A 14-year-old Filipino female was referred to evaluate and manage a growing left-sided neck mass.

She had initially developed neck swelling 10 months prior to presentation at our institution. Her previous exam and evaluation, including neck ultrasound and MRI, had noted lymphadenopathy in the left neck region, with one prominent lymph node in the left upper posterior cervical chain, and a second smaller post-auricular node. The etiology was initially thought to be infectious, secondary to a recent gingival infection, and she was treated with antibiotics without improvement.

Her left neck swelling gradually worsened over the course of several weeks and she was subsequently evaluated by multiple subspecialists. Laboratory evaluations were not revealing for an etiology. MRI of the chest/abdomen/pelvis was negative for additional lymph node or organ enlargement. Needle biopsy of the neck mass followed by flow cytometry was negative for signs of malignancy. Excision of the nodes was attempted and the smaller post-auricular node was successfully excised; however, the larger node was not able to be fully excised due to intra-operative bleeding.

Pathology on the tissue from the incisional biopsy showed no evidence of malignancy and cultures were negative. It did demonstrate reactive lymphadenopathy with follicular and interfollicular hyperplasia, increased eosinophils, focal vascular proliferation and IgG4+ cells. Serum IgG4 levels were within normal limits.

A working diagnosis of IgG4-related disease (IgG4-RD) was made, and the patient was started on 60 mg prednisone daily with near complete resolution of the neck mass over the course of several months. However, with taper down to 15 mg prednisone daily there was recrudescence, and the mass grew back to pre-treatment size when steroids were discontinued. She developed some pain with neck movement due to the mass, but there was no difficulty with breathing or swallowing. She had experienced side effects from the high-dose steroids including weight gain and irritability.

The family moved and presented to our institution to continue care.

Otherwise unremarkable including that the patient and mother denied fevers, chills, night sweats, rashes, arthralgias, myalgias, hematuria, edema, frothy urine, hearing loss, sinusitis, epistaxis, cough, shortness of breath, hemoptysis.

The patient has intellectual disability and global developmental delay. Her history was also notable for Marfanoid features on exam, including increased arm span, positive thumb and wrist signs, mild kyphosis, pectus excavatum and myopia. Family declined evaluated by genetics, echocardiography was unremarkable. She had had bilateral adenoidectomy and tonsillectomy at the age of 12 years. There was no history of recurrent or severe infections.

The patient lives with her biologic parents and two younger sisters who are all healthy. The patient's paternal grandfather died of an unknown cancer, and her mother's cousin was diagnosed with systemic lupus erythematosus. The family denied any known unusual exposures to animals, insects or toxins. The patient was born in the Philippines and moved to the United States when she was 6 years old.

The patient was afebrile and vital signs were unremarkable. She was a well-developed, well-nourished, female teenager in no apparent distress at the 88th percentile for both height and weight. There was a prominent, firm, left neck mass (Figure 1A), roughly 5 × 5 cm, which was immobile, non-tender, non-fluctuant and marked by a healed surgical scar. She had an additional small, healed surgical scar behind the left ear. She had full range of motion of all joints including her neck, but endorsed mild pain with lateral rotation. The remainder of her examination was unremarkable aside from the previously noted mild dysmorphisms.

Laboratory evaluation conducted at our institution is shown in Table 1 and Supplementary Table 1. Extensive evaluation for infectious etiology accounting for all potential exposures was unremarkable (Supplementary Table 2). C reactive protein was unremarkable and the highest erythrocyte sedimentation rate was 23 mm/h (normal <20 mm/h). Results were most notable for the presence of peripheral eosinophilia (2.9 K/uL) and highly elevated serum IgE (39,232 kU/L). Computed tomography (CT) imaging of the neck revealed left cervical chain lymphadenopathy, with a nodal mass measuring 5.4 × 3.7 × 6.3 cm (Figure 1B), and additional asymmetric nodes <1 cm scattered along the upper and lower left neck. No calcification or fluid collection was observed. Creatinine was within normal limits and there was no hematuria or proteinuria.

Pathologic re-evaluation of her biopsy (Figures 2A–D) confirmed reactive lymphoid hyperplasia with dense tissue eosinophilia including eosinophilic microabscesses, focal vascular proliferation, focal sclerosis and prominent plasmacytosis with increased IgG+ cells (>60 per high powered field, IgG4:IgG ratio 40–50%).

