Table Of ContentMEDICAL RADIOLOGY
Diagnostic Imaging and Radiation Oncology
Editorial Board
L.W. Brady, Philadelphia· M.W. Donner(t), Baltimore
H.-P. Heilmann, Hamburg· F. Heuck, Stuttgart
Radiotherapy
of Intraocular and
Orbital Tumors
With Contributions by
D.H. Abramson· W.E. Alberti· M.A. AI-Mudamgha· B.E. Amendola
L.L. Anderson· M. Astrahan . L.W. Brady· J.R. Castro· S.T. Chiu-Tsao
C.T. Chung· W.e. Cooper· W.V. Delaney· P.DePotter· S.S. Donaldson
E.D. Donnenfeld . E. Egger· E.-S. EI-Hifnawi . R.M. Ellsworth· R.G. Evans
P.J. Fitzpatrick· A.E. Flanders· U. Fuchs· e. Gailloud . e.F. Gonzalez· R. Guthoff
B.G. Haik· L.B. Harrison· P.B. Hay· J.e. Hernandez· H.J. Ingraham· H. Klaus
J.P. Kriss· J.J.W. Lagendijk· M.J. Lambo· P.K. Lommatzsch· G. Luxton
B. McCormick· I.R. McDougall· E.P. Messmer· E. Mobius· J.E. Munzenrieder
J. Noth . e. Perret· Z. Petrovich· K.G. Riedel· R.H. Sagerman . L.A. Saint-Louis
H. Schafer· J. Schipper· e.L. Shields· J.A. Shields· P. Tabor· K.E.W.P. Tan
F. Vogel· G. Vormum . R.A. Weiss· L. Zografos
Edited by
W.E. Alberti and R.H. Sagerman
Foreword by
L.W. Brady and H.-P. Heilmann
Introduction by
F.A. Jakobiec
With 282 Figures in 452 Separate Illustrations, Some in Color, and 71 Tables
Springer-Verlag
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Priv.-Doz. Dr. WINFRIED E. ALBERTI
Klinik fur Strahlentherapie und Nuklearmedizin
Alfried Krupp Krankenhaus
Alfried Krupp-StraBe 21, W-4300 Essen 1, FRG
ROBERT H. SAGERMAN, M.D., F.A.C.R.
Professor and Director
Radiation Oncology Division
State University of New York, Health Science Center
750 East Adams Street, Syracuse, NY 13210, USA
MEDICAL RADIOLOGY· Diagnostic Imaging and Radiation Oncology
Continuation of
Handbuch der medizinischen Radiologie
Encyclopedia of Medical Radiology
Library of Congress Cataloging-in-Publication Data
Radiotherapy of intraocular and orbital tumors/contributors, D.H. Abramson ... let al.]; edited by W.E.
Alberti and R.H. Sagerman; foreword by L.w. Brady and H.-P. Heilmann. p.cm. - (Medical radiology)
Includes bibliographical references and index.
ISBN-13: 978-3-642-97013-9 e-ISBN-13: 978-3-642-97011-5
DOl: 10.1007/978-3-642-97011-5
1. Eye-Tumors-Radiotherapy. 2. Eye-sockets-Tumors-Radiotherapy. I. Abramson, David H.
II. Alberti, W. III. Sagerman, Robert H., 1930- . IV. Series.
[DNLM: 1. Orbital Neoplasms-radiotherapy. 2. Retinoblastoma-radiotherapy. 3. Uveal Neoplasms
radiotherapy. WW 149 R129 1993] RC280.E9R33 1993 616.99'2840642-dc20 DNLM/DLC 92-48365
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Foreword
Malignant tumors involving the eye and orbit are relatively rare tumors. In the United
States, about 2000 eye tumors will have been diagnosed in 1992. About 75% of those
patients will have pigmented lesions involving the eye and about 20% of patients will
have retinoblastoma, with a wide variety of other types of tumors in much smaller pro
portion. In fact, the most common malignancy involving the eye actually represents
not a primary malignant tumor but a metastatic lesion, most commonly from a
primary cancer of the lung or breast.
