August 2008
Volume 49, Issue 8
Free
Anatomy and Pathology/Oncology  |   August 2008
Increasing Incidence of Ophthalmic Lymphoma in Denmark from 1980 to 2005
Author Affiliations
  • Lene D. Sjö
    From the Eye Pathology Institute, Department of Neuroscience and Pharmacology, and the
  • Elisabeth Ralfkiaer
    Department of Pathology, Rigshospitalet, Copenhagen, Denmark; the
  • Jan U. Prause
    From the Eye Pathology Institute, Department of Neuroscience and Pharmacology, and the
  • Jorgen H. Petersen
    Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark; the
  • Jakob Madsen
    Department of Hematology, Aalborg Hospital, University of Aarhus, Aarhus, Denmark; and the
  • Niels T. Pedersen
    Department of Pathology, Odense University Hospital, Odense, Denmark.
  • Steffen Heegaard
    From the Eye Pathology Institute, Department of Neuroscience and Pharmacology, and the
Investigative Ophthalmology & Visual Science August 2008, Vol.49, 3283-3288. doi:10.1167/iovs.08-1768
  • Views
  • PDF
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to Subscribers Only
      Sign In or Create an Account ×
    • Get Citation

      Lene D. Sjö, Elisabeth Ralfkiaer, Jan U. Prause, Jorgen H. Petersen, Jakob Madsen, Niels T. Pedersen, Steffen Heegaard; Increasing Incidence of Ophthalmic Lymphoma in Denmark from 1980 to 2005. Invest. Ophthalmol. Vis. Sci. 2008;49(8):3283-3288. doi: 10.1167/iovs.08-1768.

      Download citation file:


      © 2016 Association for Research in Vision and Ophthalmology.

      ×
  • Supplements
Abstract

purpose. To evaluate patient characteristics and incidence of ophthalmic lymphoma in Denmark during the period 1980 to 2005.

methods. All patients in Denmark with a diagnosis of ophthalmic lymphoma during the period 1980 to 2005 were retrieved from three different population-based registries. Specimens from all patients were collected and reclassified according to the World Health Organization (WHO) classification system. Incidence rates were calculated by using Poisson regression models.

results. A total of 228 patients with a histologically verified diagnosis of ophthalmic lymphoma were included. There was an equal distribution of males and females. The most frequent lymphoma subtype was extranodal marginal zone B-cell lymphoma (MALT [mucosa-associated lymphoid tissue] lymphoma, 55.5%) and most cases were located in the orbit (56.8%). High-grade lymphoma subtypes were found more frequently in males than in females. Incidence rates were highly dependent on the patient’s age. For all ages, a statistically significant annual average increase of 3.4% during the 26-year period was found. This increase was primarily due to a rise in the incidence of MALT lymphoma.

conclusions. In the Danish population ophthalmic lymphoma consists primarily of orbital MALT lymphoma. Although it is a rare disease in mostly elderly patients, the incidence of ophthalmic lymphoma is increasing at a rapid pace.

