Ординатура / Офтальмология / Английские материалы / Primary Intraocular Lymphoma_Chan, Gonzales_2007

14 Primary Intraocular Lymphoma

amplification of the bcl2 gene. In addition, some GCB DLBCLs exhibit amplification of the c-REL locus.40,41 The c-REL protein is a member of the NF-kB/REL family of transcription factors and is involved in transcribing NF-kB-responsive genes,42 a potential mechanism leading to cell survival and tumorogenesis. ABC DLBCLs seem to demonstrate constitutive activation of the IkB kinase, which can lead to the translocation of the transcription regulator NF-kB into the nucleus and the transcription of genes that promote cellular proliferation and survival.43 The constitutive activity of IkB kinase is not seen in GCB DLBCL. Type 3 DLBCLs, like ABC DLBCLs, seem to also show constitutive activation of the NF-kB pathway.44 Thus, this pathway seems to be an important target in treating ABC and PMB DLBCLs. This new found knowledge regarding genetic signatures has already resulted in therapy aimed at interfering with the activation of this pathway, namely an IkB kinase inhibitor, PS-1145, which has been shown to be effective against ABC DLBCLs and PMBLs, but not GCB DLBCLs.45

Gene expression profiling may allow us to classify lymphomatous diseases more specifically than our current taxonomy and offers prognostic utility.31 Indeed, there is currently no perfect prognostic indicator and the development of such a tool is tantalizing. However, there is substantial heterogeneity of gene expression even within each of the three subgroups of DLBCL31,32,46 and there is no single gene that can distinguish one subgroup from another. In addition, currently there is no standardization for the nomenclature offered by gene expression profiling. While there is no doubt that PCNSL is an NHL DLBCL, gene expression profiling is now underway to elucidate the different signatures that potentially exist within this subtype. For example, recent gene expression profiling work seems to indicate that some PCNSLs belong to GCB DLBCLs.47 Due to the paucity of PIOL cases and materials, it is almost impossible to evaluate the pattern of gene expression using gene expression profiling to classify PIOL in this fashion currently. However, as our ability to classify lymphomas based upon their gene expression profiles improves and molecular technology to analyze small samples advances, we will likely see PIOL being more specifically defined by this system in the future as well.

In its DLBCL form, PCNSL is an aggressive tumor that is usually fatal (see Treatment, Chapter 11). Less frequently, primary lymphomas of the CNS can be derived from other B-cell lymphomas, such as marginal zone B-cell lymphomas (MZBCL).48 However, in these cases, the disease is not

Classification of Lymphomas 15

intraparenchymal (being most often associated with the leptomeninges) and is clinically low-grade in nature. PIOL, like PCNSL, seems to be most often a DLBCL.

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29.Lander ES, Linton LM, Birren B, et al. (2001) Initial sequencing and analysis of the human genome. Nature 409(6822): 860–921.

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43.Davis RE, Brown KD, Siebenlist U, Staudt LM. (2001) Constitutive nuclear factor kappaB activity is required for survival of activated B cell-like diffuse large B cell lymphoma cells. J Exp Med 194(12): 1861–1874.

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Epidemiology of Primary Intraocular Lymphoma 21

youngest reported age has been a child of 2 years in Europe, though the clinical history and findings were not presented in any detail.24 The rising incidence in PCNSL has been seen in all age groups, suggesting that the increased incidence is independent of age. However, the greatest increase in incidence has been noted in patients over 60 years of age. Surawicz et al. examined the incidence rates over 8 age groups.7 The incidence rates for people 0 to 19 years of age were found to be 0.02 per 100,000 person-years; 0.37 for 20to 34-year-olds; 0.63 for 35to 44-year-olds; 0.46 for 45to 54-year-olds; 0.97 for 55to 64-year-olds; 1.46 for 65to 74-year-olds; 1.57 for 75to 84-year-olds; and for those over 85 years of age the incidence rate was 0.68 per 100,000 person-years.7 Age appears to be important in terms of prognosis, as patients under 60 years of age with PCNSL fare better than those over 60 years of age.24–26 In India, the mean age of PCNSL patients has been reported as 39.5 to 44.4 years,27 with no statistically significant change in age trend for the period of time examined (1980 through 2003). It appears, then, that PCNSL patients in India are not developing the disease at a younger age now than in the past. One of the patients from this study was 3 years of age at the time of diagnosis. What could be the explanation for the lower mean age of PCNSL patients in India compared with the more developed countries such as the United States? Sarkar et al. brings up the point that there are important differences in the population demographics in India compared with that in Western geographic locales and the United States. The life expectancy of the population of India is 64.35 years; in the United States, it is 77.71 years; in France, 79.6 years; Germany, 78.65 years; the United Kingdom, 78.38 years; and in Japan, 81.15 years.27 Also, only 4.9% of India’s population are 65 years of age or older, while in the United States 12.4% of the population are over the age of 65. On the other hand, the mean age of immunocompetent patients in the developed countries of France and Belgium has been reported as 61 years, which is similar to that in other developed nations. In a study of 32 cases of PCNSL from Japan, the median age of the patients was 61.3 years.28 Previously, Hayakawa and colleagues examined 170 patients with PCNSL in 1994.29 The mean age for Hayakawa’s particular patients was 56.7 years.

