Ординатура / Офтальмология / Английские материалы / Primary Intraocular Lymphoma_Chan, Gonzales_2007
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Health meeting on PIOL, held in September 2004*. This volume will be indispensable to any clinician dealing with posterior segment diseases and the researcher who is interested in the challenge of curing what many of us believe is a curable cancer that for now still has a high mortality and very significant morbidity.
Robert B. Nussenblatt, M.D.
Chief, Laboratory of Immunology
National Eye Institute
National Institutes of Health
Bethesda, MD
USA
September 2006
*R.B. Nussenblatt, C.C. Chan, W.H. Wilson, J. Hochman, M. Gottesman for the Ocular Lymphoma Workshop Group: International central nervous system and ocular lymphoma workshop: Recommendations for the future. Ocul Immunol Inflam 14:139–144, 2006.
Preface
In medicine and science, two inseparable sisters, a modern renaissance has occurred in which the pursuit of knowledge has provided the world with fascinating discoveries and answers to age-old questions. Perhaps one of the most shining and striking moments in this modern renaissance was the elucidation of the human genome. From this momentous project were produced tools and knowledge that could be put to use to solve other problems and answer other questions. We find, however, that in seeking out an answer, we instead discover that we have more questions than when we started out. Moreover, answers that are found in chemistry, physics, insect genetics, and so forth frequently provide researchers in seemingly unrelated fields with clues that may prove to be important in their own hunts. It is important, then, that as true renaissance scientists, we open ourselves to the knowledge that is transmitted (literally on a daily basis now) in the world of science and medicine.
The world of ophthalmology is certainly partaking in this renaissance with ever new advancements in the field. Ocular immunopathology is at the forefront of these new advancements. The immune system, involved in diverse processes from inflammation to cancer, has proven to play a central role in many diseases. Even when an organ system is seemingly tucked away from the immune system, as are the brain and intraocular structures, dysfunctions involving components of the immune system can nonetheless manifest themselves. Yet again we are left with more questions than answers in attempting to understand disease.
It is with a sense of excitement and hunger for new knowledge that we present this book, the first to be published on the subject, on primary intraocular lymphoma (PIOL). This is exciting because it is within recent memory when the first histopathological presentations of PIOL were presented in the literature. Moreover, as we acquired knowledge of the inner
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workings of the immune system, we were able to modify our thoughts on the precise cell involved in this cancer. As genetics burgeoned into a powerful science, we were able to uncover ever more information on this rare tumor. Our appetite, however, is not abated. We are perhaps more hungry now for answers than in our first descriptions of this tumor in the literature of the 1940s and 1950s.
One might think of this book, then, as a menu. In the first four chapters we seek to stimulate the appetite with discussion of the definition of primary intraocular lymphoma, historical reviews and cases of PIOL, the classification systems that once existed and those in use today, and the epidemiology in PIOL. The next two chapters deal with the clinical presentation of the disease and ways that we image PIOL. As the disease often masquerades as a uveitis, it is important to recognize the salient features of this lymphoid malignancy, especially when it occurs in patients who fit the disease profile. We then turn our attention to the pathology and immunology involved in PIOL, in two respective chapters. It is perhaps here that we ought to pause during our feast of knowledge and reflect on just how much information we have acquired on PIOL in the past six decades. No longer are we dealing with the abstract reticulum cell sarcoma, but rather an immunologically and genetically distinct entity.
From the important main courses of clinical, pathological, and immunological presentations, we then turn to the important subject of diagnostic techniques and then to the unsettled business, but absolutely essential concepts, of therapy in PIOL. It has been noted by some gastronomic connoisseurs that a dinner ending without cheese is like a beautiful woman with only one eye. Something integral is missing. Similarly, our knowledge of the best therapeutic approaches to this tumor is not complete. Yet, while perfect treatment regimens for PIOL are missing, we have made important advancements in treating this tumor and we strive to make even further developments in this arena. The more effect we have on treating this tumor, the more we can affect the prognostics associated with the disease. Prognosis is dealt with in its own chapter and it is important to recognize here that PIOL is a malignant disease where we as ophthalmologists have the opportunity to extend or save our patients’ lives. With manifestations limited to the eye (unless the brain is involved) patients will seek out, or be referred to, ophthalmologists. Therefore, it is of the utmost importance that ophthalmologists be able to identify
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possible presentations of PIOL and in appropriate cases seek out diagnostic procedures. Furthermore, it is important to consider what testing should be performed when attempting to diagnose PIOL with limited tissue specimens. Ocular pathologists and cytologists will certainly play an important role in drawing out the diagnostic plan for a patient. Finally, the ophthalmologist must guide his or her patient into appropriate care and management that is coordinated with neurooncologists. Thus, a great responsibility is shouldered by the ophthalmologist for the very quality of life of patients with PIOL.
