| Abstract|| |
Lymphadenopathy along with various systemic manifestations is commonly encountered in pediatric patients, tuberculosis being the commonest etiology. Occasional patients may present a diagnostic conundrum. Here, the authors report an unusual manifestation of Kimura disease (KD) presenting as nephrotic syndrome associated with mesenteric lymphadenitis in an 11-year-old male child. KD is a chronic inflammatory disorder of unknown etiology. It typically affects young adult males in the age range of 27-40 years and usually presents as painless itchy nodular masses in the head and neck region. The involvement of mesenteric lymph nodes along with a very young age of presentation makes it a rare case, posing a diagnostic challenge for the unsuspecting physician.
Keywords: Angiolymphoid hyperplasia with eosinophilia (ALHE), IgG4-related disease, Kimura disease, nephrotic syndrome
|How to cite this article:|
Majumder A, Sen D. Kimura disease with nephrotic syndrome in a child- A rare association. Indian J Pathol Microbiol 2019;62:437-40
| Introduction|| |
Tuberculosis (TB) is called the “great mimic;” conversely, other diseases may also rarely simulate TB. Here, we present a case of Kimura disease (KD) in a child presenting with features of subacute intestinal obstruction, mesenteric lymphadenopathy, and nephrotic syndrome. The very young age of presentation and mesenteric lymphadenopathy is a rare case.
| Case Report|| |
An 11-year-old male child presented with colicky pain abdomen of 1 week duration, associated with lethargy and anorexia. He had bilateral pedal edema with facial puffiness. Bilateral firm itchy nodular subcutaneous malar lesions were noted. Bilateral cervical lymphadenopathy and right parotid swelling were also present. His blood pressure was 150/80 mm of Hg. Abdominal examination revealed diffuse tenderness with ascites, there was no organomegaly.
On detailed interrogation, the parents gave a history of recurrent bilateral itchy subcutaneous malar masses since 8 years of age. His hemoglobin was 10.4 gm/dL and total leukocyte count was 8900/mm3( 22% eosinophils). He had thrombocytosis (platelet count-5.8 lakh/mm3) with raised erythrocyte sedimentation rate (ESR) of 52 mm/h, elevated serum creatinine (1.6 mg/dL), hypertriglyceridemia (triglyceride-294 mg/dL), and proteinuria (3.8 g/day). Mantoux test was negative. Ultrasonography revealed mesenteric lymphadenopathy, ascites, and dilated bowel loops. Magnetic resonance imaging (MRI) revealed bilateral subcutaneous malar nodules, cervical lymphadenopathy, and right parotid swelling [Figure 1].
|Figure 1: Panel of coronal T2-weighted MRI images showing bilateral malar masses (white arrows) (a); and bilateral cervical lymphadenopathy (thick white arrows) and right parotid region swelling (forked white arrow) (b)|
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Fine needle aspiration cytology (FNAC) of the cervical lymph nodes yielded scant cellular material even on repeated attempts. The smears were hemodiluted and showed a few ill-formed epithelioid granulomas in a background of lymphoid cells and RBCs [Figure 2]. No atypical cells or necrosis were noted. A provisional diagnosis of TB with nephrotic syndrome was made and he was started on antitubercular drugs.
|Figure 2: Photomicrographs of FNAC of cervical lymph node showing ill-formed epithelioid granulomas (blue arrow) (Leishman-Giemsa, 40× magnification)|
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However because of persistent pain abdomen, a diagnostic laparotomy was performed after 4 weeks. Peroperatively, mildly dilated gut loops were noted with enlarged mesenteric lymph nodes. Histopathological examination (HPE) of the mesenteric lymph nodes revealed marked germinal center hyperplasia [Figure 3]. There was focal deposition of proteinaceous material [Figure 4]a, diffuse eosinophilic infiltration, and focal eosinophilic microabscesses [Figure 4]b. Extensive sinusal and paracortical sclerosis with paracortical hyalinized vessels were noted. No necrosis, granuloma, or atypical cells were seen. Biopsy from the cutaneous lesions revealed similar findings. Consequently, a diagnosis of KD was made. Corroborative serum immunoglobulin E (IgE) level was found to be high (996 IU/mL; upper limit of normal: 150-300 IU/mL).
|Figure 3: Photomicrographs of mesenteric lymph node biopsy showing hyperplasia of germinal centers (black arrows) (H and E, 10× magnification)|
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|Figure 4: Photomicrographs of mesenteric lymph node biopsy showing (a) eosinophilic proteinaceous deposits in few germinal centers (black arrows) (H and E, 40× magnification) and (b) diffuse infiltration by eosinophils (double black arrows) (H and E, 40× magnification)|
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The patient was started on oral prednisone. He responded well to treatment with normalization of eosinophil count, IgE levels, and disappearance of proteinuria after 3 months of steroid therapy. An ultrasound abdomen done after 6 months was normal. He has been on regular follow-up with no disease recurrence.
| Discussion|| |
KD is a rare inflammatory disorder of unknown etiology. First described in China in 1937 by Kim and Szeto, it came to be known as “Kimura disease,” following an extensive study by Kimura et al. in 1948., The disease typically affects young (27-40 years) East Asian males and presents as painless, enlarging subcutaneous head and neck masses. Major salivary glands particularly the parotid gland, lymph nodes (periauricular, axillary, inguinal), oral mucosa, and limbs may be involved.