Non-Hodgkin lymphoma (NHL) is a malignant neoplasm derived from a clonal proliferation of B or T lymphocytes. It is a heterogenous group of more than 40 different subtypes that can arise both in extranodal tissue and in lymph nodes. The incidence of NHL has risen considerably in Western countries over the past decades. 1 2 In Denmark, NHL represents the seventh most common type of cancer. 3  
Ophthalmic lymphoma (lymphoma localized in the ocular region, i.e., eyelid, conjunctiva, lacrimal sac, lacrimal gland, orbit, or intraocularly) constitutes approximately 10% of all extranodal NHL, 4 and lymphoma is the most common orbital malignancy. 5 6 7 8 9 Most lymphomas arising in the ocular region are low-grade B-cell lymphomas, with a high frequency of extranodal marginal zone B-cell lymphoma (MALT [mucosa-associated lymphoid tissue] lymphoma). 10 11 12  
The etiology of ophthalmic lymphoma is largely unknown. A possible connection between ocular region MALT lymphoma and Chlamydia psittaci (C. psittaci) has been suggested. 13 However, results from various studies differ, possibly because of geographic differences. 9 14 15 16  
Knowledge of both the geographic distribution and time trends of ophthalmic lymphoma may be helpful in formulating new etiologic hypotheses. However, the coexistence of multiple NHL classification systems (e.g., Kiel, Lukes-Collins, Rappaport, Working Formulation) has complicated epidemiologic research in NHL, and incidence data on ophthalmic lymphomas are sparse. Two reports based on register data indicate that the incidence of ophthalmic lymphoma in the United States is increasing at an even higher rate than is NHL in general. 8 17 The implementation of the REAL (revised European-American Lymphoma) 18 and the World Health Organization (WHO) 19 classification systems provides new possibilities for performing reliable epidemiologic studies on ophthalmic lymphoma. 
We present a large population-based analysis of all cases of ocular adnexal, orbital, and intraocular lymphoma diagnosed in Denmark from 1980 to 2005. All lymphomas were reclassified according to the WHO classification (2001), and incidences of lymphoma in general and of specific subtypes were calculated to evaluate subtype and time trends in ophthalmic lymphoma. 
Material and Methods
Patients
The study included all biopsy-verified cases of primary and secondary lymphoma in the ocular region in Denmark during the period from 1980 to 2005. Patients were enrolled by using three different population-based registries: (1) the Eye Pathology Institute Registry, (2) the Danish Registry of Pathology, and (3) The Danish Lymphoma Group Registry. From the registries, we searched for all patients with a diagnosis of ophthalmic lymphoid lesions. Histopathologic descriptions from all patient records were reviewed. Specimens with evident descriptions of pseudolymphoma, or the now preferred term reactive lymphoid hyperplasia, were identified but not further analyzed in this study. All specimens with any suspicion of lymphoid malignancy were reviewed by histology and immunohistochemistry. 
Classification of Cases
Formalin-fixed, paraffin-embedded tissue from patients with a suspected ophthalmic lymphoma diagnosis was collected from the Eye Pathology Institute and from all Danish pathology departments. Sections were heated in a microwave oven in a TEG buffer (pH: 9) for 15 minutes, and a primary immunohistochemical panel was applied with antibodies directed against CD3, CD5, CD20, and CD79α, to differentiate between B- and T-cell lymphomas. The B-cell neoplasms were also immunophenotyped with antibodies directed against bcl-2, bcl-6, CD10, CD23, CD30, Cyclin D1, MUM-1, and κ- and λ light-chains. T-cell lymphomas were immunophenotyped with CD4, CD8, CD30, CD56, ALK-1, TIA, and granzyme B. In all cases, the mitotic rate was investigated with MIB-1. The stainings were performed with an immunochemical staining system (Techmate 500 Immunostainer; Dako, Glostrup, Denmark) that included a secondary antibody (Envision K5007; Dako). The sections were examined independently by two of the authors (LDS and ER) and were reviewed in consensus, to reclassify the lymphomas according to the WHO classification. 19  
Clinical Data
Clinical records and prebiopsy pathology requisition forms were reviewed with particular reference to year of diagnosis, sex, age, prior history of lymphoma, and sites of involvement. 
Statistical Analyses
Population data stratified by sex, age, and period were obtained from Statistics Denmark. 3 NHL incidence rates, expressing the number of new cases per 100,000 person-years were calculated for the whole population and for population subgroups according to lymphoma subtype, localization, sex, age, and period. Age was grouped in ten 10-year age groups, and period in five 5-year groups. Due to a low number of cases of the NHL subtypes diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and follicular lymphoma, it was necessary to pool periods (1980–1992 and 1993–2005). For the estimation of the effects of age, sex, and period on NHL incidence rates, we used a Poisson regression model. 20 The models were checked for interaction terms, and a goodness-of-fit test was used based on the deviance. Differences in the patients’ characteristics in NHL groups were tested with the Fisher exact test. All statistical analyses were performed with commercial software (SAS ver. 9.1; SAS, Cary, NC). 
Ethics
The investigation adhered the tenets of the Declaration of Helsinki and was approved by the local scientific ethics committee (journal no. KF 01-262201) and the Danish Protection Agency (journal no. 2005-41-5098). 
Results
A total of 228 Danish patients with a biopsy-reviewed verified diagnosis of ocular adnexal, orbital, or intraocular lymphoma were identified from the total 462 enrolled patients and were included in this study. Thirty-five cases were originally diagnosed as ophthalmic lymphoma, but were excluded from the study for technical reasons (18 cases) or because an ophthalmic location or a lymphoma diagnosis could not be confirmed (17 cases). The remaining 199 cases were identified as reactive lymphoid hyperplasia from the original histopathologic descriptions. 
Lymphoma Subclassification
Histopathologic review of the specimens showed that four lymphoma subtypes predominated: MALT lymphoma (126, 55%), DLBCL (29, 13%), MCL (20, 9%), and follicular lymphoma (17, 8%, Fig. 1 ). Twenty-one patients (9%) had B-cell lymphoma that could not be further classified because of lack of tissue specimens to perform a full immunohistochemical examination. Other subtypes found were: peripheral T-cell lymphoma, unspecified (n = 4, 2%), small lymphocytic lymphoma–chronic lymphocytic lymphoma (n = 3, 1%), Burkitt lymphoma (n = 3, 1%), precursor B-lymphoblastic lymphoma (n = 3, 1%), and anaplastic large T-cell lymphoma (n = 2, 1%; Table 1 ). 
Patient Characteristics
Most patients were elderly with a median age of 69 years (95% confidence interval [CI], 66–71; range, 5–96); 75% were older than 59 years. There was an almost equal distribution of males and females (males: 116, 51%, Table 2 ). Most lymphomas were localized in the orbit (n = 129, 57%) and the second most frequent localization was in the conjunctiva (n = 57, 25%), whereas lacrimal sac lymphoma was very rare (n = 3, 1%, Table 1 ). 
Intraocular lymphoma was diagnosed in 12 cases (5%). Of these, 10 (83%) were located in the uvea (8 in the choroid and 2 in the iris). The remaining two cases were retinal DLBCL (17%, Table 3 ). Concurrent cerebral disease was found in one of these patients. 
Ocular lymphoma was the first presenting symptom in the majority of patients (n = 184, 81%, Table 2 ). More than half of them (n = 102, 65%) had involvement only of the ocular region (stage I). Ten (6%) patients had disease involving regional lymph nodes (stage II), 8 (5%) had involvement of the lymph nodes below the diaphragm (stage III), and 35 (23%) patients had affected bone marrow at the time of diagnosis (stage IV; Tables 3 4 ). The remaining 44 cases were secondary (i.e., there was a prior history of systemic lymphoma), including 7 of 12 intraocular lymphoma cases (58%, Table 3 ). 
