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Available online at www.sciencedirect.com

ScienceDirect journal homepage: www.elsevier.com/locate/survophthal

Major review

Malignant lymphoma of the conjunctiva Marina M. Kirkegaard, MDa, Sarah E. Coupland, PhD, MBBSb, Jan U. Prause, MD, DMSca, Steffen Heegaard, MD, DMSca,c,* a

Department of Neuroscience and Pharmacology, Eye Pathology Institute, University of Copenhagen, Copenhagen, Denmark b Department of Pathology, University of Liverpool, Liverpool, UK c Department of Ophthalmology, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark

article info

abstract

Article history:

Conjunctival lymphomas constitute 25% of all ocular adnexal lymphomas. The majority

Received 8 February 2015

are B-cell non-Hodgkin lymphomas (NHLs) (98%), whereas conjunctival T-cell NHLs are

Received in revised form 6 May 2015

rare (2%). The most frequent subtype of conjunctival B-cell lymphoma is extranodal

Accepted 14 May 2015

marginal zone lymphoma (EMZL; 81%), followed by follicular lymphoma (8%), diffuse large

Available online 21 May 2015

B-cell lymphoma (3%), and mantle cell lymphoma (3%). Extranodal marginal zone lymphoma occurs slightly more often in women and, along with follicular lymphoma, presents

Keywords:

late in the seventh decade of life, whereas diffuse large B-cell lymphoma and especially

conjunctiva

mantle cell lymphoma have a predilection for the male gender and typically present in the

lymphoma

eighth decade. Extranodal marginal zone lymphoma and follicular lymphoma present

epidemiology

most frequently in the forniceal and bulbar conjunctiva. Conjunctival diffuse large B-cell

pathology

lymphoma, mantle cell lymphoma and T-cell NHLs are characterized by a short duration of

characteristics

symptoms before the first ophthalmologic consultation. External beam radiotherapy is the

treatment

treatment of choice for extranodal marginal zone lymphoma and follicular lymphoma,

survival

whereas diffuse large B-cell lymphoma, mantle cell lymphoma, and T-cell NHLs are mainly treated with chemotherapy. Conjunctival T-cell NHLs are associated with a particularly poor prognosis, with 50% of patients having progression or recurrence during a 1-year follow-up period. ª 2015 Elsevier Inc. All rights reserved.

1.

Introduction

1.1.

The conjunctiva

The conjunctiva is the mucous membrane that lines the inner surface of the eyelids and curves onto the anterior surface of the eye, where it extends to the corneoscleral limbus.113

Although it is a continual structure, the conjunctiva can be divided into 6 different topographic zones with a distinct morphology: marginal, palpebral or tarsal, orbital, forniceal, bulbar, and limbal areas.73 The conjunctiva functions as a major support tissue for the preservation of the optical function of the cornea. It is equipped with a natural, submucosal reservoir of lymphoid tissue within its substantia propria,

* Corresponding author: Steffen Heegaard, MD, DMSc, Department of Neuroscience and Pharmacology, Eye Pathology Institute, University of Copenhagen, Frederik V’s Vej 11, Copenhagen 2100, Denmark. E-mail address: [email protected] (S. Heegaard). 0039-6257/$ e see front matter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.survophthal.2015.05.001

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which belongs to the mucosal immune system of the body and is thereby able to provide immune protection for the ocular surface, including the cornea.73

1.2.

grade subtypes. EMZL and FL commonly present in patients in their late 60s, whereas DLBCL and MCL usually occur in patients in their 70s.6,19,130 Conjunctival T-cell lymphomas typically present in middle-aged and elderly individuals.31,71

Lymphoma 2.3.

Lymphoma, a malignant neoplasm derived from a monoclonal proliferation of B- or T-lymphocytes, and less frequently natural killer cells (NK-cells), may be divided into 2 major groups: Hodgkin lymphoma and non-Hodgkin lymphomas (NHLs).127 The NHLs, a large heterogeneous group of neoplasms, can be further subdivided into those originating from B-lymphocytes or their precursors (80%), T cells (14%), and NK cells (6%).127 All three lymphoma subgroups may occur in the conjunctiva and can be further classified into a number of subtypes.

2.

Frequency and demographics

2.1.

Frequency

A total of 1,014 conjunctival lymphoid neoplasms are described, 98% of which are of B-cell lineage (Tables 1 and 2). The most common subtypes of B-cell lymphoma in the conjunctiva are the low-grade extranodal marginal zone lymphoma (EMZL), with 818 identified cases (81%) and follicular lymphoma (FL), with 77 cases (8%). These are followed by the high-grade mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL), with 29 cases (3%) of each.32,45,119 The frequency of DLBCL in the conjunctiva is markedly lower than in the remaining ocular adnexal region (13%).117 Of the less common B-cell lymphoma subtypes, there are 12 lymphoplasmacytic lymphomas, 10 small lymphocytic lymphomas, and 10 plasmacytomas, which are low-grade malignancies, and 2 cases of lymphomatoid granulomatosis and 1 of Burkitt lymphoma, which are highgrade malignancies.45,88,121,144,152 Furthermore, there is also a case of multiple myeloma, which can be an aggressive or an indolent disease depending on the variant.11 The remaining 2% of reported lymphomas include 18 cases of T-cell lymphoma, 1 NK-cell lymphoma, and 6 lymphomas that could not be classified (Tables 3 and 4).4,39,66 The most frequent subtypes of T-cell lymphoma in the conjunctiva appear to be the adult T-cell lymphoma and anaplastic largecell lymphoma, with 3 cases of each reported.17,27 Moreover, there are 2 cases of mycosis fungoides and 1 case each of angioimmunoblastic T-cell lymphoma, diffuse large T-cell lymphoma, acute lymphoblastic lymphoma of T-cell type, and NK/T-cell lymphoma.29,47,54,98,145

2.2.

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Age at presentation

Conjunctival lymphoma is primarily a disease of the elderly, but has been described in patients from 33 months up to 92 years of age. There is a significant difference in age distribution among the different types of conjunctival lymphomas (Tables 1 and 3). Thus, the low-grade subtypes of conjunctival B-cell lymphoma generally present earlier than the high-

Gender

Conjunctival lymphoma in general does not appear to have a gender predilection; however, several of its subtypes do occur more often in a particular gender (Tables 1 and 3). For example, conjunctival EMZL occurs somewhat more frequently in women than in men, whereas the high-grade DLBCL and especially MCL have a predilection for male gender, with MCL occurring 5 times more frequently in men.67,69,130 Conjunctival T-cell NHLs, on the other hand, are evenly distributed between males and females.31,115

3.

Pathogenesis

3.1.

Chronic antigenic stimulation

Much attention has been focused on determining whether ocular adnexal lymphomas, especially EMZLs, are caused by chronic antigenic stimulation. The organisms suggested as contributing to the pathogenesis of conjunctival EMZL are Helicobacter pylori, Chlamydia psittaci, and hepatitis C.42,44,120 One of the hallmark characteristics of EMZL is that the neoplasia is preceded by a benign, chronic inflammation.58 Thus, EMZL appears to develop as a result of prolonged antigen stimulation that leads to loss of regulation of B-lymphocyte proliferation and differentiation.37 Several characteristics of conjunctival EMZL give rise to the suspicion that this mechanism also triggers EMZL development in the conjunctiva: 1) conjunctival EMZL is often bilateral and may show spontaneous remission, which could be the result of bilateral conjunctival infection and clearance of an antigen, respectively84,85; 2) the t(11;18)(q21;q21) translocation, which is related to oxidative damage induced by genotoxic factors such as H pylori or C psittaci infection, is present in 19% of conjunctival EMZLs148; 3) in some cases, patients with conjunctival EMZL have a history of preceding infectious conjunctivitis.42 A number of studies have investigated the association between the infectious agents and conjunctival lymphoma. A Korean study detected H pylori DNA in all 15 analyzed cases of conjunctival EMZL.78 H pylori DNA was likewise detected in tumor cells from 4 of 5 cases of conjunctival EMZL from China.21 The prevalence of C psittaci positivity in conjunctival lymphoma appears to be about 16%, summing up the results of 3 studies from Europe, 1 from China, and 1 from the USA.24 These data suggest that H pylori and C psittaci may play a role in conjunctival lymphoma. On the other hand, a Danish study of 13 cases of conjunctival EMZL demonstrated no association between H pylori and EMZL of the conjunctiva, with all investigated cases being H pylori negative.120 Likewise, in another study from China, all 16 specimens of conjunctival EMZL were both H pylori and C psittaci negative, indicating that there is possibly no association between conjunctival EMZL and the 2 microorganisms.

