagulable state in patients without associated nephrotic syndrome.[22]

Physical Examination

Patients with Kimura disease typically present with nontender subcutaneous nodules and masses in the head and neck, especially in the parotid and submandibular regions. These lesions are often associated with lymphadenopathy. Less frequently, the orbit (including the eyelids, conjunctiva, and lacrimal glands[23] ), paranasal sinuses, epiglottis, tympanic membrane, parotid gland, parapharyngeal space, palate, axilla, groin, and breast[18, 24, 25, 26] may be involved.[27, 28] Although Kimura disease mainly affects the head and neck, involvement of the extremities and inguinal lymph nodes has been reported.[29] In addition, a presentation of Kimura disease as a pulmonary hilar mass has been described.[30] Visible ischemia of the extremities may be present as a result of the hypercoagulable sequelae of Kimura disease, and related chronic diseases such as Raynaud phenomenon and acute limb ischemia (ALI) have been reported when left untreated.[7, 31, 32]

See the image below.

Fifteen-year-old boy with nontender, firm swelling Fifteen-year-old boy with nontender, firm swelling (5 cm x 3 cm) in the left cervical area of 8 months’ duration. Courtesy of Our Dermatology Online (http://www.odermatol.com/).

Causes

See Pathophysiology.

Complications

Rarely, large nodules or tumors from Kimura disease have ulcerated. After treatment, recurrence also has been reported.

Abbas et al reported one case of postsurgical facial disfigurement effectively treated with photodynamic therapy.[33]

On two known occasions, brain embolisms have occurred due to Kimura disease–induced thrombi.[34]

 

DDx

Diagnostic Considerations

Other reported differentials to consider include the following:

  • Hodgkin lymphoma [24]
  • Angioimmunoblastic T-cell lymphoma [24]
  • Langerhans cell histiocytosis [24]
  • Parasitic lypmhadenitis [24]
  • Drug-related lymphadenopathy [24]
  • Inflammatory disease of the orbit [25]
  • IgG4-related disease [35]
  • Malignant lymphoma [36]
  • Malignant tumors of the head and neck [36]
  • Castleman disease [19]

Differential Diagnoses

 

Workup

Laboratory Studies

Nearly all patients with Kimura disease demonstrate peripheral eosinophilia and elevated levels of serum IgE. In one series, the number of eosinophils was closely correlated to the sizes of the neck masses.[37]

Blood urea nitrogen, creatinine, and urinary protein levels should be obtained to exclude concomitant renal dysfunction (especially nephrotic syndrome).

Serum eosinophil cationic protein levels parallel the course of the disease.[38]

Imaging Studies

The appearance of Kimura disease on imaging modalities, including CT scanning and MRI, is variable and is thought to be due, at least in part, to the variable degrees of vascular proliferation and fibrosis within individual lesions. However, diagnostic CT imaging of cervical nodes might be preferred over MRI by virtue of objective enhancement signal-intensity properties alone. Patients presenting with Kimura disease have been found to present intensely enhanced on CT (>120 HU) when compared with other common diseases affecting cervical lymph nodes.[39] One of the largest case series to date notes the characteristic findings to be multiple ill-defined, enhancing lesions around the parotid gland, with associated lymphadenopathy.[27]

Procedures

Incisional biopsy is recommended to obtain the diagnosis of Kimura disease.

Histologic Findings

Lymphoid nodules with discrete germinal centers can occupy an area extending from the reticular dermis to the fascia and muscle. Follicular hyperplasia, marked eosinophilic infiltrate and eosinophilic abscesses, and the proliferation of postcapillary venules are characteristic histological findings.[18] Centrally, thick-walled vessels are present with hobnail endothelial cells. Immunohistochemical evaluation of the lymphoid nodules demonstrates a polymorphous infiltrate without clonality.[12, 27] Reports have also demonstrated the presence of plasmacytoid dendritic cells in a lesion of Kimura disease.[40] Histopathological examination is an effective way to establish the diagnosis.[18, 19, 41]

See the image below.

High-magnification micrograph of Kimura disease, h High-magnification micrograph of Kimura disease, hematoxylin and eosin stain. Thick-walled blood vessels with (plump) hobnail endothelial cells and abundant eosinophils. Courtesy of Nephron (own work) via Wikimedia Commons.
 

Treatment

Medical Care

Observation is acceptable if the Kimura disease lesions are neither symptomatic nor disfiguring.

Oral corticosteroids are commonly used; however, the disease frequently recurs after cessation of therapy. Intralesional corticosteroids may be effective for localized disease.[42]

Oral corticosteroids in combination with cetirizine may prove to be an effective alternative treatment to surgery to reduce related nodular masses. In one patient, continued daily cetirizine prevented recurrence 4 months after tapering steroids.[24]

Leflunomide in combination with oral prednisone may be an option for treating patients with or without renal involvement who are unresponsive to corticosteroids alone. The subject of one study remained disease free at the 12-month follow up after treatment with leflunomide and methylprednisone.[43] Leflunomide may have an antiproliferative effect on eosinophils.