IgG4-RD is a rare, chronic immune-mediated disorder that can cause fibroinflammatory lesions in nearly any organ (21). It is a predominately adult-onset condition that generally presents as multiorgan disease and may be confused early in the course for malignancy, infection, or other immune-mediated conditions. Typical pathologic findings include a lymphoplasmacytic infiltrate, storiform fibrosis, obliterative phlebitis, and IgG4+ plasma cell infiltrates (22). Serum IgG4 levels may be normal, and this finding is not central to the diagnosis (22). Characteristic radiologic findings, such as a sausage-shaped pancreas or periaortitis of the lower aorta, are strongly associated with IgG4-RD. However, no single clinical, serologic, histologic or radiographic finding is considered definitive for the diagnosis (23). An international consortium of physicians from the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) jointly issued newly updated classification criteria for IgG4-RD in 2019 (24). The diagnosis requires clinical correlation with serologic and histopathologic data. A 3-step classification process was developed comprising entry, exclusion and inclusion criteria. These criteria were validated in a large cohort of patients with robust sensitivity and specificity (24). Based on these classification criteria, peripheral eosinophilia > 3,000 cells/uL is an exclusion for IgG4-RD that our patient was just shy of fulfilling. However, her pathologic findings did not meet enough criteria to result in a diagnosis of IgG4-RD, as cells staining positive for IgG4 is insufficient to diagnosis IgG4-RD without other characteristic pathologic findings and organ involvement.

ALHE shares sufficient clinical and histopathologic features with KD that investigators in the past wondered if these entities were part of the same disease spectrum, although they are now considered by most to be distinct diseases (18, 25). While the lesions of ALHE are also generally located in the head and neck region, they tend to be smaller and are more often found in multiples (18). ALHE is also more common in females and the lesions are often described as discolored and pruritic (18). Although the peak incidence of ALHE is in the second to fourth decade of life, ALHE has been described in all age groups (25). Unlike KD, ALHE is not increased in Asian patients (18). While both ALHE and KD demonstrate vascular proliferation on histology, the vessels in ALHE are abnormal with characteristically plump, histiocytoid endothelial cells with cytoplasmic vacuoles (18, 25). ALHE demonstrates a lymphocytic infiltrate but is less likely to have dense eosinophils and typically does not have follicles (18). Peripheral eosinophilia and elevated IgE are uncommon in ALHE (18). Therefore, the laboratory findings of eosinophilia and elevated IgE combined with the histologic findings of reactive follicles and dense tissue eosinophilia including microabscesses favored a diagnosis of KD.

The hypereosinophilic syndromes (HES) are a heterogeneous group of rare disorders that should be considered when peripheral eosinophilia > 1.5 × 10⁹/L cells is present. A distinct subset of HES patients manifest with a T-cell-mediated polyclonal expansion and have what is termed lymphocytic HES (L-HES) (19, 20). L-HES affects females and males equally, and most commonly presents in between age 20 and 50 years, although it can develop in children. L-HES is most commonly characterized by cutaneous manifestations (pruritus, eczema, urticaria, angioedema) and lymphadenopathy, but symptoms can be present as the result of eosinophils in other organ systems including respiratory, cardiovascular and musculoskeletal. Serum IgE levels are often increased. Although short-term prognosis in L-HES is excellent, there is a significant predisposition to T-cell lymphoma in this disorder.

The pathogenesis of KD is unknown. Various investigators have suggested a disorder of immune dysregulation following an allergic response, consistent with the presence of eosinophilia and increased IgE (6, 9, 17, 26). The suggestion that KD patients can commonly have eczema further supports this (27). Rare immunophenotyping data is available from KD patients. Katagiri et al. reported upregulated transcript levels of IL-4, IL-5 and IL-13, but not interferon γ, in peripheral blood cells from a patient with KD (9). Hosoki et al. demonstrated increased IL-5 expressing cells in a case of pediatric KD, as well as increased IL-10 expressing cells (6). Elevated percentages of peripheral blood Th2 cells (CD4+ T cells expressing IL-4) correlated with IgE levels in KD patients in a study by Ohta et al. who also demonstrated elevated tissue IL-5 (28). Th2 cytokines not only induce IgE synthesis, but also promote infiltration of eosinophils into the tissue, both hallmarks of KD pathogenesis. Other investigators have suggested that allergic cytokines produced by basophils and mast cells also contribute to the elevation of IgE in KD (7, 8). While support for aberrant allergic disease has been shown, additional studies will be necessary to fully unravel the etiology of KD.

Standards for treatment of KD have not been established. Options include surgical excision, local radiation, combined excision and radiation, systemic corticosteroids, or, rarely, other immune modulators (5, 29). Our patient had known recrudescence of the mass following corticosteroid taper. She also had no evidence of disease outside the left neck mass. The decision was made to excise the mass for an attempt at definitive therapy (Figure 3), and the patient tolerated the procedure well. Subsequent evaluations revealed normalized inflammatory markers and peripheral eosinophils, and downtrending IgE (nadir 4,448 kU/L). One year after surgery, the patient noted the recurrence of her left sided neck mass and is considering immune modulation with cyclosporine. The patient will continue to be closely followed for the development of renal disease (26).