Bilateral disease was significantly more common in MCL (9/20, 45%) than in MALT lymphoma (13/127, 10%, P = 0.0004; Table 1 ) or all other lymphoma subtypes (6/81, 7%, P = 0.0002). 
MCL occurred only in patients older than 60 years (P = 0.005), whereas acute leukemias and Burkitt lymphoma occurred only in patients younger than 60 years (P < 0001). The high-grade lymphoma subtypes were significantly more frequent intraocularly than in the remaining ocular region (P = 0.0035, Table 1 ). 
The males were more likely to present with high-grade lymphoma than were the females (P = 0.0022, Table 2 ). Especially MCL affected males predominantly (P = 0.0017). No differences in distribution according to site of ophthalmic lymphoma were found between the males and females. 
Among the patients with MALT lymphoma, six (5%) had a preceding history of autoimmune disease. 
Incidence Data
Age-Specific Incidence Rates by Sex.
Incidence rates were highly dependent on patient age (P < 0.0001, Fig. 2 ). For both sexes, the age-specific incidence, during the period 2001 to 2005 was below 0.5 per 100,000 until age 60 years, increasing progressively with each decade until a maximum of 2.6 cases per 100,000 for males at age 90 years and 1.0 per 100,000 for females at age 80 years. Differences in incidence between males and females were not statistically significant. 
Time Trends in Incidence Rates.
The number of patients and incidence rates in different calendar periods are shown in Table 5 . Incidence rates of ophthalmic lymphoma for the whole population increased from 0.086 in 1981 to 1985 to 0.249 per 100,000 in 2001 to 2005. Adjustment for differences in the age distribution over the period confirmed this increasing tendency (P = 0.0068). The estimated changes in incidence corresponded to an annual average increase in the 26-year period of 3.4% (P < 0.0007, Table 5 ). 
For comparison, the number of cases of reactive lymphoid hyperplasia also increased with distribution according to period, as follows: 1981 to 1985, 20 cases; 1986 to 1990, 38 cases; 1991 to 1995, 28 cases; 1996 to 2000, 52 cases; and 2001 to 2005, 57 cases. 
The increase in incidence of ophthalmic lymphoma was found, both in patients with limited disease (stages I and II) and in patients with more advanced lymphomas (stages III and IV or secondary lymphoma; age-adjusted rate-ratio [RR] = 2.15, P = 0.0002 and age-adjusted RR = 1.85, P = 0.0043, respectively), between the 1980 to 1992 and the 1993 to 2005 period. 
When the lymphomas were subdivided into the four most common lymphoma subtypes, the increasing incidence was found only in the low-grade lymphomas, MALT lymphoma (age-adjusted RR, 1993 to 2005 vs. 1980 to 1992 = 1.6, P = 0.009) and follicular lymphoma (age-adjusted RR, 1993 to 2005 vs. 1980 to 1992 = 4.1, P = 0.02), whereas there was no statistically significant increase over time for the high-grade lymphoma types DLBCL and MCL. 
Furthermore, when incidence rates were analyzed according to anatomic localization in the ocular region, there was a statistically significant increase in orbital (age-adjusted RR, 1993 to 2005 vs. 1980 to 1992 = 1.6, P = 0.007) and all other extraocular lymphomas (age-adjusted RR = 1.6, P = 0.028), whereas the incidence of intraocular lymphoma remained stable between the periods 1980 to 1992 and 1993 to 2005 (age-adjusted RR = 0.93, P = 0.028). 
Discussion
In this study, we reclassified all lymphomas diagnosed in the Danish population during the period 1980 to 2005. Analyzing 263 cases, we found that 228 could be verified to be ophthalmic lymphoma. Lymphoma in the ocular region is relatively uncommon with an annual incidence of ∼2 per 100,000 in the population older than 80 years. 
In our study, there was an equal distribution between the males and females; and, consistent with other studies, ocular adnexal lymphoma was primarily MALT lymphoma, localized in the orbit, 11 12 16 21 22 whereas intraocular lymphomas were predominantly high-grade lymphomas. 23 24 25 26 More than 80% of the patients had the first presentation of disease in the ocular region. 
MCL was seen only in patients older than 60 years, whereas Burkitt lymphoma and acute leukemia were found only in patients younger than 60. Of note, high-grade lymphoma, in general, and MCL in particular were more common in the males than in the females, and MCL was frequently bilateral. These observations are in accordance with those of other studies. 21 27  
The incidence rates found in this study are comparable with those in previous studies from Western countries based on cancer registry analyses. 8 17 The use of three different population-based registries and the fact that all specimens were reviewed and reclassified gives a very reliable result in our investigation. 
We observed an increase in the incidence of orbital and ocular adnexal lymphoma, as was also found by others. 8 17 This increase could be due to a change in classification systems (i.e., some cases formerly classified as reactive lymphoid hyperplasia would be classified as MALT lymphoma, according to the REAL or WHO classification). However, we found an increase in the total number of cases of both reactive lymphoid hyperplasia and MALT lymphoma. In addition, even though MALT lymphoma was not a described entity until 1983, 28 the diagnosis went into practical use in the early 1990s, and thus the increase found from the mid-1990s to 2005 can be considered reliable. 
During the period from 1980 to 2005, we found that the annual age-adjusted incidence rate more than doubled. The increase was consistent in both males and females, and applies for the lymphoma subtypes MALT lymphoma and follicular lymphoma and for all ophthalmic localizations except intraocular lymphoma. For the lymphoma subtypes DLBCL and MCL, which are more likely to be part of a systemic disease, we found no statistically significant increase. During the same interval, the incidence rate of NHL in general has risen as well, but at a slower rate than reported in this study, and the increase seems to have stabilized during the late 1990s. 2 29  
The increasing incidence rate of ophthalmic lymphoma calls for further studies to elucidate its etiology and especially that of ophthalmic MALT lymphoma, accounting for more than 50% of the cases. MALT lymphoma arises in aggregates of lymphocytes at sites of chronic inflammation in persistent infection. 30 Microbial species do not directly transform lymphoid cells, but persistent infection induces a sustained lymphoid proliferation, thus increasing the risk of chromosomal alterations leading to malignant transformation. 30 In the gastrointestinal tract MALT lymphoma has been linked to infection with Helicobacter pylori (H. pylori), 31 and during the past few years, several studies of a possible association between ocular lymphoma and C. psittaci infection have been conducted, with inconclusive results. 9 13 14 15 16 32 33 Other infectious agents have been investigated in ocular MALT lymphoma, such as hepatitis C virus (HCV) and H. pylori, without success. 34 35 36 Thus, whether a specific infectious agent triggers ocular MALT lymphoma is still controversial. 
In conclusion, we performed a large population-based study reclassifying all cases of ophthalmic lymphoma in Denmark through a 26-year-period. We analyzed patient characteristics, lymphoma subtypes, and incidences and found that, in the Danish population, ophthalmic lymphoma consists primarily of orbital MALT lymphoma. Although a rare disease of elderly patients, the incidence of ocular adnexal lymphoma is increasing at a rapid rate in Denmark. 
 