The last decade has seen a number of major advances in the management of both
primary and secondary malignant tumors of the eye, resulting not only in excellent
survival, but also cure rates that are equivalent to those that had been previously
reported by enucleation or primary surgical techniques.
Alberti and Sagerman have compiled a masterful volume dealing with tumors of
the eye and orbit in all their parameters, from diagnosis using ophthalmological
techniques to imaging studies based on both computed tomography with and with
out contrast to the wide variety of treatment techniques, including the role for
enucleation, the role for exenteration, the role for external beam radiation therapy as
well as the role for radioactive plaques in terms of management. Other treatment
techniques have been explored, such as photocoagulation using laser beams, cry
otherapy, and segmental resection.
The data brought forth in this volume clearly demonstrates the magnitude of
change in terms of diagnosis and management of these tumors and represents a
significant and important contribution in cancer management.
HANS-PETER HEILMANN
LUTHER W. BRADY
Preface
It is human nature to want to deal with well-defined situations which are pleasant and
for which there is a favorable outcome. This is also true in the practice of medicine
and, in radiation oncology, it is often left to the most inexperienced, junior physician
to deal with those cancers for which radiation therapy has yielded poor results or led
to severe complications. Tumors of the eye and orbit fell into this category 40 years
ago. Ophthalmological oncology was but an embryonic specialty, radiations were
known to be deleterious to the eye,and the late effects of irradiating a child were
frightening. Independently, the editors learned to utilize irradiation in the manage
ment of tumors of the eye and orbit in two of the worlds most famous ophthalmo
logical institutions, the Edward S. Harkness Institute of Ophthalmology at Columbia
University's Columbia-Presbyterian Medical Center in New York City and at the Eye
Clinic at the University of Essen, where Dr. Algernon B. Reese and Dr. Gerd Meyer
Schwickerath, respectively, fostered the development of ophthalmological oncology.
Radiotherapy of Intraocular and Orbital Tumors is but a small downpayment for we
can never adequately repay A.B. Reese and G. Meyer-Schwickerath, their colleagues
and their disciples, who have taught us so much and with whom we have worked
together to develop new and better treatments with improved results and fewer
adverse reactions.
We undertook the task of editing Radiotherapy of Intraocular and Orbital Tumors
in an attempt at collating what has been learned about the use of irradiation in the
management of these lesions and to provide a current single reference. The first
edition of Tumors of the Eye was published in 1956; in the third edition (1976), P.
Tretter summarized "Radiotherapy of Ocular and Orbital Tumors" in five pages for
Dr. Reese. Similarly, N. Tapley and M. Lederman described the use of irradiation for
retinoblastoma and orbital tumors for M. Bonuik's Ocular and Adnexal Tumors
(1964). Similar chapters are contained in many other texts and in the published
proceedings of conferences, but the developing role of radiation therapy was best
found in individual articles by a laborious search of the world's literature. Even today,
one must search out radiotherapeutic techniques and results, often presented from an
ophthalmologic viewpoint, among the several recent excellent oncologic treatises,
among which are Ocular and Adnexal Tumors (F.A. lakobiec, 1978), Retinoblastoma
(1. Schipper, 1980), Diseases of the Orbit (1. Rootman, 1988), Intraoculare Tumoren
(P.K. Lommatzsch, 1989), Diagnosis and Management of Orbital Tumors (l.A.
Shields, 1989), Clinical Ocular Oncology (D.H. Char, 1989), Intraocular Tumors
(l.A. Shields, c.L. Shields, 1992), and in adult and pediatric oncology texts as well as
radiotherapy texts.
To the best of our knowledge, the only overview of radiotherapy for the eye, L'Oeil
et les Radiations Ionisantes (c. Haye, l. lammet, M.-A. Dollfus, 1965), was not
translated from the French and is no longer in print. However, there have been great
advances in surgical technique, knowledge of pathology, diagnostic and radiologic
techniques and experience with radiotherapy in the subsequent 28 years and, at the
urging of many colleagues, we decided to pool our resources and attempt to describe
ocular and orbital tumors from a radiotherapeutic viewpoint. Recognizing the diver-
VIII Preface
sity of experience and technique, and that no one could speak as a world authority for
all topics, our task was made easier by enlisting the help of 55 coauthors from Europe
and North America who very kindly contributed their special knowledge. We have
tried to provide an easy reading style by gentle editing and thank our coauthors for
their gracious acceptance of suggestions. It is not their fault, but ours, for any
inaccuracies and inconsistencies which occur. In addition, we must apologize for
any omissions and for avoiding many fascinating discussions by taking a narrow
radiotherapeutic view; there were already too m,any pages and illustrations. Never
theless, as noted in scholarly fashion in the introduction, F.A. lakobiec has pointed
out several areas worthy of inclusion in a second edition.
