Kimura disease (KD) is a chronic progressive immune disease of unknown origin involving superficial lymph nodes and soft tissues of the head and neck, and is a rare disease. The cause of the disease is still unknown. The main clinical manifestations of the disease are painless subcutaneous soft tissue masses in the head and neck, frequent involvement of large salivary glands and peripheral lymph nodes, and increased peripheral blood eosinophils and serum immunoglobulin E. Histopathology is characterized by lymphocytic infiltration. Histopathology is characterized by lymphocytic infiltration, vascular hyperplasia and local eosinophilic infiltration. Lesions with asymptomatic and non-invasive appearance can be temporarily observed. Current treatments include surgery, drug therapy and radiation therapy.
1 Introduction
Kimura disease (KD) is a chronic progressive immune disease of unknown origin involving superficial lymph nodes and soft tissues of the head and neck [1, 2]. Kimura disease was first described in 1937 by Kim Hyeonjae [3] and seven other cases under the name of “eosinophilic lymphogranuloma”, and was systematically described in 1948 by Kimura et al [4], who later called it Kimura disease internationally. The main clinical manifestations of the disease are painless subcutaneous soft tissue masses on the head and neck, frequent involvement of large salivary glands and peripheral lymph nodes, and increased peripheral blood eosinophils and serum immunoglobulin E.
2 Epidemiology
Young and middle-aged men are more commonly seen than women, with 70% of patients aged 20-50 years, and Kugn et al [5] reported a median age of 28 years. The male to female ratio is about 4 to 7:1, and some literature reports that the male to female ratio can be as high as 6 to 10:1. The exact prevalence is unknown.
Kimura disease is prevalent in Asian populations and has been reported in the Western literature, but most are still of Asian descent, with a low incidence in other ethnic groups. However, a retrospective analysis [5] of 21 patients diagnosed with Kimura disease by histopathology at the U.S. Army Institute of Pathology found the following racial distribution: 7 white, 6 black, 6 Asian, 1 Hispanic, and 1 Arab. Therefore, if the disease is clinically suspected, a clinical differential diagnosis should be made in patients of any race.
3 Etiology
The etiology of this disease is unclear. It may be related to autoimmunity, allergy, tumor, insect bite or parasitic infection. So far, these theories have not been confirmed.
The pathogenesis of the disease is unclear, but it has been hypothesized that it may be due to the induction of IgE-mediated type I metaplasia by certain antigens or alteration of the immunoregulatory role of T cells, which leads to the release of lymphokines [6]. There is some evidence that TH2 cells can play a role, but more in-depth studies are still needed.
4 Pathology
Pathologically, the masses have no perithelium and are not clearly demarcated from the surrounding tissue. Microscopically, a large number of capillaries were seen, and the endothelial cells of the vessels were swollen and proliferated significantly, resulting in thickening of the vessel wall and even lumen obstruction. In the endothelial hyperplasia area, there is a large number of lymphocytes and eosinophils infiltration, lymphoid follicle formation, and sometimes the formation of a germinal center, a large number of eosinophils can be found, and there are small blood vessels and fibrous tissue proliferation [7]. The eosinophils are densely packed and form limited foci of “eosinophilic microabscesses”. The lymphatic follicles in the affected lymph nodes are actively proliferating, the growth centers are enlarged, and eosinophils infiltrate the cortex, medulla, and subepithelium; in severe cases, the lymph node structure disappears, and lymph nodes with discontinuous growth centers may be seen extending from the reticular dermis to the fascial and muscular layers.
There are no specific changes in the epidermis of the lesion, and infiltration of lymphocytes and eosinophils can be seen around the blood vessels in the upper and middle dermis. Most of the pathology has many lymphoid follicle-like structures and eosinophil infiltration, small blood vessels can be dilated, and fat septa and fat lobules are heavily infiltrated with eosinophils.
Capillary hyperplasia is not its characteristic change. However, when it is present, the proliferating vessels are masses of canalized vessels with flat endothelial cells, without vacuoles, epithelioid or histiocytic cells, often with lymphoid follicles, active germinal centers are often seen, and interstitial fibrosis is common.
5 Clinical manifestations
The duration of the disease is usually long, in some cases up to 10 years or more. The main clinical manifestations are subcutaneous swelling of the head and neck (76%), local lymph node involvement (31%), parotid and mandibular gland involvement (43%), and renal involvement (12%-16%).
5.1 Subcutaneous masses: The most common clinical manifestation is multiple soft tissue masses, mainly painless masses, mostly without conscious symptoms, often located in the maxillofacial region, especially in the parotid region. The masses have unclear borders and are mostly large, deep subcutaneous masses, even involving muscles, which can adhere to the skin and have poor mobility, with a diameter of 1 to 10 cm. However, the surface skin is generally normal. 40% to 100% have pruritus and hyperpigmentation, mostly in the skin of the mass [8]. Local lymph node enlargement is often associated.
