Are You Confident of the Diagnosis?

What you should be alert for in the history

Kimura’s disease (also referred to as subcutaneous eosinophilic lymphoid granuloma) can be diagnosed with confidence under the right clinical context in endemic populations. It typically presents as painless soft tissue nodules (1-10cm in diameter). Small pink to red papules can also be present, singly or in multiples. Lesions a few centimeters in diameter have been described.

Characteristic findings on physical examination

These papules and nodules are most frequently located on the head and neck region (Figure 1). The periauricular region is by far the most frequent location. Lymphadenopathy of the cervical and supraclavicular lymph nodes is usually present. Lymphadenopathy may be the only sign of the disease, and may be the reason the patient seeks medical care. Involvement of the salivary glands is common. Most cases follow an indolent and chronic course.

Figure 1.

Reddish nodule on the scalp.

Kimura’s disease occurs most frequently on the head and neck of young Asian men. Common sites of involvement include the parotid glands and other salivary glands. Less frequent sites of involvement include the kidneys (as nephrotic syndrome), nerves, orbits, and the spermatic cords.

Most lesions are asymptomatic, but pruritus or pain may be part of the disease.

Expected results of diagnostic studies

Laboratory findings include peripheral eosinophilia (in nearly all patients), and elevated IgE and erythrocyte sedimentation rate (ESR) levels. The diagnosis is generally made histologically, with a lymph node biopsy and skin biopsy.

The common histological features on lymph node biopsy are a preserved lymph node architecture, florid germinal centers, eosinophilic infiltrate, and increased number of postcapillary venules. Other features include sclerosis, karyocytosis in both germinal centers and the paracortex, vascularization of the germinal centers, proteinaceous deposits in germinal centers, necrosis of germinal centers, eosinophic abcesses, and atrophic venules in sclerotic areas (Figure 2, Figure 3, Figure 4).

Figure 2.

Prototypical lymph node in Kimura’s disease (H&E) (x40). (Courtesy of Michael Bayerl, MD)

Figure 3.

Eosinophilic microabscess within a lymph node in Kimuras disease (H&E) (x400). (Courtesy of Michael Bayerl, MD)

Figure 4.

Polykaryocyte (H&E) (x1000). (Courtesy of Michael Bayerl, MD)

Immunostaining supports the inflammatory or reactive nature of Kimura’s disease. B cells and T cells are located normally within the appropriate nodal regions. Bcl-2 staining has been found to be negative. A polyclonal pattern of lambda and kappa chains has been described.

Epstein Barr virus has only rarely been isolated from the lesions, and the virus is not felt to play a role in pathogenesis. The same is true for human herpes virus 8 (HHV-8). IgE has been shown to be deposited in an increased amount within the germinal centers.

Diagnosis confirmation

The differential diagnosis of Kimura’s disease includes:

1. Angiolymphoid hyperplasia with eosinophilia (ALHE) (which presents mostly in women and does not often have regional lymphadenopathy). In addition and most importantly, the vascular endothelial cells in ALHE have nuclei of varied sizes and shapes, and hemosiderin deposits, which are not seen in Kimura’s disease.

2. Head and neck malignancy (this can readily be distinguished by histological features on biopsy)

3. Lymphoma (Hodgkin’s and immunoblastic T-cell lymphoma). These can be distinguished by abnormal clonal lymphocyte proliferation and immunohistochemistry staining.

4. Castleman’s disease

5. Churg-Strauss allergic granulomatosis

A comparison of Kimura’s disease to ALHE is summarized in Table I.

Table I.
Kimura’s Disease ALHE
Rare Rare
Young Asian males Middle-aged females
Deep dermal and subcutaneous location Superficial epidermal and dermal location
Head and neck region Head and neck region
Can involve lymph nodes and salivary glands Does not involve salivary glands, rarely involves lymph nodes
Idiopathic Idiopathic
Chronic inflammatory condition Reactive inflammatory condition, but possibly neoplastic
Indolent waxing and waning clinical course Indolent waxing and waning clinical course
Associated with nephrotic syndrome Rare cases of renal disease reported
Almost all with eosinophilia Approximately 25% with eosinophilia
Elevated serum IgE Normal IgE
No malignant degeneration reported No malignant degeneration reported

The histology of Kimura’s disease, compared to ALHE, is summarized in Table II.