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Table 1 e Clinical and staging characteristics of conjunctival B-cell lymphoma Characteristics

EMZL

Total number of cases 818 Gendera Male 115 Female 121 Age (years)a 36) Ann Arbor stage IE 223 IIE 7 IIIE 3 IVE 6 Not specified 579

FL

DLBCL

MCL

LL

SLL

BL

PL

Myeloma

LG

77

29

29

12

10

1

10

1

2

6 7

11 6

10 2

1

2 1

1

3 4

2 1 0 0 0 3 1 0 30 9

0 0 0 3 3 0 5 0 11 4

0 0 0 0 3 2 5 1 11 8

9 2

14 1

7 8

1 3 1

2

2 2 2

2

5 8

2

1

1

1

1

1 1 1 1

1

1 1

1

1 1

1 2 2 0 0 1 1 2 6 1

1

2

6 1 4 2 2

1 1

1 3

1

2

5

1

8

1

1

1

1

2 1 1 1 5 (2e6)

0.75 (0.5e3)

2.5 (1e7)

7 1

10 1 1 2 15

3

1

1

1 2 23

11

9

69

6 (2e
24) 1

5

1

2

BL, Burkitt lymphoma; DLBCL, diffuse large B-cell lymphoma; EMZL, extranodal marginal zone lymphoma; FL, follicular lymphoma; LG, lymphomatoid granulomatosis; LL, lymphoplasmacytic lymphoma; MCL, mantle cell lymphoma; PL, plasmacytoma; SLL, small lymphocytic lymphoma. a Not specified for all cases.

Furthermore, it has been suggested that there is a pathogenic link between hepatitis C virus and EMZL located in the ocular adnexa. In a study from Italy, 1 of 15 patients with conjunctival lymphoma showed hepatitis C virus positivity.44 In contrast, an Austrian study did not detect hepatitis C virus in any cases of conjunctival EMZL.50 Regarding antigenic stimulation implicated in the pathogenesis of the remaining lymphoma types in the conjunctiva, Epstein-Barr virus contributes to the origin of Burkitt lymphoma, NK/T-cell lymphoma, and lymphomatoid

granulomatosis.121,142 In line with these observations, the reported cases of conjunctival NK/T-cell lymphoma and lymphomatoid granulomatosis had an underlying EpsteinBarr virus infection.121,142 In the case of conjunctival Burkitt lymphoma, on the other hand, evidence of Epstein-Barr virus infection was found in the adenoidal tissue, but not in the tumor cells, which does not support a direct role of Epstein-Barr virus in the oncogenesis of conjunctival Burkitt lymphoma.144 Furthermore, the human T-cell lymphotropic virus type 1 is implicated in the development of the very

447

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Table 2 e Treatment and outcome for patients with conjunctival B-cell lymphoma Characteristics Total number of cases Treatmenta Observation only Surgery Cryotherapy (þother treatment) Antibiotic therapy (þ/ other treatment) IFN-a Monoclonal antibodies EBRT EBRT and rituximab Chemotherapy Chemotherapy and EBRT Chemotherapy and rituximab Radiation doses (range, Gy)a Recurrence or progressiona

EMZL

FL

DLBCL

MCL

LL

SLL

BL

PL

Myeloma

LG

818

77

29

29

12

10

1

10

1

2

2 1

1

4

32 16 2 35 30 11 68 13 3 6 20e50 74

2 1 1

5 1 1 0 1 4e30 3

3

3

2

2 1 2

8 1 2

1

3

4

2

3 1

30e40 3

1

25e40 1

BL, Burkitt lymphoma; DLBCL, diffuse large B-cell lymphoma; EBRT, external beam radiotherapy; EMZL, extranodal marginal zone lymphoma; FL, follicular lymphoma; IFN-a, interferon alfa; LG, lymphomatoid granulomatosis; LL, lymphoplasmacytic lymphoma; MCL, mantle cell lymphoma; PL, plasmacytoma; SLL, small lymphocytic lymphoma. a Not specified for all cases.

aggressive adult T-cell lymphoma. Consistent with this finding, the 3 cases of adult T-cell lymphoma located in the conjunctiva had an underlying human T-cell lymphotropic virus infection.17,76,131 These studies suggest a remarkable difference in the association between antigenic stimulation and conjunctival lymphoma across geographic regions and even among studies from the same geographic region. Several attempts have been made to explain such differences. Variability in the methodology used to detect the microorganisms’ DNA could account for the variability.56 Another explanation may be that the presence of these microorganisms’ DNA is not etiologically related to the occurrence of conjunctival lymphoma, and thus, the observed variability is merely a reflection of the variability in exposure to those microorganisms on the conjunctival surface.56

from concurrent conjunctival EMZL and Sjo¨gren syndrome described in a case report.140 Nonetheless, a relatively large number of studies, with the main focus on EMZL, have not detected any manifestations of autoimmune diseases in patients with conjunctival lymphoma.15,26,68,77,87,88,106,108 Thus, reports indicate that underlying autoimmune disease is relatively rare in patients with conjunctival EMZL. The high-grade DLBCL may also be correlated with autoimmune diseases. In fact, in 2 large studies of patients with Sjo¨gren syndrome, DLBCL was described as the most common lymphoma subtype.135,139 The correlation between conjunctival DLBCL and autoimmune diseases is, however, yet to be assessed, which is also the case for the remaining types of conjunctival lymphoma.

3.2.

Several chromosomal aberrations occur in lymphomas located in the ocular adnexal region, to which the conjunctiva belongs. These include translocations, inactivating mutations, and trisomies.

Autoimmune disorders

A number of autoimmune disorders are associated with an increased risk of lymphoma.35,40 An Austrian study found that a large majority of patients with extragastric EMZL have an underlying autoimmune disease.147 Because of this correlation, much attention has been focused on determining whether ocular adnexal lymphoma, especially EMZL, is caused by autoimmune disorders. Autoimmune disorders such as Sjo¨gren syndrome and systemic lupus erythematosus have been reported to frequently affect the ocular adnexa.5,14 There is, however, limited information available about the correlation between autoimmune disorders and conjunctival lymphoma in particular. In a study which assessed 4 cases of conjunctival EMZL, 1 patient was shown to have Sjo¨gren syndrome and another was suffering from Hashimoto thyroiditis.51 Another study included 8 cases with simultaneous polyclonal hypergammaglobulinemia and ocular adnexal EMZL, 1 of them being a conjunctival EMZL patient, who also was affected by Sjo¨gren syndrome.75 Furthermore, there is 1 patient suffering

3.3.

3.3.1.

Genetic abnormalities

Extranodal marginal zone lymphoma

The 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.57 All these translocations, except for the one involving FOXP1 gene, lead to the formation or upregulation of proteins (API2-MALT1 fusion protein, MALT1, and Bcl-10) that ultimately lead to activation of the nuclear factor kB, which controls the transcription of DNA.80 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.148 The t(14;18)(q32;q21) translocation is found in around 15%e20% of ocular adnexal EMZLs and is described in the conjunctiva in particular.20,30,91 Another 15%e20% of ocular

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Table 3 e Clinical characteristics and treatment of conjunctival T-cell non-Hodgkin lymphomas Characteristics

Anaplastic large-cell lymphoma

Angioimmunoblastic T-cell lymphoma

Diffuse large T-cell lymphoma

Acute lymphoblastic lymphoma (T-cell type)

NK/T-cell lymphoma

Mycosis fungoides

Unspecified subtype

3

3

1

1

1

1

2

6

2 1 15e77

1 2 3e85 1 2

1

1

1

3

3

72

1 63

47

1

1

1

1

1

1

41 1

1

2

2 4 53e76 2 4

2

6

2 40e42

3 1

3

2

1 1 1

3 1

1 2

1 1 1 1

1

1 1 1

2 1 1 1

1 1

2

1 3 1

0.1e4

1 2e8

4

3

1 2

1

8

1

1

1 3 4 1 1 1 3 1 1 3e12

2 1

1 3 2

1 1 1 2 1 2

2

1

1 2

1 2

2

EBRT, external beam radiotherapy; NK, natural killer. a Not specified for all cases. b Daclizumab (anti-Tac, Zenapax; Roche Pharmaceuticals, Nutley, NJ).

1

2 4

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Total number of cases Gender Male Female Age (years) Primary Secondary Laterality Unilateral Bilateral Anatomic location Tarsus Fornix Caruncle þ/ plica semilunaris Limbus Bulbus Symptoms/objective findings Tumor Chemosis Hyperemia Discharge Corneal symptoms/findings Scleritis/episcleritis Symblepharon B-symptoms Symptom duration (range, months) Ann Arbor stage IE >IE Not specified Treatment (initial)a Observation only Surgery Cryotherapy (þother therapy) Monoclonal antibodiesb EBRT Chemotherapy Chemotherapy and EBRT Chemotherapy and Rituximab Recurrence or progressiona

Adult T-cell leukemia/ lymphoma

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Table 4 e Clinical and treatment characteristics of conjunctival NK-cell lymphoma Characteristics

Angiocentric NK-cell lymphoma

Number of cases Gender Age at presentation (years) Laterality Symptoms Ann Arbor stage Treatment Outcome

1 Female 5 Unilateral Tumor IE Observation Disease free at 48 months

NK, natural killer.

adnexal EMZL patients carry the t(3;14)(p14;q32) translocation, whereas t(1;14)(p22;q32) occurs in approximately 10% of these.20,30,123 Additionally, t(5;14)(q34;q32) and t(9;14)(p24;q32) translocations have been recognized as potentially taking part in the development of ocular adnexal EMZL and their roles need further investigation, which also regards the newly detected (5;11)(q33;p11.2) translocation in a case of conjunctival EMZL.28,30 Trisomy of chromosomes 3 and 18 is another cytogenetic abnormality associated with EMZL.86,109,134 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.108,134 Trisomy of these chromosomes is often associated with the t(14;18)(q32;q21) and t(3;14)(p14;q32) translocations.123,124 Finally, another genetic aberration relevant to lymphomagenesis of ocular adnexal EMZL is inactivation of the A20 (TNFAIP3) gene located on chromosome 6q23.3. This abnormality is seen in approximately 20% of translocation-negative ocular adnexal EMZL cases; however, its prevalence in conjunctival EMZL in particular needs to be investigated.13,22,23,53

3.3.2.

