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Limited Wegener granulomatosis of the orbit complicated by Streptococcus anginosis (milleri group) infection.

Introduction

Orbital inflammatory pseudotumors and orbital infections are rare, but critical, organ and life-threatening conditions [1-4]. Herein, we present a case of a recurrent, sclerosing orbital inflammatory pseudotumor due to limited Wegener granulomatosis (WG) that was complicated by opportunistic infection with the commensal bacteria Streptococcus anginosis, part of the Streptococcus milleri group (SMG) (S. anginosis, S. constellatus, S. intermedius) [5], which show a predilection to form abscesses in the head and neck [6-10].

[FIGURE 1 OMITTED]

Case report

An otolaryngologist referred a 79-year-old woman for treatment of a right orbital mass 5 years ago. At that time, she presented with symptoms of slight pain and swelling around the right ear accompanied by right lower lid retraction and minimal lid edema and erythema. Vision was 20/25 OD and 20/50 OS with slight restriction of ocular motility and a 5-mm exophthalmos OD (Fig. 1). Her medical history included a mitral valve murmur detected in early childhood, bilateral lens implants for cataracts (remote), varicose vein surgery (remote), and use of dentures, but no history of dental abscesses or sinusitis. Computed tomography (CT) showed a mass with infiltrative, destructive features involving the inferior lateral orbit extending through the lateral orbital wall, temporal fossa and skull base associated with bone erosion. The mass had a small, central lucent area, a suspected region of necrosis. Lateral orbitotomy and debulking was performed. The bulk of the mass was grey-white and had a gritty, firm texture. The central portion of the mass, corresponding to the lucent area on CT, contained yellow friable and granular (purulent) material, which was cultured and grew a few, scant colonies of coagulase negative Staphylococcus and Streptococcus (subtyped as 'not enterococccus or Streptococcus pneumoniae'). This result was considered a contaminant at that time.

[FIGURE 2 OMITTED]

Histologically, the sclerotic nodules exhibited hyalinized, thick collagen bundles arranged in a storiform pattern associated with a sparse lymphocytic and plasma cell rich infiltrate. Within and at the edge of fragments of sclerotic tissue, granular, degenerated collagen and basophilic debris was identified corresponding to the abscess seen by imaging and at gross dissection. Stellate and linear areas of degenerated collagen and necrotic inflammatory cells and fibroblasts were evident throughout the sclerotic nodules. In addition, foci of granulomatous inflammation and regions of granulation tissue harboring hemosiderin were present (Fig. 2). Gram, acid-fast bacillus and Grocott methenamine silver stains were negative for bacteria, mycobacteria and fungus.

Post-operatively, the patient was treated with intravenous antibiotics and, as an outpatient, with oral cephalexin followed by an additional 2-week course of amoxicillin clavulanate. Blood cultures were negative. Tests for antineutrophil cytoplasmic autoantibodies (ANCA), angiotensin-converting enzyme (ACE), VDRL (Venereal Disease Research Laboratory), and Lyme titers were negative. These tests were repeated 1 and 2 years later and remained negative. Her erythrocyte sedimentation rate was increased at 35 mm. A rheumatology consult to evaluate for associated systemic disease was negative. A repeat CT scan 2 months after the operation demonstrated a smaller, inferior lateral orbital mass, without any lucent regions.

For the next 4.5 years, the patient's orbital disease remained stable, but the exophthalmos and right lower lid retraction persisted. Because of symptomatic mitral valve insufficiency, she had valvuloplasty and annuloplasty surgery 50 months after her first orbital surgery. At this time, she was also noted to have an increased blood sugar level, suggestive of early diabetes mellitus. Four months after heart surgery, she noted decreased right eye vision, tearing, bloody discharge in her tears, and worsening ptosis of the right upper lid. These symptoms were associated with a large palpable temporal mass, mild periorbital erythema, exotropia with reduced right eye motility, lower lid retraction, right eye dryness due to exposure, and 5 mm exophthalmos. Visual acuity was 20/70 OD and 20/60 OS with a right afferent pupil defect (APD). No fever, localized tenderness, pain, edema or significant lesional erythema was associated with the temporal and orbital mass. Review of systems was negative. ANCA and serum protein electrophoresis tests were negative. CT scan showed features similar to her CT scan 4.5 years before, but now the mass showed more widespread infiltration of the right orbit, extension to the temporal fossa, and a lucent area (corresponding to the palpable cutaneous mass) in the temporal fossa (Fig. 3). A right lateral orbitotomy with exploration with debulking of the temporal fossa and orbital region was performed. During exploration of the temporal fossa, a large pocket of yellowish, granular material was aspirated and sent for culture. The surrounding tissues in the temporal fossa and the lateral orbital region contained gritty, fibrotic, firm tissue similar to the tumor found on first presentation. A defect of the lateral orbital wall was found, communicating with the temporal fossa. Cultures of the abscess grew 4+ Streptococcus; subtyped specifically as Streptococcus anginosus and 1+ coagulase negative Staphylococcus epidermidis. Cultures for acid-fast bacilli and fungi were negative.