We would like to express thanks to the Deutsche Forschungsgemeinschaft in Bonn,
Germany, and the Deutsche Krebshilfe, Bonn, Germany, for supporting Dr. Alberti's
experimental work with external beam therapy, plaque irradiation and hyperthermia
(Chaps. 39, 40) of the eye which was done in cooperation with members of the Eye
Clinic, University of Essen (Prof. Dr. med. M.H. Foerster, Prof. Dr. med. N.
Bornfeld). The authors express their thanks to the Alfried Krupp van Bohlen und
Halbach-Stiftung, Essen, Germany, for their generous support, which made it poss
ible to include so many color photographs. Thanks also to Ms. Ursula Davis, Mr. Rick
Mills and Ms. Ingrid Haas, who did such an excellent job in preparing the book.
We also thank Andrea Roos-Detische and Maureen Knopp for typing so many
manuscripts and for seeing to a myriad of chores. Without their excellent secretarial
help, we could not have finished our task.
WIN FRIED E. ALBERTI
H.
ROBERT SAGERMAN
Introduction
Radiotherapy of Intraocular and Orbital Tumors fills a resource void that has existed
for too long in both ophthalmology and radiation oncology. Beginning with the
seminal clinical and pathologic investigations of the late Algernon B. Reese (Reese
1976) and his associates (one of whom was Dr. Robert Sagerman) at Columbia
Presbyterian Medical Center in New York, ophthalmic oncology has emerged over
the past 40 years as a full-fledged subspecialty of ophthalmology, replete with modern
molecular genetic insights into retinoblastoma (Dryja 1993) and lymphoproliferations
(Neri et al. 1987; Jakobiec et al. 1987; Knowles et al. 1989). Flourishing ocular
oncologic clinical services are now found in many medical centers and eye institutes in
the United States and Europe.
Because of the rarity of most classes of intraocular and adnexal tumors (under the
rubric of adnexa in ophthalmology are included the structures supporting the integrity
and functioning of the globe - the eyelids, the conjunctiva, the tear production and
drainage apparatuses, and the orbital soft tissues and bones), certain clinical services
have focused on specific families of entities, such as lesions of the orbit, intraocular
tumors, conjunctival and eyelid tumors, and so on. It has, therefore, taken experts
from many centers worldwide to assemble a comprehensive work on the subject of
the radiotherapeutic management of patients with intraocular tumors, extraocular
tumors, and simulating inflammatory conditions. My congratulations are conse
quently warmly extended to the co-editors, Dr. Alberti and Dr. Sagerman, who along
with their other authoritative contributors have produced a magesterial treatise.
From my own experience as a practicing ophthalmic oncologist and ophthalmic
pathologist, I am aware of a number of remaining challenging areas in which
radiotherapists can better guide ophthalmic oncologists in the future. While retino
blastoma is a more radiosensitive tumor than uveal melanoma, there is a third and
rarer class of very radiosensitive intraocular neoplasm constituted by the lympho
proliferations (Rankin et al. 1993). Of these, the most common is ocular/CNS large
cell lymphoma, characteristically of B-cell lineage and formerly called reticulum cell
sarcoma or microgliomatosis. The eye and the brain are conjoined, sometimes slightly
dyssynchronously, with disease in about 80% of cases (usually in the absence of
systemic nodal lymphoma), although a distinct minority of cases of uniocular and
bilateral retinal and vitreous disease may either not be associated with brain disease or
else the latter may develop many years later. How best to work up these patients and
how best to treat the globe with radiotherapy and/or chemotherapy must still be
delineated.
