Expression of the interleukin-21 and phosphorylated extracellular signal regulated kinase 1/2 in Kimura disease.

OBJECTIVE: To investigate the expressions of interleukin (IL)-21 and phosphorylated extracellular signal regulated kinase 1/2 (pERK1/2) in Kimura disease (KD) and to correlate the findings with clinical and prognostic variables. METHODS: Immunohistochemical analysis of IL-21 and pERK1/2 was performed in 18 cases of KD and five gender- and age-matched control samples. Clinical data were extracted and patients followed up for a mean period of 32.1 months. RESULTS: After a mean follow-up period of 32.1 months (range 1-102 months), recurrence was diagnosed as the end point for seven patients-that is, a 44% (7/16) cumulative recurrence rate. In comparison with gender- and age-matched controls, patients showed strong in situ expressions of IL-21 and pERK1/2, respectively (p<0.05). Patients with strong IL-21 staining intensity and overexpression of pERK1/2 had a lower recurrence rate than those with moderate staining intensity (p=0.049, p=0.019, respectively). However, differences were not statistically significant by gender, age, eosinophils, location, multiplicity, laterality, size, duration and primary outbreak. pERK1/2 was the independent prognostic factor (p=0.020), while age, gender, eosinophils, multiplicity, laterality, size, duration, primary outbreak and expression of IL-21 were not. CONCLUSIONS: This study suggests that the IL-21/pERK1/2 pathway is activated in KD, and pERK1/2 might be considered as a potential prognostic indicator in KD.

Angiolymphoid hyperplasia with eosinophilia developing within a port wine stain.

A 19-year-old male with a port wine stain on the base of his neck presented with a 5-month history of gradual thickening of the involved skin which interfered with clothing and caused repeated bleeding. The lesion was excised and histopathologic examination revealed angiolymphoid hyperplasia with eosinophilia (ALHE) arising from the pre-existing port wine stain - a rare finding with only one previously reported case. Additionally the lesion was associated with elevated serum renin levels which virtually normalized following excision of the lesion. We further demonstrated the expression of angiotensin converting enzyme and angiotensin II receptors 1 and 2 by the lesion and discuss the possible role of the renin-angiotensin system in this condition.

Increased expression of thymic stromal lymphopoietin and its receptor in Kimura's disease.

OBJECTIVE: The objective of this study was to investigate the expression of thymic stromal lymphopoietin (TSLP) and TSLP receptor (TSLPR) in Kimura's disease (KD). METHODS: Using parotid gland tissues from KD patients and control subjects, we quantified the expression levels of mRNA for TSLP, interleukin (IL)-25, IL-33, and their receptors by massively parallel sequencing. We also performed immunohistochemical analysis of TSLP and TSLPR, and counted cells immunoreactive for these proteins by the polymer immunocomplex and double immunofluorescence methods. RESULTS: The levels of mRNA for TSLP, TSLPR, and IL-25R, but not IL-25, IL-33, or IL-33R, were significantly elevated in parotid gland tissues from the KD group as compared to the control group. Immunohistochemical analysis revealed that TSLP- and TSLPR-positive cells were significantly increased in number in parotid gland tissues from KD patients. Double immunofluorescence staining showed that TSLP and TSLPR were localized mainly in CD68-positive macrophages and tryptase-positive mast cells, respectively. CONCLUSIONS: Overexpression of TSLP and TSLPR might contribute to the pathogenesis of KD through interactions between macrophages and mast cells. Regulation of TSLP/TSLPR signaling may be a potential therapeutic approach for KD.

[Expressions of interleukin-21 and interleukin-22 in Kimura's disease].

