INTRODUCTION — Once thought to be the same disorder, angiolymphoid hyperplasia with eosinophilia (ALHE) and Kimura disease are now considered to be distinct disorders both clinically and histologically (table 1) [1-3]. However, features of both diseases have been observed to overlap in some patients [4,5].

ALHE is an uncommon, benign vasoproliferative disorder of unclear etiology that presents with solitary or multiple, pink to red-brown, dome-shaped papules or nodules, most frequently located in the head and neck region (picture 1). First described in 1969, ALHE has also been called "epithelioid hemangioma," "histiocytoid hemangioma," "inflammatory angiomatous nodule," "intravenous atypical vascular proliferation," "papular angioplasia," "inflammatory arteriovenous hemangioma," and "pseudopyogenic granuloma" [6,7].

Kimura disease is a rare, chronic inflammatory disorder of unknown etiology characterized by the development of subcutaneous lymphoid masses, usually in the head and neck region; regional lymphadenopathy; peripheral eosinophilia; and elevated levels of serum immunoglobulin E (IgE) (picture 2) [8]. It has been described in China and Japan as "eosinophilic hyperplastic lymphogranuloma" or "atypical granulation associated with hyperplastic abnormalities in the lymphoid tissue" [8,9].

This topic will discuss the clinical manifestations, diagnosis, and treatment of ALHE and Kimura disease. Other diseases associated with tissue and peripheral eosinophilia are discussed separately.

●(See "Eosinophilic cellulitis (Wells syndrome)".)

●(See "Eosinophil biology and causes of eosinophilia".)

●(See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis".)

ANGIOLYMPHOID HYPERPLASIA WITH EOSINOPHILIA

Epidemiology — The prevalence and incidence of angiolymphoid hyperplasia with eosinophilia (ALHE) are unknown. ALHE occurs in patients of all ages with a peak incidence in the second to fourth decades of life (mean age of 38 years); six percent of cases occur in children [10]. Overall, there is no sex predilection. ALHE has been reported most commonly and with similar frequency in Asian and White persons, with less than five percent of cases reported in Black persons [10].

Pathogenesis — The pathogenesis of ALHE is unknown. Several hypotheses have been suggested, including:

●Reactive process, triggered by prior trauma [11-13]; infection (human T-lymphotropic virus, human herpes virus 8, human polyomavirus 6) [12,14-16]; insect bites [6]; tetanus toxoid vaccine [17].

●Neoplastic vasoproliferative process (ie, a benign vascular tumor) [18,19].

●Atopic reaction [17].

●CD4 T cell lymphoproliferative disorder with T cell receptor gene rearrangement and monoclonality [20,21].

●Infectious process, with possible association with HIV [22].

●Hormonal imbalance associated with pregnancy, oral contraceptive use, and elevated serum estrogen levels. There are several reports of association between hyperestrogenic states and onset or progression of ALHE, with conflicting results of histologic staining for estrogen and progesterone receptors [14,23-25].

●Arteriovenous malformation or shunting [12,14,26].

None of the above-mentioned triggers or mechanisms have been definitively proven nor have they been shown to consistently impact the clinical presentation or prognosis of ALHE.

Clinical manifestations — ALHE typically presents with pink to red-brown, firm, dome-shaped papules or nodules (picture 1). Lesions can also display scaling, ulceration, and/or bleeding. Lesions are single in approximately one-half of the cases [10]. When multiple lesions occur, they typically cluster in the same body region, although multifocal distributions have been reported [27].

In a systematic review of published cases and cases series including 908 patients, the most common locations for ALHE were the ear (36 percent), particularly the postauricular area (14 percent), face (28 percent), and scalp (17 percent) [10]. However, ALHE can affect virtually any region of the body, including the extremities and genitals [10].

Rare extracutaneous cases of ALHE affecting the orbit [28-30], oral mucosa [31], colon [18,32], and bone [33,34] have also been reported. Regional lymph node involvement rarely occurs in ALHE but is present in nearly all patients with Kimura disease [35-37].

In most patients, ALHE lesions are asymptomatic. Itching, bleeding, or pain have been reported in 37, 25, and 20 percent of patients, respectively, and are more likely to occur in patients with multiple lesions [10].