Other manifestations include single or multiple subcutaneous nodules, which are also usually located mainly on the head or neck, especially in the peri-auricular, parotid, or mandibular regions. The eyelids, orbits, and lacrimal glands may also be involved, but this is rare. Masses in the extremities have also been reported [9].
5.2 Local lymph node involvement: In more than half of the cases, in addition to the subcutaneous masses, there is concurrent invasion of the lymph nodes and other sites, such as the oral cavity, axilla, groin, and trunk. Patients may present with independent enlarged painless lymph nodes or lymphadenopathy without significant features. There may be no subcutaneous soft tissue changes. Although Kimura disease predominantly affects the head and neck, extremity and inguinal lymph node involvement has also been reported.
5.3 Parotid and mandibular gland involvement: A common clinical manifestation, which may be unilateral in onset. There are also cases of bilateral parotid painless masses with a history of more than 13 years [10].
5.4 Renal involvement: as the disease progresses, some patients may have a combination of renal injury after several months, mainly manifesting as nephrotic syndrome, and membranous lesions are most common, with proteinuria in 12%-16% [1]. However, the relationship between the two is unknown.
6 Laboratory and ancillary tests
6.1 Blood tests: 98% of patients have elevated peripheral blood eosinophils and elevated serum immunoglobulin E. Serum urea nitrogen (BUN), creatinine (Cr) and urine protein levels should be checked to exclude combined impaired renal function or nephrotic syndrome.
6.2 CT scan or MRI: It can help to understand the extent of lesion involvement. CT shows diffuse enlargement of the parotid gland with poorly defined masses and involvement of subcutaneous tissues, and bead-like lymph nodes are often seen around the parotid gland, submandibular and deep upper neck. There is no specific manifestation of disease imaging, and enhanced scans can enhance both the lesion tissue and the involved lymph nodes, but there is generally no bone destruction, unlike malignant masses.
6.3 Pathological examination: The clinical diagnosis of this disease depends on the pathological examination of the specimen to determine. Histopathology is characterized by lymphocytic infiltration, vascular hyperplasia and local eosinophilic infiltration.
7 Differential diagnosis
Kimura disease should be differentiated from the following diseases.
7.1 Angiolymphoid Hyperplasia with Eosinophilia (ALHE): ALHE is seen in various ethnic groups and is more common in young and middle-aged women, with a variable duration, chronic or self-limiting, and may subside, recur or persist for many years, but no malignancy has been reported.The cause of ALHE is not yet clear. The clinical manifestations are diverse, and are usually found on the skin of the head and neck, with sites around the ear and forehead, and occasionally involving the trunk and extremities, etc. It is easy to misdiagnose and miss the diagnosis. Clinically, the possibility of this disease should be considered for head and neck swellings, especially for light red to brownish red papules, plaques or subcutaneous nodules, and the diagnosis finally relies on characteristic pathological changes.
The characteristic pathological features of ALHE are: marked vascular hyperplasia, epithelioid or histiocytic endothelial cells with large nuclei, vacuoles within the eosinophilic cytoplasm, thickening of the vessel wall, thrombus formation within the vessel, overproliferation of endothelial cells that may cause obstruction or disappearance of the lumen, variable numbers of eosinophils and lymphocytes, perivascular or diffuse infiltration, no eosinophilic abscesses, few lymphoid follicles and active The lymphatic follicles and active germinal centers are rarely seen, and interstitial fibrosis is rare.
ALHE and Kimura disease were previously considered to be the same disease, but are now considered to be clinically and histologically distinguishable as two separate disorders; ALHE may represent an anatomic abnormality secondary to inflammation of the arteriovenous vessels, whereas Kimura disease may represent a primary inflammatory process secondary to vascular proliferation. Case reports of the coexistence of these two disorders have recently been reported [11].
7.2 Cylindroma (Cylindroma): also known as turban tumor, is a tumor originating from the sweat gland and is often multiple. It occurs most frequently in females, with a female to male ratio of 2:1. Several individuals in a family can be affected. It occurs on the scalp. The tumor is a hemispherical nodule of variable size, from a few millimeters to several centimeters in diameter, pink or red in color, with a smooth surface and a hard, tough texture. Multiple nodules resemble multiple small tomatoes and sometimes cover the entire scalp. There is no hair on the nodules or only very sparse hair is present. They grow slowly and are usually asymptomatic, but may be painful. Cylindromas are benign and are often complicated by hair epithelioma. Malignant changes are rare. Histopathology shows well-defined tumors without envelope, located in the dermis. The tumor lobules consist of fasciculated or cylindrical basophilic epithelial cell masses surrounded by a hyaline membrane. The nuclei of the cells at the center were large and lightly stained, ovoid; the nuclei of the peripheral cells were small, basophilic and densely stained, round, and the peripheral cells were arranged in a fenestrated pattern.
