The “ocular adnexum” is the comprehensive name for those tissues that sustain and give strength to the globe, including the conjunctiva, the lids, and the orbital soft tissues and bones. It holds the lacrimal gland and is extended on the lacrimal drainage and lacrimal sac. Ocular adnexal lymphomas (OALs) involve the orbit in approximately 45% of cases, the lacrimal gland in 26% of cases, the conjunctiva in 25% of cases, the eyelid in 8% to 9% of cases, and are relatively rare in the lacrimal sac.^1,2,3 Ocular lymphomas can occur at any age. They are most commonly developed in patients in the fifth to seventh decades of life, and are slightly more prevalent in women.⁴ Ocular adnexal lymphoid tumors are very rare in children.⁵ About 80% to 90% of primary OALs are extranodal marginal zone B-cell lymphomas of mucosa-associated lymphoid tissue (MALT lymphomas).^3–4 Although specific lymphoma subtypes are particularly linked to certain outcomes, location, unilateral or bilateral disease, and extension into the deep soft tissues, other clinical signs can also provide valuable information for the risk of relapse and disease-specific survival.^6,7,8 This chapter will review the epidemiology, etiology, clinical presentation, management, and outcomes for OAL.

The globe, excluding the cornea and limbal rim, and the external surface of the superior and inferior eyelids, is covered with a mucous membrane, the conjunctiva. The surface is layered by a nonkeratinizing squamous epithelium with a variable number of goblet cells. The conjunctiva may be divided into the bulbar conjunctiva that is freely movable and delicate, the tarsal or palpebral conjunctiva that is firmly attached to the inner surface of the inferior and superior eyelids, and the forniceal-orbital where the conjunctival tissue is redundant and loose.⁹ Two other references of the ocular surface are the plica semilunaris and the caruncle. The first is a nasal fold of redundant conjunctiva. The caruncle is a fleshy mass lying at the median interpalpebral inner canthus composed of the conjunctiva and lid tissues.

The lids have four layers: (1) the outer skin with elastic and baggy scant subcutaneous tissue, (2) the orbicularis striated muscle, (3) the dense fibrous tarsal plate holding the meibomian glands, and (4) the inner adherent tarsal conjunctiva layer. The lymphatic drainage of the lateral portion of the lid goes to the preauricular and intraparotid lymph nodes, and the medial lymphatic drainage goes to the submental and submandibular nodes. A clinically important landmark is the insertion of the levator palpebrae superioris. This structure attaches to the medial orbital rims and terminates in the upper lid penetrating the orbital septum. The ligaments are reinforced by orbital fibrous connective tissue and fascia expansion of the extraocular rectus muscles.

Each orbit has a volume of about 30 mm³ bounded by several bones. It contains a wide variety of tissues: neural, adipose, muscle, vascular excluding lymphatics, connective, and cartilage. The bony orbital walls contact with the paranasal sinuses. The lacrimal gland is accommodated in a shallow lacrimal fossa located in the anterosuperolateral orbit and measures 20 × 12 × 5 mm. It is split in a larger orbital lobe and a smaller palpebral lobe. Fluid from the main and accessory lacrimal gland is drained by the lacrimal canaliculi into the lacrimal sac and then into the nasal cavity. Unlike the parotid gland, the lacrimal gland does not possess lymph nodes. However, the parenchyma of the lobules contains dispersed lymphocytes and plasma cells. The glands drain into the superficial parotid lymph nodes.

The eye-associated lymphoid tissue (EALT), which comprehensively forms the immune system of the eye, is recognized as a component of the MALT found in different organs of the body.^10–11 MALT is composed of lymphoid cells situated in and closely underneath the epithelium. These cells detect antigens and induce an immune response. EALT includes the lacrimal gland, the conjunctiva-associated lymphoid tissue (CALT), and the lachrymal drainage-associated lymphoid tissue (LDALT).⁹

In normal conditions, the eye and orbit are devoid of native lymphoid tissue. The surface of the eye is covered by an immune system, providing detection and response to external antigens.¹² From birth to 3 or 4 years of age, the ocular surface is usually devoid of CALT.¹³ The lymphatic tissue develops after antigen stimulation and plasma cells secrete IgA, an important molecule present in the tears with activity against individual pathogens. This associated lymphoid tissue comprises the lacrimal gland and the lacrimal sac. Lymphocytes are present in the lamina propia (misleadingly called adenoid layer) and within the epithelium. Local immune responses also include the formation of lymphocytic aggregates and high endothelial venules. Chronic antigen stimulation initiates a reactive lymphoid infiltrate with polyclonality in the conjunctival tissues. The locations of lymphoid follicles are the upper and lower tarsal conjunctiva, and fornix. These locations are concordant with the most common sites of conjunctival lymphomas.