Follicular lymphoma

The genetic hallmark of FL is the t(14;18)(q32.3;q21.3) translocation, present in approximately 85% of FLs, including ocular adnexal FLs, and has also been found in conjunctival FL. This translocation involves BCL2 and IGH genes and leads to overexpression of the antiapoptotic protein BCL2.7,25,65,83,110 Furthermore, t(3;14)(q27;q32) translocation, involving BCL6 and IGH, as well as trisomy 3, gains of chromosome 1, and deletion of chromosome 1p36 have been detected in FL, which all lead to the upregulation of genes involved in NF-kB signaling and cell proliferation.7,61,92,128 Although it is likely that these alterations also play a role in the pathogenesis of FL of the conjunctiva, further studies are needed to address this issue specifically.

3.3.3.

Mantle cell lymphoma

At the genetic level, MCL is the most homogeneously defined entity among B-cell NHLs. 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 and results in the overexpression of the cyclin D-1

449

gene, leading to severe dysregulation of the cell cycle control and enhanced proliferation.60,95,97,107,141

3.3.4.

Other subtypes

The remaining types of lymphoma described in the conjunctiva are likewise associated with specific genetic characteristics.34,36,46,55,101,126 These, however, have been described neither for the conjunctival lymphomas in particular nor for the ocular adnexa. As evidence suggests that the frequency of particular molecular alterations varies according to the site of origin, more studies are needed to be able to determine their relevance.30

4. Symptoms, objective findings, and other features 4.1.

Symptoms and objective findings

Conjunctival lymphomas, especially of low-grade type, do not cause many symptoms, with the most common symptom being a salmon-colored mass of the conjunctiva (Tables 1 and 3; Figs. 1A and 1B).6,16,64 Other possible symptoms and signs are relatively uncommon and include chemosis, hyperemia, ptosis, dryness, pain, discharge, epiphora, ectropion, pterygium, symblepharon, photophobia, corneal symptoms, and so-called “B-symptoms.”18,52,152 On ocular examination, the different types of conjunctival lymphoma frequently present with distinct clinical features. Typical conjunctival EMZL presents as a fleshy, often mobile, nonlobulated salmon-pink patch (Fig. 2).16,28,151 Conjunctival FL, likewise, has a salmon-pinkish appearance, but in contrast to EMZL, often presents as a multinodular lesion (Fig. 3).129,132 DLBCL has been described as a mass similar to that presenting in EMZL but with a grayish color of the lesion besides the more common salmon-pink shade.69,105 Patients with MCL frequently present with a large mass, the color of which may vary from salmon-pink to dark red.67,149 Of the less common conjunctival B-cell lymphomas, SLLs seem to have an appearance of the typical nonlobulated salmon-pink mass.111,138 Conjunctival plasmacytomas often share this appearance; however, deviations from the typical salmonpink color are rather frequent in plasmacytomas. They may have a red, grayish-pink, or grayish-white color.12,143,152 Conjunctival T-cell lymphomas, like the rest of the conjunctival lymphomas, are most commonly pink, nonlobulated lesions.17,27 Other clinical findings differentiate T-cell lymphomas from the remaining types. Thus, conjunctival T-cell lymphomas present more frequently with other findings, and these are often more severe than those which accompany B-cell lymphomas. They include numerous corneal signs, episcleritis, scleritis, and symblepharon.17,31,54 Although the different subtypes of conjunctival lymphoma often have distinct clinical features and a specific appearance, exceptions are not uncommon, and thus, for example, conjunctival FL may present as a uniform salmon-pink patch, and cases of conjunctival EMZL and T-cell NHL may present as multinodular lesions.1,114,115 Furthermore, pediatric conjunctival lymphoma often presents differently from adult

450

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Fig. 1 e A and B: Bilateral salmon-colored tumor of the conjunctiva in a 64-year-old male. C: Magnetic resonance imaging of both eyes showing bilateral increased enhancement of the conjunctiva (arrows). D: Mantle cell lymphoma showing a monotonous pattern of small cells. The nuclei are irregular with inconspicuous nucleoli and scant cytoplasm (hematoxylineosin; bar [ 50 mm). E: The tumor cells bind anti-k antibodies (brown, bar [ 50 mm). F: The tumor cells react with anti-cyclin D-1 (bar [ 50 mm). conjunctival lymphoma of the same subtype, frequently exhibiting a firm, elevated globoid mass.72,99

4.2.

malignancies.69,76,149 Such differences may be explained by the quicker evolution of symptoms associated with the aggressive lymphomas.

Duration of symptoms 4.3.

The duration of symptoms before first ophthalmologic consultation varies with the type of the lymphoma and appears to be correlated with its aggressiveness (Tables 1 and 3). Patients suffering from EMZL and FL experience symptoms for relatively long periods of time before consulting an ophthalmologist. Their median symptom duration is 4 and 5 months, respectively, with the longest recorded symptoms lasting more than 3 years.118,129 The picture is, however, markedly different for the high-grade subtypes of B-cell lymphoma and the lymphomas of T-cell lineage. Patients suffering from conjunctival DLBCL, MCL, and T-cell NHL consult an ophthalmologist on average 3 times earlier than those with the aforementioned low-grade lymphomas. Symptom durations down to 3 days have been recorded in these aggressive

Laterality

Conjunctival lymphoma usually presents as a unilateral lesion (Tables 1 and 3). Unilateral presentation is seen approximately 3 times more often than bilateral disease among EMZLs and even more frequently among FLs.1,16,132 Although the dominance of unilateral presentation also appears to apply to the aggressive T-cell lymphoma and DLBCL, this is not the case for MCL patients, more than half of whom have bilateral manifestation of the lymphoma.4,82,102

4.4.

Anatomic location

The location where the tumor presents in the conjunctiva varies between the different types of lymphoma (Tables 1 and 3).

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conjunctival T-cell NHL is usually a secondary disease (80%), whereas B-cell lymphoma of the conjunctiva is mainly characterized by primary presentation (80%).59,71,82 Moreover, there are significant differences in the distribution of primary and secondary disease among the low-grade and the highgrade B-cell NHLs. Only approximately every sixth patient with EMZL and every fifth case of FL is diagnosed with secondary involvementdin contrast to DLBCL, with a quarter of patients having secondary disease, and especially the more aggressive MCL, with almost half of all cases being secondary lymphomas.82,96,129 Furthermore, plasmacytoma is always a primary disease, whereas myeloma and lymphomatoid granulomatosis are systemic malignancies.60,64,81

Fig. 2 e Salmon-colored tumor mass of the bulbar conjunctiva and the upper fornix in a 62-year-old female with extranodal marginal zone lymphoma.

The most prominent is the difference between B-cell and T-cell NHL in the frequency of limbal involvement. Only 1% of conjunctival B-cell lymphomas are found in the limbal area, whereas approximately 30% of all T-cell lymphomas occur in this region.17,54,90 Regarding the individual subtypes, EMZL is most commonly encountered in the forniceal area, where approximately half of all EMZLs are located, followed by bulbar presentation, whereas tarsal and especially limbal locations are rare in EMZL.15,85,94 Similar findings apply to FL, which is likewise mainly found in the bulbar and forniceal conjunctiva.1,48 Because of the sparse number of cases of the remaining types of lymphoma, there are no clear tendencies regarding their location.

4.5.

Systemic disease

Secondary disease is relatively infrequent in patients with conjunctival lymphoma, but its frequency varies greatly depending on the type of lymphoma and is associated with the lymphoma’s aggressiveness (Tables 1 and 3). Thus,

5.

The initial evaluation of patients with a potential conjunctival lymphoma requires careful ophthalmologic examination and adequate tissue sampling for histopathologic diagnosis. If conjunctival lymphoma is identified, further procedures are indicated for accurate staging. A complete staging procedure includes a full-body positron emission tomography and computed tomography or magnetic resonance imaging (MRI) and bone marrow biopsy.102 Recently, the question has been raised as to how effective the neuroimaging techniques are in diagnosing conjunctival involvement. One study found that magnetic resonance imaging of the orbit had a low yield in the diagnosis of conjunctival EMZL, with more than 80% of studied patients having negative MRIs despite obvious conjunctival lymphomas. In the remaining cases, magnetic resonance imaging did not change the diagnosis or add any useful clinical information. Thus, an ophthalmologic examination remains the gold standard in diagnosing conjunctival involvement.93 With that said, should a conjunctival lymphoma be diagnosed, a full clinical workup should be performed to detect distant disease. For this purpose, computed tomography and positron emission tomography have been found to be valuable tools, with respective sensitivities of around 70% and 85%. Frequently, these imaging techniques add clinically meaningful information to the diagnosis of conjunctival lymphoma, leading to “upstaging” and change of treatment modality.125

5.1.