Peripheral eosinophilia occurs in up to 20 percent of patients with ALHE [14]. Elevated serum immunoglobulin E (IgE) levels are not a feature of ALHE but are more commonly present in Kimura disease [1]. (See 'Kimura disease' below.)

Pathology — ALHE is histologically characterized by a predominant vascular component and by an inflammatory infiltrate. The vascular component comprises thick- and thin-walled vessels lined by plump endothelial cells [38]. These cells also occur in clumps that appear solid or sometimes contain small lumina. They are epithelioid-like, with a large vesicular nucleus and abundant eosinophilic or clear cytoplasm, and are characteristic of ALHE [6,12,14,39]. Mitoses and atypia are typically not present.

Associated with the vascular and endothelial proliferations is a stromal diffuse infiltrate composed predominantly of B and T lymphocytes, with variable numbers of eosinophils. Plasma cells and mast cells are also present. The infiltrate may occasionally form distinct follicles with reactive germinal centers. The stroma may be fibrous or myxoid in character.

Diagnosis — The diagnosis of ALHE is based upon the recognition of consistent clinical findings (ie, erythematous, dome-shaped papules and nodules, most often located on the scalp or on the ear and periauricular area (picture 1)) and the identification of characteristic histopathologic findings on a lesion biopsy. (See 'Pathology' above.)

A large punch biopsy or excisional biopsy deep to the dermal and subdermal component are appropriate for diagnosis. Standard hematoxylin and eosin staining is typically adequate for identification of the characteristic histologic findings and distinction between ALHE and Kimura disease. Immunohistochemistry and special stains are generally not required.

Histochemically, endothelial cells of ALHE are positive for nonspecific esterase, acid phosphatase, succinic dehydrogenase, cytochrome oxidase, nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase, and present faint or absent alkaline phosphatase activity [40]. None of these markers, however, are specific to ALHE.

Differential diagnosis — The differential diagnosis of ALHE includes Kimura disease and a broad range of skin lesions that may share clinical features with ALHE [4,5,39,41-46]. In most cases, a skin biopsy and careful clinicopathologic correlation lead to the correct diagnosis.

The differential diagnosis between ALHE and Kimura disease is summarized in the table (table 1). (See 'Kimura disease' below.)

Examples of other conditions that may be considered in the differential diagnosis of ALHE are:

●Cylindroma – Cylindromas are slow-growing, benign tumors that often present on the head and neck as red, pink, or bluish papules and nodules, ranging from a few millimeters to several centimeters in size (picture 3A-B). Histologically, cylindroma consists of small aggregations of basaloid keratinocytes closely opposed to one another in a pattern resembling interconnecting pieces of a jigsaw puzzle. (See "Cutaneous adnexal tumors".)

●Kaposi sarcoma – Kaposi sarcoma (KS) is an angioproliferative disorder that requires infection with human herpes virus 8 that occurs in four epidemiologic forms (ie, AIDS-related, endemic or African, organ transplant-associated, classic). Cutaneous lesions of KS appear as red, brown, or purple patches, plaques, or nodules (picture 4). A skin biopsy demonstrating dermal proliferation of interlacing bundles of spindle cells with variable nuclear polymorphism and poorly defined, slit-like vessels and an associated inflammatory infiltrate composed of lymphocytes and plasma cells is diagnostic. (See "Classic Kaposi sarcoma: Epidemiology, risk factors, pathology, and molecular pathogenesis" and "AIDS-related Kaposi sarcoma: Clinical manifestations and diagnosis".)

●Bacillary angiomatosis – Bacillary angiomatosis is caused by infection with Bartonella henselae or Bartonella quintana and usually occurs in HIV-infected or immunocompromised patients. It presents with red or purple papules and nodules often located on the face or extremities (picture 5A-B). Histologic examination shows lobular vascular proliferations of vessels lined by plump endothelial cells with clusters of neutrophils and lymphocytes; Warthin-Starry stain demonstrates clumps of small pleomorphic bacilli. (See "Epidemiology and clinical manifestations of Bartonella infections in persons with HIV", section on 'Bacillary angiomatosis'.)