Extranodal marginal zone lymphomas (EMZLs) of the conjunctiva and orbit are often preceded by chronic inflammation and reactive lymphoid hyperplasia at the site of lymphoma development. The etiology is usually unknown.¹⁴ The current hypothesis of lymphomagenesis of extranodal marginal zone B-cell lymphoma of MALT type includes the following steps: antigenic driven reactive lymphoid hyperplasia, clonal expansion and proliferation of B cells, genetic alterations, and sustained growth of abnormal populations of B cells that develop specific gene mutations that ultimately lead to continued proliferation and immortality. According to this hypothesis, histologically suspicious lymphoid infiltrates should be studied for B-cell or plasma cell clonality using various methods, including immunohistochemistry, flow cytometry, in-situ hybridization, and/or molecular gene rearrangement methods (usually PCR-based) for the IGH gene.

Because of the clinicopathologic similarities between conjunctival and gastric MALT lymphomas, several studies have evaluated for the presence and role of infectious organisms in the pathogenesis of the disease: Helicobacter pylori (H. pylori),^{15,16,17,18,19} Chlamydophila psittaci (C. psittaci), C. pneumoniae,^{20,21,22,23,24} hepatitis C virus (HCV),²⁵ and herpes virus have been studied in OALs. In one study including 31 patients with ocular adnexa MALT lymphoma, 10 (32%) had gastric H. pylori, and 3 of them were also positive for C. psittaci.¹⁸ The patients with ocular adnexal MALT lymphoma showed no response. The same group reported that 80% of 40 patients carried C. psittaci. Interestingly, most of the lymphomas were MALT subtype, and have lymphoma regression following antibiotic treatment with doxycycline.^21–22 Another series revealed no evidence of H. pylori, C. psittaci, or C. pneumoniae.^26,27,28 A link between HCV infection, liver cancer, and B-cell lymphomas has been clearly documented; a study of ocular adnexal MALT lymphoma revealed that 13% of 55 patients had HCV seropositivity.²⁵ Furthermore, the authors claimed that HCV is associated with aggressive behavior.²⁵ The variability of these results among different patient cohorts has been interpreted as due to geographic variations in the prevalence of infectious agents and variability of used methods to identify the organism. In the absence of well-controlled and randomized studies, the relationship of infectious agents and OALs should be taken cautiously.²⁹ Rare associations were observed in Epstein–Barr virus and natural killer/T-cell lymphomas. Interestingly, evolving diffuse large B-cell lymphoma from low-grade OAL has been reported in the setting of Ig4 chronic dacryoadenitis, coexistent with autoimmune conditions such as Sjögren disease, Hashimoto thyroiditis, myasthenia gravis, Graves disease, rheumatoid arthritis, discoid lupus, mucous membrane pemphigoid, and autoimmune diseases unclassified.^30–31