Fig. 3 e Multinodular lesion of the bulbar conjunctiva and the lower fornix in a 51-year-old man with follicular lymphoma.

Diagnosis

Histopathologic examination

Classification of the lymphoma is a complex procedure, which involves investigation of morphologic and immunohistochemical features of the tumors. Formalin-fixed, paraffinembedded tissue sections are stained with hematoxylin-eosin to evaluate the morphology and analyzed immunohistochemically using antibodies directed against CD3, CD5, CD20, and CD79a to differentiate between B- and T-cell NHL. Subsequently, small cell lymphomas are immunophenotyped with antibodies directed against CD10, CD23, cyclin D-1, Bcl-2, Bcl-6, MUM-1, MIB-1, and k and l light chains, whereas large B-cell lymphomas are immunophenotyped with CD10, CD30, Bcl-2, Bcl-6, MUM-1, and MIB-2. T-cell NHLs are immunophenotyped with antibodies directed against CD4, CD8, CD30, CD56, ALK-1, MIB-2, TIA, and granzyme B.117

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Staging

Conventionally, conjunctival lymphoma is clinically staged using the Ann Arbor staging system. With this staging system, approximately 10% of the low-grade EMZLs and FLs are classified as a higher than stage IE disease. This is in contrast to the high-grade DLBCL, with three times as many patients with a lymphoma of stage higher than IE, MCL with approximately half of all patients in this category, and T-cell lymphoma with a great majority of patients having a disease higher than stage IE (Tables 1 and 3).2,54,66,100 The Ann Arbor staging system has been criticized for having a number of shortcomings, including having a disproportionately high number of patients characterized as presenting with stage IE tumors, as it does not distinguish among lymphomas based on anatomic location, extent of primary tumor infiltration, multicentricity, or bilaterality.33,79 To overcome the limitations of the Ann Arbor staging system, the American Joint Committee on Cancer has proposed the tumor, node, metastasis (TNM) staging system for lymphomas in the ocular adnexa, which does take the aforementioned aspects into account.33,49,79 Using the TNM staging system, approximately a quarter of conjunctival EMZL patients are diagnosed with a stage above T1N0M0 or stage bT1N0M0, which indicates that this staging system provides a more even distribution of the lower and the higher stages of conjunctival lymphoma.79

7.

Treatment

Determining the optimal treatment for a patient with conjunctival lymphoma requires a multidisciplinary approach by a team consisting of ophthalmologists, radiotherapists, and hematologists. A number of important criteria must be considered: 1) the histopathologic subtype of lymphoma, 2) the extent of the lymphoma, 3) patient- and disease-related prognostic factors, and 4) the effect on the eye and visual function.38,122 There are numerous treatment methods for conjunctival lymphomas. These include chemotherapy, external beam radiotherapy (EBRT), brachytherapy, immunotherapy with interferon-a and monoclonal antibodies, and milder options such as cryotherapy, antibiotic treatment, surgery, and observation only. For conjunctival lymphoma, in general, the most frequently applied treatment modality is low-dose radiotherapy, applied to a third of all patients. The choice of therapy, however, varies greatly according to the type of the lymphoma (Tables 2 and 3).

7.1.

External beam radiotherapy

It appears that EBRT is the treatment of choice when managing the indolent EMZL, FL, lymphoplasmacytic lymphoma, small lymphocytic lymphoma, and plasmacytoma. Together, these malignancies are managed with EBRT in a third of all cases.1,64,78,111 While still being a rather common treatment alternative for aggressive lymphomas, EBRT is only applied in

approximately every fifth patient with high-grade B-cell lymphoma and T-cell lymphoma.29,63 The radiation doses given to patients with low-grade conjunctival lymphomas were rather moderate in the reported studies, ranging from 20 Gy up to 50 Gy. Most of these patients received the treatment over 15 sessions.1,18,143 The radiation doses applied in conjunctival T-cell lymphoma were likewise rather low; however, almost half of these patients received additional treatment.4,115 The effectiveness of EBRT in treatment of low-grade conjunctival lymphomas is high, with 80% of patients not experiencing progression or recurrence during a 5-year follow-up period.3,8,77 Possible side effects of EBRT include radiation retinopathy, a rare but severe complication, as well as dry eye syndrome, cataract formation, and orbital fat-tissue reduction.85

7.2.

Chemotherapy

The more aggressive types of conjunctival lymphoma are primarily managed using chemotherapy, applied in approximately half of T-cell NHLs and DLBCLs and in even more conjunctival MCLs.54,67,69 As indicated, chemotherapy is not as popular in the treatment of conjunctival EMZL, FL, and plasmacytoma and is only chosen for approximately 10%e 20% of patients.104,114,146 Chemotherapy may be administered as a single agent or a combination regimen. Chlorambucil is the most frequently used single-agent chemotherapy treatment, whereas combination chemotherapy for conjunctival lymphoma includes CVP (cyclophosphamide, vincristine, prednisolone) and CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine [Oncovin; Lilly, Indianapolis, IN], prednisolone), which in turn may be used in combination with rituximab (R-CHOP).8,18,74,89,114 Chemotherapy has a good efficacy in both low-grade and high-grade B-cell lymphomas, as well as T-cell lymphomas of the conjunctiva, being able to eliminate 65% and 70% of conjunctival lesions of the latter 2 types, respectively, and in nearly all low-grade B-cell lymphomas.8,72,114,144 Regarding side effects and complications after chemotherapy, chlorambucil has a favorable toxicity profile.9

7.3.

Monoclonal antibodies

Immunotherapy with monoclonal antibodies, particularly rituximab and daclizumab, has been proposed as a treatment option for patients with conjunctival lymphoma. Monoclonal antibodies have been applied in 5% of conjunctival EMZLs (rituximab) and in 2 cases of T-cell lymphoma (daclizumab) as the only treatment.17,43,76 Although the trials published so far have been limited, the existing studies suggest that intralesional rituximab is well tolerated and produces a good response, with approximately 75% of patients being progression or recurrence free during a 1-year follow-up period.10,43,94 Rituximab is frequently used in combination with chemotherapy or EBRT. These combinations have been reported in EMZL, FL, DLBCL, and MCL of the conjunctiva.67,69,104,132

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7.4.

Interferon-a

Local immunotherapy with interferon-a, which is injected subconjunctivally inside the lesion, is another treatment option for conjunctival lymphoma patients but has only been reported in the treatment of conjunctival EMZL. Studies of this promising treatment modality show remarkable long-term effectiveness, with approximately 85% of patients being progression or recurrence free during a 5-year follow-up period.15,16 Side effects after local injection of interferon-a include temporary conjunctival chemosis at the site of injection, a transient flu-like syndrome, and less commonly, pain, instant burning, subconjunctival hemorrhage, photophobia, and preauricular lymph node hypertrophy.15,16

7.5.

Brachytherapy

Another option is beta-ray brachytherapy using a bidirectional 90Sr-90Y ophthalmic applicator. The total doses at the surface of the applicator are often high, varying between 40 Gy and 80 Gy.103 This treatment may be considered effective, as 70% of treated patients remain progression or recurrence free during a median follow-up period of 6 years. In principle, the depth-dose distribution of 90Sr-90Y applicators has the remarkable advantage of being able to reduce the irradiation of orbital and ocular structures such as the lens and the lacrimal gland.103 Nonetheless, and at least in part because of the use of high doses, this technique carries a risk of late complications, higher than those observed in patients treated with EBRT. Acute toxicities after the treatment include conjunctivitis, keratitis, blurred vision, photophobia, and dermatitis. Late complications affect the cornea and the lens.103

7.6.

Surgery

Complete excision with no subsequent treatment may be performed in conjunctival lymphoma. This alternative has mainly been used in the management of the low-grade lymphomas, especially when they present as encapsulated lesions.16,19,48 Because of tumor microinfiltration into the surrounding tissue, however, the risk of recurrence is high if no other treatment is administered, with approximately every third patient having progression or recurrence during a 3-year follow-up period.8,19

7.7.

Observation without treatment

The indolence of some conjunctival lymphomas frequently allows no treatment at all, but only observation. Approximately 15% of EMZL patients are managed by observation, making it one of the most frequently applied strategies for this subtype.133,150 Observation without treatment is rarely used for the more aggressive types of conjunctival lymphoma.6,98 Although conjunctival EMZLs are frequently and often successfully observed without treatment, this approach carries higher recurrence and progression rates than most other strategies, with every third patient having recurrence or progression during a 5-year follow-up period; therefore, this treatment alternative is considered inferior.85,136

7.8.