●Pyogenic granuloma – Pyogenic granuloma, also called lobular capillary hemangioma, is a benign vascular tumor of the skin characterized by rapid growth over weeks to months and a friable surface that bleeds profusely after minor trauma (picture 6). Histologically, there is a proliferation of capillary vessels with stromal edema and a mixed inflammatory infiltrate. (See "Pyogenic granuloma (lobular capillary hemangioma)".)

●Insect bite reaction – Chronic reactions to insect or arthropod bites, including nodular scabies (picture 7), are histologically characterized by a dense inflammatory infiltrate of lymphoid cells and histiocytes, with an admixture of eosinophils and plasma cells and atypical mononuclear cells with hyperchromatic nuclei. A history of exposure and the presence of symptoms (eg, intense pruritus) may help in differentiating these lesions.

●B cell pseudolymphoma and T cell pseudolymphoma – B cell pseudolymphoma and T cell pseudolymphoma represent reactive, localized lymphoproliferative responses to a variety of antigenic stimuli, including arthropod bites, Borrelia infection (Borrelia lymphocytoma), metal implants, metal pierced earrings, tattoo dyes, and drugs. They present as solitary or multiple, skin-colored or red nodules or plaques, preferentially located on the face or chest (picture 8A-C). Histologically, B cell pseudolymphoma shows a mixed infiltrate of small lymphocytes, histiocytes, eosinophils, and plasma cells, often with formation of lymphoid follicles; polymerase chain reaction analysis for Borrelia DNA is positive in Borrelia lymphocytoma cutis. T cell pseudolymphoma shows a diffuse or nodular infiltrate composed of small to medium-sized CD4⁺ T lymphocytes. (See "Cutaneous B cell pseudolymphomas" and "Cutaneous T cell pseudolymphomas".)

●Primary cutaneous B cell lymphomas – Primary cutaneous follicle center lymphoma (picture 9) and, less frequently, primary cutaneous marginal zone lymphoma may present with solitary or clustered papules and nodules on the head and neck. In contrast to the cutaneous pseudolymphomas, the primary cutaneous B cell lymphomas often show immunoglobulin heavy chain (IgH) gene rearrangement and atypical-appearing B cells. (See "Primary cutaneous follicle center lymphoma" and "Primary cutaneous marginal zone lymphoma".)

●Primary cutaneous acral CD8⁺ T cell lymphoma – Primary cutaneous acral CD8⁺ T cell lymphoma is a new provisional entity in the World Health Organization (WHO) 2016 classification of the cutaneous T cell lymphomas. This cutaneous lymphoma often presents with a solitary, painless nodule on the ear (picture 10) or, less frequently, the nose and distal extremities [47]. (See "Primary cutaneous T cell lymphomas, rare subtypes", section on 'Primary cutaneous acral CD8+ T cell lymphoma'.)

●Cutaneous angiosarcoma – Cutaneous angiosarcoma is a rare, malignant vascular tumor that occurs most frequently in older individuals [48,49]. The face and scalp are common sites of involvement (picture 11). Histologically, abnormal, pleomorphic, malignant endothelial cells are the hallmark of angiosarcoma and can be rounded, polygonal, or fusiform and have an epithelioid appearance; in well-differentiated areas, abnormal endothelial cells form functioning vascular sinusoids continuous with normal vascular channels [48].

●Epithelioid hemangioendothelioma – Epithelioid hemangioendothelioma (EHE) is a rare, malignant soft tissue tumor of endothelial origin characterized by indolent clinical behavior [50,51]. Cutaneous EHE presents as an asymptomatic, erythematous papule, nodule, or plaque, most often located on the limbs. Histopathologically, EHE consist of a poorly circumscribed neoplasm with infiltrative growth pattern composed of cords or solid aggregates of ovoid, cuboidal, or short spindle cells with an abundant eosinophilic cytoplasm [51].

Treatment — There is no consensus regarding the optimal treatment for ALHE. Therapeutic options include surgical excision, destructive therapies (eg, laser therapy, cryotherapy, radiation therapy, electrosurgery), and medical therapies, such intralesional and systemic corticosteroids, systemic antibiotics, oral isotretinoin, oral pentoxifylline, and methotrexate [10]. However, none of these treatments has been evaluated in randomized trials, and limited evidence of efficacy is derived from case reports and small case series.

