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Idiopathic fibroinflammatory disease of the face, eyelids, and periorbital membrane with immunoglobulin G4-positive plasma cells.

The sclerosing form of idiopathic orbital inflammation (also called pseudotumor and probably better designated as fibroinflammatory disease) constitutes a small subset of noninfectious inflammatory diseases, which overall comprise roughly 5% to 8% of orbital biopsies. (1-3) It is an aggressive, quasineoplastic (tumefactive) subtype that poses many diagnostic and therapeutic challenges. It is characterized by an intractably spreading and progressively collagenizing stroma that infiltrates the orbital structures and contains a dispersion of lymphocytes, which may be organized into widely separated lymphoid aggregates with or without germinal centers. There may also be accompanying polymorphonuclear and eosinophilic leukocytes, particularly in childhood cases. (3) Granulomatous inflammation and angiodestructive inflammation are generally absent. Clinically and pathologically, the disease must be distinguished from Wegener granulomatosis, its closest simulant. (4) In the past, the spectrum of pseudotumors has often been subsumed with ocular adnexal lymphoid neoplasms, both hypercellular reactive follicular hyperplasias and small cell monoclonal B-cell proliferations usually devoid of a prominent collagenous stroma. (1,2)

Most fibroinflammatory lesions are localized to the orbit, but multifocal systemic disease with involvement of the mediastinum and/or retroperitoneum along with the orbit is well known to occur. (1) A relationship of orbital lesions has been suggested recently to a new entity of immunoglobulin G4 (IgG4)-related inflammatory diseases. Autoimmune sclerosing pancreatitis, retroperitoneal fibrosis, and sclerosing cholangitis are examples of preferential sites, although other loci of disease embrace the kidney, lung, prostate, and even the hypophysis. (5) We report a variant of orbital fibroinflammatory disease with prominent IgG4 plasma cells in the biopsied tissues that had an unusual clinical presentation; we do not believe that the present constellation of findings has been described previously in the literature. It entailed a massive facial swelling with an interconnected and contiguous sclerosing orbital process. Retention of excellent visual acuity and extraocular motility was paradoxically permitted because the orbital component mostly centered on involvement of the periorbital fibrous membrane (periosteum) covering the inner aspect of the orbital bones.


A 46-year-old white man had a swelling excised from the right upper gingival area in 1987. Unfortunately, the excised tissue was not examined histopathologically. After this intervention, a nasofacial lesion slowly developed superior to the surgical site. It extended from the right lateral nasal region to involve the facial tissues just anterior to the maxilla and superior to the level of the orbital rim to encompass the lower eyelid. Tenderness, evidence of lymphadenopathy, paresthesias or facial numbness, neck masses, and thyroid abnormalities were not detected. The nasopharynx, oral cavity, oropharynx, larynx, and vocal cords were normal on serial examinations performed every 6 to 12 months. His medical history was remarkable for chronic atrial fibrillation.

In 2001, a computed tomography scan revealed bilateral mucus retention cysts of the maxillary sinuses and a soft tissue mass over the anterior wall of the right antrum, with some evidence of osseous thinning and irregularity of the roof of the sinus representing either invasion or bony erosion. An open biopsy of the deep right nasofacial mass via a right lateral rhinotomy was performed. Microscopic evaluation disclosed collagenous replacement of adipose tissue and skeletal muscle with acute and chronic inflammation. Special stains for organisms were negative, and these included Grocott methenamine silver, periodic acid-Schiff, and Ziehl-Nielson for acid-fast bacilli. An infectious disease consultation was obtained, and local and systemic infections were ruled out.


The facial lesion continued to slowly but inexorably grow during many years. The patient underwent repeated facial "reconstructive" surgeries performed by a general plastic surgeon. Details of the surgeries were not available; the patient described them as superficial and not deep and achieved no discernible cosmetic or functional benefit. Five years later, in 2006, he sought an opinion for progressive prominence of his right eye, with upper and lower eyelid swelling, accompanied by conjunctival chemosis and low-grade proptosis. Vision was normal in both eyes, there were no signs of optic nerve compression, and extraocular movements were normal. Excessive facial scar tissue was present, which was very firm and edematous and extended to the right temple, upper and lower eyelids, lateral nasal wall, nasal ala, and right upper lip. The right lower eyelid was particularly thickened laterally, causing malposition. Exophthalmometry could not be precisely interpreted because of massive facial distortion. Five millimeters of lagophthalmos was present, with no evidence of exposure keratopathy. He was referred to the Oculoplastics Service at the Massachusetts Eye and Ear Infirmary (Boston, Massachusetts) for further treatment in July 2007 (Figure 1, A).