Table II.
Kimura’s Disease ALHE
Flat endothelial cells Plump endothelial cells
Associated with lymphoid follicle aggregates, some necrosis present with eosinophil infiltration Endothelial cells protrude into the vessel lumen
Endothelial cells do NOT contain cytoplasmic vacuoles Endothelial cells contain cytoplasmic vacuoles
Some increase in the vascularity Increased vascularity surrounding larger vessel
Minimal smooth muscle in vasculature walls Prominent smooth muscle in vasculature
Prominent fibrosis Fibrous and/or myxoid stroma
Nodular and diffuse dense eosinophilic infiltrate (eosinophilic abscess) with lymphocytes Dense perivascular and interstitial infiltrate that contains lymphocytes, eosinophils and plasma cells, mast cells, and macrophages
Associated fibrosis Fibrosis lacking
No ulceration Ulceration +/-
Can affect muscle Does not penetrate much past deep dermis, occasional subcutaneous tissue involvement
Who is at Risk for Developing this Disease?

Young Asian men are at the greatest risk of developing Kimura’s disease. Rare cases have been reported in non-Asians.

Kimura’s disease is endemic in Asia and was first described in China in 1937. It was formally named Kimura’s disease in the Japanese literature in 1948. Men with the disease outnumber women with the disease by a substantial number (up to 10:1). The disease is most commonly seen in the third to fifth decades of life.

What is the Cause of the Disease?
Etiology
Pathophysiology

Although the cause of Kimura’s disease is unknown, it is thought to be an immune-mediated disorder of chronic inflammation and not a neoplasm. The presence of eosinophils has led some to consider this a hypersensitivity reaction, with a Th2-mediated response (IL-4, IL-5, and subsequent eosinophilia).

Systemic Implications and Complications

Kimura’s disease is associated with allergic conditions such as asthma, rhinitis, and eczema. There are also reports of associated renal abnormalities such as steroid-responsive renal proteinuria and nephrotic syndrome. It is therefore important to query about these conditions in newly diagnosed patients and work up patients for these conditions.

Routine complete blood count (CBC), differential, and platelet count, as well as blood urea nitrogen (BUN), creatinine, and a urinalysis looking for proteineuria should be performed two to three times per year. Nephrology consult should be requested.

Treatment Options

Treatment options are summarized in Table III.

Table III.
Medical Treatment Other Treatments Surgical Treatment
Observation after conclusive diagnosis Local radiation therapy Complete surgical excision
Oral corticosteriods, prednisone (1mg/kg and taper over 2-4 weeks)    
Intralesional steroidsKenalog 10-40mg/cc    
Cetirizine 10mg per day    
Cyclosporine (2.5mg/kg divided twice daily)    

Optimal Therapeutic Approach for this Disease

The treatment of Kimura’s disease has mainly involved oral corticosteriods, 1mg/kg and tapered over a period of 2-4 weeks. The termination of corticosteroids often results in relapse.

For this reason, surgical excision can offer a good cosmetic outcome and should be considered in those with small nodules that are unlikely to destroy vital structures..

A case report of cetirizine (10mg/day for 1-2 months) is of interest and this treatment is worth trying before undergoing excision or radiation therapy.

Radiation should be considered for patients who are resistant to steroids and for young patients in whom the long-term side effects of steroids may be more deleterious than a limited course of radiation.

Patient Management

Although there is no potential for malignant transformation of Kimura’s disease, patients should be monitored for the side effects of treatment choices and the aforementioned associated conditions. In addition, many patients may relapse or become refractory to steroid therapy, therefore long-term follow-up is necessary.

An MRI of the head and neck can be used to evaluate for the presence of the disease. MRI is more specific than CT scan.

Otolaryngology and ophthalmology evaluations should be done at the time of diagnosis. If there is any abnormality on urinalysis, a nephrology consult is required. Repeating urinalysis every 3-4 months is reasonable to monitor for renal disease. Proteinuria is a reason for nephrology consultation.

Lastly, a biopsy should be performed, as it is important to rule out malignancy.

Unusual Clinical Scenarios to Consider in Patient Management

Although nephropathy is rarely associated with Kimura’s disease, it is important to rule it out with a urinalysis and a 24-hour urine protein excretion analysis if the urinalysis is abnormal. Appropriate referral to a nephrologist is required, and other diagnostic studies (creatinine clearance and kidney biopsy) may be necessary. Since patients can readily respondto steroids, which prevent progression of renal disease, it is important to recognize this rare association.

