Case 1 -

Eosinophilic Angiocentric Fibrosis Associated with Granuloma Faciale Leon Barnes University of Pittsburgh Medical Center Pittsburgh, PA

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History: This 60 year old man presented in 2004 with a widened nasal septum which was excised. The lesion has now recurred and involves both nares. There is no adenopathy or history of systemic disease. In addition, he has recently developed a 3 cm skin lesion of the right frontotemporal scalp that was first noticed several months ago. (Case courtesy of Damion Kistler, MD, Mercy Health Center, Oklahoma City, OK). Case 1 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 1 - Slide 2 Click to view with ImageScope Click to view with a Web-Based Viewer Case 1 - Figure 1 Case 1 - Figure 2 Case 1 - Figure 3 Case 1 - Figure 4 Case 1 - Figure 5 Case 1 - Figure 6 Case 1 - Figure 7 Case 1 - Figure 8 Case 1 - Figure 9 Case 1 - Figure 10 Case 1 - Figure 11 Introduction: Eosinophilic angiocentric fibrosis (EAF) is an exceedingly rare, slowly progressive, obstructive, fibroinflammatory disorder of unknown etiology that predilects the nasal cavity and occasionally the paranasal sinuses, larynx, orbit and gingiva [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28]. It was first described by Holmes and Panje in 1983 under the rubric "intranasal granuloma faciale", based on its histologic resemblance to cutaneous granuloma faciale [1]. The term "eosinophilic angiocentric fibrosis" was subsequently proposed by Roberts and McCann in 1985 and has since been accepted for this disorder [2]. As of to date, there have been forty (40) cases of EAF reported in the English literature [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28]. The following is a review of these reports. Clinical Features: EAF is slightly more common in women (23 cases, 57.5%) then men (17 cases, 42.5%) and occurs in patients averaging 48 years of age (median 49 years, range 19-79 years). The nasal cavity is by far the most common location (Table 1). It has also been described in the paranasal sinuses, orbit, larynx, and gingiva. EAF evolves slowly over the course of many years and, in the nasal cavity, typically involves the septum and lateral cartilaginous wall, resulting in a tumor-like expansion of these sites with progressive unilateral or bilateral obstruction. Pain and epistaxis are uncommon [9]. With the exception of a 19 year old woman who presented with disease localized to the right maxillary sinus, almost all patients with sinus and orbital involvement have had coexistent nasal disease [25]. Patients with orbital EAF have experienced proptosis, nasolacrimal duct obstruction, epiphora and/or diplopia [17, 21, 23, 26, 27]. Only two examples of EAF of the larynx have been described [2, 3]. Both patients presented with isolated subglottic stenosis associated with difficulty in breathing. The area of stenosis ranged from 4 mm to 2 cm in length. Although EAF may involve multiple contiguous anatomic sites (nasal cavity, paranasal sinuses, orbit), there is only one reported case of non-contiguous multifocal disease involving the nasal cavity and gingiva [24]. No cases, thus far, have been described below the clavicles. Some patients with EAF have had additional disorders, usually granuloma faciale (see discussion below) but also psoriasis, Wegener's granulomatosis, inflammatory bowel disease and cocaine abuse [8, 10, 20, 28]. Etiology: The etiology is unknown. Allergy and trauma have been proposed. The presence of tissue eosinophilia and the fact that 11 out of 40 patients (27.5%) in this review have had allergies or potentially allergic-based diseases does lend credence to an allergic etiology. The allergies or allergic-based diseases have included hypersensitivity to penicillin, "antibiotics and environmental agents", wood dust, and fiberglass; urticaria; hayfever; asthma; and allergic rhinitis [2, 3, 4, 6, 10, 11, 17, 26, 27, 28]. At least three (7.5%) individuals have had mild peripheral eosinophilia [13, 26, 27]. The role of trauma is marginal at best. Most of the traumatic episodes have been in the form of surgical procedures performed on the sinonasal tract. It is not always apparent whether these surgical procedures really antedated the onset of EAF or whether EAF was actually the reason for the procedure. Imaging: CT and