If an antigen evades the innate immune system, it will be attacked by the adaptive system, which manifests specificity for its target antigen and prepares for future challenges. The adaptive immune mechanism is composed of normally silent players, which, when activated, proliferate and create mechanisms for defense. Cellular effectors are represented by T (thymus) lymphocytes (T cells) and B (bone marrow) lymphocytes (B cells). T cells regulate and assist the active immune response. B cells, when differentiated into plasma cells, produce antibodies (immunoglobulin (Ig)) and are responsible for humoral immunity. Humoral immunity is recognized by antibody production, T helper cell lymphocytic activation, and cytokine production. The cell-mediated immune response involves activation of phagocytes, antigen-specific cytotoxic T cells, and release of various cytokines. Both the innate and adaptive immune systems comprise humoral and cell-mediated components.
A specific type of T cell is the T-helper cell (TH), also called CD4+ T cells. TH cells generally help activity by releasing cytokines. TH1 cells maximize the killing efficacy of macrophages and proliferation of cytotoxic T cells (type 1 cell-mediated response), defending against viruses and other intracellular pathogens, eliminating malignant cells, and stimulating delayed-type hypersensitivity skin reactions. TH2 cells stimulate B cells into proliferation, induce B-cell antibody class switching, and increase neutralizing IgG, IgM, and IgA antibody production (type 2 humoral immunity) to help eliminate extracellular organisms.
Acute inflammation is histologically characterized by neutrophils, which are polymorphonuclear leukocytes and have phagocytic activity (Fig. 11.2A). Variations include eosinophils in parasitic infections and basophils (termed mast cells when in tissue) in allergic conditions. In chronic or prolonged inflammation, the neutrophil infiltrate is replaced with mononuclear cells such as monocyte-derived macrophages, lymphocytes, and plasma cells (Fig. 11.2B).
In particular cases of chronic infection, granulomas may develop. A granuloma consists of a highly organized collection of lymphocytes and epithelioid macrophages, which sometimes fuse to form giant cells (Fig. 11.2C). In autoimmune disease, activated macrophages often are a major factor causing damage. Tissue destruction by inflammatory cells leads to functiolaesa, and collateral normal tissue may be damaged. In the stage of resolution and repair, proliferating fibroblasts deposit collagen, leaving scarred, hyalinized remains. One extreme of such scarring is sclerosing inflammation, consisting of excess fibrosis with scant inflammatory cells (Fig. 11.2D). As with other types of chronic inflammation, sclerosing inflammation is poorly understood, as it does not follow the classic transition from acute inflammation to chronic inflammation.
Medical Therapy
Medical treatment targets the inflammatory response, irrespective of the underlying cause. Medicines are usually introduced in the order of their safety profile, but also depending on the stage, activity and severity of disease, organ damage, and quality of life (Box 11.1).
First-line therapies include corticosteroids (usually methylprednisolone), but the high doses and prolonged duration needed for treatment induce numerous systemic adverse effects, including insomnia, weight gain, mood changes, psychosis, hyperglycemia, acne, and bone demineralization.
Second-line regimens are the antimetabolites (methotrexate, azathioprine, mycophenolate mofetil), T-cell inhibitors (cyclosporin, tacrolines), and alkylating agents (cyclophosphamide, chlorambucil).
The new biologic agents suppress inflammation in a more targeted fashion by selectively addressing one aspect of the immune response, hence with fewer side effects than are seen with systemic corticosteroids. They include the tumor necrosis factor-α (TNF-α) inhibitors (infliximab, etanercept, adalimab) and rituximab, directed against CD20-positive B cells. All these nonsteroidal drugs, including the antimalarial drug hydroxychloroquine and leflunomide, are also referred to as disease-modulating rheumatoid arthritis drugs (DMRADs).