Figure 1.
 
(A) Typical conjunctival lymphoma presenting as a painless salmon-colored tumor in the conjunctiva of a 65-year-old male. (B) Magnetic resonance image of the eye of a 65-year-old female with a 2-year history of proptosis. The tumor spread from the left lacrimal gland (arrow) and infiltrated the orbit diffusely (★). On histopathologic examination, the tumor was found to be a MALT lymphoma. (C) Orbital MALT lymphoma characterized by a diffuse pattern of small centrocyte-like cells in an 81-year-old female. Hematoxylin-eosin stain. (D) MALT lymphoma (same patient as C) with preserved germinal centers shown by CD23 staining (brown) of the follicular dendritic cells. CD23 staining. (E) Diffuse large B-cell lymphoma in the right lower eyelid. The tumor cells have pleomorphic nuclei with irregularly distributed chromatin and up to three nucleoli. Mitoses (arrow) are frequently seen. The 80-year-old male died 6 months after diagnosis (hematoxylin-eosin; ×400). (F) Diffuse large B-cell lymphoma in the conjunctiva of a 73-year-old female. The mitotic activity was high as shown by the MIB-1 nuclear staining (brown). (G) Cyklin D1 positivity in an orbital MCL in a 85-year-old male, with no prior history of lymphoma. Subsequent staging revealed involvement of the bone marrow and axillary and inguinal lymph nodes. Cyklin D1 staining. (H) Typical nodular pattern in a follicular lymphoma in a 45-year-old female. A full-body CT-scan exposed a retroperitoneal tumor, and chemotherapeutic treatment was initiated. Hematoxylin-eosin. Magnification: (C, D, F) ×200; (E, G) ×400; (H) ×100.
Figure 1.
 
(A) Typical conjunctival lymphoma presenting as a painless salmon-colored tumor in the conjunctiva of a 65-year-old male. (B) Magnetic resonance image of the eye of a 65-year-old female with a 2-year history of proptosis. The tumor spread from the left lacrimal gland (arrow) and infiltrated the orbit diffusely (★). On histopathologic examination, the tumor was found to be a MALT lymphoma. (C) Orbital MALT lymphoma characterized by a diffuse pattern of small centrocyte-like cells in an 81-year-old female. Hematoxylin-eosin stain. (D) MALT lymphoma (same patient as C) with preserved germinal centers shown by CD23 staining (brown) of the follicular dendritic cells. CD23 staining. (E) Diffuse large B-cell lymphoma in the right lower eyelid. The tumor cells have pleomorphic nuclei with irregularly distributed chromatin and up to three nucleoli. Mitoses (arrow) are frequently seen. The 80-year-old male died 6 months after diagnosis (hematoxylin-eosin; ×400). (F) Diffuse large B-cell lymphoma in the conjunctiva of a 73-year-old female. The mitotic activity was high as shown by the MIB-1 nuclear staining (brown). (G) Cyklin D1 positivity in an orbital MCL in a 85-year-old male, with no prior history of lymphoma. Subsequent staging revealed involvement of the bone marrow and axillary and inguinal lymph nodes. Cyklin D1 staining. (H) Typical nodular pattern in a follicular lymphoma in a 45-year-old female. A full-body CT-scan exposed a retroperitoneal tumor, and chemotherapeutic treatment was initiated. Hematoxylin-eosin. Magnification: (C, D, F) ×200; (E, G) ×400; (H) ×100.
Table 1.
 
Distribution of Lymphoma within the Ophthalmic Region According to Lymphoma Subtype
Table 1.
 
Distribution of Lymphoma within the Ophthalmic Region According to Lymphoma Subtype
Lymphoma Subtype n Bilateral n (%, CI) Eyelid n (%, CI) Conj. n (%, CI) Lacr. Sac n (%, CI) Lacr. Gland n (%, CI) Orbit n (%, CI) Intraocular n (%, CI)
All lymphomas 228 28 (12, 8–17) 11 (5, 2–8) 57 (25, 19–30) 3 (1, 0–3) 16 (7, 4–10) 129 (57, 50–63) 12 (5, 2–8)
Low-grade types 147 14 (10, 5–14) 7 (5, 1–8) 44 (30, 23–37) 2 (1, 0–3) 10 (7, 3–11) 83 (56, 48–64) 0
 MALT 126 13 (10, 5–17) 5 (4, 0–7) 40 (31, 23–40) 1 (1, 0–2) 6 (5, 2–8) 74 (58, 50–67) 0
 FL 17 1 (6, 0–17) 1 (6, 0–17) 4 (24, 3–44) 0 3 (18, 0–36) 9 (53, 29–77) 0
 SLL/CLL 3 0 1 (33, 0–87) 0 1 (33, 0–87) 1 (33, 0–87) 0 0
High-grade types 61 10 (16, 7–26) 4 (7, 0–13) 9 (15, 6–24) 1 (2, 0–5) 4 (7, 0–13) 35 (57, 45–70) 8 (13, 5–22)*
 DLBCL 29 1 (3, 0–10) 1 (3, 0–10) 2 (7, 0–16) 0 3 (10, 0–21) 19 (66, 48–83) 4 (14, 1–26)
 MCL 20 9 (45, 23–67), † 0 7 (35, 14–65) 1 (5, 0–15) 1 (5, 0–15) 11 (55, 33–77) 0
 PTL, NOS 4 0 2 (50, 1–99) 0 0 0 1 (25, 0–67) 1 (25, 0–67)
 BL 3 0 0 0 0 0 1 (33, 0–87) 2 (67, 13–100)
 B-ALL 3 0 0 0 0 0 2 (67, 13–100) 1 (33, 0–87)
 T-ALCL 2 0 1 (50, 0–100) 0 0 0 1 (50, 0–100) 0
BCL, uncl. 21 4 (20, 2–38) 0 4 (20, 2–38) 0 2 (10, 0–23) 11 (55, 33–77) 4 (15, 0–31)
Table 2.
 