The second major class of intraocular lymphoid neoplasm used to be called
"lymphoid hyperplasia or pseudotumor" of the uvea and is now regarded as a low
grade monoclonal B-cell proliferation frequently featuring germinal centers in the
choroid and iris. The earliest expressions in the choroid are multiple creamy infiltrates
which can be static for prolonged periods of time (Jakobiec et al. 1987), but over 5-10
years the entire uvea becomes diffusely thickened, frequently with evidence of
extraocular episcleral extension behind the globe or into the conjunctiva. About 10%
of these patients are found to have a systemic lymphoma, which is usually an
x
Introduction
immunoglobulin-producing dyscrasia such as Waldenstrom's macroglobulinemia. The
last category is a systemic nodal or extranodallymphoma that metastasizes to the eye
and typically involves the uvea rather than the retina; this is well managed by ocular
radiotherapy, much as metastatic carcinoma to the choroid (and orbit) can be
successfully managed with this modality.
With respect to orbital tumors, radiotherapy for rhabdomyosarcoma, lymphoma,
lacrimal gland epithelial tumors, and lacrimal sac epithelial tumors has been well
covered in this work, even if there is room for continuing improvement in radio
therapy or multi modality therapy. Radiotherapy can also be utilized for the treatment
of orbital histiocytic disorders (lakobiec et al. 1980; Netland et al. 1993b). Regarding
this textbook, there is another heterogeneous and unaddressed group of malignant
orbital soft tissue and fibro-osseocartilaginous tumors that needs radiotherapeutic
elucidation: namely, malignant fibrous histiocytoma, hemangiopericytoma, fibrosar
coma, angiosarcoma, leiomyosarcoma, granulocytic sarcoma (chloroma), primary
orbital melanoma, alveolar soft part sarcoma, osteosarcoma and chondrosarcoma,
endodermal sinus tumor, malignant peripheral nerve sheath tumor, and liposarcoma
(Croxatto and Font 1982; Font and Hidayat 1982; lakobiec et al. 1985, 1989; lakobiec
1991; Netland et al. 1993a; Sassani et al. 1993).
Most of these parlous conditions can be treated by radical surgery - exenteration -
but it would be very advantageous to more accurately define the indications for
radiotherapy after incomplete excisions in patients with eyes that continue to have
useful vision, and most compellingly for patients who do not have useful vision in the
other eye. Another orbital radiotherapy indication that needs further refinement is for
the juvenile pilocytic astrocytoma of the optic nerve, more conventionally referred to
as optic nerve glioma (Stern et al. 1980; lakobiec et al. 1984; Levin and lakobiec
1992). These tumors are cytologically benign but may need to be treated by chemo
therapy and/or radiotherapy when there is threat of intracranial extension or presump
tive involvement of the chiasm and/or the hypothalamic region and the ventricular
system. Patients with primary optic nerve sheath meningiomas, who are usually
women in their forties (70% of cases) at presentation, have been recommended to
have radiotherapy if their vision is declining but still good (surgery would be far
more risky for preservation of vision); this is a controversial topic requiring further
critical engagement by radiotherapists (Smith et al. 1981; Kupersmith et al. 1987;
Kennerdell et al. 1988).
The subject of idiopathic inflammations of the orbit (lakobiec and Font 1986) is
desperately in need of more solid radiotherapeutic codification. Graves' orbitopathy
is essentially an autoimmune inflammation of the extraocular muscles, generally
sparing the orbital fat. There is a seductive logic for introducing low doses of radio
therapy early in the disease, when there is evidence of proptosis and extraocular
motility disturbance but not necessarily compressive optic neuropathy. Early in
terruption of the evolution of the disease - which begins as a lymphocytic irritation
of the fibroblasts of the extraocular muscles leading them to initially produce water
binding mucopolysaccharides and later restrictive and contracting extracellular col
lagen - makes eminent sense, before the irreversible muscular cirrhosis ensues. The
absence of significant complications in terms of radiation-induced optic neuropathy
and retinopathy gives comfort that this approach could be very valuable. Often,
patients are entered into radiotherapy today after they have proved to be either
unresponsive to systemically administered corticosteroids or have become intolerant
to the large doses that are required for control of their orbital symptoms and optic
nerve compression.