453

Antibiotics

After the discovery of the potential role of the infectious agents in the pathogenesis of conjunctival lymphoma, antibiotics were used to treat conjunctival EMZL. They have been applied in around 15% of all conjunctival EMZLs, either alone or in combination with other therapy.70,78 In one study, 70% of conjunctival EMZL patients achieved either complete or partial remission or stable disease after 6 weeks of doxycycline alone.70 This, however, needs to be further investigated, keeping in mind that the prevalence of the infectious agents in patients with conjunctival lymphoma is variable; hence, antibiotic treatment without prior testing for infectious agents is not recommended.51

7.9.

Cryotherapy

Cryotherapy has been applied in a few cases as supplemental treatment of conjunctival lymphoma after excision or other form of therapy.4,136 Cryotherapy is mainly used to eliminate subclinical, microscopic tumor cells and prevent recurrence.116

8.

Prognosis

Conjunctival lymphomas generally have a good prognosis, with 90% of patients not experiencing progression or recurrence during a 1-year follow-up period (Tables 2 and 3). In particular, the low-grade B-cell NHLs have a favorable prognosis. Only 9% of the EMZL patients experienced progression or recurrence during a 1-year follow-up period, and even fewer in FL cases.48,117,133 In addition, there were no progressions or recurrences among the indolent conjunctival plasmacytomas.64,112 The low progression or recurrence rates also appear to apply to the high-grade DLBCLs, whereas conjunctival MCL carries a somewhat worse prognosis, with around 15% of patients having progression or recurrence during a 1-year follow-up period.18,82,105 The picture is, however, distinctly different for the conjunctival T-cell NHL (Table 3). Approximately half of these patients experience progression or recurrence during a follow-up period of 1 year. Thus, conjunctival T-cell NHLs have a much worse prognosis than those of B-cell lineage.17,145 Not only does the type of conjunctival lymphoma have a prognostic significance but also the various clinical features carry prognostic value. One of the negative prognostic factors is Ann Arbor stage higher than IE, which is prognostic for both B-cell and T-cell NHL.16,71 Age more than 50 years is prognostic for T-cell lymphomas, as these patients are 3 times more likely to have progression or recurrence of the disease.41,69,137 Furthermore, it seems that for conjunctival T-cell lymphomas, nonbulbar location (including the caruncle or plica semilunaris and the limbus) confers a worse prognosis.17,76,145 Finally, it is important to mention that, although conjunctival lymphoma appears to have a good prognosis, long-term follow-up is necessary because the risk of mortality continues to exist after many years.62

454

9.

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Conclusion

When handling and treating patients with conjunctival lymphoma, the histopathologic subtype and clinical stage are the best indicators of prognosis. The various World Health Organization subtypes of conjunctival lymphoma are unique entities associated with distinct clinical features, behavior, and prognosis and must therefore be managed accordingly. The low-grade conjunctival EMZL and FL usually present late in the seventh decade of life as primary, unilateral lesions of the bulbar or forniceal conjunctiva. They are usually minimally symptomatic with a long period of time elapsing before the first ophthalmologic consultation. EBRT is the treatment of choice for these lymphoma subtypes, which are associated with a favorable prognosis. The more aggressive MCL and DLBCL of the conjunctiva occur most frequently in men in their eighth decade of life. MCL is usually a secondary disease with bilateral manifestation, is more symptomatic than the indolent lymphomas, and has a short duration of symptoms. It is commonly managed with chemotherapy and is associated with a worse prognosis than the low-grade subtypes. DLBCL frequently shares similar features, apart from the fact that it often presents as a unilateral tumor and has a more favorable prognosis than MCL. Conjunctival T-cell NHL, a highly aggressive malignancy that most commonly presents in middle-aged and elderly individuals as a secondary disease, is accompanied by relatively severe symptoms of short duration with the tumor often localized at the limbus. These lymphomas are commonly treated with chemotherapy and have the poorest prognosis of all conjunctival lymphomas. Further studies are required, especially regarding pathogenesis and genetics, to understand the development of various lymphoma subtypes and thereby improve the treatment.

10.

Method of literature search

The PubMed search engine was used to perform literature searches in the MEDLINE database for the terms “conjunctival lymphoma,” “conjunctival reticulosarcoma,” and “conjunctival lymphosarcoma” up to November 2014. The reviewed publications were written in English, although selected English abstracts for papers in another language were reviewed and included if appropriate. The histologic subtypes of non-Hodgkin lymphoma have had several denominations, according to the histologic classification schemes in use at the time, namely Rappaport classification (1956), Lukes-Collins classification (1975), Kiel classification (1975), New Working Formulation for Clinical Use (1982), and the currently used REAL classification (1994). Each of these subtype denominations, which are defined in Jaffe et al. 2001,60 has been used in the literature search in combination with the term “conjunctiva” and included in the review with their corresponding REAL classification names.

11.

Disclosures

The authors declare no proprietary or commercial interest in any product mentioned or concept discussed in this article.

references

1. Abd Al-Kader L, Sato Y, Takata K, et al. A case of conjunctival follicular lymphoma mimicking mucosa-associated lymphoid tissue lymphoma. J Clin Exp Hematop. 2013;53:49e52 2. Adachi A, Tamaru J, Kaneko K, et al. No evidence of a correlation between BCL10 expression and API2-MALT1 gene rearrangement in ocular adnexal MALT lymphoma. Pathol Int. 2004;54:16e25 3. Agarwal PK, Lim LT, Fern A. Atypical conjunctival CD5 positive mucosa-associated lymphoid tissue (MALT) lymphoma. Semin Ophthalmol. 2012;27:46e7 4. Al-Muammar A, Hodge WG, Farmer J. Conjunctival T-cell lymphoma: a clinicopathologic case report. Ophthalmology. 2006;113:459e61 5. Arevalo JF, Lowder CY, Muci-Mendoza R. Ocular manifestations of systemic lupus erythematosus. Curr Opin Ophthalmol. 2002;13:404e10 6. Aspiotis M, Gorezis S, Asproudis I, et al. Primary mantle cell lymphoma of the conjunctiva: a case report. Virchows Arch. 2006;449:472e5 7. Azumi A, Hirai K, Tamura Y, et al. A case of follicular lymphoma derived from the conjunctiva. Nihon Ganka Gakkai Zasshi. 2002;106:420e5 8. Baldini L, Blini M, Guffanti A, et al. Treatment and prognosis in a series of primary extranodal lymphomas of the ocular adnexa. Ann Oncol. 1998;9:779e81 9. Ben Simon GJ, Cheung N, McKelvie P, et al. Oral chlorambucil for extranodal, marginal zone, B-cell lymphoma of mucosaassociated lymphoid tissue of the orbit. Ophthalmology. 2006;113:1209e13 10. Benabid L, Desablens B, Defossez T, et al. New treatment for orbital non-Hodgkin’s lymphoma: 2 cases treated with rituximab. J Fr Ophtalmol. 2005;28:769e71 11. Benjamin I, Taylor H, Spindler J. Orbital and conjunctival involvement in multiple myeloma. Report of a case. Am J Clin Pathol. 1975;63:811e7 12. Bhargava S, Gupta MC, Vyas K, et al. Solitary plasmocytoma of conjunctiva. J All India Ophthalmol Soc. 1967;15:38e9 13. Bi Y, Zeng N, Chanudet E, et al. A20 inactivation in ocular adnexal MALT lymphoma. Haematologica. 2012;97:926e30 14. Bjerrum KB. Primary Sjogren’s syndrome and keratoconjunctivitis sicca: diagnostic methods, frequency and social disease aspects. Acta Ophthalmol Scand Suppl 2000;1e37 15. Blasi MA, Gherlinzoni F, Calvisi G, et al. Local chemotherapy with interferon-alpha for conjunctival mucosa-associated lymphoid tissue lymphoma: a preliminary report. Ophthalmology. 2001;108:559e62 16. Blasi MA, Tiberti AC, Valente P, et al. Intralesional interferon-alpha for conjunctival mucosa-associated lymphoid tissue lymphoma: long-term results. Ophthalmology. 2012;119:494e500 17. Buggage RR, Smith JA, Shen D, et al. Conjunctival T-cell lymphoma caused by human T-cell lymphotrophic virus infection. Am J Ophthalmol. 2001;131:381e3 18. Cahill M, Barnes C, Moriarty P, et al. Ocular adnexal lymphoma-comparison of MALT lymphoma with other histological types. Br J Ophthalmol. 1999;83:742e7