Clinical Data According to Lymphoma Subtype
Table 2.
 
Clinical Data According to Lymphoma Subtype
Lymphoma Subtype Number (%, CI) Males n (%, CI) Median Age Both Sexes, y (Range) Patients with Ophthalmic Lymphoma as First Presenting Symptom n (%, CI)
All lymphomas 228 (100) 116 (51, 44–57) 69 (5–96) 184 (81, 76–86)
Low-grade types 147 (64, 58–70) 66 (45, 37–55) 69 (8–96) 127 (88, 80–91)
 MALT 126 (55, 49–62) 58 (46, 37–54) 69 (8–92) 116 (92, 85–96)
 FL 17 (7, 4–11) 7 (41, 18–65) 63 (45–96) 11 (65, 42–87)
 SLL/CLL 3 (1, 0–3) 1 (33, 0–87) 75 (62–75) 0
High-grade types 61 (27, 21–33) 42 (69, 57–80)* 72 (5–95) 42 (69, 57–80)
 DLBCL 29 (13, 8–17) 13 (45, 27–63) 77 (17–95) 23 (79, 59–89)
 MCL 20 (9, 5–12) 17 (85, 69–100), † 75 (60–90) 11 (55, 33–77)
 PTL, NOS 4 (2, 0–3) 3 (75, 33–100) 61 (31–77) 3 (75, 33–100)
 BL 3 (1, 0–3) 2 (67, 13–100) 41 (34–55) 1 (33, 0–87)
 B-ALL 3 (1, 0–3) 2 (67, 13–100) 9 (5–34) 2 (67, 13–100)
 T-ALCL 2 (1, 0–2) 2 (100, 90–100) 45 (35–55) 2 (100, 90–100)
BCL, uncl. 21 (9, 5–12) 11 (55, 33–77) 63 (18–77) 15 (71, 50–90)
Table 3.
 
Intraocular Lymphoma
Table 3.
 
Intraocular Lymphoma
Subtype Stage Retina (n) Uvea (n)
DLBCL I 1 0
III 0 1
Ns 1 0
Sec. intraoc. 0 1
PTL, NOS IV 0 1*
BL Sec. intraoc. 0 2
B-ALL Sec. intraoc. 0 1*
BCL, uncl. I 0 1
Sec. intraoc. 0 3
Table 4.
 
Extraocular Ophthalmic Lymphoma
Table 4.
 
Extraocular Ophthalmic Lymphoma
Lymphoma Subtype/Stage Orbit (n) Ocular Adnexa (n)
MALT
 I 45 28
 II 1 1
 III 3 0
 IV 12 6
 Ns 9 11
FL
 I 3 3
 II 0 1
 III 1 2
 Ns 1 0
DLBCL
 I 9 1
 II 0 2
 IV 3 0
 Ns 4 1
MCL
 II 0 2
 IV 7 2
PTL, NOS
 I 0 1
 II 1 0
BL
 II 1 0
B-ALL
 IV 2 0
T-ALCL
 I 0 1
 III 1 0
BCL, uncl.
 I 5 4
 II 1 0
 IV 1 1
 Ns 1 1
Figure 2.
 
Age-specific ophthalmic lymphoma incidence rates for males and females in Denmark during the period 2001 to 2005. The rates are calculated based on all data in a Poisson regression model adjusted for period. Incidence rates in the 5-year periods from 1981 to 2000 were proportional to the ones depicted here, although lower, as shown in Table 3 . Incidence rates were highly dependent on patient age (P < 0.0001) with a maximum incidence rate of 2.6 per 100,000 for males and 1.0 per 100,000 for females. Differences in incidence between males and females were not statistically significant (P = 0.766).
Figure 2.
 
Age-specific ophthalmic lymphoma incidence rates for males and females in Denmark during the period 2001 to 2005. The rates are calculated based on all data in a Poisson regression model adjusted for period. Incidence rates in the 5-year periods from 1981 to 2000 were proportional to the ones depicted here, although lower, as shown in Table 3 . Incidence rates were highly dependent on patient age (P < 0.0001) with a maximum incidence rate of 2.6 per 100,000 for males and 1.0 per 100,000 for females. Differences in incidence between males and females were not statistically significant (P = 0.766).
Table 5.
 
Incidence of Ophthalmic Lymphoma from 1981 to 2005 in Denmark
Table 5.
 