The second major type of idiopathic orbital inflammation that is not due to
an infection, a retained foreign body, or a recognizable systemic disease has his
torically been termed "pseudotumor," but some experts prefer to call the condition
Introduction XI
idiopathic or nonspecific orbital inflammation (non-Graves') (Jakobiec and Font
1986). Idiopathic orbital inflammation or pseudo tumor must be distinguished on the
one hand from Graves' disease and on the other from the lymphoid tumors, both
benign and malignant (Jakobiec and Knowles 1990). In addition to endocrinological
studies which point toward the diagnosis of Graves' orbitopathy, there are other
clinical and radiographic means for distinguishing the two entities. In pseudotumor
the extraocular muscles may be inflamed (frequently involving the tendons, which are
spared in Graves' orbitopathy), but also there is typically inflammation of the orbital
fat, or of the Tenon's-level tissue outside of the sclera, the connective tissues around
the dura of the optic nerve, and the lacrimal gland. Each one of these sites may be
individually affected or affected in any combination (Jakobiec and Font 1986).
The most dramatic presentation of orbital pseudotumor is as an abrupt inflam
matory episode simulating infectious orbital cellulitis, with erythema of the eyelids,
chemosis of the conjunctiva, motility disturbances, and, rarely, at the outset visual
decline, especially if the peridural orbital connective tissues are inflamed ·behind the
eye. The second presentation is subacute, with less declarative inflammatory signs
leading to proptosis or a motility disturbance; in some instances a metastatic car
cinoma can be simulated if there is accompanying pain. Finally, the rarest variant is
the sclerosing pseudotumor, which inexorably congeals all of the orbital tissues in
fibrosis, and may ultimately extend outside of the orbit into an adjacent sinus, thereby
behaving in a quasi-neoplastic invasive fashion.
Pseudotumor is a therapeutic no-man's land and is generally treated by systemically
administered corticosteroids during the early explosive stages (often 80-100 mg per
day for several weeks with slow tapering), in an effort to prevent progression of the
fibrosis of the orbital structures. If the patient does not respond to systemic cor
ticosteroid administration, relapses upon their discontinuation, or, worse, still dis
plays progression even under their coverage, then many clinicians, on a poorly defined
basis, resort either to systemic chemotherapy (e.g. cyclophosphamide) or radio
therapy. Earlier reports representing success with radiotherapy for orbital inflam
matory pseudotumor may have lumped lymphoid tumors together with inflammations
(Kim and Roth 1978; Donaldson et al. 1980; Sergott et al. 1981; Orcutt et al. 1983;
Fitzpatrick and Macko 1984). This confused area is sorely in need of sharpening the
indications for radiotherapy.
It is imperative, therefore, to segregate out the inflammatory pseudotumor patients
defined as stringently as possible from those who have genuinely neoplastic lym
phoid tumors; however, to confuse the matter further, the latter may be rarely
predominantly situated in one or more of the extraocular muscles (Hornblass et al.
1987), as opposed to being more typically located in the fat and lacrimal gland. The
idiopathic orbital inflammations or pseudotumors histopathologically are hypocellular
and fibrosing processes that feature a polymorphous infiltrate of scattered lym
phoid aggregates with or without germinal centers (signaling the presence of B
lymphocytes), eosinophilic leukocytes, dispersed lymphocytes (many of which are T
cells), plasma celis, and polymorphonuclear leukocytes. If there is any evidence of
granulomatous inflammation or an unambiguous angiocentric and angiodestructive
pattern (not to be confused with nondestructive and nondiagnostic perivascular
lymphocytic cuffing), consideration should be given to a systemic disease, most often
Wegener's granulomatosis (which now can be verified by the serum ANCA study -
the anti neutrophilic cytoplasmic antibody test) - or much less often polyarteritis
nodosa if there is an absence of granulomatous inflammation (Davenport 1992;
Soukasian et al. 1992). Radiotherapy for biopsy-proved orbital vasculitis should be
avoided because it may worsen the condition; systemic chemotherapy is the preferred
method of treatment (Garrity et al. 1986). It appears that radiotherapy may add more
insult to the already destructive process engendered by the vasculitis itself.