There are no clear explanations for why kidney disease occurs in these patients, but there are theories. The first theory is that the kidney is an innocent bystander to an aberrant immunological/allergic reaction, with deposition of antigen-antibody complex within the organ. The second theory is that the abnormal Th2 response drives an imbalance of autoantibodies, some of which erroneously recognize self antigen, in this case renal tissue, as abnormal, causing damage.

Along the same lines, some propose an excessive immunological reaction to a foreign stimulus such as an arthropod reaction in a predisposed individual setting off a cascade of autoantibody production. To date, no infectious etiology has been found.

Kidney biopsies have shown mesangioproliferative glomerulonephritis (MPGN), minimal-change disease, and focal segmental glomerulosclerosis. MPGN is the most common form of kidney disease seen in Kimura’s disease.

In addition, although this condition is seen mostly in Asian men, there have been cases reported in non-Asian men.

Some authors have used the term angiolymphoid hyperplasia with eosinophilia (AHLE) as a synonym for Kimura’s disease. It is this author’s opinion that they are two distinct entities. ALHE is typically seen in middle-aged women and is more superficial in location, whereas Kimura’s disease is seen predominately in young Asian males, and is found deeper in the dermal and subcutaneous tissues.

Most cases involve the head and neck region, but it has been reported in the groin, axilla, and extremities.

What is the Evidence?

Sud, K, Saha, T, Kakkar, N. “Kimura's disease and minimal-change nephrotic syndrome”. Nephrol Dial Transplat. vol. 11. 1996. pp. 1349-51. (This interesting case report showed a Kimura's disease associated with minimal-change disease that responded to steroid treatment.)

Friedmann, I. “Pathological lesions of the external auditory canal”. J Royal Soc Med. vol. 83. 1990. pp. 34-7. (This review of the histopathological features of various external auditory meatus diseases discusses some of the distinguishing features between Kimura's disease and angiolymphoid hyperplasia with eosinophilia [ALHE].)

Jani, A, Coulson, M. “Kimura's disease: a typical case of a rare disorder”. West J Med. vol. 166. 1997. pp. 142-4. (An excellent case report and review of a patient with Kimura's disease, refractory to steroid treatment, successfully treated with surgical excision)

Itami, J, Arimizu, N, Miyoshi, T, Ogata, H, Miura, K. “Radiation therapy in Kimura's disease”. Acta Oncol. vol. 28(4). 1989. pp. 511-4. (A case series of ten patients with Kimura's disease, refractory to steroid therapy, successfully treated with radiation)

Googe, PB, Haris, NL, Mihm, MC. “Kimura's disease and angiolymphoid hyperplasia with eosinophilia: two distinct histopathological entities”. J Cutan Pathol. vol. 14. 1987. pp. 263-71. (An excellent case series review that shows the histopathological distinctions between Kimura's disease and angiolymphoid hyperplasia with esosinophilia)

Kimura, T, Yoshimura, S, Ishikawa, E. “Unusual granulomata combined with hyperplasia changes in lymphatic tissue”. Trans Soc Pathol Jpn. vol. 13. 1948. pp. 179-80. (The first description of Kimura's disease in the Japanese literature)

Ben-Chetrit, Amir, G, Shalit, M. ” Cetirizine: an effective agent in Kimura's disease”. Arthritis & Rheumatism . vol. 53. 2005. pp. 117-8. (A short case report of a patient responding to therapy with cetirizine)

Chen, H, Thompson, LD, Aguilera, NS, Abbondanzo, SL. “Kimura's disease: a clinicopathologic study of 21 cases”. American J Surg Pathol. vol. 28. 2004. pp. 505-13. (A nice review of the clinical and histological characteristics of twenty-one patients with Kimura's disease)

Briggs, PL. ” Kimura disease is not angiolymphoid hyperplasia with eosinophilia: clinical and pathological correlation with literature review and definition of diagnostic criteria”. An Bras Dermatol. vol. 2. 2006. pp. 167-73. (Wonderful comparison of Kimura's and ALHE. Both clinical and histological characteristics are discussed in detail.)

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