s u r v e y o f o p h t h a l m o l o g y 6 0 ( 2 0 1 5 ) 4 4 4 e4 5 8

19. Cai J, Liu X, Cheng J, et al. MicroRNA-200 is commonly repressed in conjunctival MALT lymphoma, and targets cyclin E2. Graefes Arch Clin Exp Ophthalmol. 2012;250:523e31 20. Cerrone M, Collina F, De Chiara A, et al. BCL10 expression and localization in ocular adnexa MALT lymphomas: a comparative cytogenetic and immunohistochemical study. Histol Histopathol. 2014;29:77e87 21. Chan CC, Smith JA, Shen DF, et al. Helicobacter pylori (H. pylori) molecular signature in conjunctival mucosaassociated lymphoid tissue (MALT) lymphoma. Histol Histopathol. 2004;19:1219e26 22. Chanudet E, Huang Y, Ichimura K, et al. A20 is targeted by promoter methylation, deletion and inactivating mutation in MALT lymphoma. Leukemia. 2010;24:483e7 23. Chanudet E, Ye H, Ferry J, et al. A20 deletion is associated with copy number gain at the TNFA/B/C locus and occurs preferentially in translocation-negative MALT lymphoma of the ocular adnexa and salivary glands. J Pathol. 2009;217:420e30 24. Chanudet E, Zhou Y, Bacon CM, et al. Chlamydia psittaci is variably associated with ocular adnexal MALT lymphoma in different geographical regions. J Pathol. 2006;209:344e51 25. Chao DT, Korsmeyer SJ. BCL-2 family: regulators of cell death. Annu Rev Immunol. 1998;16:395e419 26. Charlotte F, Doghmi K, Cassoux N, et al. Ocular adnexal marginal zone B cell lymphoma: a clinical and pathologic study of 23 cases. Virchows Arch. 2006;448:506e16 27. Clarke B, Legodi E, Chrystal V, et al. Systemic anaplastic large cell lymphoma presenting with conjunctival involvement. Arch Ophthalmol. 2003;121:568e70 28. Clement CG, Potluri VR, Gonzales J, et al. Translocation (5; 11) in a conjunctival MALT lymphoma. Int J Clin Exp Pathol. 2011;4:722e6 29. Cook BE Jr, Bartley GB. Acute lymphoblastic leukemia manifesting in an adult as a conjunctival mass. Am J Ophthalmol. 1997;124:104e5 30. Coupland SE. Molecular pathology of lymphoma. Eye (Lond). 2013;27:180e9 31. Coupland SE, Foss HD, Assaf C, et al. T-cell and T/natural killer-cell lymphomas involving ocular and ocular adnexal tissues: a clinicopathologic, immunohistochemical, and molecular study of seven cases. Ophthalmology. 1999;106:2109e20 32. Coupland SE, Hellmich M, Auw-Haedrich C, et al. Prognostic value of cell-cycle markers in ocular adnexal lymphoma: an assessment of 230 cases. Graefes Arch Clin Exp Ophthalmol. 2004;242:130e45 33. Coupland SE, White VA, Rootman J, et al. A TNM-based clinical staging system of ocular adnexal lymphomas. Arch Pathol Lab Med. 2009;133:1262e7 34. Cowling VH, Turner SA, Cole MD. Burkitt’s lymphomaassociated c-Myc mutations converge on a dramatically altered target gene response and implicate Nol5a/Nop56 in oncogenesis. Oncogene. 2014;33:3519e27 35. Cuttner J, Spiera H, Troy K, et al. Autoimmune disease is a risk factor for the development of non-Hodgkin’s lymphoma. J Rheumatol. 2005;32:1884e7 36. Dal Bo M, Tissino E, Benedetti D, et al. Microenvironmental interactions in chronic lymphocytic leukemia: the master role of CD49d. Semin Hematol. 2014;51:168e76 37. de Jong D, Aleman BM, Taal BG, et al. Controversies and consensus in the diagnosis, work-up and treatment of gastric lymphoma: an international survey. Ann Oncol. 1999;10:275e80 38. Decaudin D, de Cremoux P, Vincent-Salomon A, et al. Ocular adnexal lymphoma: a review of clinicopathologic features and treatment options. Blood. 2006;108:1451e60

455

39. Ely SA, Werner A, Chadburn A. An angiocentric orbital lesion with an immature natural killer cell immunophenotype. Hum Pathol. 2001;32:339e42 40. Engels EA, Cerhan JR, Linet MS, et al. Immune-related conditions and immune-modulating medications as risk factors for non-Hodgkin’s lymphoma: a case-control study. Am J Epidemiol. 2005;162:1153e61 41. Farmer JP, Lamba M, Merkur AB, et al. Characterization of lymphoproliferative lesions of the conjunctiva: immunohistochemical and molecular genetic studies. Can J Ophthalmol. 2006;41:753e60 42. Ferreri AJ, Guidoboni M, Ponzoni M, et al. Evidence for an association between Chlamydia psittaci and ocular adnexal lymphomas. J Natl Cancer Inst. 2004;96:586e94 43. Ferreri AJ, Ponzoni M, Martinelli G, et al. Rituximab in patients with mucosal-associated lymphoid tissue-type lymphoma of the ocular adnexa. Haematologica. 2005;90:1578e9 44. Ferreri AJ, Viale E, Guidoboni M, et al. Clinical implications of hepatitis C virus infection in MALT-type lymphoma of the ocular adnexa. Ann Oncol. 2006;17:769e72 45. Ferry JA, Fung CY, Zukerberg L, et al. Lymphoma of the ocular adnexa: a study of 353 cases. Am J Surg Pathol. 2007;31:170e84 46. Fiskvik I, Beiske K, Delabie J, et al. Combining MYC, BCL2 and TP53 gene and protein expression alterations improves risk stratification in diffuse large B-cell lymphoma. Leuk Lymphoma 2014;1e8 47. Fradkin AH, Ruiz RS, Sloane JA. Mycosis fungoides involving the caruncle. Am J Ophthalmol. 1969;68:719e22 48. Gaffar M, Thebpatiphat N, Przygodzki R, et al. Primary follicular lymphoma of the conjunctiva in a 6-year-old child. J AAPOS. 2010;14:538e40 49. Graue GF, Finger PT, Maher E, et al. Ocular adnexal lymphoma staging and treatment: American Joint Committee on Cancer versus Ann Arbor. Eur J Ophthalmol. 2013;23:344e55 50. Gruenberger B, Woehrer S, Troch M, et al. Assessment of the role of hepatitis C, Helicobacter pylori and autoimmunity in MALT lymphoma of the ocular adnexa in 45 Austrian patients. Acta Oncol. 2008;47:355e9 51. Grunberger B, Hauff W, Lukas J, et al. ‘Blind’ antibiotic treatment targeting Chlamydia is not effective in patients with MALT lymphoma of the ocular adnexa. Ann Oncol. 2006;17:484e7 52. Holds J, Buchanan A, Hanson R. Intralesional interferonalpha for the treatment of bilateral conjunctival mucosaassociated lymphoid tissue lymphoma. Pediatr Blood Cancer. 2012;59:176e8 53. Honma K, Tsuzuki S, Nakagawa M, et al. TNFAIP3/A20 functions as a novel tumor suppressor gene in several subtypes of non-Hodgkin lymphomas. Blood. 2009;114:2467e75 54. Hu FR, Lin JC, Chiang IP, et al. T-cell malignant lymphoma with conjunctival involvement. Am J Ophthalmol. 1998;125:717e9 55. Hunter ZR, Xu L, Yang G, et al. The genomic landscape of Waldenstrom macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis. Blood. 2014;123:1637e46 56. Husain A, Roberts D, Pro B, et al. Meta-analyses of the association between Chlamydia psittaci and ocular adnexal lymphoma and the response of ocular adnexal lymphoma to antibiotics. Cancer. 2007;110:809e15 57. Inagaki H. Mucosa-associated lymphoid tissue lymphoma: molecular pathogenesis and clinicopathological significance. Pathol Int. 2007;57:474e84