Incidence of Ophthalmic Lymphoma from 1981 to 2005 in Denmark
Period Patients (n) Incidence per 100,000 (CI) Age-Adjusted Rate Ratio (CI)*
1981–1985 22 0.086 (0.057–0.131) 1.00 (1.00–1.00)
1986–1990 44 0.171 (0.128–0.231) 1.58 (0.94–2.70)
1991–1995 38 0.147 (0.107–0.202) 1.60 (0.94–2.71)
1996–2000 50 0.189 (0.143–0.249) 1.78 (1.06–2.98)
2001–2005 69 0.249 (0.196–0.316) 2.41 (1.47–3.93)
GrovesFD, LinetMS, TravisLB, DevesaSS. Cancer surveillance series: non-Hodgkin’s lymphoma incidence by histologic subtype in the United States from 1978 through 1995. J Natl Cancer Inst. 2000;92:1240–1251. [CrossRef] [PubMed]
ClarkeCA, GlaserSL. Changing incidence of non-Hodgkin lymphomas in the United States. Cancer. 2002;94:2015–2023. [CrossRef] [PubMed]
Statistics Denmark. www.statistikbanken.dk. Accessed June 2007.
FreemanC, BergJW, CutlerSJ. Occurrence and prognosis of extranodal lymphomas. Cancer. 1972;29:252–260. [CrossRef] [PubMed]
JohansenS, HeegaardS, BøgeskovL, PrauseJU. Orbital space-occupying lesions in Denmark 1974–1997. Acta Ophthalmol Scand. 2000;78:547–552. [CrossRef] [PubMed]
SeregardS, SahlinS. Panorama of orbital space-occupying lesions: the 24-year experience of a referral centre. Acta Ophthalmol Scand. 1999;77:91–98. [CrossRef] [PubMed]
ShieldsJA, ShieldsCL, ScartozziR. Survey of 1264 patients with orbital tumors and simulating lesions: The 2002 Montgomery Lecture, part 1. Ophthalmology. 2004;111:997–1008. [CrossRef] [PubMed]
MargoCE, MullaZD. Malignant tumors of the orbit: analysis of the Florida Cancer Registry. Ophthalmology. 1998;105:185–190. [CrossRef] [PubMed]
VargasRL, FalloneE, FelgarRE, et al. Is there an association between ocular adnexal lymphoma and infection with Chlamydia psittaci?—the University of Rochester experience. Leuk Res. 2006;30:547–551. [CrossRef] [PubMed]
BardensteinDS. Ocular adnexal lymphoma: classification, clinical disease, and molecular biology. Ophthalmol Clin North Am. 2005;18:187–197. [CrossRef] [PubMed]
ChoEY, HanJJ, ReeHJ, et al. Clinicopathologic analysis of ocular adnexal lymphomas: extranodal marginal zone B-cell lymphoma constitutes the vast majority of ocular lymphomas among Koreans and affects younger patients. Am J Hematol. 2003;73:87–96. [CrossRef] [PubMed]
CouplandSE, HellmichM, Auw-HaedrichC, LeeWR, SteinH. Prognostic value of cell-cycle markers in ocular adnexal lymphoma: an assessment of 230 cases. Graefes Arch Clin Exp Ophthalmol. 2004;242:130–145. [CrossRef] [PubMed]
FerreriAJ, GuidoboniM, PonzoniM, et al. Evidence for an association between Chlamydia psittaci and ocular adnexal lymphomas. J Natl Cancer Inst. 2004;96:586–594. [CrossRef] [PubMed]
DaibataM, NemotoY, TogitaniK, et al. Absence of Chlamydia psittaci in ocular adnexal lymphoma from Japanese patients. Br J Haematol. 2006;132:651–652. [CrossRef] [PubMed]
MulderMM, HeddemaER, PannekoekY, et al. No evidence for an association of ocular adnexal lymphoma with Chlamydia psittaci in a cohort of patients from the Netherlands. Leuk Res. 2006;30:1305–1307. [CrossRef] [PubMed]
RosadoMF, ByrneGE, Jr, DingF, 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;107:467–472. [CrossRef] [PubMed]
MoslehiR, DevesaSS, SchairerC, FraumeniJF, Jr. Rapidly increasing incidence of ocular Non-Hodgkin lymphoma. J Natl Cancer Inst. 2006;98:936–939. [CrossRef] [PubMed]
HarrisNL, JaffeES, SteinH, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood. 1994;84:1361–1392. [PubMed]
JaffeES, HarrisNL, SteinH, VardimanJW. World Health Organization Classification of Tumors: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. 2001;IARCPress Lyon, France.
FromeEL. The analysis of rates using Poisson regression models. Biometrics. 1983;39:665–674. [CrossRef] [PubMed]
FerryJA, FungCY, ZukerbergL, et al. Lymphoma of the ocular adnexa: a study of 353 cases. Am J Surg Pathol. 2007;31:170–184. [CrossRef] [PubMed]
Tovilla-CanalesJL, PomarJL, CeronJR. Lymphoproliferative disorders of the ocular adnexa. Curr Opin Ophthalmol. 2004;15:401–405. [CrossRef] [PubMed]
ChanCC, BuggageRR, NussenblattRB. Intraocular lymphoma. Curr Opin Ophthalmol. 2002;13:411–418. [CrossRef] [PubMed]
CouplandSE, AnastassiouG, BornfeldN, HummelM, SteinH. Primary intraocular lymphoma of T-cell type: report of a case and review of the literature. Graefes Arch Clin Exp Ophthalmol. 2005;243:189–197. [CrossRef] [PubMed]
JahnkeK, KorfelA, KommJ, et al. Intraocular lymphoma 2000–2005: results of a retrospective multicentre trial. Graefes Arch Clin Exp Ophthalmol. 2006;244:663–669. [CrossRef] [PubMed]
Levy-ClarkeGA, ChanCC, NussenblattRB. Diagnosis and management of primary intraocular lymphoma. Hematol Oncol Clin North Am. 2005;19:739–749. [CrossRef] [PubMed]
LooiA, GascoyneRD, ChhanabhaiM, ConnorsJM, RootmanJ, WhiteVA. Mantle cell lymphoma in the ocular adnexal region. Ophthalmology. 2005;112:114–119. [CrossRef] [PubMed]
IsaacsonP, WrightDH. Malignant lymphoma of mucosa-associated lymphoid tissue: a distinctive type of B-cell lymphoma. Cancer. 1983;52:1410–1416. [CrossRef] [PubMed]
HoweHL, WingoPA, ThunMJ, et al. Annual report to the nation on the status of cancer (1973 through 1998), featuring cancers with recent increasing trends. J Natl Cancer Inst. 2001;93:824–842. [CrossRef] [PubMed]
IsaacsonPG. Update on MALT lymphomas. Best Pract Res Clin Haematol. 2005;18:57–68. [CrossRef] [PubMed]
ParsonnetJ, HansenS, RodriguezL, et al. Helicobacter pylori infection and gastric lymphoma. N Engl J Med. 1994;330:1267–1271. [CrossRef] [PubMed]
ChanudetE, ZhouY, BaconCM, et al. Chlamydia psittaci is variably associated with ocular adnexal MALT lymphoma in different geographical regions. J Pathol. 2006;209:344–351. [CrossRef] [PubMed]
LiuYC, OhyashikiJH, ItoY, et al. Chlamydia psittaci in ocular adnexal lymphoma: Japanese experience. Leuk Res. 2006;30:1587–1589. [CrossRef] [PubMed]
ArnaudP, EscandeMC, LecuitM, et al. Hepatitis C virus infection and MALT-type ocular adnexal lymphoma. Ann Oncol. 2007;18:400–401. [PubMed]
GoebelN, SerrA, MittelviefhausH, ReinhardT, BogdanC, Auw-HaedrichC. Chlamydia psittaci, Helicobacter pylori and ocular adnexal lymphoma: is there an association?—the German experience. Leuk Res. 2007;31:1450–1452. [CrossRef] [PubMed]
SjoNC, FoeghP, JuhlBR, et al. Role of Helicobacter pylori in conjunctival mucosa-associated lymphoid tissue lymphoma. Ophthalmology. 2007;114:182–186. [CrossRef] [PubMed]
Figure 1.
 
