Lymphomas involving the eye and the ocular adnexa

Purpose of review To describe recent advances in the understanding of the pathogenesis of the most common malignant lymphomas that occur as primary and secondary tumors in ocular tissues. Recent findings Advances have been made in the understanding of the genetic alterations in mucosa-associated lymphoid tissue lymphomas, including various chromosomal translocations, such as the most recently described t(3;14)(p14.1;q32) involving the FOXP1 gene. Further, the development of ocular adnexal mucosa-associated lymphoid tissue lymphomas has been associated with Chlamydia psittaci in some geographic areas. Subdivision of diffuse large B-cell lymphoma into clinically prognostic groups had been achieved on the basis of gene expression profiles using complementary DNA microarrays. Tumor-infiltrating cells, such as macrophages, have been demonstrated to be of prognostic significance in follicular lymphoma. Summary Understanding of the ocular adnexal and intraocular lymphomas has advanced with progress in lymphoma classification systems, namely the World Health Organization lymphoma classification. This knowledge is being fine tuned with advances in technology, such as complementary DNA microarrays. The clinical significance of this scientific progress has yet to be determined.


Introduction
The lymphomas are malignant neoplasms derived from a clonal proliferation of B or T lymphocytes. They can be divided into two major groups: Hodgkin lymphoma and non-Hodgkin lymphoma (NHL) [1]. The NHLs are a large heterogeneous group of neoplasms that can be further subdivided according to the cell of origin. About 80% of NHLs arise from B lymphocytes or their precursors, 14% develop from T cells, and 6% from natural killer cells [1].
For many years, the Working Formulation [2] and the Kiel lymphoma classification [3] were used predominantly in America and Europe, respectively. In 1994, the International Lymphoma Study Group [4] established the Revised European American Lymphoma (REAL) classification, which incorporated elements of both classification systems and was based on the morphologic, immunophenotypic and genetic, and clinical features of the various lymphoma entities. It was the first lymphoma classification that included both nodal and extranodal tumors. Owing to its high degree of reproducibility, the REAL classification has now been updated under the auspices of the World Health Organization (WHO) and is called the WHO Lymphoma Classification [1].
Lymphomas of the eye and its adnexa are relatively uncommon, accounting for approximately 10% of all extranodal malignant lymphomas [5]. Most are primary tumors and are usually NHLs of B-cell type: the most common primary lymphoma subtype occurring in the ocular adnexa is the low-grade malignant extranodal marginal zone B-cell lymphoma of MALT type (mucosa-associated lymphoid tissue) [6][7][8]. The most common lymphoma arising from ocular tissues is the socalled primary intraocular lymphoma, which is a diffuse large B-cell lymphoma (DLBCL) of high-grade malignancy arising in the retina [9]. Secondary ophthalmic lymphoma, which arises from systemic disease, can occur both in the ocular adnexa and intraocularly [10]. The most common secondary lymphoma subtype occurring in the ocular adnexa is follicular lymphoma, and that most frequently occurring in tissues within the eye is DLBCL.
In this review, we briefly describe the most recent advances in the understanding of the most common and important types of B-NHL occurring in ophthalmic tissues, i.e. the MALT lymphomas, the DLBCL, and follicular lymphomas. Additional varied secondary ophthalmic manifestations of lymphomas are also summarized.

Extraocular lymphomas: primary tumors
The three most frequent primary B-NHLs of the ocular adnexa are briefly discussed in order of frequency.