MRI scans typically show a moderately enhancing soft tissue mass with or without erosion and/or destruction of septal cartilage and bone [3, 4, 8, 11, 14, 16, 17, 18, 20, 21, 23]. No abnormalities have been detected on imaging of the chest. Laboratory Data: Laboratory evaluation has been sporadic and often incomplete. Although, complete blood counts, erythrocyte sedimentation rates, rheumatoid factor, antinuclear antibodies, C3, C4, C-reactive protein and electrophoresis are usually normal, Narayan and Douglas-Jones have reported a patient with an abnormal erythrocyte sedimentation rate (51mm/hour) and elevated proteins on serum electrophoresis [3, 6, 9, 11, 13, 16, 20, 23, 24, 26]. Three patients (7.5%) have had a mild peripheral eosinophilia [13, 26, 27]. Thirteen patients had tests for C-ANCA and, of these, three were positive [6, 8, 9, 10, 11, 13, 16, 17, 18, 21, 23]. In the case of Loane et al., the patient was regarded as having both EAF and Wegener's granulomatosis [10]. The titer of C-ANCA rose from 1:40 to 1:640 during the active phase of Wegener's granulomatosis. The other two patients with positive C-ANCA had no other evidence of Wegener's granulomatosis [9, 13]. Pathology: The pathology of EAF consists of two phases – early and late – both of which may be seen in a single biopsy suggesting that the condition is continually evolving [2]. The early lesion is more "inflammatory", then "fibrous" and consists of numerous eosinophils with admixed lymphocytes, plasma cells and occasionally neutrophils arranged in a nodular and/or diffuse pattern. At times, the cellular infiltrate extends into the walls of small blood vessels with leukocytoclasis. As the lesion matures, inflammation becomes less intense, stromal fibrosis ensues, and small blood vessels acquire a characteristic "onion-skin" type of perivascular fibrosis. Stromal necrosis is uncommon and granulomas and giant cells are not seen. The process typically involves soft tissue but may also surround and/or involve cartilage and/or bone. Lymphoid aggregates are sparse to absent. The involved blood vessels are predominantly capillaries and venules. Although arterioles are stated to be uninvolved, I believe I have seen vessels of this type involved in the disease process. In one case, no extra-cellular deposits of IgG, IgM, IgA, IgE, or C3 were seen [2]. Immunohistochemistry: The inflammatory infiltrate is polytypic with admixture of T- and B-cells, without a specific pattern of distribution and without light chain restriction [9]. The stromal cells are positive for vimentin and negative for S-100, CD34, actin and desmin [28]. Eosinophilic Angiocentric Fibrosis and Granuloma Faciale: Granuloma faciale (GF) is an uncommon dermatosis of unknown cause which typically presents as 0.5-8.0 cm red, brown or purple papules, nodules or plaques on the face, hence the term "faciale" [29, 30]. It is more common in men (62% of cases) and occurs in all age groups, (though rare in children) with a mean age of 53 years. The lesions may be single (62% of cases) or multiple (38% of cases) with the most common sites of occurrence, in descending order of frequencies, being the cheek, nose, eyelids and lips. Extrafacial GF, either occurring alone or in association with facial lesions, are unusual but have been described on the scalp, shoulder, arm, trunk and vulva [29, 30]. GF is rarely recognized clinically and usually mistaken for sarcoid, lymphoma, lupus or basal cell carcinoma [30]. With the exception of occasional pruritus, the lesions are asymptomatic. There are no systemic manifestations or laboratory findings, other than rare peripheral eosinophilia. GF is often resistant to therapy. Numerous modalities have been employed, including steroids and laser therapy, with variable results [29]. The natural course of the disease is characterized by chronicity, recurrence and onset of new lesions [30]. Histologically, GF is characterized by a dense cellular infiltrate centered in the mid-dermis associated with a prominent Grenz zone. The inflammation usually consists of an abundance of eosinophils with admixed neutrophils, lymphocytes, plasma cells and histiocytes with foci of leukocytoclastic angiitis. Older lesions exhibit fibrosis often with hemosiderin deposits. There is much interest and speculation on whether EAF and GF are related or represent a