(A) Typical conjunctival lymphoma presenting as a painless salmon-colored tumor in the conjunctiva of a 65-year-old male. (B) Magnetic resonance image of the eye of a 65-year-old female with a 2-year history of proptosis. The tumor spread from the left lacrimal gland (arrow) and infiltrated the orbit diffusely (★). On histopathologic examination, the tumor was found to be a MALT lymphoma. (C) Orbital MALT lymphoma characterized by a diffuse pattern of small centrocyte-like cells in an 81-year-old female. Hematoxylin-eosin stain. (D) MALT lymphoma (same patient as C) with preserved germinal centers shown by CD23 staining (brown) of the follicular dendritic cells. CD23 staining. (E) Diffuse large B-cell lymphoma in the right lower eyelid. The tumor cells have pleomorphic nuclei with irregularly distributed chromatin and up to three nucleoli. Mitoses (arrow) are frequently seen. The 80-year-old male died 6 months after diagnosis (hematoxylin-eosin; ×400). (F) Diffuse large B-cell lymphoma in the conjunctiva of a 73-year-old female. The mitotic activity was high as shown by the MIB-1 nuclear staining (brown). (G) Cyklin D1 positivity in an orbital MCL in a 85-year-old male, with no prior history of lymphoma. Subsequent staging revealed involvement of the bone marrow and axillary and inguinal lymph nodes. Cyklin D1 staining. (H) Typical nodular pattern in a follicular lymphoma in a 45-year-old female. A full-body CT-scan exposed a retroperitoneal tumor, and chemotherapeutic treatment was initiated. Hematoxylin-eosin. Magnification: (C, D, F) ×200; (E, G) ×400; (H) ×100.
Figure 1.
 
(A) Typical conjunctival lymphoma presenting as a painless salmon-colored tumor in the conjunctiva of a 65-year-old male. (B) Magnetic resonance image of the eye of a 65-year-old female with a 2-year history of proptosis. The tumor spread from the left lacrimal gland (arrow) and infiltrated the orbit diffusely (★). On histopathologic examination, the tumor was found to be a MALT lymphoma. (C) Orbital MALT lymphoma characterized by a diffuse pattern of small centrocyte-like cells in an 81-year-old female. Hematoxylin-eosin stain. (D) MALT lymphoma (same patient as C) with preserved germinal centers shown by CD23 staining (brown) of the follicular dendritic cells. CD23 staining. (E) Diffuse large B-cell lymphoma in the right lower eyelid. The tumor cells have pleomorphic nuclei with irregularly distributed chromatin and up to three nucleoli. Mitoses (arrow) are frequently seen. The 80-year-old male died 6 months after diagnosis (hematoxylin-eosin; ×400). (F) Diffuse large B-cell lymphoma in the conjunctiva of a 73-year-old female. The mitotic activity was high as shown by the MIB-1 nuclear staining (brown). (G) Cyklin D1 positivity in an orbital MCL in a 85-year-old male, with no prior history of lymphoma. Subsequent staging revealed involvement of the bone marrow and axillary and inguinal lymph nodes. Cyklin D1 staining. (H) Typical nodular pattern in a follicular lymphoma in a 45-year-old female. A full-body CT-scan exposed a retroperitoneal tumor, and chemotherapeutic treatment was initiated. Hematoxylin-eosin. Magnification: (C, D, F) ×200; (E, G) ×400; (H) ×100.
Figure 2.
 
Age-specific ophthalmic lymphoma incidence rates for males and females in Denmark during the period 2001 to 2005. The rates are calculated based on all data in a Poisson regression model adjusted for period. Incidence rates in the 5-year periods from 1981 to 2000 were proportional to the ones depicted here, although lower, as shown in Table 3 . Incidence rates were highly dependent on patient age (P < 0.0001) with a maximum incidence rate of 2.6 per 100,000 for males and 1.0 per 100,000 for females. Differences in incidence between males and females were not statistically significant (P = 0.766).
Figure 2.
 
Age-specific ophthalmic lymphoma incidence rates for males and females in Denmark during the period 2001 to 2005. The rates are calculated based on all data in a Poisson regression model adjusted for period. Incidence rates in the 5-year periods from 1981 to 2000 were proportional to the ones depicted here, although lower, as shown in Table 3 . Incidence rates were highly dependent on patient age (P < 0.0001) with a maximum incidence rate of 2.6 per 100,000 for males and 1.0 per 100,000 for females. Differences in incidence between males and females were not statistically significant (P = 0.766).
Table 1.
 
Distribution of Lymphoma within the Ophthalmic Region According to Lymphoma Subtype
Table 1.
 