7.3 Kaposi’s sarcoma (Kaposi’s sarcoma): a relatively rare malignant tumor in elderly men. About 30% of people diagnosed with AIDS in North America and Europe have this sarcoma. Kaposi’s sarcoma occurs in multiple lesions and is usually first found in the skin of the lower extremities as a hard, slightly elevated nodule that gradually expands in all directions and becomes purple in color. The skin and mucosal lymph nodes in the upper gastrointestinal tract are the most common sites of development, followed by progressive invasion of the liver, spleen, intestines, brain, lungs, pancreas and testes. Once Kapozi’s sarcoma occurs, it mostly dies in 1 to 1.5 years. If an opportunistic infection occurs at the same time, the death of the patient is accelerated.
In addition, Kimura disease should be associated with Dermatofibrosarcoma Protuberans, Pyogenic Granuloma, Eosinophilic granuloma, Lymphoma, Mikulicz disease Mikulicz disease, Nodal metastasis, Reactive lymphadenopathy, Salivary gland tumor are distinguished.
8 Treatment
Asymptomatic and non-invasive lesions can be temporarily observed. At present, treatment mainly includes surgery, drug therapy and radiation therapy.
8.1 Surgical treatment: Clinically, single local tumor is usually resected surgically first, because it is easy to recur after resection, and the recurrence rate can be as high as 40%. Most people believe that adding low-dose radiotherapy after surgery or combined application of glucocorticoid therapy after surgery obviously improves the cure rate.
8.2 Drug therapy: The goal of drug therapy is to reduce the disease state and reduce comorbidities.
Immunosuppressants suppress the immune system’s response to different stimuli.
Cyclosporine (CsA) was shown to be helpful in various skin manifestations [12-14].The mechanism of action of CsA is divided into immune-mediated and non-immune-mediated. It can suppress some humoral immunity and mainly cell-mediated immune responses, such as delayed cutaneous allergic reactions, allograft rejection, experimental allergic meningitis, and graft and host disease in different organs. The application of cyclosporine in patients who have undergone surgery or radiotherapy may maintain eosinophils in the normal range and reduce relapses. In adults, the dose is 3-5 mg/kg/d based on ideal body weight.
Cyclophosphamide has been reported to cause remission in patients with Kimura disease. However, in most cases, the lesions relapse after cessation of treatment.
Intra-lesion injections or oral steroids can shrink the nodules, but rarely cure the disease. Prednisone reduces the degree of inflammation by reversing increased hair cell permeability and inhibiting the activity of peripheral blood mononuclear cells. The starting dose for adults is 60 mg/d orally, decreasing by 10 mg weekly for 6 weeks. Inflammatory dermatitis is treated with Triamcinolone, which decreases the degree of inflammation due to inhibition of polymorphonuclear leukocytes and reversal of capillary infiltration. For local inflammatory lesions, intra-focal injections may be useful. The adult intra-focal injection dose is 0.3 mL (concentration of 5-10 mg/mL , i.e., a total dose of 1.5-3 mg). The dose for children <12< span=""> years of age is undetermined, and children >12 years of age may be administered as adults.
Hemorheologic agents (Pregnancy
Hemorheologic agents are primarily used to treat vascular diseases. Pentoxifylline may alter the rheological capacity of red blood cells, thereby reducing the viscosity of the blood. Oral administration of hexoketococine has been reported to be effective in Kimura disease, but relapsed after discontinuation of the drug [15]. Adults are given 400 mg twice daily with meals (based on a single case reported by Hongcharu et al.)
Vitamin A-like (Pregnancy
Retinoids): these agents regulate cell growth and differentiation. One case reported remission with trans-retinoic acid in combination with prednisone, but no recurrence within 12 months after discontinuation [16]. Adults were given 45 mg/m2/d orally in two divided doses (based on a single case report by Boulanger).
In the presence of renal damage, corticosteroids and immunosuppressive agents may be used. However, recurrence is also common after discontinuation of the drug.
8.3 Radiation therapy: Given the benign nature of Kimura disease, radiation therapy is generally used only for recurrent, or persistent, lesions with cosmetic damage. It is also believed that the lesion tissue is more sensitive to radiotherapy and can be used for those who are not suitable for surgery, or applied preoperatively or postoperatively to reduce the size of the mass, facilitate surgery and reduce recurrence. It is also believed that among all treatment methods, radiation therapy is the most effective, and the best treatment is 26 Gy-30 Gy for 2-3 weeks with conventional split dose, and the irradiation field includes the lesion and swollen area, and recurrence is rare if the dose is >26 Gy [17]. Hareyama et al [18] reported that treatment with a radiation dose of 26-30 Gy resulted in a control rate of 74% with local therapy.