Surgical excision is in most cases the preferred treatment modality for ALHE. In a review of 593 patients with ALHE for whom information on treatments and outcomes was available, 44 percent of patients were treated with surgical excision [10]. Recurrence was reported in approximately 40 percent of cases, after a mean time of four years.

Laser therapy and radiation therapy have been used in a small number of patients with success rates similar to surgical excision [10]. Intralesional, topical, and systemic corticosteroids, cryotherapy, electrosurgery, systemic antibiotics, argon laser, oral isotretinoin, topical antibiotics, oral dapsone, and oral pentoxifylline have all been tried in ALHE with treatment success rates ranging from 0 to <35 percent [10]. There are a few reports of successful use of propranolol for ALHE, alone or in combination with surgical excision [28,52,53].

Prognosis and follow-up — The overall prognosis of ALHE is good. However, recurrences are common with all treatment modalities. Predictors of recurrence after surgical excision include younger age of disease onset, longer disease duration, presence of multiple lesions, and symptomatic lesions [10]. Spontaneous resolution has been reported in only three percent of cases [10].

Patients with ALHE should undergo periodic clinical examination for disease recurrence, development of multiple lesions, and development of symptoms (eg, pruritus, pain, bleeding lesions).

KIMURA DISEASE

Epidemiology — The precise prevalence and incidence of Kimura disease are unknown. It occurs predominantly in young men of Asian descent, with a peak incidence in the second and third decade of life [54-58]. However, Kimura disease has been also reported in other ethnic groups and in young children [56,58,59].

Pathogenesis — The pathogenesis of Kimura disease is unknown. Trauma, infection, an immunoglobulin E (IgE)-mediated hypersensitivity reaction, or an autoimmune process have been postulated as possible causes.

Clinical manifestations — The classical presentation of Kimura disease is a painless, subcutaneous nodule or mass 1 to 7 cm in diameter located in the head and neck region and, in most cases, accompanied by regional lymphadenopathy (picture 2) [1,35-37,56]. Isolated lymphadenopathy can be the initial presentation in some patients.

Extracutaneous sites of involvement include the parotid, orbit, oral cavity, and nasal sinuses [60-62]. Systemic symptoms are usually absent.

Laboratory tests show peripheral blood eosinophilia and elevated serum IgE levels in virtually all patients [35-37].

Renal disease, including minimal change disease, mesangial proliferative glomerulonephritis, and membranous nephropathy, has been reported in approximately 20 percent of patients and approximately 12 to 16 percent develop nephrotic syndrome [1,63-67]. Some patients may have proteinuria before the onset of skin lesions [68].

Pathology — Kimura disease lesions usually display a dense inflammatory infiltrate composed of lymphocytes, plasma cells, histiocytes, and eosinophils with eosinophilic microabscesses, multiple lymphoid follicles with germinal centers, presence of IgE in germinal centers, and dermal sclerosis [1,39,69]. The vascular component is less prominent than in angiolymphoid hyperplasia with eosinophilia (ALHE) and consists of hyperplastic small blood vessels lined by endothelial cells that are flat or cuboidal without the epithelioid or histiocytoid appearance as in ALHE [1,3]. Stromal fibrosis is seen in virtually all cases.

Histopathologic features of the regional lymph nodes include preserved nodal architecture; follicular hyperplasia with reactive germinal centers and well-formed mantle zones; IgE deposition in the germinal centers; eosinophilic infiltrates in interfollicular areas, sinusoid, and perinodal soft tissue; and proliferation of postcapillary venules [70]. Stromal fibrosis is also seen in lymph nodes.

Immunohistochemical studies revealed CD20⁺ germinal centers with prominent staining of CD23⁺ dendritic reticular cells, surrounded by numerous interfollicular CD3⁺, and CD4⁺ or CD8⁺ T cells, supporting the reactive nature of Kimura disease [71].

Diagnosis — The diagnosis of Kimura disease is based upon the clinical findings and the demonstration of typical histopathologic findings in a biopsy of the subcutaneous mass and/or enlarged lymph node. Computerized tomography (CT) and magnetic resonance imaging (MRI) may be useful to determine the size and depth of subcutaneous nodules and masses in Kimura disease and the involvement of surrounding tissues [60,72-74].