Practical Pathway to Diagnosis
Clinical Features and Imaging
A careful history and clinico-radiologic examination are the first guiding steps toward elucidating the cause of orbital inflammation (Fig. 11.3). The patient demographics of the idiopathic and non-IgG4–related autoimmune disorders tend to differ from those of the lymphoproliferative disorders and IgG4-RD (Fig. 11.4). The signs and symptoms of orbital inflammation vary, depending on etiology, anatomic focus, and the amount of mass and fibrosis. Many orbital inflammatory conditions lack a characteristic clinical sign but, indeed, share clinicoradiologic features. In some conditions, however, the finding of characteristic ocular inflammation and periorbital involvement allows refinement of the diagnosis (Figs. 11.5 and 11.6) In general, involvement of both orbits, simultaneous or sequential, favors the diagnosis of autoimmune disease, although the idiopathic and lymphoproliferative disorders can also present this way.
Tissue Biopsy
The next step to narrow the vast differential diagnosis is a tissue biopsy. A biopsy may be unnecessary in selected conditions with pathognomonic clinicoradiologic features and a contributory medical history, or when the risk of surgical damage outweighs the benefit. The latter is particularly of concern in lesions located in the orbital apex, optic nerve sheath, superior orbital fissure, and sclera. The risk to compromise function following sampling of a lacrimal gland mass is relatively low because of disease-related gland atrophy commonly discovered in inflammatory lesions. To obtain an adequate and representative diagnostic tissue biopsy, the following guidelines are recommended (Box 11.2).
Systemic corticosteroids, or other immunosuppressants, should be withheld in the weeks before the biopsy so as not to mask the pathologic findings. If the patient is receiving corticosteroids, the medication should be stopped several weeks before the surgery. If this is not possible, the lowest possible dose should be given.
Incisional or excisional biopsy is preferred to fine-needle aspiration biopsy because of the need for morphologic assessment. In addition, aspiration biopsy is technically not feasible in a solid, rubbery tumor, which is often encountered in the idiopathic and autoimmune disorders. Conversely, fine-needle aspiration biopsy of the orbital mass can be useful in specific cases, especially with suspected lymphoma or metastasis usually to confirm the diagnosis.
The specimens should be as large as possible and fixed in formalin for paraffin embedding that is used for histology, immunohistochemistry, immunophenotyping, and molecular genetic studies for polymerase chain reaction. The other sample(s) should be submitted as fresh tissue in saline for flow cytometry and other ancillary testing, particularly when a lymphoproliferative lesion is suspected. For firm, white, avascular lacrimal gland lesions of presumed idiopathic origin, “the rule of 3” is advised. This refers to taking a minimum of three large biopsy samples: one for fixing in formalin, one for fresh submission, and one for “the cure,” since debulking surgery may be therapeutically beneficial in patients with idiopathic dacryoadenitis.
Where possible, sampling should cover all areas of the mass. The periphery may represent secondary inflammation, as in some lymphoproliferative or other neoplastic lesions. The sample should be obtained from their core. By contrast, the periphery may feature specific inflammation leading to a diagnosis, with the core consisting of fibrosis only. Specifically for the lacrimal gland, sampling of the orbital lobe is preferred – unless the mass is confined to the palpebral lobe – via a transcutaneous approach. This prevents damage to the main excretory lacrimal ducts from the palpebral portion, which empty in the superolateral fornix.
Soft, flaccid masses are often lymphoproliferative and are susceptible to crush artefacts with excessive handling. To minimize tissue damage while sampling, the use of blunt anatomic forceps or gentle small-bore suction is preferred over tooth forceps, and a surgical blade is preferred over scissors.
When available, prior biopsy samples from different organs should be collected for review by the same pathologist, for evidence of systemic disease.
If only minimal, nonspecific inflammation without other pathologic changes is the sole finding in the biopsy specimen, or when pathology is inconsistent with the clinicoradiologic context, a repeat biopsy at an additional site of the lesion is recommended.