Gender. Brain tumors in general seem to exhibit a male predilection (although meningiomas show a female preponderance).7 For example, one

22 Primary Intraocular Lymphoma

study reported that glioblastomas, anaplastic astrocytomas, oligodenrogliomas, anaplastic oliogdendrogliomas, ependymomas, mixed gliomas, astrocytomas not otherwise specified, medulloblastomas, and germ cell tumors are more common in men than in women.7 PCNSLs also predominate in men, with the incidence of CNS lymphomas in men being reported as 0.60 per 100,000 person years; in women, the rate is 0.28 per 100,000 person years.7 Other studies have yielded male to female ratios of 1.4 to 2:1. Male to female relative risk has been described as being approximately 2.25.7 Though a male preponderance seems to be the rule, there have been studies in which a decidedly female predominance exists. In a study of ocular and cerebral lymphomas from France, Cassoux and colleagues retrospectively reviewed 44 cases of PIOL with and without CNS involvement, 36 being female and eight being male (male to female ratio of 1 to 4.5).30 However, another study looking at an immunocompetent PCNSL population from France and Belgium, had a male to female ratio of practically 1:1 (127 female patients and 121 male patients over a 15-year period, from 1980 to 1995).24

Ethnics. Examination of the incidence rates of CNS lymphoma in American whites and African-Americans has shown that there seems to be no ethnical preference with respect to these two major ethnicities in the United States.7 Whites were shown to have a brain lymphoma incidence rate of 0.42 per 100,000 person-years, while African-Americans had an incidence rate of 0.49, a difference that was not statistically significant.7

Using the Lymphoma Study Group classification system,31 Shibamoto from Hayabuchi’s group32 looked at trends in PCNSL in Japan (between 1995 and 1999) as a follow-up to their previous examination during the period from 1985 to 1994. The four-years study revealed 101 patients with PCNSL, while the study from 1985 to 1994 yielded 157 immunocompetent patients. Kuratsu33 reported an annual overall age-adjusted incidence rate for all intracranial tumors of nearly 11/100,000, with 4.6% of the 2129 patients with primary CNS tumors having malignant lymphoma. Meanwhile, Hayakawa and colleagues examined 170 patients with PCNSL in 1994.29 The mean age for Japanese patients was 56.7 years and 93 patients were male (54.7%) while 77 were female (45.3%). Hayabuchi and colleagues reported on findings obtained from the CNS Lymphoma Study Group Members, a PCNSL consortium of medical centers throughout

Epidemiology of Primary Intraocular Lymphoma 23

Japan.34 This group analyzed 466 cases of PCNSL in patients testing HIVnegative, obtained during the period from of 1985 to 1994. The researchers found that the male to female ratio was 1.45:1 and that the median age was 60 years, the parameters being similar to those in the United States. Interestingly, 20 tumors (8.5%) were of the T cell immunophenotype, while from other studies such tumors made up less than 2% of all PCNSLs.35 Another 214 tumors (45.9%) and 232 (49.8%) were unclassifiable or unknown.

In Korea, an analysis of 3221 CNS tumors yielded 76 cases of PCNSL, with a median age of 54 years and a male to female ratio of 1.3:1.36 These cases made up 2.4% of the total number of cases from the study carried out from 1997 to 1998. A prior study, from 1983 to 1987, had yielded 23 cases out of 894 (or 0.9%). Thus, Korea showed a trend of increasing incidence of PCNSL.

In India, it has been reported that diagnoses of PCNSL have exhibited an increasing trend.27 Sarkar retrospectively analyzed 116 cases of PCNSL from two clinical centers, one in Northern India and the other in Southern India over a 24-year period. PCNSL cases increased in incidence 3.5-fold from two cases per year in the early 1980s to 7 in the early 2000s. The disease affected males more than females, with a male to female ratio up to 2.3:1.

Although amongst some geographic locations, e.g. the United States and some Western European countries, the incidence rates of PCNSL have increased, in other areas this has not been the case. In Alberta, Canada, PCNSL incidence rates were reported not to have increased.37 PCNSL patients were retrospectively reviewed over a two-decade period covering the years from 1975 to 1996. PCNSLs were found to represent 0.96% of all the cases of NHL during the period of time studied. The late 1970s showed an incidence rate of 0.178 immunocompetent cases per million population, compared with 1.642 cases in 1996, though there was no statistically significant change in this incidence rate. The median age of patients studied in this population was 64 years and a male to female ratio of 3:2 was found. Similar findings have been reported in Scotland.38

Table 4.1 summarizes the epidemiology of several large PIOL case series in the literature. PIOL is a malignancy for which the average age of the patients is the late 50s and with no gender preference reported in predominately white population studies.30,39–44 However, reports from some centers have noted a female preponderance in their cases.30,40