DEFINITION, CLASSIFICATION, AND

CHANGING PARADIGM IN ORBITAL

INFLAMMATORY DISEASE

In understanding orbital inflammatory disease, it is important to separate lymphoproliferative processes from the discussion of inflammatory disorders, since they are distinct entities that can be clearly defined pathologically and should no longer be included with the inflammatory processes. The noninfectious orbital inflammations can be viewed as either nonspecific or specific. In our series of patients with inflammation reviewed between 1976 and 1988, we have noted that 70% of noninfectious lesions were nonspecific while 30% were specific. Data from 2001 of all patients show that the ratio is now 1:1, demonstrating a significant shift toward specificity in diagnosis. The nonspecific inflammations are clinically acute and subacute, and are probably best understood in terms of their anatomic localization. We have defined these as myositic, lacrimal, anterior, diffuse, or apical, each of which have a constellation of findings based on their location. On the other hand, specific inflammations are defined on the basis of identification of a specific pathogen, specific local and=or systemic constellation of findings, or a specific kind of pathology. Examples of specific inflammation include microbial infection, granulomatous inflammation, many different types of vasculitis, and sclerosing inflammation (2). In the instance of vasculitic and granulomatous disorders,

For example, Wegener’s granulomatosis is distinct from some of the hypersensitivity or leukocytoclastic angiitides (3). Tables 1 and 2 outline the features of nonspecific and specific inflammations.

ROLE OF BIOPSY

We have noted that biopsy has allowed definition of more specific constellations, such as Wegener’s granulomatosis that

occur within the orbit (3). It has also led to a redefinition of lesions, such as sclerosing inflammation and xanthogranulomatous disease that have a very specific histopathology and constellation of findings. Indeed, 70% of our own biopsied inflammations have been associated with the discovery of a specific disorder, many of which have systemic implications as reported by Hamedani in this symposium. This paradigm should be applied carefully in the diagnosis of patients with so-called ‘‘nonspecific orbital inflammatory disease,’’ particularly if the patient has an atypical onset, a particular location involved, or associated systemic findings. Our tendency is to define inflammations as a specific disorder before accepting a diagnosis of nonspecific orbital inflammatory diseases, particularly in certain locations, such as the lacrimal gland or the orbital apex. In the lacrimal gland, a high percentage (50%) of biopsied inflammatory lesions was associated with systemic disease. The range of diagnoses that we have experienced with lacrimal inflammations includes Wegener’s granulomatosis (including in children), sclerosing inflammation, Sjo¨gren’s syndrome, sarcoidal reactions, and autoimmune diseases. Apical disease tends to be associated with either sight-threatening or even life-threatening disorders, and should rarely be accepted as nonspecific without meticulous investigation and consideration of biopsy.

Because of the paradigm shift based on our own experience, we tend to analyze orbital disease by defining the anatomy, looking at the pathology in terms of types of reactions that are based on the cell type and the focus of the infiltrate, then look for associated systemic or local features, and specific pathologic patterns thereby arriving at more specific diagnoses (Fig. 1).

Myositis is a good example of this shifting paradigm. In our experience, this disorder presents in an isolated, recurrent, or atypical fashion. Isolated myositis is acute or subacute, and typically when involving a single muscle is likely to be characterized by a single episode without systemic associations. On the other hand, recurrent myositis by definition is characterized as having repeated acute episodes or progressive sequential involvement of muscles. It typically involves

Table 2 Examples of Specific Inflammations of the Orbit

Infections and infestations

Microbial

Fungal

Mucormycosis

Aspergillosis

Tuberculosis and syphilis

Parasitic

Echinococcosis

Cysticercosis

Other specific inflammations

Vasculitis

Wegener’s granulomatosis

Other respiratory vasculitides

Polyarteritis nodosa

Hypersensitivity (leukocytoclastic vasculitis)

Sclerosing inflammation of the orbit

Granulomatous inflammation

Foreign body granuloma

Sarcoidal inflammation

Xanthogranulomatous inflammation

Transitional lesions

Kimura’s disease

Sjo¨gren’s syndrome

Sinus histiocytosis with massive lymphadenopathy

Castleman’s disease

more than one muscle in the first episode, and there is a higher incidence of associated systemic disorders. Finally, patients with atypical myositis (e.g., painless, characterized by a prolonged course, or with compressive features) should undergo biopsy, since this category has included such disorders as sclerosing inflammation, giant cell myositis (possibly associated with pericarditis and risk to life) (4), reactive lymphoid lesions, and more recently inflammation dominated either by T-cells or CD20-positive cells, which may have specific therapeutic implications. This definition of myositic disorders allows for a management algorithm that considers biopsy for bilateral, recurrent, and atypical presentations (Fig. 2).

THE ROLE OF IMMUNE MEDIATORS IN

SPECIFIC INFLAMMATIONS

Sclerosing inflammation was redefined by ourselves in a multicenter study done in the early 1990s (2,5). We define this inflammation as a de novo primary sclerosing process of the orbit with potential multisystem involvement (in particular, mediastinal and retroperitoneal fibrosis) that has a tendency to relentless progression. We found that the immunohistologic profile demonstrated a T-cell lymphocyte dominance with histiocytes and macrophages that was similar to retroperitoneal fibrosis. These new insights obtained from pathologic, pathophysiologic, and clinical inferences underline the necessity to understand the role or specific inflammatory and immune mediators. For example, T- and B-cells are found in different ratios depending on the nature of the disease process and may play an important role in inducing specific kinds of responses, such as fibroplasia. Indeed we found that in sclerosing inflammation and more recently in xanthogranulomatous disease that T-cells appear to play a significant role in the induction of either fibroplasia or a xanthogranulomatous reaction. In the case of thyroid orbitopathy, evidence suggests that in the early stages of the disease, T-cells play an important role with regard to activation of the fibroblast, leading to the production of glycosaminoglycans and fibrosis. With regard to adult xanthogranulomatous disease, as reported by Sivak in this symposium, there appear to be four syndromes with different local and constitutional features. The immunohistopathologic profile indicates a cytotoxic, T-cell mediated, local fibroblastic and lipophagic process in Erdheim–Chester disease and adult-onset asthma with peri-ocular xanthogranuloma (AAPOX). Systemic studies in this population also suggest a B-cell mediated component in AAPOX and necrobiotic xanthogranuloma. The T-cells implicated are of a cytotoxic CD8 cell type.

In thyroid orbitopathy, the orbital connective tissue, lipocytes, and possibly the extraocular muscles are thought to be targeted by T-lymphocytes as well. Activated lymphocytes