Serology
The indicators of inflammation, such as CRP, high erythrocyte sedimentation rate, leukocytosis, and low albumin levels, are often normal in patients with inflammation limited to the orbit. However, a serologic workup for autoimmune disease may lend support to the diagnosis (see Chapter 4). It includes testing for antineutrophil cytoplasmic antibodies (ANCA); angiotensin-converting enzyme (ACE); anti-Sjögren syndrome antigens (anti-SSA (Ro) and anti-SSB (La)); antinuclear antibodies (ANA); rheumatoid factor (RF); anticitrullinated protein antibodies (ACPA), including anticyclic citrullinated peptide antibodies (anti-CCP); and IgG4. This is assessed on an individual basis, and not all tests are required in every case. Importantly, a serologic autoimmune workup should not be used as mere screening to waive a biopsy. First, autoimmune disease confined to the orbit is frequently associated with negative serum markers, probably because the disease load is small. Second, some of these markers have a relatively low specificity. Serum IgG4 levels, for example, can be normal because of limited disease or the prozone phenomenon and are by no means unique for IgG4-RD.2,3
Final Diagnosis
The diagnosis is reached when the pathologic findings are complementary to the clinical assessment, history, imaging, and, if applicable, to disease-specific serologic markers. In this respect, the sole tissue finding of nonspecific inflammation, or a positive IgG4 stain, is not sufficient to diagnose, respectively, IOI or IgG4-RD.4,5 The diagnosis of these conditions also demands the appropriate clinicoradiologic and pathologic appearance. On indication, the patient is referred to other specialists for a systemic workup or disease staging.
Idiopathic Orbital Inflammation
IOI is a fascinating but poorly understood orbital-specific disorder not associated with systemic disease. The recognition of orbital myositis dates back to 1903, when Gleason described a patient with the clinical symptoms of a rapid onset, aggressive bilateral orbital tumor, but which showed inflamed extraocular muscles on histopathologic examination. In 1905, Birch-Hirschfeld reported on a series of patients presenting with orbital tumor that consisted of inflammatory tissue only and coined the term orbital pseudotumor. Unfortunately, this diagnosis became a popular term for unidentifiable diseases.
IOI is characterized by an enlarged orbital structure or mass that causes nonspecific inflammation, fibrosis, and, in the lacrimal gland, damage. In patients with involvement of the extraocular muscles (idiopathic myositis) or lacrimal gland (idiopathic dacryoadenitis), there is an increased prevalence of autoimmune diseases not directly related to orbital inflammation, such as regional enteritis (Crohn disease) in the myositic subtype.6–9
Pathogenesis
The immunopathogenesis remains to be identified. It may be considered a process rather than a specific disease, based on the diversity of presentation and the unpredictable course.10 An infectious antigenic precursor has been suggested, which is supported by findings of an aberrant (cell-mediated) TH1 pathway, as well as increased levels of toll-like receptors, despite absence of bacteria or increased amounts of viruses in specimens of IOI.11–13 Mast cells have been reportedly linked to the fibrogenesis in IOI, and there is evidence for a role of fibrocytes, which have features of both immune cells and fibroblasts.14,15 In idiopathic dacryoadenitis, TH2-mediated B-cell humoral immunity has been implicated in the pathogenesis of the lymphoid follicular type, and TH1-mediated cellular immunity in the sclerotic type.16
Epidemiology
IOI occurs in all age groups, but the incidence peaks at 50 years in dacryoadenitis and at 30 years in myositis. It is slightly more prevalent in females, without racial preference.
Classification
IOI is classified into four anatomic groups. When limited to the lacrimal gland, it is called idiopathic dacryoadenitis, which is the most common anatomic variant (Fig. 11.7). When limited to one or several extraocular muscles, it is called idiopathic orbital myositis. Less frequently, the lesion involves several structures of the orbit, grossly referred to as diffuse IOI (Fig. 11.8). Rarely, it affects the optic nerve sheath and is called idiopathic optic perineuritis.