There are hypotheses for the origin of PIOL, which are discussed in another chapter and it is here that we are struck with the fact that we still have much to learn about the fundamental problems that allow for a lymphoma to occur in the eye. This chapter is followed by another describing animal models of the disease developed at the National Eye Institute, in order to begin to understand some of the fundamental mechanisms involved in PIOL.
We end our book with illustrative cases that presented at the National Eye Institute. Some of these cases are classical presentations of PIOL, while others proved to be more challenging, both diagnostically and therapeutically. These cases are useful in that they allow the reader to follow some of the typical diagnostic and therapeutic techniques that are commonly employed.
The topic of PIOL is certainly a full plate and not always easy to digest. We feel that we have presented the important concepts and future directions in this disease in a manner that will allow the reader to better understand this most interesting cancer. We also wish to inform the reader that this story is far from complete. We and others around the world continue to work on elucidating the factors and mediators involved in this cancer and ways that important components of the disease might be modulated for therapeutic benefit. We hope that this book will whet the appetite of our readers and produces in them a hunger similar to ours for understanding PIOL.
We wish to thank the National Eye Institute and the Howard Hughes Medical Institute Research Scholars Program for their support. We also thank our colleagues, the physicians who refer patients to the NEI and the staff who work on the PIOL cases at the NEI. We are deeply indebted to the more than 100 patients who have contributed to our
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understanding of the disease, and to their families for their support during such a challenging time. Finally, we save our most profound thanks to our families and friends, whose love and encouragement helped us through the writing process of this book.
Chi-Chao Chan, M.D.
John Alexander Gonzales, M.D.
Contents
Dedication |
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . |
v |
Foreword by Prof W. R. Green . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . |
vii |
|
Foreword by Prof R. B. Nussenblatt . . . . . . . . . . . . . . . . . . . . . . . . . . . |
ix |
|
Preface |
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . |
xi |
Chapter 1 |
Definition of Primary Intraocular Lymphoma . . . . . . |
1 |
Chapter 2 |
History of Primary Intraocular Lymphoma |
|
|
(1950s–1970s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . |
3 |
Chapter 3 |
Classification of Lymphomas . . . . . . . . . . . . . . . . . . . . |
9 |
Chapter 4 |
Epidemiology of Primary Intraocular |
|
|
Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . |
19 |
Chapter 5 |
Clinical Manifestations of PIOL . . . . . . . . . . . . . . . . . . |
43 |
Chapter 6 |
Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . |
79 |
Chapter 7 |
Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . |
94 |
Chapter 8 |
Immunology of PIOL . . . . . . . . . . . . . . . . . . . . . . . . . . |
113 |
Chapter 9 |
Diagnostic Approaches . . . . . . . . . . . . . . . . . . . . . . . . . |
132 |
Chapter 10 |
Management and Treatment of PIOL . . . . . . . . . . . . . . |
161 |
Chapter 11 |
Prognosis in PIOL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . |
194 |
Chapter 12 |
Hypotheses on the Origin of PIOL . . . . . . . . . . . . . . . . |
210 |
Chapter 13 |
Experimental Models of PIOL . . . . . . . . . . . . . . . . . . . |
222 |
Chapter 14 |
Summary and Algorithm . . . . . . . . . . . . . . . . . . . . . . . |
235 |
Chapter 15 |
The Future of PIOL . . . . . . . . . . . . . . . . . . . . . . . . . . . . |
243 |
Chapter 16 |
Case Illustrations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . |
249 |
Author Index |
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . |
269 |
Subject Index |
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . |
277 |
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Chapter 1
Definition of Primary Intraocular
Lymphoma
Primary intraocular lymphoma (PIOL) is a neoplasm, most frequently of B-cell, and rarely, T-cell, origin arising from or initially presenting in the sub-retinal pigment epithelium (RPE), retina and vitreous.1–6 PIOL of the B-cell type is a non-Hodgkin’s lymphomatous process of the diffuse large B-cell histologic type and its distinction lies in the fact that it is a subtype of primary central nervous system lymphoma (PCNSL). The neurosensory retina is, in fact, an extension of the CNS. Indeed, the neurosensory retina and retinal pigment epithelium are derived from the same neuroectoderm that forms the CNS during embryogenesis. And, like the retina, the CNS is an immunologically privileged organ as well.