Distribution of Lymphoma within the Ophthalmic Region According to Lymphoma Subtype
Lymphoma Subtype n Bilateral n (%, CI) Eyelid n (%, CI) Conj. n (%, CI) Lacr. Sac n (%, CI) Lacr. Gland n (%, CI) Orbit n (%, CI) Intraocular n (%, CI)
All lymphomas 228 28 (12, 8–17) 11 (5, 2–8) 57 (25, 19–30) 3 (1, 0–3) 16 (7, 4–10) 129 (57, 50–63) 12 (5, 2–8)
Low-grade types 147 14 (10, 5–14) 7 (5, 1–8) 44 (30, 23–37) 2 (1, 0–3) 10 (7, 3–11) 83 (56, 48–64) 0
 MALT 126 13 (10, 5–17) 5 (4, 0–7) 40 (31, 23–40) 1 (1, 0–2) 6 (5, 2–8) 74 (58, 50–67) 0
 FL 17 1 (6, 0–17) 1 (6, 0–17) 4 (24, 3–44) 0 3 (18, 0–36) 9 (53, 29–77) 0
 SLL/CLL 3 0 1 (33, 0–87) 0 1 (33, 0–87) 1 (33, 0–87) 0 0
High-grade types 61 10 (16, 7–26) 4 (7, 0–13) 9 (15, 6–24) 1 (2, 0–5) 4 (7, 0–13) 35 (57, 45–70) 8 (13, 5–22)*
 DLBCL 29 1 (3, 0–10) 1 (3, 0–10) 2 (7, 0–16) 0 3 (10, 0–21) 19 (66, 48–83) 4 (14, 1–26)
 MCL 20 9 (45, 23–67), † 0 7 (35, 14–65) 1 (5, 0–15) 1 (5, 0–15) 11 (55, 33–77) 0
 PTL, NOS 4 0 2 (50, 1–99) 0 0 0 1 (25, 0–67) 1 (25, 0–67)
 BL 3 0 0 0 0 0 1 (33, 0–87) 2 (67, 13–100)
 B-ALL 3 0 0 0 0 0 2 (67, 13–100) 1 (33, 0–87)
 T-ALCL 2 0 1 (50, 0–100) 0 0 0 1 (50, 0–100) 0
BCL, uncl. 21 4 (20, 2–38) 0 4 (20, 2–38) 0 2 (10, 0–23) 11 (55, 33–77) 4 (15, 0–31)
Table 2.
 
Clinical Data According to Lymphoma Subtype
Table 2.
 
Clinical Data According to Lymphoma Subtype
Lymphoma Subtype Number (%, CI) Males n (%, CI) Median Age Both Sexes, y (Range) Patients with Ophthalmic Lymphoma as First Presenting Symptom n (%, CI)
All lymphomas 228 (100) 116 (51, 44–57) 69 (5–96) 184 (81, 76–86)
Low-grade types 147 (64, 58–70) 66 (45, 37–55) 69 (8–96) 127 (88, 80–91)
 MALT 126 (55, 49–62) 58 (46, 37–54) 69 (8–92) 116 (92, 85–96)
 FL 17 (7, 4–11) 7 (41, 18–65) 63 (45–96) 11 (65, 42–87)
 SLL/CLL 3 (1, 0–3) 1 (33, 0–87) 75 (62–75) 0
High-grade types 61 (27, 21–33) 42 (69, 57–80)* 72 (5–95) 42 (69, 57–80)
 DLBCL 29 (13, 8–17) 13 (45, 27–63) 77 (17–95) 23 (79, 59–89)
 MCL 20 (9, 5–12) 17 (85, 69–100), † 75 (60–90) 11 (55, 33–77)
 PTL, NOS 4 (2, 0–3) 3 (75, 33–100) 61 (31–77) 3 (75, 33–100)
 BL 3 (1, 0–3) 2 (67, 13–100) 41 (34–55) 1 (33, 0–87)
 B-ALL 3 (1, 0–3) 2 (67, 13–100) 9 (5–34) 2 (67, 13–100)
 T-ALCL 2 (1, 0–2) 2 (100, 90–100) 45 (35–55) 2 (100, 90–100)
BCL, uncl. 21 (9, 5–12) 11 (55, 33–77) 63 (18–77) 15 (71, 50–90)
Table 3.
 
Intraocular Lymphoma
Table 3.
 
Intraocular Lymphoma
Subtype Stage Retina (n) Uvea (n)
DLBCL I 1 0
III 0 1
Ns 1 0
Sec. intraoc. 0 1
PTL, NOS IV 0 1*
BL Sec. intraoc. 0 2
B-ALL Sec. intraoc. 0 1*
BCL, uncl. I 0 1
Sec. intraoc. 0 3
Table 4.
 
Extraocular Ophthalmic Lymphoma
Table 4.
 
Extraocular Ophthalmic Lymphoma
Lymphoma Subtype/Stage Orbit (n) Ocular Adnexa (n)
MALT
 I 45 28
 II 1 1
 III 3 0
 IV 12 6
 Ns 9 11
FL
 I 3 3
 II 0 1
 III 1 2
 Ns 1 0
DLBCL
 I 9 1
 II 0 2
 IV 3 0
 Ns 4 1
MCL
 II 0 2
 IV 7 2
PTL, NOS
 I 0 1
 II 1 0
BL
 II 1 0
B-ALL
 IV 2 0
T-ALCL
 I 0 1
 III 1 0
BCL, uncl.
 I 5 4
 II 1 0
 IV 1 1
 Ns 1 1
Table 5.
 
Incidence of Ophthalmic Lymphoma from 1981 to 2005 in Denmark
Table 5.
 
Incidence of Ophthalmic Lymphoma from 1981 to 2005 in Denmark
Period Patients (n) Incidence per 100,000 (CI) Age-Adjusted Rate Ratio (CI)*
1981–1985 22 0.086 (0.057–0.131) 1.00 (1.00–1.00)
1986–1990 44 0.171 (0.128–0.231) 1.58 (0.94–2.70)
1991–1995 38 0.147 (0.107–0.202) 1.60 (0.94–2.71)
1996–2000 50 0.189 (0.143–0.249) 1.78 (1.06–2.98)
2001–2005 69 0.249 (0.196–0.316) 2.41 (1.47–3.93)
×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×