Mucosa-associated lymphoid tissue lymphomas
The MALT lymphomas are low-grade B-cell lymphomas that occur mostly in the gastrointestinal tract, particularly in the stomach. Since their first description by Isaacson and Wright [11] in 1983, it has become apparent that MALT lymphomas arise in a variety of extranodal sites, such as the salivary glands, thyroid, skin, ocular adnexa, lung and urogenital tract. Regardless of the site of origin, MALT lymphomas have similar clinical, pathologic, and molecular features (Table 1) [12].
Recently, several cytogenetic alterations have been demonstrated in MALT lymphomas, including those occurring as either primary or secondary tumors in the ocular adnexa (Table 1) [12,13 ]. Most affect a common signaling pathway and, thus, share a common pathogenesis. The common karyotypic alterations that characterize MALT lymphomas include trisomies 3 and 18 as well as the translocations t(11;18)(q21;q21), t(14;18)(q32;q21), t(1;14)(p22;q32), and the newly discovered t(3;14) (p14.1;q32) involving the FOXP1 gene [12,13 ]. The frequency of these translocations in MALT lymphoma is summarized in Table 1. These chromosomal alterations have proven to be of prognostic significance, particularly in gastric MALT lymphomas. It remains to be determined whether particular chromosomal abnormalities occur in primary ocular adnexal MALT lymphomas, and others in secondary ones. In addition, the chromosomal translocations are yet to be correlated with location (e.g. conjunctiva versus orbit), and their prognostic value in ocular adnexal lymphoma (OAL) is still to be determined.
Another area that has received particular interest recently is the possible role of exogenous antigens, such as Chlamydia psittaci, in the pathogenesis of ocular adnexal MALT lymphomas. A possible association of both primary and secondary MALT lymphomas of the ocular adnexa with C. psittaci created much excitement initially [14]; however, other studies could not demonstrate this microorganism in relatively large cohorts [15,16]. Chanudet et al. [17 ] suggest that there may be geographic variation in the distribution of this microorganism, and, consequently, possibly differences in its significance in the lymphomagenesis in ocular adnexal MALT lymphomas. The clinical relevance of this finding is considerable, as antimicrobials could be included in the armamentarium for treatment of these tumors.

Diffuse large B-cell lymphoma
Depending on which series is evaluated, DLBCLs represent either the second or third most frequent primary B-NHL subtype occurring in the ocular adnexa [7,18,19]. In addition they are the major subtype of primary intraocular lymphomas, but the most common subgroup of systemic lymphomas that secondarily infiltrate the eye (see below). The latter fact is not surprising considering that systemic DLBCL is one of the most common types of lymphoma in adults, accounting for approximately 30-40% of cases of NHL [1]. These tumors are heterogeneous in their morphology, antigenic profile and molecular genetic features (Table 1).
Recently, Alizadeh and associates [20] investigated the gene expression signatures of systemic DLBCLs using lymphochip complementary DNA microarrays and showed that overall survival after chemotherapy was significantly greater in patients with high gene expression levels, which are characteristic of normal germinal centre B cells. These results were confirmed by other groups [21,22] using both unsupervised and supervised statistical methods. Three biologically and clinically distinct subgroups of DLBCL have been identified, each with a specific gene expression signature: type 1 DLBCLs resemble germinal centre B cells (approximately 50% of cases); type 2 share features with activated B cells (approximately 30% of cases); and the third group is termed type 3 [20,21]. These findings suggest that the subgroups of DLBCL arise from different stages of normal B-cell development, perhaps representing distinct entities. To date, no expression profiling studies on ocular DLBCLs have been reported, and, therefore, it remains to be determined whether the ocular adnexal DLBCLs, as well as the primary or secondary intraocular DLBCLs, can be subdivided into one or more of the abovementioned prognostic groups on the basis of their gene expression profile.

Follicular lymphoma
Follicular lymphoma is a neoplasm of follicle centre cells (centrocytes and centroblasts) that has at least a partially follicular pattern [1]. Areas of diffuse or even pure diffuse growth patterns can, however, occur (Table 1). In European studies, follicular lymphoma is the third most commonly occurring primary B-NHL in the ocular adnexa [7,18] but is the most common secondary lymphoid tumor of the ocular adnexa (see below)  [6,24,25,29].
The symptoms and signs of S-OALs are quite variable but are not significantly different from those of patients presenting with primary ocular adnexal lymphomas (P-OALs). It is, therefore, essential to determine disease stage in all patients with OAL prior to starting therapy, so that systemic disease is detected.

Intraocular lymphoma
Lymphomas occurring in intraocular structures can be divided into three main groups: primary intraocular lymphoma; primary uveal lymphoma; and secondary intraocular (uveal) lymphoma. The first two entities are mentioned very briefly before the secondary tumors are discussed. For detailed accounts of these tumors, the reader is referred to the respective articles on clinical, histopathological and treatment aspects of intraocular lymphoma.