Urinalysis, blood tests for protein and albumin levels and kidney function, and a kidney biopsy may be performed to assess renal involvement in patients with signs and symptoms of nephrotic syndrome. (See "Overview of heavy proteinuria and the nephrotic syndrome".)

Differential diagnosis — The differential diagnosis of Kimura diseases is broad and includes ALHE and other malignant and nonmalignant conditions associated with peripheral lymphadenopathy. (See "Peripheral lymphadenopathy in children: Etiology" and "Evaluation of peripheral lymphadenopathy in adults".)

The clinical, laboratory, and histopathologic features of Kimura disease and ALHE are summarized in the table (table 1).

Examples of uncommon conditions that may enter the differential diagnosis of Kimura disease are:

●Unicentric Castleman disease – Unicentric Castleman disease (UCD) is a rare, asymptomatic lymphoproliferative disorder presenting in young adults with one or more enlarged lymph nodes in a single body region. Histologically, UCD is characterized by expansions of morphologically benign lymphocytes that usually leave the structure of the underlying lymph node at least partially intact. Histopathologic subtypes of UCD include hyaline vascular, plasma cell, or mixed. (See "Unicentric Castleman disease".)

●Eosinophilic granulomatosis with polyangiitis – Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) is a multisystem disorder characterized by chronic rhinosinusitis, asthma, and prominent peripheral blood eosinophilia. Most patients have skin lesions and tender, subcutaneous nodules on the extensor surfaces of the arm, particularly the elbows, hands, and legs (picture 12). Biopsy of these lesions usually reveals granulomatous inflammation, an eosinophilic infiltrate, and vasculitis of small and medium-sized vessels. (See "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)".)

●Toxoplasma lymphadenitis – In Toxoplasma lymphadenitis, the lymph nodes have large reactive follicles with well-developed germinal centers that are infiltrated by clusters of epithelioid histiocytes, as well as interfollicular collections of monocytoid B cells. Serology can confirm the diagnosis. (See "Toxoplasmosis: Acute systemic disease".)

●Hodgkin lymphoma – Hodgkin lymphoma (HL) is a B cell lymphoma with a bimodal peak incidence around age 20 and 65. Most patients with classic HL present with painless, localized, peripheral lymphadenopathy, typically involving the cervical region. Histopathologic examination of an involved lymph node shows the presence of diagnostic Reed-Sternberg cells in an inflammatory background containing a variable number of small lymphocytes, eosinophils, neutrophils, histiocytes, plasma cells, fibroblasts, and collagen fibers. (See "Hodgkin lymphoma: Epidemiology and risk factors".)

●Angioimmunoblastic T cell lymphoma – Angioimmunoblastic T cell lymphoma (AITL) is a peripheral T cell lymphoma usually presenting with the acute onset of a systemic illness and generalized lymphadenopathy. In rare cases, an asymptomatic, generalized lymphadenopathy is the presenting symptom. The diagnosis is established by a lymph node biopsy interpreted in the context of the clinical presentation. Histologic features include effaced nodal architecture, prominent arborizing high endothelial venules, and a polymorphous infiltrate of reactive lymphocytes, immunoblasts, plasma cells, and small to large atypical CD3⁺ and CD4⁺ lymphocytes. (See "Clinical manifestations, pathologic features, and diagnosis of angioimmunoblastic T cell lymphoma".)

Other uncommon causes of unexplained, persistent cervical or generalized lymphadenopathy in children and adults are discussed separately. (See "Peripheral lymphadenopathy in children: Etiology", section on 'Uncommon but important causes' and "Evaluation of peripheral lymphadenopathy in adults", section on 'Uncommon causes'.)

Treatment — The preferred initial treatment for localized Kimura disease is surgical excision. Other treatment approaches include surgical excision with postoperative low-dose radiation therapy, radiation therapy alone, and medical therapies [57,75,76].

Systemic immunosuppressive therapy with oral corticosteroids [77-80], cyclosporine [81-83], mycophenolate mofetil or mycophenolic acid [84,85], and leflunomide plus methylprednisolone [86] has been used in a limited number of patients with multifocal disease and in patients with associated nephrotic syndrome.