The computed tomography scan obtained during his initial visit at the Infirmary revealed thickening of the right nasal ala and cheek. Osteolysis of the greater wing of the right sphenoid bone was associated with an extensive extraconal right orbital soft tissue mass (Figure 1, B). The mass also hugged the lateral and inferior orbital bones, with erosion through the infraorbital fissure and canal (Figure 1, C). Pronounced thickening of the periorbital membrane progressed along the lateral (Figure 1, C) and superior (Figure 1, D) orbital osseous perimeters. The medial orbital wall displayed the same thickening, with erosion of the thin lamina papyracea and extension toward the nasolacrimal duct (Figure 1, D). An infratemporal fossa density was observed without any concomitant involvement of the pterygopalatine fossa. A right orbital biopsy was obtained through a lateral orbitotomy. Additional fragments of tissue were removed with debulking of the midfacial mass and anterior orbital mass to reduce the extent of the tumor. A right lateral canthoplasty with release and relaxation of the deep fissures of the involved soft tissue around the orbit was performed to allow more normal apposition of the eyelids. Postoperatively, there was no pain or discomfort. The patient was started on systemic steroids but was lost to follow-up after 3 months. It was later learned that he had died from a cardiac arrhythmia. An autopsy was not performed.



The microscopic slides and blocks of paraffin-embedded tissue from the last biopsy performed at the Massachusetts Eye and Ear Infirmary on September 11, 2007, were the only specimens available for review and further study; neither slides nor blocks could be retrieved from the earlier biopsies at the other institutions. Multiple firm, white fragments of excised tissue measured 3.2 x 2.5 x 0.5 cm in aggregate. Histopathologically, abundant fibrocollagenous tissue without conspicuous capillarity contained widely separated collections of lymphocytes without follicular center cells; these aggregates displayed ramifying networks of capillaries (Figure 2, A). No granulomatous elements were observed in the midst of the collagenous mass. Small muscular vessels exhibited compression or obliteration of their lumens from concentric collagenous onion-skinning in the absence of inflammatory cells in their walls. Small nerve units were also caught up in this scarifying process, which failed to show necrobiotic foci, fibrinoid material, or nuclear dust. A denser inflammatory infiltrate of lymphocytes, plasma cells, histiocytes, and rare eosinophilic leukocytes was present at the edge of the collagenous mass, where it extended into the adjacent orbital fat (Figure 2, B). Capillary proliferation featuring plump endothelial cells was observed in this tissue. The cutaneous tissue fragments were densely collagenized, with dispersed lymphocytes. Deep fissures in the tissue harbored a discontinuous lining of mononucleated histiocytes and foreign body giant cells surrounding keratinous epidermal debris. Perl reaction demonstrated the presence of iron, signifying blood breakdown products.

Immunohistochemical staining revealed a light distribution of CD3/CD5-positive T cells within the collagenous tissue, together with CD68-positive and lysozyme-positive histiocytes. The widely separated lymphoid clusters contained a roughly equal mixture of CD20-positive B lymphocytes (Figure 2, C) and CD3/5-positive T lymphocytes (Figure 2, C, inset). CD10-positive follicular center B cells were not detected. IgG4-positive plasma cells were discovered to be most numerous within the lymphoid aggregates (Figure 2, D) and less prominent within the fibrosclerotic tracts. A reticule was used to quantify the number of IgG4-positive plasma cells in the lymphoid aggregates in 5 high-power fields (x400), and the numbers were then averaged. The average count of IgG4-positive plasma cells per high-power field was greater than 35 (35.2, with a range of 12-52 per high-power field). In situ hybridization for [kappa] and [lambda] light chain determinants showed that the plasma cells were polytypic. The mononuclear and multinucleated cells lining the cutaneous fissures were CD45, CD68, and lysozyme-positive.


The propensity for periorbital membrane involvement in the current case is quite atypical for orbital fibroinflammatory disease, and it explains why the extraocular muscle and optic nerve functioning was unhampered. Histopathologic evaluation of the biopsies revealed the classic findings of idiopathic sclerosing inflammation. (1) Most of the lesion's volume (more than 90%) was composed of fibrosclerosis; only a small portion consisted microscopically of widely separated lymphoid aggregates or lightly dispersed inflammatory cells. The leading edge abutting the orbital fat was the richest in inflammatory cells. The diaspora of lymphoid aggregates without germinal centers (absence of CD10-positive cells) contained CD3/CD5-positive T lymphocytes and CD20-positive B cells in roughly equal numbers, signaling a truly inflammatory infiltrate. The k and X light chain determinants in the plasma cells and lymphocytes were also expressed in a polytypic fashion, as demonstrated with in situ hybridization. The broad bands of fibrosclerosis were populated mostly with CD68-positive histiocytes and CD3/CD5-positive T cells, although not to the total exclusion of a few CD20-positive B cells.