Clinical Features
The onset is acute to subacute. Pain is present in most of the myositic cases but less often in nonmyositic cases (81% and 67%, respectively).17–19 Both orbits are affected in an incidence range between 8% and 14% of IOI (also the sclerosing subtype) and idiopathic myositis and in 20% of idiopathic dacryoadenitis.8,17–21 In idiopathic dacryoadenitis, half of the patients present with a dry eye and 20% with (epi)scleritis superolaterally.18
Idiopathic myositis can affect any muscle, commonly the horizontal rectus muscles.17 The inflamed muscle is usually identified by episcleritis at the site of its insertion. The muscle displays weakened function and is particularly painful when stretched, which should not be interpreted as restrictive motility8 (Fig. 11.9). When different muscles become involved during recurrences, it is referred to as migratory idiopathic myositis.22
Investigations
A trial of systemic corticosteroids demonstrating clinical responsiveness to approximately 1 mg/kg/day of prednisolone for 3 to 7 days should not replace biopsy as a means of diagnosing IOI. It improves the symptoms in 80% of nonsclerotic IOI but also those of various other inflammatory lesions, including specific proliferative lesions.23–25
On radiographic imaging, idiopathic dacryoadenitis is marked by a well-defined enlarged lacrimal gland, occasionally spilling into the surrounding orbital and eyelid tissue or with lateral or superior rectus muscle enlargement18 (Fig. 11.7B). Idiopathic orbital myositis features diffuse enlargement of one or several muscle(s). Anterior tendon involvement is a less reliable radiologic marker than traditionally taught, since it is present in less than 50% of idiopathic myositis and present in 43% of lymphoid and 6% of thyroid muscles8,17,26,27 (Figs. 11.9 and 11.10).
The IOI pseudotumor, particularly the sclerosing variant, has ill-defined borders, diffusely involves several orbital structures, and is usually located in the superior and lateral orbit.19–21 IOI may extend beyond the orbit, via the superior orbital fissure into the cavernous sinus and the middle cranial space, or via the inferior orbital fissure into the pterygopalatine and infratemporal fossa28,29 (Fig. 11.8). Extraorbital extension is associated with bone changes such as erosion, destruction, sclerosis, or remodeling in 36% of cases.29
Pathology
Tissue biopsy is important since IOI is diagnosed by exclusion. However, in idiopathic orbital myositis with its characteristic clinical and radiologic picture, a muscle biopsy is usually not performed. A muscle biopsy is required when there are atypical features of nonthyroid orbital myositis, including absence of pain, all muscles being affected, nodular muscle enlargement, and restrictive eye motility (Fig. 11.11).
Histologically, IOI consists of a lymphoplasmacytic infiltrate, mixed with neutrophils and eosinophils and occasionally with histiocytes and macrophages. In IOI, unlike in the most common lymphoproliferative lesions, the T cells outnumber the B cells.30 The infiltrate can be focally organized in lymphoid follicles, usually with reactive germinal centers. The presence of fibrosis is mandatory for the diagnosis but should be distinguished from that of a normal and aged lacrimal gland.31,32 In the lacrimal gland, early destruction of the acini and later the ducts is observed, whereas in the muscle, normal striations are lost with degeneration of the myofibers.6,33 When dense sclerosis predominates, along with a scarce inflammatory infiltrate, the lesion is classified as sclerosing IOI, which is considered a separate condition and should prompt the investigation to rule out systemic diseases such as IgG4-RD.34
Management
A good initial response to high-dose (60–80 mg) systemic corticosteroids, either oral or intravenous, is observed in almost all cases of typical acute myositis and in about 80% of nonmyositic cases.8,24,25,35 Corticosteroids are particularly useful in combined compressive optic neuropathy.24 However, roughly half of cases relapse on tapering or ceasing, rendering a 37% efficacy to corticosteroids as a definitive cure.24 Sclerosing IOI is only 33% corticosteroid responsive, with a 42% relapse rate.19
Surgical debulking of the lacrimal gland mass is successful in 80% of cases and considerably reduces the relapse rate to 8% and so is 74% efficient as a cure.6 One approach, combining both diagnosis and therapy in one surgical procedure, is to remove a large section of the involved tissue, not only providing biopsy material but also reducing the tumor load. The benefit of debulking is also reported in diffuse IOI, particularly in the sclerosing lesions.19,36,37
In nondebulkable IOI, myositis, diffuse, or apical lesions, valuable alternatives to systemic corticosteroids are repetitive perilesional corticosteroids or, in mild cases, nonsteroidal anti-inflammatory drugs.17,38 In severe, recurrent or recalcitrant cases with a high morbidity, methotrexate with radiotherapy and biologic drugs such as rituximab or infliximab are used respectively as second-line and third-line regimens.6–8,24,39
Orbital Granulomatosis with Polyangiitis (Wegener Granulomatosis)
Granulomatosis with polyangiitis (GPA) was previously known by the eponym Wegener granulomatosis. It is a proteinase 3-reactive–ANCA-associated vasculitis (PR3-AAV), characterized by necrotizing granulomatous inflammation, usually involving the upper and lower respiratory tract, and necrotizing vasculitis affecting predominantly the small-sized and medium-sized vessels of the respiratory and renal systems.40 It was first described clinically at the turn of the twentieth century by Peter McBride, who reported “on a case of rapid destruction of the nose and face,” and histopathologically by Heinz Karel Ernst Klinger. In 1936, Friedrich Wegener proposed that the disease should be considered a clinicopathologic triad since it involves primarily three systems: vascular, respiratory, and renal.