456

s u r v e y o f o p h t h a l m o l o g y 6 0 ( 2 0 1 5 ) 4 4 4 e4 5 8

58. Isaacson PG, Mu¨ller-Hermelink HK, Piris MA, et al. Extranodal marginal zone B-cell lymphoma (MALT lymphoma), in Jaffe ES, Harris NL, Stein H, et al (eds) World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, IARC Press; 2001, pp 157e60 59. Isola V, Mazzacane D, Defelice N, et al. Malignant conjunctival T cell lymphoma diagnosed by punch biopsy as a primary manifestation of systemic cancer. Clin Ophthalmol. 2012;6:777e80 60. Jaffe ES, Harris NL, Stein H, et al. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, IARCPress; 2001 61. Jardin F, Gaulard P, Buchonnet G, et al. Follicular lymphoma without t(14;18) and with BCL-6 rearrangement: a lymphoma subtype with distinct pathological, molecular and clinical characteristics. Leukemia. 2002;16:2309e17 62. Jenkins C, Rose GE, Bunce C, et al. Clinical features associated with survival of patients with lymphoma of the ocular adnexa. Eye (Lond). 2003;17:809e20 63. Jereb B, Lee H, Jakobiec FA, et al. Radiation therapy of conjunctival and orbital lymphoid tumors. Int J Radiat Oncol Biol Phys. 1984;10:1013e9 64. Jiang J, Liu Y, Wang F, et al. An unusual occurrence of solitary extramedullary plasmacytoma in the conjunctiva. Oncol Lett. 2012;4:245e6 65. Katzenberger T, Kalla J, Leich E, et al. A distinctive subtype of t(14;18)-negative nodal follicular non-Hodgkin lymphoma characterized by a predominantly diffuse growth pattern and deletions in the chromosomal region 1p36. Blood. 2009;113:1053e61 66. Khalil HA, de Keizer RJ, Kluin PM, et al. Clinical course and pathologic features of conjunctival non-Hodgkin’s lymphoma. A report of six cases. Graefes Arch Clin Exp Ophthalmol. 1990;228:246e51 67. Khanlari M, Bagheri B, Vojdani R, et al. Conjunctival mass as an initial presentation of mantle cell lymphoma: a case report. BMC Res Notes. 2012;5:671 68. Kim KH, Kim TM, Go H, et al. Clinical significance of tumorinfiltrating FOXP3þ T cells in patients with ocular adnexal mucosa-associated lymphoid tissue lymphoma. Cancer Sci. 2011;102:1972e6 69. Kim NJ, Khwarg SI. Primary diffuse large B-cell lymphoma of the palpebral conjunctiva. Can J Ophthalmol. 2007;42:630e1 70. Kim TM, Kim KH, Lee MJ, et al. First-line therapy with doxycycline in ocular adnexal mucosa-associated lymphoid tissue lymphoma: a retrospective analysis of clinical predictors. Cancer Sci. 2010;101:1199e203 71. Kirn TJ, Levy NB, Gosselin JJ, et al. Peripheral T-cell lymphoma presenting as sclerouveitis. Cornea. 2012;26:1147e9 72. Kirwan C, Ngan BY, Halliday W, et al. Primary conjunctival anaplastic large cell lymphoma in a child. J AAPOS. 2013;17:437e9 73. Knop N, Knop E. Conjunctiva-associated lymphoid tissue in the human eye. Invest Ophthalmol Vis Sci. 2000;41:1270e9 74. Kohlhof JK, Driemel O, Muller-Richter UD. Re-re-relapse of a MALT lymphoma of the conjunctiva. Klin Monbl Augenheilkd. 2008;225:727e30 75. Kubota T, Moritani S, Yoshino T, et al. Ocular adnexal mucosa-associated lymphoid tissue lymphoma with polyclonal hypergammaglobulinemia. Am J Ophthalmol. 2008;145:1002e6 76. Larson TA, Hu M, Janik JE, et al. Interleukin-2 receptor targeted therapy of ocular disease of HTLV-1-associated adult T-cell leukemia. Ocul Immunol Inflamm. 2012;20:312e4

77. Lee DH, Sohn HW, Park SH, et al. Bilateral conjunctival mucosa-associated lymphoid tissue lymphoma misdiagnosed as allergic conjunctivitis. Cornea. 2001;20:427e9 78. Lee SB, Yang JW, Kim CS. The association between conjunctival MALT lymphoma and Helicobacter pylori. Br J Ophthalmol. 2008;92:534e6 79. Lee SE, Paik JS, Cho WK, et al. Feasibility of the TNM-based staging system of ocular adnexal extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). Am J Hematol. 2011;86:262e6 80. Lucas PC, Yonezumi M, Inohara N, et al. Bcl10 and MALT1, independent targets of chromosomal translocation in malt lymphoma, cooperate in a novel NF-kappa B signaling pathway. J Biol Chem. 2001;276:19012e9 81. Lugassy G, Rozenbaum D, Lifshitz L, et al. Primary lymphoplasmacytoma of the conjunctiva. Eye (Lond). 1992;6(Pt 3):326e7 82. Mannami T, Yoshino T, Oshima K, et al. Clinical, histopathological, and immunogenetic analysis of ocular adnexal lymphoproliferative disorders: characterization of malt lymphoma and reactive lymphoid hyperplasia. Mod Pathol. 2001;14:641e9 83. Masir N, Campbell LJ, Goff LK, et al. BCL2 protein expression in follicular lymphomas with t(14;18) chromosomal translocations. Br J Haematol. 2009;144:716e25 84. Matsuo T, Ichimura K, Yoshino T. Spontaneous regression of bilateral conjunctival extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue. J Clin Exp Hematop. 2007;47:79e81 85. Matsuo T, Yoshino T. Long-term follow-up results of observation or radiation for conjunctival malignant lymphoma. Ophthalmology. 2004;111:1233e7 86. Matteucci C, Galieni P, Leoncini L, et al. Typical genomic imbalances in primary MALT lymphoma of the orbit. J Pathol. 2003;200:656e60 87. McKelvie PA, McNab A, Francis IC, et al. Ocular adnexal lymphoproliferative disease: a series of 73 cases. Clin Experiment Ophthalmol. 2001;29:387e93 88. Meunier J, Lumbroso-Le Rouic L, Dendale R, et al. Conjunctival low-grade non-Hodgkin’s lymphoma: a large single-center study of initial characteristics, natural history and prognostic factors. Leuk Lymphoma. 2006;47:1295e305 89. Minasian MC, Sharma A, Richman PI, et al. Conjunctival MALT lymphoma: an usual cause of red eye. Postgrad Med J. 1999;75:423e4 90. Mondal SK. Mucosa-associated lymphoid tissue lymphoma in conjunctiva. Indian J Pathol Microbiol. 2008;51:407e8 91. Murga Penas EM, Hinz K, Biller L, et al. Frequency of chromosomal aneuploidies and deletions of the RB and TP53 genes in MALT lymphomas harboring the t(14;18)(q32;q21). Cancer Genet Cytogenet. 2006;164:81e3 92. Nanjangud G, Rao PH, Teruya-Feldstein J, et al. Molecular cytogenetic analysis of follicular lymphoma (FL) provides detailed characterization of chromosomal instability associated with the t(14;18)(q32;q21) positive and negative subsets and histologic progression. Cytogenet Genome Res. 2007;118:337e44 93. Nasser QJ, Pfeiffer ML, Romaguera J, et al. Clinical value of magnetic resonance imaging and other baseline testing for conjunctival mucosa-associated lymphoid tissue lymphoma. Leuk Lymphoma. 2014;55:1013e7 94. Nuckel H, Meller D, Steuhl KP, et al. Anti-CD20 monoclonal antibody therapy in relapsed MALT lymphoma of the conjunctiva. Eur J Haematol. 2004;73:258e62 95. Oka K, Ohno T, Yamaguchi M, et al. PRAD1/Cyclin D1 gene overexpression in mantle cell lymphoma. Leuk Lymphoma. 1996;21:37e42

s u r v e y o f o p h t h a l m o l o g y 6 0 ( 2 0 1 5 ) 4 4 4 e4 5 8

96. Orii K, Kobayashi H, Ueno M, et al. Mantle cell lymphoma with multiple extranodal involvement. Rinsho Ketsueki. 1997;38:520e5 97. Panayiotidis P, Kotsi P. Genetics of small lymphocyte disorders. Semin Hematol. 1999;36:171e7 98. Patel DS, Rundle P, Salvi SM, et al. Conjunctival angioimmunoblastic T-cell lymphoma. Ocul Oncol Pathol. 2015;1:71e6 99. Perry LJ, Jakobiec FA, Rubin PA. Conjunctival pediatric follicular lymphoma. Arch Ophthalmol. 2012;130:941e3 100. Precupanu CM, Validire P, Le´vy C, et al. Primary high-grade ocular adnexal lymphoma: clinicopathological characteristics and prognostic factors of a single-centre series. Am J Hematol. 2010;85:372e5 101. Rajkumar SV. Multiple myeloma: 2013 update on diagnosis, risk-stratification, and management. Am J Hematol. 2013;88:226e35 102. Rasmussen P, Sjo LD, Prause JU, et al. Mantle cell lymphoma in the orbital and adnexal region. Br J Ophthalmol. 2009;93:1047e51 103. Regueiro CA, Valcarcel FJ, Romero J, et al. Treatment of conjunctival lymphomas by beta-ray brachytherapy using a strontium-90-yttrium-90 applicator. Clin Oncol (R Coll Radiol). 2002;14:459e63 104. Rigacci L, Nassi L, Puccioni M, et al. Rituximab and chlorambucil as first-line treatment for low-grade ocular adnexal lymphomas. Ann Hematol. 2007;86:565e8 105. Robinson L, McKellar M, Fitzharris B, et al. Topical mitomycin C for the local treatment of a primary diffuse large B-cell lymphoma of the palpebral conjunctiva. Clin Experiment Ophthalmol. 2009;37:891e2 106. Rosado MF, Byrne GE Jr, Ding F, et al. Ocular adnexal lymphoma: a clinicopathologic study of a large cohort of patients with no evidence for an association with Chlamydia psittaci. Blood. 2006;107:467e72 107. Royo C, Salaverria I, Hartmann EM, et al. The complex landscape of genetic alterations in mantle cell lymphoma. Semin Cancer Biol. 2011;21:322e34 108. Ruiz A, Reischl U, Swerdlow SH, et al. Extranodal marginal zone B-cell lymphomas of the ocular adnexa: multiparameter analysis of 34 cases including interphase molecular cytogenetics and PCR for Chlamydia psittaci. Am J Surg Pathol. 2007;31:792e802 109. Schiby G, Polak-Charcon S, Mardoukh C, et al. Orbital marginal zone lymphomas: an immunohistochemical, polymerase chain reaction, and fluorescence in situ hybridization study. Hum Pathol. 2007;38:435e42 110. Schraders M, de Jong D, Kluin P, et al. Lack of Bcl-2 expression in follicular lymphoma may be caused by mutations in the BCL2 gene or by absence of the t(14;18) translocation. J Pathol. 2005;205:329e35 111. Scullica L, Manganelli C, Turco S, et al. Bilateral non-Hodgkin lymphoma of the conjunctiva. Eye (Lond). 1999;13(Pt 3a):379e80 112. Seddon JM, Corwin JM, Weiter JJ, et al. Solitary extramedullary plasmacytoma of the palpebral conjunctiva. Br J Ophthalmol. 1982;66:450e4 113. Sehu KW, Knop Lee WR. Ophthalmic Pathology: An Illustrated Guide for Clinicians. Malden, Oxford, BMJ Books/ Blackwell Pub; 2005, pp 40e59 114. Seker M, Ozdemir B, Bilici A, et al. Bilateral conjunctival MALT lymphoma mimicking chronic conjunctivitis. Onkologie. 2010;33:317e20 115. Shields CL, Shields JA, Eagle RC. Clinicopathologic reports, case reports, and small case series: rapidly progressive T-cell lymphoma of the conjunctiva. Arch Ophthalmol. 2002;120:508e9 116. Shields JA, Shields CL, De Potter P. Surgical management of conjunctival tumors. The 1994 Lynn B. McMahan Lecture. Arch Ophthalmol. 1997;115:808e15