OBJECTIVE: To investigate the expressions of interleukin (IL)-21 (IL-21) and IL-22 in patients with Kimura's disease (KD). METHODS: Expressions of IL-21 and IL-22 were examined immunohistochemically in 36 patients with KD and 7 normal controls. The integral absorbance (IA) of the two groups was compared. Meanwhile, clinical data were reviewed. RESULTS: The IA of IL-21 [M(Q): 1 373 418 (1 800 926)] and IL-22 [M(Q): 462 086(484 672)] in KD was significantly higher than those in normal controls [M(Q): 70 445(44 658), 51 599(71 241), P < 0.05]. The overexpression of IL-21 was significantly associated with pruritus (Z = -1.993, P < 0.05). Moreover, IL-21 was identified for disease recurrence (Z = -2.303, P < 0.05). There was a significant association between the expression of IL-22 and the number of affected sites (Z = -1.979, P < 0.05). In addition, IL-22 was significantly higher in the high-eosinophils group than in the low-eosinophils group (Z = -2.025, P < 0.05). There was no association between IL-21, IL-22 and age, gender, laterality, maximum size. CONCLUSIONS: IL-21 and IL-22 may be involved in the pathogenesis of KD.

Notch-1 and Ki-67 receptor as predictors for the recurrence and prognosis of Kimura's disease.

Kimura's disease (KD) is a rare chronic disease with unknown origin. It remains controversial in KD's diagnosis, treatment, transformation and need further research. The aim of this study is to investigate the clinicopathologic features of KD and the relationship between the expression of Notch-1, Ki-67 receptor and the recurrence of KD. The hematoxylin and eosin sections and clinical data of 40 patients diagnosed with KD were examined retrospectively. Specimens were available in these 40 cases. Notch-1 and Ki-67 expression were examined using IHC (immunohistochemistry staining) analysis. Of 40 cases of KD (average age, 38.4 years; median age, 36.0 years), 34 cases (85.0%) were clinically seen to involve swelling of the head and neck region. Notch-1 and Ki-67 have a high expression in recurrent patients. High expression of Notch-1 receptor and Ki-67 tended to be found in patients who relapsed. This is the first study to discuss the correlation among Notch-1, Ki-67 and recurrent KD. These results suggest both of the markers may act as promising predictors for the recurrence and prognosis of KD. However, Notch-1 immunoexpression had no statistically significant association with the Ki-67 proliferation index.

Conjunctival angiolymphoid hyperplasia with eosinophilia in a child.

Angiolymphoid hyperplasia with eosinophilia is a rare benign vascular proliferation with lymphocytic and eosinophilic infiltrate. Angiolymphoid hyperplasia with eosinophilia presents as single or multiple dome-shaped papules or plaques involving the dermis and subcutaneous tissues of the head and neck region. Conjunctival angiolymphoid hyperplasia with eosinophilia is rare, with only two previous case reports.

Epithelioid hemangioma (angiolymphoid hyperplasia with eosinophilia) arising on the extremities.

BACKGROUND: Epithelioid hemangioma (EH) is a benign vascular proliferation usually accompanied by a mixed inflammatory infiltrate. METHODS: Skin biopsy specimens from four patients with EH on the extremities were studied. Architecture, extent of vascular proliferation and the presence of epithelioid endothelial cells were evaluated. The features of the inflammatory infiltrate were also assessed, including the distribution, depth, predominant cell type, presence of germinal centers, and distribution and number of CD30+ cells. RESULTS: All cases showed the typical lobular pattern of small vessels centered about a 'feeder' vessel. Larger vessels were lined by epithelioid endothelial cells. The mixed inflammatory infiltrate was nodular, perivascular and periadnexal. Germinal centers were seen in two cases. Large activated CD30+ lymphocytes were seen in all cases. CONCLUSIONS: EH can lead to diagnostic confusion with cutaneous lymphoma and other entities, especially when its mixed inflammatory infiltrate predominates over its vascular component and contains large activated CD30+ lymphocytes. Awareness that the presence of CD30+ activated lymphocytes is not specific for lymphoma and recognition of the vascular component is critical for proper diagnosis of EH.

D2-40 highlights lymphatic vessel proliferation of angiolymphoid hyperplasia with eosinophilia.