IgG4-positive plasmacytic infiltrates have recently become a marker for a sclerosing variant of fibroinflammatory diseases. (5) These cells in inflammatory lesions were initially detected in the pancreas (6) and are now known to be associated with multisystem IgG4-positive fibrosing disorders, including sclerosing cholangitis, sclerosing sialadenitis, and retroperitoneal fibrosis. (5) Among sclerosing lesions of the orbit, IgG4-secreting plasma cells have been documented in allegedly chronic sclerosing dacryoadenitis, which in one report served as the soil out of which emerged 3 lacrimal gland IgG4-positive lymphomas (2 extranodal marginal zone and 1 follicular lymphoma). (7) Our critical review of these and other published cases of sclerosing dacryoadenitis, (8-10) however, leads us to conclude that most represent a different type of lesion (reactive lymphoid hyperplasia) from what we are reporting here. Virtually all of these reported lacrimal gland lesions (ours was not found in the lacrimal gland) were hypercellular lymphoid masses subdivided by variably prominent bands of collagen, reflecting thickenings of the interlobular septa. Equally compelling for our reinterpretation is that most were bilateral lacrimal gland diseases, (8-10) whereas inherently sclerosing masses usually tend to affect only one orbit. (1) As demonstrated by photomicrographs, the lymphoid component constituted far more than 80% of the total volume of the lesions. (7-10) In one study, (8) on sequential biopsies, collagenization became somewhat more prominent, but a densely cellular follicular organization was nonetheless preserved. This retrospective determination helps to explain the potential of the lacrimal lesions to evolve into lymphoma.

In contrast, IgG4-positive sclerosing pancreatitis is dominated by advancing fibrosis without lymphoid follicles11 and most closely resembles the current orbital lesion as well as retroperitoneal fibrosis, both of which are also typically bereft of follicles. These conditions are not noted for their precursor role in spawning lymphomas. (1,2) Probably the closest analogy that can be drawn from another organ is the difference between Hashimoto thyroiditis and Riedel struma. (1) The precise role of IgG4-positive plasma cells in eliciting fibrosis in nonlacrimal orbital soft tissue lesions or in those of other sites has yet to be determined, as well as whether these cells are a mere marker or an epiphenomenon. Unlike the lacrimal gland, which has its own intrinsic intralobular lymphoplasmacytic architecture with lymphatics, (12) the orbital fibromuscular and fibroadipose soft tissues are devoid of a standing population of inflammatory cells, and furthermore lack lymphatic channels.

Fibrotic masses displaying infiltrating IgG4-positive plasma cells can also be associated with elevated serum IgG4 levels. (6) Neild et al, (13) in their review of 12 cases of idiopathic retroperitoneal fibrosis, reported a rapid clinical response to glucocorticoid treatment during the acute-phase response of elevated serum IgG. They noted that the number of IgG4-staining cells in the tissues did not necessarily correlate with elevated serum IgG levels. A favorable response to steroid therapy has also been documented by another group. (14) Sato et al (9) found that IgG4 serum levels remained elevated in remission when measured after treatment. This finding may be due to residual IgG4-secreting plasma cells located subclinically elsewhere in the body outside of the field of the clinically responsive and regressing lesions. (9) In our case, the average number of IgG4-positive plasma cells (>35 per high-power field) was considerably increased compared with what has been regarded as nonspecific. (13,15) There are, however, no comparative data on other types of orbital inflammation (eg, Graves disease) regarding the extent of IgG4-positive plasmacytic infiltration in orbital soft tissue fibroinflammatory processes that do not involve the lacrimal gland but instead are situated in muscle or fat.