Cyclosporine has been reported to induce remission in patients with Kimura disease.[44, 45, 46] A dose of 5 mg/kg/d was effective, but the lesions may recur upon cessation of therapy.[47]

Intravenous immunoglobulin (IVIG) was used in one patient as a steroid-sparing agent, and he remained disease free more than 6 years after follow-up.[48]

Oral pentoxifylline has been reported to be effective in one patient with Kimura disease; however, the lesions relapsed after discontinuation of therapy.[49]

All trans-retinoic acid in combination with prednisone has resulted in remission of Kimura disease in one patient, and he remained disease free 12 months after discontinuation of all therapy.[50]

Imatinib may be an effective treatment for Kimura disease, based on advances in research for therapy in hypereosinophilic syndrome, but further investigation is necessary.[12]

Photodynamic therapy has been used successfully in one patient who experienced recurrence of disease after initial surgical management.[33]

Radiotherapy has occasionally been used to treat recurrent or persistent Kimura disease lesions. A report by Hareyama et al[51] described the use of radiotherapy at dosages of 26-30 Gy; local control was achieved in 74% of lesions. Another study demonstrated that radiotherapy (20-45 Gy) was more effective than local excision and steroid treatment, with local response rates of 64.3% versus 22.2%, respectively. No adverse effects were observed during a mean follow-up period of 65 months.[52] New technology such as three-dimensional printing is being explored for preventing collateral damage during radiotherapy bolus delivery to radiosensitive areas such as the head and neck.[53] However, considering the benign nature of Kimura disease, radiation should be reserved for recurrent or disfiguring lesions.

The largest retrospective meta-analysis of Kimura disease treatment to date (n=639) concluded that surgical resection with low-dose postoperative radiotherapy resulted in the lowest recurrence rate of Kimura disease. Furthermore, it suggested that corticosteroid therapy should be a second-line option for treatment, owing to the potential adverse effects of long-term corticosteroid use and the high rates of recurrence when used alone.[54] The same conclusions were made in another study comparing recurrence rates in 46 patients who underwent steroid therapy, surgical excision, radiotherapy, or surgical excision with radiotherapy.[42]

Surgical Care

Conservative surgical excision has been considered the treatment of choice for Kimura disease.[42, 55] Recurrence after surgery is frequently observed.

Consultations

Consultation with an otolaryngologist or ophthalmologist should be considered for further evaluation depending on the extent and location of the disease.

 

Medication

Medication Summary

The goals of pharmacotherapy for Kimura disease are to reduce morbidity and to prevent complications.

Immunosuppressants

Class Summary

Immunosuppressants suppress the response of the immune system to diverse stimuli.

Cyclosporine (Sandimmune, Neoral)

Cyclosporine has been demonstrated to be helpful in a variety of skin disorders. It is a cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions, such as delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft versus host disease for a variety of organs. For children and adults, base dosing on ideal body weight.

Triamcinolone (Amcort, Aristocort)

Triamcinolone is used for inflammatory dermatosis responsive to steroids. It decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing capillary permeability. Intralesional injections may be used for localized skin disorders.

Prednisone (Orasone, Deltasone, Meticorten, Sterapred)

Prednisone may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte activity.

Leflunomide (Arava)

Leflunomide is a novel immunosuppressant used to treat a number or immunosuppressing diseases. Leflunomide may have an antiproliferative effect on eosinophils.

Hemorheologic agents

Class Summary

These agents are used to treat vascular disease.

Pentoxifylline (Pentoxil, Trental)

Pentoxifylline may alter rheology of red blood cells, which, in turn, reduces blood viscosity.

Retinoids

Class Summary

These agents regulate cell growth and differentiation.

Tretinoin (Vesanoid)

Tretinoin may inhibit granulocyte differentiation.

Antihistamines, 2nd Generation

Class Summary

Second-generation antihistamines, also known as less-sedating or low-sedation antihistamines, produce less sedation than traditional H1 blockers because they are less lipid-soluble and only cross the blood-brain barrier in small amounts. They also have longer half-lives, allowing less frequent dosing.

Cetirizine (Aller-Tec, Children's Zyrtec Allergy, Children's Zyrtec Hives Relief)

Cetirizine may inhibit eosinophil activity and differentiation. Cetirizine forms a complex with histamine for H1-receptor sites in blood vessels, the gastrointestinal (GI) tract, and the respiratory tract. It is available as a 5- or 10-mg tablet and as a syrup containing 1 mg/mL (5 mg/5 mL [tsp]).