Angiolymphoid hyperplasia with eosinophilia (ALHE) is a benign, uncommon idiopathic condition, characterized by cutaneous papules or nodules, whose etiopathogenesis is still unclear. It has been considered an angioproliferating lesion (epithelioid hemangioma) since histologically it is marked by a proliferation of blood vessels, accompanied by an inflammatory infiltrate, consisting mainly of lymphocytes and eosinophils. We present a case of ALHE assessed immunohistochemically for D2-40-a new marker for lymphatic endothelial cells. A biopsy specimen obtained from the same anatomical area of a healthy individual served as a normal control. The ALHE specimen showed increased number of lymphatic vessels when stained for D2-40, whereas the endothelial cells lining blood vessels were negative. The specificity of D2-40 for lymphatic vessels was further substantiated by studying Factor VIII-related antigen expression in consecutive sections of both ALHE and the control specimen. A reverse pattern was appreciated-blood vessels showed Factor VIII positive labeling, whereas lymphatic endothelial cells remained unlabeled. We therefore assume that apart from the lymphocytic infiltrate in the lesion, the recognized lymphoid component in ALHE is due to lymphatic vessel proliferation as well. Hence, this condition may be considered as possibly derived from lymphatic endothelium.

Simultaneous presentation of Kimura disease and angiolymphoid hyperplasia with eosinophilia.

Kimura disease and angiolymphoid hyperplasia with eosinophilia are rare disease entities that can manifest as subcutaneous nodules, plaques, or papules of the head and neck, and less commonly the orbit and ocular adnexa. The merits of each entity have been debated with regard to whether they are truly individual or are separate points on a single spectrum. Current opinion favors the former. This clinicopathologic report of a patient who presented with a right lower eyelid mass with pathologic features consistent with Kimura disease and a left conjunctival mass with features consistent with angiolymphoid hyperplasia with eosinophilia poses a challenge to the notion that these are distinct conditions.

Angiolymphoid hyperplasia with eosinophilia showing prominent granulomatous and fibrotic reaction: a morphological and immunohistochemical study.

Angiolymphoid hyperplasia with eosinophilia is an uncommon condition that usually presents in early to middle-aged adults as multiple red nodules or plaques, most commonly on the head and neck. It can also occur on the trunk and limbs, and rarely at other sites such as the breast and oral mucosa. Although one-third of these lesions recur, surgical excision is curative. The histopathological hallmark is the presence of blood vessels with plump epithelioid endothelial cells. The nonvascular component consists of histiocytes, plasma cells, eosinophils, and lymphocytes. The occurrence of numerous giant cells in the stroma of angiolymphoid hyperplasia with eosinophilia is extremely unusual and such a finding in association with diffuse granulomatous/fibrous reaction has not been reported. We describe such a lesion that developed in the wrist of a 34-year-old pregnant female.

[Kimura disease and epithelioid hemangioma: a comparative study of 12 cases].

OBJECTIVE: To investigate the clinicopathologic features, immunophenotypes and differential diagnosis of Kimura's disease (KD) and epithelioid hemangioma (EH). METHODS: Nine cases of KD and three cases of EH were evaluated by light microscopy and immunohistochemistry. RESULTS: In this series, KD occurred predominantly in males, whereas EH had a female predilection. Both KD and EH arose most frequently in the head and neck region. However, KD usually presented as multiple subcutaneous nodules or swellings and was accompanied by lymphadenopathy in some cases. On the other hand, EH appeared only as a small skin nodule or red plaque. Histologically, both lesions may involve the dermis or subcutis. All the 9 KD cases displayed florid hyperplasia of lymphoid tissue, of which, 7 cases exhibited formation of lymphoid follicles and active germinal centers. Proliferation of post-capillary venules were seen between follicles. They were lined by plump or attenuated endothelial cells. Large number of eosinophils aggregated around the vessels or adjacent to the follicles, formation of microabscesses were observed in 3 cases. All the 3 EH cases showed prominent proliferation of vessels (capillary-sized in 2 cases and small to medium-sized in 1 case). The vessels were lined by epithelioid endothelial cells with abundant eosinophilic cytoplasm. The endothelial cells also proliferated within the lumen in 1 case and grew in sheets or cords adjacent to the vessel walls in 2 cases. Some endothelial cells contained intracytoplasmic vacuoles, suggesting formation of primitive vessels. Associated inflammatory component was noted in 2 cases. Lymphoid follicles however were not present and eosinophil infiltration was not as prominent as in KD. Immunohistochemical study in KD revealed B cells in the lymphoid follicles and mostly T cells in the interfollicular regions. In EH, the epithelioid endothelial cells showed strong reactivity to CD31 and factor VIII-related antigen. CONCLUSIONS: KD and EH are two distinctive entities. The former represents a lymphoid hyperplasia and the latter represents a benign vascular tumor. Recognition of the clinical characteristics and morphologic features of KD and EH is very important in making this distinction.