spectrum of a single disease, differing only in anatomic site (mucosal vs. cutaneous) [1, 2, 8, 18]. In support of this hypothesis are: (a) 10 of the 40 (25%) cases of EAF in this review were associated with GF. The chance association of these two rare entities occurring with this frequency would be most unusual; (b) Both EAF and, with few exceptions, GF occur almost exclusively above the clavicles; and (c) Both share many histologic similarities, differing mainly in the degree of perivascular "onion-skin" fibrosis seen in EAF compared to GF. More work, however, is needed to explore this potential relationship. The 10 patients who had concomitant GF are summarized in Table 2. GF appeared as a solitary lesion in seven cases and as multifocal lesions in three. In one instance, GF presented in an extrafacial site (left scapula) [24]. The temporal relationship of EAF and GF is highly variable. In four cases, GF preceded the onset of EAF by as much as 18 years [17]. In two cases, the lesions were diagnosed simultaneously; and in the remaining four cases, GF appeared after the onset of EF. Differential Diagnosis: The differential diagnosis includes inflammatory myofibroblastic tumor (IMT, inflammatory pseudotumor), Churg-Strauss syndrome (CSS), Wegener's granulomatosis (WG), and angiolymphoid hyperplasia with eosinophilia (ALHE). Of these, IMF may be the most problematic. IMF can occur in any site, including mucous membranes, and may contain eosinophils [31]. Perivascular "onion-skin" fibrosis (POF), however, is usually not seen in IMF. The presence of a large component of spindle cells positive for smooth muscle actin, muscle specific actin and/or desmin would also favor IMT. Anaplastic lymphoma kinase (ALK) is positive in some cases of IMT but has not been evaluated in EAF. CSS is characterized by a diagnostic triad of (1) asthma, often severe; (2) systemic vasculitis that varies from granulomatous to non-granulomatous; and (3) peripheral and tissue eosinophilia [32]. It is also associated with P-ANCA in 40-80% of cases. The presence of these findings and the absence of POF should allow one to distinguish CSS from EAF. WG may be localized or generalized and is characterized by necrosis, granulomatous inflammation, vasculitis, absence of significant eosinophilia (about 5% of WG may be associated with eosinophilia), and an elevated and rising titer to C-ANCA [32]. As previously indicated, one case of EAF was associated with C-ANCA and WG; and in two others, C-ANCA was only marginally elevated but with no other manifestation of WG. ALHE, in contrast to EAF, contains prominent lymph aggregates and blood vessels lined by "epithelioid-histiocytic" endothelial cells that are frequently vacuolated and arranged in a "tombstone-like" pattern [33]. Treatment and Prognosis: EAF is an indolent, slowly progressive disorder that often evolves over many years. Surgical debulking and/or excision is the treatment of choice and recurrence and/or persistence of disease is frequent. Oral and intralesional steroids, immunosuppressive agents, dapsone, laser therapy, cryotherapy, and radiation have been tried with variable, but usually poor results [3, 9, 12, 14, 18, 19, 22, 23]. Recurrence develops in the same anatomic area and, to date, no cases have been described below the clavicles. Table 1: Distribution of 40 cases of EAF Site (s) Number Nasal cavity 24 Nasal cavity - sinus 5 Nasal cavity - sinus - orbit 4 Orbit - sinus 2 Larynx 2 Maxillary sinus 1 Nasal cavity - orbit 1 Nasal cavity - gingiva 1 Table 2: Cases of EAF associated with GF Reference Age/sex Single vs. multiple lesions of GF Onset of GF in relation to EAF Location Holmes [1] 49 M Multiple After Left forehead, Right forehead Roberts [2] 59 F Single After Bridge of nose Burns [8] 38 M Multiple Before Right malar promince,Right ala of nose, Bridge of nose, Left and right temporal area Tabaee [13] 79 M Single Before (2.5 years) Right nasal dorsum Narayan [16] 72 F Single After Skin of nose Paun [17] 37 F Single Before (18 years) Left frontonasal region Yung [18] 66 F Single Same time Right cheek Yung [18] 45 F Multiple Same time Bridge of nose,Left Cheek Holme [19] 72 F Single After Bridge of nose Nigar [24] 67 F Single Before Left scapula References Holmes DK and Panje WR, Intranasal granuloma faciale. 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