457

117. Sjo LD. Ophthalmic lymphoma: epidemiology and pathogenesis. Acta Ophthalmol. 2009;87:1e20, Thesis 1. 118. Sjo LD, Heegaard S, Prause JU, et al. Extranodal marginal zone lymphoma in the ocular region: clinical, immunophenotypical, and cytogenetical characteristics. Invest Ophthalmol Vis Sci. 2009;50:516e22 119. Sjo LD, Ralfkiaer E, Prause JU, et al. Increasing incidence of ophthalmic lymphoma in Denmark from 1980 to 2005. Invest Ophthalmol Vis Sci. 2008;49:3283e8 120. Sjo NC, Foegh P, Juhl BR, et al. Role of Helicobacter pylori in conjunctival mucosa-associated lymphoid tissue lymphoma. Ophthalmology. 2007;114:182e6 121. Song JY, Pittaluga S, Dunleavy K, et al. Lymphomatoid granulomatosisda single institute experience: pathologic findings and clinical correlations. Am J Surg Pathol. 2015;39:141e56 122. Stefanovic A, Lossos IS. Extranodal marginal zone lymphoma of the ocular adnexa. Blood. 2009;114:501e10 123. Streubel B, Vinatzer U, Lamprecht A, et al. T(3;14)(p14.1;q32) involving IGH and FOXP1 is a novel recurrent chromosomal aberration in MALT lymphoma. Leukemia. 2005;19:652e8 124. Streubel B, Lamprecht A, Dierlamm J, et al. T(14;18)(q32;q21) involving IGH and MALT1 is a frequent chromosomal aberration in MALT lymphoma. Blood. 2003;101:2335e9 125. Sullivan TJ, Valenzuela AA. Imaging features of ocular adnexal lymphoproliferative disease. Eye (Lond). 2006;20:1189e95 126. Sun L, Li M, Huang X, et al. High-resolution genome-wide analysis identified recurrent genetic alterations in NK/T-cell lymphoma, nasal type, which are associated with disease progression. Med Oncol. 2014;31:71 127. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, IARC Press; 4th ed, 2008 128. Tagawa H, Karube K, Guo Y, et al. Trisomy 3 is a specific genomic aberration of t(14;18) negative follicular lymphoma. Leukemia. 2007;21:2549e51 129. Taghipour Z, Miratashi S, Nazemian M, et al. Primary follicular lymphoma of the conjunctiva in a 12 year-old male. Iran J Ped Hematol Oncol. 2013;3:83e5 130. Takada S, Yoshino T, Taniwaki M, et al. Involvement of the chromosomal translocation t(11;18) in some mucosaassociated lymphoid tissue lymphomas and diffuse large B-cell lymphomas of the ocular adnexa: evidence from multiplex reverse transcriptase-polymerase chain reaction and fluorescence in situ hybridization on using formalinfixed, paraffin-embedded specimens. Mod Pathol. 2003;16:445e52 131. Takahashi K, Sakuma T, Onoe S, et al. Adult T-cell leukemia with leukemic cell infiltration in the conjunctiva. A case report. Doc Ophthalmol. 1993;83:255e60 132. Takahira M, Okumura H, Minato H, et al. Primary conjunctival follicular lymphoma treated with the anti-CD20 antibody rituximab and low-dose involved-field radiotherapy. Jpn J Ophthalmol. 2007;51:149e51 133. Tanimoto K, Kaneko A, Suzuki S, et al. Primary ocular adnexal MALT lymphoma: a long-term follow-up study of 114 patients. Jpn J Clin Oncol. 2007;37:337e44 134. Tanimoto K, Sekiguchi N, Yokota Y, et al. Fluorescence in situ hybridization (FISH) analysis of primary ocular adnexal MALT lymphoma. BMC Cancer. 2006;6:249 135. Theander E, Henriksson G, Ljungberg O, et al. Lymphoma and other malignancies in primary Sjogren’s syndrome: a cohort study on cancer incidence and lymphoma predictors. Ann Rheum Dis. 2006;65:796e803 136. Tiemann M, Haring S, Heidemann M, et al. Mucosaassociated lymphoid tissue lymphoma in the conjunctiva of a child. Virchows Arch. 2004;444:198e201

458

s u r v e y o f o p h t h a l m o l o g y 6 0 ( 2 0 1 5 ) 4 4 4 e4 5 8

137. Ting DS, Mansoor Q, Mathew S, et al. Caruncular tumor as the first sign of T-cell lymphoma relapse. Semin Ophthalmol. 2015;30:139e41 138. Tiu RV, Singh AD, Workman J, et al. Concomitant conjunctival mucosa-associated lymphoid tissue lymphoma and small lymphocytic lymphoma associated with immunoglobulin M macroglobulinemia successfully treated with intensity modulated radiation therapy. Leuk Lymphoma. 2010;51:952e5 139. Tonami H, Matoba M, Kuginuki Y, et al. Clinical and imaging findings of lymphoma in patients with Sjogren syndrome. J Comput Assist Tomogr. 2003;27:517e24 140. Topalkara A, Ben-Arie-Weintrob Y, Ferry JA, et al. Conjunctival marginal zone B-cell lymphoma (MALT lymphoma) with amyloid and relapse in the stomach. Ocul Immunol Inflamm. 2007;15:347e50 141. Vaandrager JW, Schuuring E, Zwikstra E, et al. Direct visualization of dispersed 11q13 chromosomal translocations in mantle cell lymphoma by multicolor DNA fiber fluorescence in situ hybridization. Blood. 1996;88:1177e82 142. Vockerodt M, Yap LF, Shannon-Lowe C, et al. The EpsteinBarr virus and the pathogenesis of lymphoma. J Pathol. 2015;235:312e22 143. Vyas MC, Vyas SP, Chaudhary RK. Primary extramedullary solitary plasmacytoma of conjunctivada case report. Indian J Ophthalmol. 1984;32:181e3 144. Weisenthal RW, Streeten BW, Dubansky AS, et al. Burkitt lymphoma presenting as a conjunctival mass. Ophthalmology. 1995;102:129e34

145. Widmer S, Tinguely M, Egli F, et al. Lethal Epstein-Barr virus associated NK/T-cell lymphoma with primary manifestation in the conjunctiva. Klin Monbl Augenheilkd. 2005;222:255e7 146. Williams BK Jr, Tsui I, McCannel TA. Spectral-domain optical coherence tomography of conjunctival mucosa-associated lymphoid tissue lymphoma with presumed choroidal involvement. Graefes Arch Clin Exp Ophthalmol. 2010;248:1837e40 147. Wohrer S, Troch M, Streubel B, et al. MALT lymphoma in patients with autoimmune diseases: a comparative analysis of characteristics and clinical course. Leukemia. 2007;21:1812e8 148. Ye H, Liu H, Attygalle A, et al. Variable frequencies of t(11;18)(q21;q21) in MALT lymphomas of different sites: significant association with CagA strains of H pylori in gastric MALT lymphoma. Blood. 2003;102:1012e8 149. Yoo SB, Kim YA, Jeon YK, et al. CD5-undetected by immunohistochemistry, t(11;14)(q13;q32)-positive conjunctival mantle cell lymphoma: a case report. Pathol Res Pract. 2008;204:779e83 150. Yoon JS, Ma KT, Kim SJ, et al. Prognosis for patients in a Korean population with ocular adnexal lymphoproliferative lesions. Ophthal Plast Reconstr Surg. 2007;23:94e9 151. Yu CS, Chiu SI, Ng CS, et al. Localized conjunctival mucosaassociated lymphoid tissue (MALT) lymphoma is amenable to local chemotherapy. Int Ophthalmol. 2008;28:51e4 152. Yumori JW, Ilsen P, Bright DC. Conjunctival plasmacytoma. Optometry. 2010;81:234e9