Angiolymphoid hyperplasia with eosinophilia associated with pregnancy: a case report and review of the literature.

A case of angiolymphoid hyperplasia with eosinophilia (ALH) is reported in a 33-year-old woman who developed an auricular nodule during the second trimester of her pregnancy. Angiolymphoid hyperplasia with eosinophilia usually occurs on the head and neck of young adults and is more common in women than in men. Characteristic histologic features of ALH present in this case included proliferation of thick-walled blood vessels lined by prominent endothelial cells, infiltration of the interstitium by chronic inflammatory cells (mainly eosinophils), and presence of lymphoid follicles with germinal centers. The auricular tumor was completely excised. Thirteen months after excision, the patient remains tumor free. Although there are not many case reports on ALH during pregnancy or involving use of oral contraceptive pills, sex hormones may play a role in the pathogenesis of ALH. This hypothesis, in the context of cases previously described in the literature, and the differential diagnosis of ALH are discussed.

Angiolymphoid hyperplasia with eosinophilia (epithelioid hemangioma) of the lung: a clinicopathologic and immunohistochemical study of two cases.

Two cases of primary angiolymphoid hyperplasia with eosinophilia (epithelioid hemangioma) (ALHE/EH) of the lung are described. Both patients are white, a 60-year-old man and a 27-year-old woman. One patient had a long-standing history of asthma, and the other had symptomatology related to the pulmonary mass. Wedge resections were performed in both cases, and both lesions shared similar histopathologic changes, mainly the presence of a tumor mass with a marked presence of eosinophils in the background, lymphoid hyperplasia, and marked proliferations of small-caliber vessels. Immunohistochemical studies using leukocyte common antigen, L-26, and UCHL-1 nicely stained the lymphoid component of the lesion, and CD31 clearly outlined the vascular component of the process. Clinical follow-up demonstrated that the woman died of status asthmaticus, and the man was alive and well 1 year after surgical resection of the lesion. Both cases highlight the ubiquitous distribution of ALHE/EH and underscore the importance of keeping these lesions in the differential diagnosis of vascular and lymphoid lesions of the lung.

Angiolymphoid hyperplasia with eosinophilia involving the cubital nerve.

A tumor involving cubital nerve was resected and studied; it was classified as an angiolymphoid hyperplasia with eosinophilia (ALHE). Immunohistochemical and molecular study was done both to confirm the reactive nature of the process and rule out the presence of clonal T or B cell rearrangement. This lesion has been designated as epitheloid hemangioma [Coindre (1994) Ann Pathol 14:426]. Typically, ALHE occurs in the skin and the subcutaneous tissue, and extracutaneous involvement is rare. No cases of ALHE affecting a nerve have been described, but a case of Kimura's disease, the lesions of which have repeatedly been confused with ALHE, has been reported involving median nerve.

Kimura's disease with unusual eosinophilic epithelioid granulomatous reaction: a finding possibly related to eosinophil apoptosis.