[FIGURE 3 OMITTED]

Histopathologic evaluation of the orbital mass demonstrated a fibro-inflammatory mass characterized by hyalinized, hypocellular, central sclerosis bordered by hypercellular areas of fibrosing granulation tissue. The sclerotic collagen bundles were arranged in a storiform pattern and associated with scattered, dense mixed infiltrates consisting mostly of plasma cells, but also lymphocytes, and sparse infiltrates of neutrophils, eosinophils, and macrophages. Focally, neutrophils and nuclear debris surrounding small vessels could be found, some associated with mild angiocentric fibrosis and luminal narrowing or obliteration. These aforementioned changes were interpreted to represent chronic localized fibrosing vasculitis (CLFV) [11-13]. In addition, areas of collagen mummification (sclerotic collagen with loss of fibroblast nuclear detail), stellate and linear areas of degenerated collagen bundles associated with basophilic debris, regions of granular degeneration of collagen bundles and scattered aggregates of macrophages (granulomatous inflammation) were identified. All of these latter changes have been described in limited WG (Fig. 4) [14]. Gram, acid-fast bacillus and Grocott methamine silver stains were negative for bacteria, mycobacteria and fungus. Immunohistochemistry was performed to evaluate for the possibility of plasmacytosis, inflammatory myofibroblastic tumor [15], and IgG4related sclerosing disease [16]. Antibodies to kappa and lambda light chains demonstrated a polyclonal pattern. No spindle cell expression of CD34, actin, desmin, or ALK-1 was identified. IgG4 plasma cells represented less than 5% of IgG positive plasma cells. Pathologic consultation from the Massachusetts General Hospital of both debulking specimens was obtained and was in agreement with the diagnosis of limited WG.

[FIGURE 4 OMITTED]

Post-operatively, intravenous cephalexin was given, followed by doxycycline, then amoxicillin clavulanate for 2 weeks when culture and sensitivity results became available. An additional 6-week course of ceftriaxone was given on the recommendation of an infectious disease specialist. During this post-operative period, cutaneous and orbital inflammation decreased, and her visual acuity and extra-ocular motility improved. At 12 months follow-up, her orbital findings are stable; she does not have any systemic complaints; and ANCA testing is negative.

Discussion

Sclerosing orbital pseudotumor is a unique subtype of inflammatory orbital pseudotumor, which is a fibro-inflammatory mass arising in the orbit without any identifiable cause such as infection, cancer, or a systemic inflammatory disorder (e.g., connective tissue disease, localized or systemic vasculitis) [1,2,17,18]. Our patient presented with two uncommon disorders, either of which could be the cause of her recurrent sclerosing inflammatory orbital pseudotumor: limited WG or Streptococcus anginosis (SMG) orbital infection. Vasculitis can be the consequence of direct infection of vessel walls, or an indirect, immune-mediated consequence of infection [12]. No signs of infective vasculitis were found in her tissue samples; therefore, the active and chronic localized fibrosing signs of vasculitis are primary (idiopathic, e.g., limited WG), or secondary, a reactive immune phenomenon to local or systemic infection. Significantly absent were clinical and laboratory signs of systemic infection and periocular cutaneous, dental or sinus bacterial infection that could account for hematogeneous spread to, or direct extension of infection and destruction of the orbit. Moreover, her orbital abscess was not associated with the typical symptoms of infection: marked pain and tenderness, warmth, edema, and erythema [3,4]. Also, SMG infection is typically opportunistic and predisposing factors include mucosal barrier trauma, diabetes, congenital heart disease, prior surgery and immunosuppression [6,19-21]. Indeed, SMG orbital abscess has been reported in systemic WG, where the immunosuppressive therapy masked its signs and delayed treatment [21]. Considering all these facts, this patient's primary pathologic event is probable limited WG, with sclerotic or necrotic tissue secondarily infected, as it represented a region of least resistance (locus minoris resistentiae), presumptively due to poor vascularity and/or degeneration of collagen. This secondary SMG infection could have been acquired during her cardiac surgery from mucosal barrier trauma causing an asymptomatic bacteremia that seeded the sclerotic pseudotumor and/or necrotic areas. However, subclinical, orbital infection may have existed ab initio as bacteria were cultured at the time of her first surgery, albeit scant colonies. Occult infection and subclinical inflammation could potentially have induced or exacerbated her localized vasculitis resulting in an enlarging, symptomatic orbital pseudotumor, active limited WG [22,23].