On the other hand, the prominence of IgG4-positive plasma cells in IgG4-related autoimmune pancreatitis and retroperitoneal fibrosis has been more intensively studied. (5,13,15) According to Kamisawa et al, (15) both "moderate" (tissue counts of 11-30 IgG4-positive plasma cells per high-power field) and "marked" (>30 IgG4-positive plasma cells per high-power field) degrees of infiltration were considered diagnostic of IgG4-related sclerosing autoimmune pancreatitis. Neild et al (13) reported a grade 2 infiltration of 20 to 50 IgG4-positive plasma cells per high-power field to be significant in cases with IgG4-related idiopathic retroperitoneal fibrosis when compared with controls. Sato et al (9) reported 21 cases of IgG4-related orbital sclerosing masses (17 of which had lacrimal gland involvement, whereas the other soft tissue lesions were not well characterized) and considered a count as low as 10 IgG4-positive plasma cells per high-power field to be significant. As mentioned above, most of these lacrimal cases in our opinion were not adequately sclerosing to be deemed intrinsically pseudotumors as opposed to lymphoid hyperplasias with a component of reactive fibrosis. Because the IgG4-positive cell count in our case was obtained after a 20-year duration of the disease, one can only speculate what shifts might have occurred in the lymphoplasmacytic composition, perhaps away from a higher proportion at an earlier stage. Our patient died unexpectedly from a cardiac arrhythmia, so we were unable to evaluate his serum IgG4 levels. To repeat, this parameter does not necessarily correlate with the density of IgG4 plasma cells in the particular tissues that are biopsied, because other sites might be subclinically involved. (13)


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(3.) Mottow-Lippa L, Jakobiec FA, Smith M. Idiopathic inflammatory orbital pseudotumor in childhood: II: results of diagnostic tests and biopsies. Ophthalmology. 1981;88(6):565-574.

(4.) Ahmed M, Niffenegger JH, Jakobiec FA, et al. Diagnosis of limited ophthalmic Wegener granulomatosis: distinctive pathologic features with ANCAtest confirmation. Int Ophthalmol. 2008;28(1):35-46.

(5.) Kamisawa T, Okamoto A. IgG4-related sclerosing disease. World J Gastroen terol. 2008;14(25):3948-3955.

(6.) Hamano H, Kawa S, Horiuchi A, et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med. 2001;344(10):732-738.

(7.) Cheuk W, Yuen HK, Chan AC, et al. Ocular adnexal lymphoma associated with IgG4+ chronic sclerosing dacryoadenitis: a previously undescribed complication of IgG4-related sclerosing disease. Am JSurgPathol. 2008;32(8):1159-1167.

(8.) Cheuk W, Yuen HK, Chan JK. Chronic sclerosing dacryoadenitis: part of the spectrum of IgG4-related Sclerosing disease? Am J Surg Pathol. 2007;31(4):643-645.

(9.) Sato Y, Ohshima K, Ichimura K, et al. Ocular adnexal IgG4-related disease has uniform clinicopathology. Pathol Int. 2008;58(8):465-470.

(10.) Takahira M, Kawano M, Zen Y, et al. IgG4-related chronic sclerosing dacryoadenitis. Arch Ophthalmol. 2007;125(11):1575-1578.

(11.) Zhang L, Notohara K, Levy MJ, et al. IgG4-positive plasma cell infiltration in the diagnosis of autoimmune pancreatitis. Mod Pathol. 2007;20(1):23-28.

(12.) Wieczorek R, Jakobiec FA, Sacks EH, Knowles DM. The immunoarchitecture of the normal human lacrimal gland: relevancy for understanding pathologic conditions. Ophthalmology. 1988;95(1):100-109.

(13.) Neild GH, Rodriguez-Justo M, Wall C, Connolly JO. Hyper-IgG4 disease: report and characterisation of a new disease. BMC Med. 2006;4:23.

(14.) Kamisawa T, Yoshiike M, Egawa N, et al. Treating patients with autoimmune pancreatitis: results from a long-term follow-up study. Pancreatology. 2005; 5(2-3):234-238 ; discussion 238-240.

(15.) Kamisawa T, Funata N, Hayashi Y, et al. A new clinicopathological entity of IgG4-related autoimmune disease. J Gastroenterol. 2003;38(10):982-984.

Manisha Mehta, MD; Frederick Jakobiec, MD, DSc; Aaron Fay, MD

Accepted for publication April 15, 2009.

From the Department of Ophthalmology (Drs Mehta, Jakobiec, and Fay), the David G. Cogan Laboratory of Ophthalmic Pathology (Drs Jakobiec and Mehta), and the Facial Plastic and Reconstructive Surgery Service (Dr Fay), Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Frederick A. Jakobiec, MD, DSc, David G. Cogan Laboratory of Ophthalmic Pathology, Massachusetts Eye and Ear Infirmary, 243 Charles St, Boston, MA 02114 (e-mail: Fred_Jakobiec@meei.
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Author:Mehta, Manisha; Jakobiec, Frederick; Fay, Aaron
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Clinical report
Geographic Code:1USA
Date:Aug 1, 2009
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