We report and discuss a case of Kimura's disease with an unusual eosinophilic epithelioid granulomatous reaction. A 3-year-old Japanese boy with eosinophilia and a high concentration of IgE developed lymphadenopathy and multiple cervical masses. A lymph node biopsy demonstrated the infiltration of eosinophils in the stroma, which is consistent with the findings of Kimura's disease. Interestingly, a number of apoptotic eosinophils was detected in the infiltrating eosinophils. Multiple epithelioid granulomas with central eosinophilic abscesses and necrosis were also observed. Macrophages and giant cells had phagocytosed the apoptotic eosinophils at the edge of the granulomas. In situ terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) assay showed that the TUNEL-positive eosinophils were both in the macrophages and in the central eosinophilic abscesses of the granulomas. These findings suggest that the eosinophils had undergone an accelerated apoptosis in this case of Kimura's disease, and that the epithelioid granulomas were produced by phagocytosis of the apoptotic eosinophils by macrophages.

Association of galectin-9 with eosinophil apoptosis.

BACKGROUND: There is no information whether galectin-9 (a novel eosinophil chemoattractant) was associated with pathogenesis of eosinophilic disorders. METHODS: We assessed the expression of galectin-9 with imunostaining and in situ hybridization both in the lesion of angiolymphoid hyperplasia with eosinophilia, and peripheral blood eosinophils of eosinophilic patients (E-Eos) in comparison with those of normal volunteers (N-Eos). Regulation of expression of galectin-9 on eosinophils and the effect of galectin-9 on apoptosis of eosinophil were also evaluated. RESULTS: Many eosinophils infiltrating the site were positive for galectin-9. Surface and intracellular immunoreactive galectin-9 was more evident in E-Eos than N-Eos. When eosinophils were cultured with IL-5 in vitro, the surface galectin-9 expression of E-Eos was significantly downregulated, although that of N-Eos was not affected. Treatment of eosinophils with dexamethasone or anti-Fas antibody significantly upregulated the surface galectin-9 expression of E-Eos. In contrast, dexamethasone partially downregulated the surface galectin-9 of N-Eos, although anti-Fas antibody failed to affect on the surface galectin-9 expression. We also found that recombinant galectin-9 significantly suppressed apoptosis of E-Eos (p = 0.0431), whereas it apparently enhanced apoptosis of N-Eos (p = 0.0173). Furthermore, dexamethasone-induced apoptosis of N-Eos was significantly suppressed by galectin-9 (p = 0.0431), whereas galectin-9 failed to induce significant change in dexamethasone-induced apoptosis of E-Eos. In contrast, apoptosis induced by anti-Fas antibody in both N-Eos (p = 0.0431) and E-Eos (p = 0.0431) was enhanced by galectin-9. CONCLUSIONS: These findings suggested that galectin-9 was produced by eosinophils, and galectin-9 showed heterogeneous effects and kinetics to eosinophils, and this factor might be one of crucial factors in eosinophilic inflammation.

Angiolymphoid hyperplasia with eosinophilia of the tongue: report of a case and review of the literature.

Angiolymphoid hyperplasia with eosinophilia (ALHE) is an uncommon disorder manifested as solitary or multiple nodules in dermis and subcutaneous tissue of head and neck region. ALHE affecting tongue is very rare. We report a 56-year-old man with ALHE of the tongue and review the previously reported cases of ALHE of the tongue.

Angiolymphoid hyperplasia with eosinophilia: report of a lesion mimicking soft tissue tumor of extremely long duration.

We present a large sized lesion of the right upper arm in which characteristics of the angiolymphoid hyperplasia with eosinophilia (ALHE) intermingled with those of Kimura's disease (KD). The laboratory findings, the prominent vascular proliferation and the features of endothelial cells were suggestive of ALHE. However, the long duration of the disease, the site of involvement, the abundant lymphoid component forming lymph follicles with germinal centers and the fibrosis are features of KD. In agreement with other reports, our case shows that clinicopathologically there is an overlap between ALHE and KD.