Pathogenesis
The pathogenic pathway in GPA is considered a combination of environmental events such as bacteria and toxins and genetic risk. A role of ANCA pathogenicity has been suggested. ANCA are antibodies against the antigens present within the granules of neutrophils and monocytes and are thought to be responsible for tissue damage via interactions with neutrophils and endothelial cells.
Epidemiology
GPA most often occurs in the fourth and fifth decades of life, with an equal frequency in males and females. It appears that whites, especially from Northern Europe, are more commonly affected compared with other racial groups.
Classification
GPA can be broadly separated into two distinct clinical presentations: systemic or generalized and regional or limited.
Generalized GPA is a life-threatening problem. Before the advent of systemic chemotherapy, systemic GPA was a fatal condition, with a mean survival of only 5 months and 82% mortality within 1 year. Cytotoxic agents such as cyclophosphamide improved these numbers, with up to 90% remission rate.41
Whether limited GPA is a subtype of generalized GPA or a separate entity remains unclear. Limited GPA most commonly affects the upper respiratory tract including the nasopharynx and paranasal sinuses, with the orbits secondarily involved.42 The orbit specialist is more likely to encounter the limited form of GPA.43
Orbital GPA presents in three relatively distinct patterns: extraconal orbital mass in close proximity to diseased paranasal sinuses, diffuse mass filling the entire orbit, and lacrimal gland mass.44 All of these patterns are associated with sinus disease that is typically destructive.
Clinical Features
Orbital GPA has a subacute onset and manifests bilaterally in 30% to 55% at first presentation and 85% at follow-up.44,45 Orbital pain is present in varying numbers from 20% to 80%.43,45,46 Ocular manifestations of GPA related to vasculitis – also often painful – are associated in 30% to 55% of the orbital masses.44,47 A saddle nose deformity resulting from destruction of the intranasal cartilaginous support manifests in half of cases before the orbital mass48 (Fig. 11.12). The lacrimal gland mass – often bilateral – presents as painful or painless dacryoadenitis. The eyelid skin can exhibit specific changes at the site of the inflamed orbit. These include xanthelasmata-like lesions – referred to as the “yellow lid sign” – with orbital masses and brawny discoloration with dacryoadenitis.44,49 (Fig. 11.13).