A dysregulated T-cell immune response is implicated in the pathogenesis. Supposedly an IgE-mediated Type I hypersensitivity reaction triggered by viral or parasitic infection results in increased production of interleukins 4, 5, and 13 by the TH2 cells. High serum and tissue concentrations of IgE along with increased levels of circulating major basic proteins (MBP) demonstrated in patients with active KD validate this theory.,
An emerging hypothesis is the close association between KD and immunoglobulin G4-related disease (IgG4-RD). Chronic antigen exposure leading to a dysregulated immune response is believed to be the underlying etiopathogenesis in both the conditions. IgG4-RD is an immune-mediated fibroinflammatory condition, characterized by tumefactive fibrosclerosing lesions in different organs, most notably the pancreas and salivary glands. Patients exhibit high serum levels of IgG4 along with local infiltration by IgG4-positive plasma cells. Eosinophilia along with increased IgE levels has been noted in IgG4-RD, whereas patients with KD may exhibit raised serum IgG4 and infiltration by IgG4-positive plasma cells., However, IgE expression, which is routinely seen in the follicular dendritic cells and eosinophilic microabscesses in KD, is absent in IgG4-RD. Also, the very high levels of serum IgG4 and Ig4-positive plasma cells that characterize IgG4-RD are not encountered in KD. Histopathologically, both are characterized by fibrosis and sclerosis of the affected organs. Larger studies are needed to determine if both diseases represent a spectrum of the same entity or whether the similarities are purely coincidental.
The diagnostic histopathological features of KD are prominent lymphoid cell infiltrate admixed with eosinophils, plasma cells, and mast cells along with formation of follicles and germinal centers. Well-defined peripheral mantle zones are noted along with proliferation of postcapillary venules. Multinucleated Warthin-Finkeldey type polykaryocytes are often seen in the germinal centers. There is interstitial fibrosis along with IgE deposition, seen as an eosinophilic, proteinaceous material. Diffuse eosinophilia along with eosinophilic microabscess formation often leads to folliculolysis. Phagocytosis of apoptotic eosinophils may lead to formation of multiple epithelioid granulomas, thereby simulating TB on FNAC smears.,,
Distinguishing KD from other neoplastic as well as non-neoplastic diseases on histopathology is often challenging. The neoplastic conditions that mimic KD disease include Hodgkin's disease, T-cell lymphomas, and Histiocytosis X, whereas the non-neoplastic entities include TB, angiolymphoid hyperplasia with eosinophilia (ALHE), dermatopathic lymphadenopathy, and various parasitic infections. Sclerosis, polykaryocytes, and extensive eosinophilic infiltration admixed with plasma cells in lymph nodes in young patients may simulate Hodgkin's Lymphoma, whereas a peripheral blood eosinophilia may suggest a parasitic or allergic etiology. The disease entity most commonly misdiagnosed as KD is ALHE, which is a distinct disease entity with a different clinical outcome. A detailed clinical history along with pathological correlation is therefore required to arrive at the correct diagnosis.
Although histopathology is confirmatory, imaging by computerized tomography (CT) or MRI helps suggest the diagnosis and delineate extent of lesions. On CT scan, the lesions appear as iso- to hyperdense well-defined nodules or ill-defined infiltrative lesions exhibiting variable heterogeneous enhancement. On MRI, the lesions are variably hyperintense to muscle on T1-weighted and T2-weighted images and exhibit gradual progressive heterogeneous enhancement. On diffusion-weighted imaging (DWI), the associated reactive cervical lymph nodes show a higher signal intensity, high-early contrast enhancement and low-apparent diffusion coefficient values.,,
KD is usually self-limited though renal impairment has been reported. Proteinuria may occur in 12-16% of patients, of which two-thirds may progress to nephrotic syndrome. The spectrum of renal pathology includes minimal change disease, mesangioproliferative, and membranous nephropathy. The renal manifestation may be attributed to immune complex-mediated damage or a dysregulated helper T-cell response. Renal and mesenteric venous thromboses have also been reported.,
The treatment of KD remains controversial. Surgical resections are associated with frequent relapse. Patients with nephrotic syndrome and renal involvement usually respond well to treatment with systemic steroids. Immunomodulating agents such as cyclosporine, leflunomide along with irradiation remain the last line of management in recalcitrant cases with variable outcome.,,
| Conclusion|| |
KD can rarely afflict children and be easily missed. Suspected cases should be studied for any coexisting IgG4-RD to not only validate the relationship between these entities but also for better understanding of various immune-mediated complex disorders.
The study was performed in a manner to conform with the Helsinki Declaration of 1975, as revised in 2000 and 2008 concerning Human and Animal Rights and the authors followed the policy concerning Informed Consent.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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Department of Pathology, Military Hospital Jodhpur, Jodhpur - 342 006, Rajasthan
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3], [Figure 4]