Extraocular lymphoproliferative lesions and lymphomas may occur in the orbit, conjunctiva, lacrimal gland, lacrimal sac, and rarely in the eyelid skin. OALs represent 1% to 2.5% of all lymphomas and approximately 5% to 15% of extranodal lymphomas.^32,33,34 With very few exceptions, intraocular and adnexal lymphomas are non-Hodgkin B-cell lymphomas representing 10% to 15% of orbital, conjunctival, eyelid, and lacrimal sac tumors.³⁵ Most lymphomas involving the ocular adnexa are primary (78% to 92%), and the rest are secondary (8% to 22%).^{32,33,34,35,36} An estimated 5% of non-Hodgkin lymphoma patients develop OAL during the course of their disease.³⁷ The vast majority of adnexal lymphomas are low-grade marginal zone lymphomas (MZLs). According to the World Health Organization (WHO) classification of lymphoid tissues, MZL of the ocular adnexa is designated as EMZL of MALT.³⁷ Nevertheless, since the behavior of OAL varies, it is convenient to use EMZL for primary lymphomas in the orbit and restrict the term MALT to the conjunctiva lacrimal gland and lacrimal sac.³⁸ A noncomprehensive list of lymphomas affecting the OAL is summarized in Table 74-1. Because many of these studies have not separated conjunctiva, orbit, and lacrimal gland lesions from those of other origins, it is difficult to track the incidence and characteristics of the lymphomas in specific periocular sites.

Intraocular lymphomas, although exceedingly rare, may encompass highly aggressive primary central nervous system lymphomas (so-called primary vitreoretinal lymphoma), primary choroidal lymphomas, and secondary disseminated lymphomas. Statistical data disclosed a rapid and increasing incidence of ocular and adnexal non-Hodgkin lymphoma between 1975 and 2001.³⁴ The diagnosis of OAL is commonly a challenge for the pathologist. Because of location and complexity of the ocular tissues, biopsies are generally very small and artifacts frequently make difficult the cytologic and architectural characteristics required to distinguish between malignant and reactive lymphoid hyperplasia. In the past, histologically indeterminate lymphoproliferative lesions containing scattered large atypical cells, increased interfollicular mitotic activity, and cells with irregular nuclear outlines were designated as atypical lymphoid hyperplasia (ALH) of the ocular adnexa. The reported incidence was 3% to 12% of OAL.^3,39 Curiously, those lesions showed recurrences and may progress to low-grade lymphomas. Up to 45% of patients with histologically indeterminate lesions of the ocular adnexa ultimately develop disseminated disease.⁴⁰ Currently, these cases are mostly absorbed into the EMZL.⁴

Immunoglobulin heavy (IGH) and light chain gene and clonality rearrangements have demonstrated IgH rearrangement in as many as 80% of the reported cases of OAL (MALT).^32,36,37,41 All chromosomal alterations affect a common signaling pathway, resulting in activation of the nuclear factor-κB complex, leading to transcription of several genes contributing to lymphomatous transformation, cell proliferation, and survival. High-resolution single nucleotide polymorphism array is a useful method to discriminating OALs from benign lymphoproliferative diseases.

Translocations which have been found to be important for the pathogenesis of EMZL in the ocular adnexal region are t(11;18)(q21;q21) involving API2 and MALT1, t(14;18)(q32;q21) involving IGH and MALT1, t(3;14)(p14;q32) involving FOXP1 and IGH, and t(1;14)(p22;q32) involving Bcl-10 and IGH.⁴² The t(11;18)(q21;q21) translocation is present in approximately 20% of conjunctival EMZLs and is related to oxidative damage induced by genotoxic factors.⁴³ The t(14;18)(q32;q21) translocation is found in around 15% to 20% of ocular adnexal EMZLs and is described in the conjunctiva in particular.^44,45,46 Another 15% to 20% of ocular adnexal EMZL patients carry the t(3;14)(p14;q32) translocation, whereas t(1;14)(p22;q32) occurs in approximately 10% of these.^44,45,47 Trisomy of chromosomes 3 and 18 is another cytogenetic abnormality associated with EMZL.^48,49,50 Gains of chromosome 3 are rarely found in EMZL of the conjunctiva, whereas trisomy 18 is very common in conjunctival EMZL, found in as many as 67% of patients.^50,51 Trisomy of these chromosomes is often associated with the t(14;18)(q32;q21) and t(3;14)(p14;q32) translocations.^47,52 The t(14;18)(q32.3;q21.3) translocation is present in approximately 85% of FLs, including ocular adnexal FLs, has also been found in conjunctival FL. This translocation involves BCL2 and IGH gene. As for MCL, the t(11;14)(q13;q32) translocation occurs in more than 95% of MCL cases, including ocular adnexal MCL, and has also been found in conjunctival MCL. This chromosomal translocation involves cyclin D-1 (CCND1) and IGH.