None of these treatments has been evaluated in randomized trials. Limited evidence of efficacy is based on small case series and single case reports.

Recurrence is common after any type of treatment. In a review of 25 cases of Kimura disease, recurrence occurred in 20 to 100 percent of patients after surgical and medical therapies [80]. A pooled analysis of 22 small case series including 570 patients with Kimura disease treated with surgical excision and/or radiation therapy found that patients treated with surgical excision alone had a fivefold higher risk of recurrence compared with patients treated with surgery followed by radiation therapy [75].

Prognosis and follow-up — The overall prognosis of Kimura disease is good. Spontaneous resolution has been reported in a single case report [87]. No cases of malignant transformation have been reported [5,88,89]. The prognosis for patients with associated renal involvement is variable, depending upon the form and severity of nephropathy. There is one report of remission of membranous nephropathy in a patient with Kimura disease after surgical excision of a left axillary mass [90]. (See "Overview of heavy proteinuria and the nephrotic syndrome".)

Patients with Kimura disease should be monitored for disease recurrence and development of renal disease.

SUMMARY AND RECOMMENDATIONS

●Angiolymphoid hyperplasia with eosinophilia (ALHE) and Kimura disease, once thought to be the same disorder, are now considered to be distinct disorders both clinically and histologically (table 1). (See 'Introduction' above.)

●ALHE is an uncommon, benign vasoproliferative disorder of unclear etiology that presents with asymptomatic, solitary or multiple, pink to red-brown, dome-shaped papules or nodules, most frequently located in the head and neck region (picture 1). (See 'Clinical manifestations' above.)

●ALHE is histologically characterized by a predominant vascular component comprised of thick- and thin-walled vessels lined by characteristic plump, epithelioid-like endothelial cells and by a stromal infiltrate predominantly composed of B and T lymphocytes with variable numbers of eosinophils, plasma cells, and mast cells. (See 'Pathology' above.)

●The diagnosis of ALHE is based upon the recognition of consistent clinical findings and the identification of characteristic histopathologic findings on a lesion biopsy. (See 'Diagnosis' above.)

●There is no consensus regarding the optimal treatment for ALHE. Surgical excision is in most cases the preferred treatment modality. Other therapeutic options include destructive therapies (eg, laser therapy, cryotherapy, radiation therapy, electrosurgery) and medical therapies (eg, intralesional and systemic corticosteroids, systemic antibiotics, oral isotretinoin). (See 'Treatment' above.)

●The overall prognosis of ALHE is good. However, recurrence is common. (See 'Prognosis and follow-up' above.)

●Kimura disease is a rare, chronic inflammatory disorder of unknown etiology occurring predominantly in young men of Asian descent. It is characterized by the development of subcutaneous lymphoid masses, usually in the head and neck region; regional lymphadenopathy; peripheral eosinophilia; and elevated levels of serum immunoglobulin E (IgE) (picture 2). Extracutaneous sites of involvement include the parotid, orbit, oral cavity, and nasal sinuses. Approximately 20 percent of patients develop renal disease and nephrotic syndrome. (See 'Clinical manifestations' above and 'Epidemiology' above.)

●The diagnosis of Kimura disease is based upon the clinical findings and examination of a biopsy of the subcutaneous mass and/or enlarged lymph node. Histologically, Kimura disease is characterized by a dense inflammatory infiltrate composed of lymphocytes, plasma cells, histiocytes, and eosinophils with eosinophilic microabscesses, multiple lymphoid follicles with germinal centers, presence of IgE in germinal centers, and dermal sclerosis. (See 'Diagnosis' above and 'Pathology' above.)

●The preferred initial treatment for localized Kimura disease is surgical excision. Other treatment approaches include surgical excision with postoperative low-dose radiation therapy, radiation therapy alone, systemic corticosteroids, and other immunosuppressive agents. (See 'Treatment' above.)

●The overall prognosis of Kimura disease is good, although the disease has a chronic, relapsing course. The prognosis for patients with associated renal involvement is variable, depending upon the form and severity of nephropathy. (See 'Prognosis and follow-up' above.)