Given the variability in the histologic appearance of EAF according to the age of the lesion, diagnosis can be challenging, and several other entities occurring in the upper aerodigestive tract should be considered in the histologic differential diagnosis; specifically, granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis (EGPA), sinonasal inflammatory polyps, epithelioid hemangioma, invasive fungal rhinosinusitis, Langerhans cell histiocytosis, rhinoscleroma, inflammatory myofibroblastic tumor, and fibromatosis (see Table 2).

GPA and EGPA are systemic vasculitides characterized by small-vessel vasculitis, necrosis, and granulomatous inflammation. EAF can be distinguished from GPA and EGPA by the absence of necrosis and granulomatous inflammation. Clinical serologic studies can also be used in evaluation of these entities, as most patients with GPA have PR3-ANCA, and a significant minority of patients with EGPA have MPO-ANCA [20, 21]. It is important to note that an elevated serum IgG4 can be seen in up to 75% of patients with EGPA [22]; however, the peripheral eosinophilia typical of EGPA has not been reported in patients with EAF [21].

Sinonasal inflammatory polyps share some histologic features with EAF, specifically, their eosinophil-rich, mixed inflammatory infiltrate. However, characteristic findings of sinonasal inflammatory polyps include subepithelial edema and hyalinization of the basement membrane, neither of which are seen in EAF [23]. Furthermore, inflammatory polyps typically occur as multiple polypoid lesions throughout the sinonasal tract in patients with allergic disease and do not present as enlarging mass lesions.

Angiolymphoid hyperplasia with eosinophilia (ALHE), also known as epithelioid hemangioma, is characterized by a vaguely lobular capillary proliferation composed of epithelioid endothelial cells with abundant eosinophilic cytoplasm. There is a background of dense lymphocytic inflammation and admixed eosinophils. The epithelioid morphology of the endothelial cells and lack of notable fibrosis help to differentiate ALHE from EAF [24].

Invasive fungal rhinosinutitis (IFRS) typically has a more rapid clinical onset than EAF and invariably shows necrosis and tissue invasive fungal forms on histologic evaluation. As compared with EAF, IFRS exhibits a more scant inflammatory response, as patients are typically immunocompromised, and fibrosis is absent [25].

Langerhans cell histiocytosis (LCH) characteristically shows a dense mononuclear inflammatory cell infiltrate with admixed eosinophils, which could potentially mimic the mixed chronic and eosinophilic inflammation of EAF. However, LCH typically lacks a significant lymphoplasmacytic component, and instead is composed of histocytes with abundant eosinophilic cytoplasm, reniform nuclei, and a typical immunophenotype (S100+, CD1a+, and Langerin/CD207+). Fibrosis is typically absent [26].

Rhinoscleroma may show overlapping histologic features with EAF, particularly in more chronic stages of infection. While early stages of rhinoscleroma demonstrate a dense inflammatory infiltrate composed of abundant foamy macrophages (“Mikulicz cells”) containing gram-negative bacilli with an associated plasma cell population, later stages may show more overlap with EAF due to significant fibrosis.27 At this stage, both rhinoscleroma and EAF may be pauci-inflammatory, but typically EAF retains an eosinophilic infiltrate [6].

Inflammatory myofibroblastic tumor (IMT), which occurs very rarely in the sinonasal tract, is characterized by a proliferation of spindled myofibroblasts, some of which have a ganglion-cell like appearance with eccentric nuclei, vesicular chromatin, and small nucleoli. The background stroma is often myxoid, and there is a brisk associated inflammatory infiltrate comprised of lymphocytes, plasma cells, neutrophils and eosinophils. While both IMT and EAF can show an inflammatory infiltrate, the atypical spindle cell/ganglion-like cell population of IMT is absent in EAF. Additionally, the majority of IMT cases harbor anaplastic lymphoma kinase (ALK) gene rearrangements [9].

While other lesions with a prominent fibrous stroma including angiofibroma and fibromatosis may arise in the differential diagnosis for EAF in the later stages, neither of these entities has a notable inflammatory infiltrate.9.