PIOL is distinct from the other lymphomatous processes inside the eye much more commonly including metastatic systemic lymphoma to the eye, which typically affects the uveal tract and ocular adnexa via hematogenous routes; and the extremely rare extranodal marginal zone B- cell lymphoma (mucosa-associated lymphoid tissue lymphoma) that affects the choroid.7–9 In addition, although a subtype of PCNSL, PIOL may arise de novo in the neurosensory retina rather than metastasizing from a primary non-ocular CNS structure.
As an immunologically privileged organ, the internal tissues of the eye are normally protected from inflammatory processes mediated by the immune system’s B- and T-cells. Thus, the induction of inflammatory conditions within the eye is intriguing, as inflammatory B- and T-cells are not typically found there. Equally intriguing is the development of lymphomatous processes involving these same cells from which the eye is normally protected.
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What is most curious about PCNSL and PIOL is the recent increase in prevalence in these malignancies. Certainly the rising prevalence of immunodeficiency states can explain part of this phenomenon,10 but concurrent rises in the prevalence rate in immunocompetent patients warrant an in-depth look into this fascinating disease process. To that end, this book serves to be a guide into the history, diagnosis, management and treatment of PIOL, as well as providing insights into the future progress yet to be made in this most interesting and fatal malignancy.
References
1.Levy-Clarke GA, Chan CC, Nussenblatt RB. (2005) Diagnosis and management of primary intraocular lymphoma. Hematol Oncol Clin North Am 19(4): 739–749.
2.Chan CC. (2003) Primary intraocular lymphoma: clinical features, diagnosis, and treatment. Clin Lymphoma 4(1): 30–31.
3.Chan CC. (2003) Molecular pathology of primary intraocular lymphoma.
Trans Am Ophthalmol Soc 101: 275–292.
4.Chan CC, Buggage RR, Nussenblatt RB. (2002) Intraocular lymphoma. Curr Opin Ophthalmol 13(6): 411–418.
5.Chan CC, Wallace DJ. (2004) Intraocular lymphoma: update on diagnosis and management. Cancer Control 11(5): 285–295.
6.Merle-Beral H, Davi F, Cassoux N, et al. (2004) Biological diagnosis of primary intraocular lymphoma. Br J Haematol 124(4): 469–473.
7.Coupland SE, Joussen A, Anastassiou G, Stein H. (2005) Diagnosis of a primary uveal extranodal marginal zone B-cell lymphoma by chorioretinal biopsy: case report. Graefes Arch Clin Exp Ophthalmol 243(5): 482–486.
8.Coupland SE, Foss HD, Hidayat AA, et al. (2002) Extranodal marginal zone B cell lymphomas of the uvea: an analysis of 13 cases. J Pathol 197(3): 333–340.
9.Colovic MD, Jankovic GM, Cemerikic-Martinovic V, et al. (1998) Primary intraocular marginal zone B-cell (MALT) lymphoma. Eur J Haematol 60(1): 61–62.
10.Eby NL, Grufferman S, Flannelly CM, et al. (1988) Increasing incidence of primary brain lymphoma in the US. Cancer 62(11): 2461–2465.
Chapter 2
History of Primary Intraocular
Lymphoma (1950s–1970s)
Though rare, lymphomatous processes affecting the intraocular structures have been reported since the 1940s and early 1950s.1–3
To understand the historical significance of primary intraocular lymphoma, we need to consider one of the first widely accepted classification systems of lymphomas in general. In 1966, Henry Rappaport classified tumors of the hematopoietic system according to their characteristic morphology and their resemblance to normal, non-neoplastic cellular components (see Chapter 3, “Classification of Lymphomas”). At that time, lymphomas were divided into three groups based on cytology: reticulum cell sarcoma, lymphosarcoma, and Hodgkin’s disease.4 In addition, a follicular form of lymphoma was also noted that recapitulated normal follicles in the lymph nodes. Rappaport’s description of the salient features of reticulum cell sarcoma, was based upon the malignant cells’ resemblance to the reticular cell (a pluripotent stem cell, according to Rappaport) or its histiocytic or lymphocytic derivatives. In Rappaport’s definition, a reticulum cell sarcoma was a “tumor of reticular tissue composed predominantly of neoplastic histiocytes in various stages of maturation and differentiation.” In its more differentiated form, the reticulum cell sarcoma was composed of cells with distinct cell borders harboring a pale cytoplasm and nuclei resembling those of epithelioid histiocytes (oval), fibroblasts (ovoid or elongated), or monocytes (indented and lobulated). Less differentiated reticulum cell sarcomas were noted to have round or oval nuclei, occasionally with indentations or irregular borders, and containing prominent nucleoli. The vacuolated cytoplasm in either form of differentiation could be variable, sometimes being scant and at other times abundant. As for the origin of reticulin fibers, Rappaport speculated
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