XII Introduction
There are a number of clarifications that I think should be made about the
lymphoid neoplasms, notably in contradistinction to idiopathic orbital inflammations.
The lymphocytic tumors are monomorphous hypercellular proliferations, generally
devoid of the prominent fibrotic stroma and admixed inflammatory cell types which
characterize the pseudotumors. The lymphoid hyperplasias or pseudolymphomas
are composed of a majority of T lymphocytes with a minority of polyclonal B
lymphocytes, whereas the monoclonal lesions are virtually always monotypic B-cell
proliferations with a minority of interspersed T lymphocytes. There is a vanishingly
rare occurrence of T-cell lymphomas in the ocular adnexa, and despite its systemic
frequency, Hodgkin's disease of the globe or the ocular adnexa is a bona fide curiosity
(Jakobiec 1989). The benign and malignant lymphoid tumors are observed in older
patients and grow as unifocal masses exhibiting on imaging studies angulated or arc
like margins usually without bone destruction (Yeo et al. 1982); they are well
tolerated masses, typically without pain and erythema.
A fundamental way of conceptualizing the difference between an idiopathic in
flammation and a lymphoid tumor is that the former is in some sense a reactive
process (for example, an antigen-antibody complex disease), whereas the latter is
truly an autonomous proliferation (Jakobiec and Knowles 1990). Substantiation for
the concept of lymphoproliferative autonomy is provided through the immunologic
detection of a deranged T-helperfT-suppressor ratio, which is greatly enhanced in the
T cell-rich pseudolymphomas or lymphoid hyperplasias (Knowles and Jakobiec 1983),
and which could be a stimulus conducive to the development of B-cell clones. In
most immunophenotypically polyclonal lesions, molecular genetic techniques have
detected the emergence of one or more small monoclonal populations (Neri et al.
1987; Jakobiec et al. 1987; Knowles et al. 1989).
The precise anatomic localization of ocular adnexal lymphoid tumors is of great
importance in predicting their potential association with systemic disease: lacrimal
gland and other orbital sites have approximately a 30%-35% incidence of systemic
disease, conjunctival lesions (salmon patches) a 20% likelihood, but most impor
tantly, preseptallid lesions without involvement of the deeper orbital tissues have the
highest incidence of systemic disease, around 70% (Knowles et al. 1990). If there is no
systemic disease requiring treatment discovered on workup (chest X-ray, complete
blood count, serum protein immunoelectrophoresis, CT body scanning of the thorax
and abdomen, bilateral iliac crest bone marrow biopsies, rheumatoid factor, antinu
clear antibody, sedimentation rate), then the orbital or conjunctival lesions are
extremely well managed, as outlined in this text, with appropriate doses of radio
therapy geared toward the level of cytologic differentiation.
Even high-grade orbital lymphomas still have only a 45% -50% chance of as
sociated systemic disease (Knowles et al. 1990) so that cytology should not dictate
whether systemic chemotherapy is administered. Bilateral ocular adnexal lymphoid
tumors do not necessarily betoken systemic lymphoma (McNally et al. 1987; Knowles
et al. 1990); if no evidence of systemic disease is discerned after a workup (the
situation in 60% -65% of cases), then bilateral orbital radiotherapy has been found
to be efficacious. There seems to be a peculiar predilection for some subsets of
lymphocytes to be attracted either to the lacrimal gland (which is the most common
site for orbital bilaterality) or to other antigenic determinants of the orbital soft tissues
without obligating systemic lymphoma (a phenomenon of lymphocytic homing some
times referred to ecotaxis). This concept of ocular adnexal bilaterality without
obligatory systemic disease is a difficult one for systemic hematologists and oncologists
to deal with, but it has been verified in a clinicopathologic study with almost 5 years of
follow-up (Knowles et al. 1990).
Two final issues with clinical implications arising from the study of ocular adnexal
lymphoid tumors are the question of whether the majority of these lesions is truly
primary in the orbit when no disease is found on systemic workup and whether a