Primary retinal lymphoma
Primary retinal lymphoma is generally referred to, imprecisely, as primary intraocular lymphoma. Briefly, this is a high-grade malignant B-cell lymphoma that affects the retinal pigment epithelium, sensory retina, vitreous, and optic nerve, usually sparing the uveal tract. Typically, it occurs in patients in the 6th or 7th decade of life (median age, 64 years) [43] with a female to male ratio of approximately 1.2 : 1. The ocular disease usually presents in isolation, but central nervous system (CNS) disease often develops before or subsequent to the ocular manifestations [9,[44][45][46][47]. The combined manifestation of lymphoma in cerebral and ocular sites is referred to as oculocerebral lymphoma. Systemic dissemination of primary intraocular lymphoma is rare. Despite improvements in therapy [48,49], the prognosis in primary intraocular lymphoma is generally still poor.

Primary uveal lymphoma
Primary uveal lymphoma is a low-grade B-cell neoplasm of MALT type (see above), occurring usually unilaterally in men in the 5th or to 6th decades of life [50,51,52 ]. The prognosis for primary choroidal lymphoma is very good, with only exceptional cases of systemic dissemination or of CNS involvement [53,54].

Secondary intraocular lymphoma
Secondary intraocular lymphoma usually arises in the uvea, without involvement of the neurosensory retina [47,55,56]. Predominantly retinal disease without uveal infiltration has been reported but is exceptional [57,58 ]. Rarely, systemic lymphoma can present with anterior segment disease such as pseudohypopyon or iridal infiltration [59][60][61]. Other unusual manifestations of secondary intraocular lymphoma include optic disk swelling [62], serous macular detachments [63 ], and a lymphoma-associated retinopathy [64]. The exact incidence of secondary intraocular lymphoma is uncertain and probably will remain so as the number of autopsies performed decreases worldwide.
Morphologically, it may be difficult to determine whether an ocular DLBCL is a primary or secondary tumor. Retinal infiltration usually indicates primary intraocular lymphoma whereas uveal involvement suggests secondary disease; however, there are always exceptions to any rule [57,58 ]. Coupland [73 ,74,75 ] with sequencing of the poly-merase chain reaction products may indicate whether clonal proliferations have originated from the same tumor or from two distinct primary lymphomas.

T or T/natural killer cell lymphoma
Ocular lymphomas of non-B-cell type are rare and represent approximately 1-3% of all lymphoproliferative lesions in these sites [7,76 ,77]. Most non-B-cell lymphomas are an extension of the tumor stage of mycosis fungoides or secondary manifestations of a systemic T-cell lymphoma [78 ,79-92]. Primary T-cell lymphomas of the ocular adnexa are very rare, with less than 10 presumed cases being reported in the literature to date [77,[93][94][95][96][97]. Similarly, primary intraocular lymphomas of T-cell type without involvement by mycosis fungoides are exceptional [98 ,99-101].
Lymphoma and the eye Coupland and Damato 527 Recent ophthalmic literature has described the rare primary and secondary involvement of the ocular tissues by T/natural killer cell lymphoma [93,102 ], adult T-cell lymphoma in conjunction with systemic leukemia, and associated with human T-cell lymphotrophic virus type I infection [78 ,103-105]. All of these lymphoma entities are very aggressive, and patients usually die soon after initial diagnosis.

Conclusion
Much progress has been made in the understanding of malignant lymphomas in general. The WHO lymphoma classification has improved our ability to subtype the malignant lymphomas into particular entities, which are characterized by particular morphologic, immunophenotypical, and molecular biologic features. Further fine tuning of this comprehension of lymphomagenesis has been recently achieved with the application of the new technologies, e.g. complementary DNA microarrays. Much remains to be learned about the pathogenesis of the lymphomas affecting ocular and ocular adnexal tissues. The new methods must be applied in these tumors with the hope of optimizing patient treatment.

References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 577).