GPA is marked by high morbidity with considerable damage to the orbital soft tissues and bones. Forty percent of patients evolve to orbital socket contracture, characterized by enophthalmos, restrictive eye motility, chronic orbital pain, and optic nerve compression50 (Fig. 11.12). Other complications include conjunctivonasal fistula and chronic infectious orbital abscess formation.43,45,51,52 Visual function is impaired in 73% of cases, of which 19% result in blindness.45
Investigations
Imaging, combining computed tomography (CT) and magnetic resonance imaging (MRI), shows an extraconal infiltrative mass, medially or inferiorly located, in close proximity to the diseased paranasal sinus.46,53,54 Sinus disease is combined with bone destruction in between 21% and 46% of cases and can best be appreciated on CT.43,44,47 Destruction of the nasal cavity and turbinates, in particular loss of the nasal septum, is typical for GPA.47,54 The lesion can be located in the apex only or extend intracranially.43,55 A similar radiologic pattern of sinonasal destructive process involving the midline with a contiguous orbital mass can result from chronic intranasal cocaine use.56
Diffuse intraconal and extraconal orbital infiltration, referred to as a “wall-to-wall” tumor, is pathognomonic for – usually advanced – GPA. Lacrimal gland GPA presents as diffusely enlarged glands, usually isolated, or occasionally in combination with an orbital fat mass.44
Testing for PR3-ANCA is useful to support the diagnosis.57 However, the value is reserved as ANCAs are positive in as few as 20% of the patients with limited orbital GPA (see Chapter 4).43,47
Pathology
GPA is characterized by the “histologic triad” of vasculitis, necrosis, and granulomatous inflammation with or without giant cells. In the orbit, however, this triad is found in roughly half of cases, as an orbital tissue sample may be too small to contain vessels58,59 (Fig. 11.13C and D). Secondary diagnostic features include a rich polymorphous inflammatory infiltrate consisting of neutrophils, eosinophils, lymphocytes, plasma cells, and macrophages, as well as mummification of collagen or granular degeneration.44,59,60 Notably, increased numbers of IgG4-positive plasma cells are found in 86% of orbital and lacrimal gland GPA lesions.61
Management
Orbital management is identical to that of systemic disease, with outcome measures assessing not only stage and activity of disease but also damage and quality of life. Corticosteroids are used for induction therapy of remission; however, their dosage and duration are not well defined. Maintenance therapy involves corticosteroids in conjunction with, or switching to, methotrexate, azathioprine, cyclophosphamide, mycophenolate mofetil, or rituximab. Rituximab was found clinically beneficial in refractory orbital disease.55,62,63There is a high prevalence of comorbidity such as infections, cardiovascular events, and malignancies, which contribute to the outcome and which usually result from the treatment rather than from the disease.
Once orbital socket contracture has established, medical immunosuppressive therapy fails.50 In such cases, and other cases with persistent proptosis, surgical debulking is considered to relieve pain and compressive optic neuropathy.45
Allergic Granulomatosis (Churg-Strauss Syndrome)
A closely related systemic vasculitis that may occasionally affect orbital tissues is allergic granulomatosis, also known as eosinophilic granulomatosis with polyangiitis (EGPA), first described by Drs. Churg and Strauss in 1951.64 This autoimmune vasculitis is also associated with positive ANCA titers and develops in the context of previous or existing airway allergic hypersensitivity.
Pathogenesis
EGPA is usually considered a TH2-mediated disease with CD4 T cells promoting allergic and eosinophilic reactions through secretion of cytokines. Resident endothelial and epithelial cells are also thought to produce eotaxin-3 and CCL17, which attract eosinophils, a diagnostic feature of this syndrome.65
Clinical Features
There are three stages described in EGPA, although they may not necessarily present sequentially and the severity of each stage may vary among individuals.66
The allergic stage precedes or occurs concurrently with the generalized syndrome in 90% of individuals and consists of asthma and/or allergic rhinitis, with rhinorrhea, nasal obstruction, and recurrent nasal polyps. The asthma usually develops several years before other disease manifestations but may worsen with onset of the syndrome.
The eosinophilic stage is recognized by elevated eosinophil counts in blood and within the affected organs, most commonly the lungs and the digestive tract.
Systemic symptoms include fever, weight loss, and night sweats along with organ-specific complaints of asthma or abdominal pain with gastrointestinal bleeding.
The vasculitic stage defines the syndrome and is characterized by inflammation of small and medium vessels with secondary necrosis in the involved organs. Severe complications may arise, depending on the targeted tissues, including ulcerations, perforations and peritonitis of the gastrointestinal tract, or eosinophilic myocarditis and myocardial infarction.
There are fewer than 20 case reports of orbital tissue involvement, including the lacrimal gland, conjunctiva, orbital fat, and muscle. The presentation may be a chronic inflammatory mass with pathology showing eosinophilic granulomas (EGs) or a more fulminant orbital inflammation with features of necrotizing vasculitis. In many of these cases, aside from a background history of asthma or rhinitis, the orbital disease was the first manifestation of the syndrome.67
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