Ocular involvement in WG occurs in 50-60% of cases and can be the presenting feature in up to 16% of patients [24]. WG ocular disease ranges from conjunctivitis, episcleritis, scleritis, granulomatous sclero-uveitis, ciliary vessel vasculitis, retinal vasculitis, nasolacrimal obstruction, dacryocystitis, and in our patient, sclerosing orbital pseudotumor [14,25]. Pathologically, the classic triad of vasculitis, necrosis, and granulomatous inflammation characterizes WG and is found in 54% of orbital biopsies [26], and these findings were found in both her specimens. Furthermore, limited orbital WG shows distinctive fibrotic and necrotic changes consisting of granular degeneration and mummification of collagen as well as plasma cell rich infiltrates [14]. The full spectrum of these pathologic changes reported for limited orbital WG were evident in this patient. While a positive c-ANCA test would lend further support, as c-ANCA testing is sensitive and specific for ocular WG [14,24], c-ANCA is absent in a minority of limited orbital WG [27,28]. Moreover, positive results correlate with disease activity and extent, ranging from 32 to 67% in active limited WG to 90-96% in active systemic disease [28,29]. A small risk for progression to multi-organ involvement exists for patients with limited WG [30,31]. For patients with WG, relapse can be associated with persistent, subclinical inflammation and chronic carriage of Staphylococcus aureus [123,32,331]. Conversely, antimicrobial therapy, co-trimoxazole, is effective in active WG limited to the upper airways [32]. Debulking and antimicrobial therapy in our patient without use of immunosuppressants may be explained by decrease in antigen burden and consequential inflammation. However, as the patient still has residual, sclerotic disease with unknown inflammatory activity, the potential for additional recurrences and progression exists.

CLFV, which has been reported in the eyelid[13], is a unique variant of small vessel vasculitis that shows patterned and/or angiocentric fibrosis and is found in localized vasculitis syndromes like granuloma faciale and some cutaneous inflammatory pseudotumors as well as in systemic vasculitic syndromes like erythema elevatum diutinum and WG [11,34,35]. The underlying pathogenesis of fibrosing vasculitis is suspected to represent recurring episodes of immunecomplex mediated small vessel vasculitis due to a persistent, local antigen that leads to a cycle of vasculitis-granulation tissue-vasculitis-granulation tissue resulting in progressive accumulation of (layered) fibrous tissue [11,36]. In this instance, local orbital bacterial infection could have been the source of antigens that initiated, maintained and/or exacerbated vasculitis and fibrosis found in this patient. The other extravascular findings of orbital WG, mummification and granular degeneration of collagen and geographic areas of necrosis are the consequence of persistent vasculitis leading to obliteration of vessels and end organ ischemia.

Teaching point

Biopsy and culture of any degenerated material are crucial in the evaluation and management of patients presenting with the signs and symptoms of an orbital mass. Apart from absence of c-ANCA, this patient's orbital pseudotumor showed all of the pathognomonic signs of limited orbital WG: CLFV (patterned fibrosis, plasma cell rich infiltrates), granulomatous inflammation, necrosis, and granular degeneration and mummification of collagen bundles. Classics signs of orbital infection were absent, but bacteria were cultured from the necrotic area of the primary and recurrent tumor, the latter of which was found to be the opportunistic, abscess forming SMG. Antigen is considered a positive regulator of immune responses [37]. In WG, the antigen(s) that cause its characteristic inflammatory damage are unknown; however, it is becoming evident that bacterial infection may play a role in inducing or exacerbating its inflammation1321. Occult bacterial infection of this patient's sclerotic tumor may have played a role in initiating and/or aggravating limited WG. Conversely, for WG patients on long-term immunosuppressive therapy, the sudden onset of orbital and ocular symptoms may herald an orbital abscess and not relapsing WG [21].

DOI: 10.1102/1470-5206.2010.0022

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Sabah A. Shah (a), Dale R. Meyer (a), Llewellyn Foulke (b) and J. Andrew Carlson (b)

(a) Ophthalmic Plastic Surgery, Lions Eye Institute, Department of Ophthalmology, Albany Medical Center, Albany, NY12208, USA; (b) Department of Pathology, Albany Medical Center, Albany, NY12208, USA

Corresponding address: J. Andrew Carlson, MD, FRCPC, Division of Dermatopathology and Dermatology, Albany Medical College MC-81, Albany, NY 12208.

Email: carlsoa@mail.amc.edu

Date accepted for publication 14 October 2010
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Author:Shah, Sabah A.; Meyer, Dale R.; Foulke, Llewellyn; Carlson, J. Andrew
Publication:Grand Rounds
Date:Jan 1, 2010
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