Tumors metastatic to the orbit: A changing picture

Tumors metastatic to the orbit: A changing picture

SURVEY OF OPHTHALMOLOGY VOLUME 35 . NUMBER 1 . JULY-AUGUST 1990 MAJOR REVIEW Tumors Metastatic to the Orbit : A Changing Picture ROBERT A. GOLDB...

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SURVEY OF OPHTHALMOLOGY

VOLUME 35 . NUMBER 1 . JULY-AUGUST 1990

MAJOR REVIEW

Tumors Metastatic to the Orbit : A Changing Picture ROBERT A. GOLDBERG, M.D .,3 JACK ROOTMAN, M.D ., F.R.C.S., '-' AND ROY A. CLINE, M.D., F.R.C.S x

Departments of 'Ophthalmology and z1 atholo , Vancouver General Hospital, University of British Coluanbia, Vancouver, B-C., Canada, and the Jules Stein Eye Institute, University of California Los Angeles School of Medicine, Los Angeles. California

Abstract. Clinical characteristics of tumors metastatic to the orbit are related to primary tumor biology, and vary substantially among the various primary types . Common known primary sites include breast, lung, prostate, and melanoma . Tumor presentations can be classified into four generalized syndromes of mass, infiltrative, inflammatory, and functional effects . We found the infiltrative syndrome of presentation to be more column than for other types of orbital neoplasm . Accurate diagnosis often depends on recognition of the types of dinical syndromes and on the use of diagnostic modalities such as computed tomography, magnetic resonance imaging, fine needle aspiration biopsy, and open biopsy . Special histologic techniques arc often useful in determining the origin of these often poorly differentiated tumors, and can provide a basis for specific bornonal therapy- Ophthalmnlugists play a vital role in the diagnosis OF metastati( cancer; the orbital tumor was the presenting sign of systemic cancer in 42% of the cases reviewed . Although the overall prognosis for patients with metastatic cancer is quite poor, specific therapy is available for a growing number of cancers . Timely intervention based on accurate diagnosis can dramatically improve the duration and quality of life with selected tumors . Surv Ophthalmol 35 :1-24, 1990)

Key words . chemotherapy metastasis - needle biopsy

computed tomography - magnetic resonance imaging orbital tumor - radiotherapy

Since the first report by Horner " of cancer metastatic to the orbit, ophthalmologists have been fascinated by these bloodborne messengers of systemic disease. Their clinical presentations are as diverse as the biology of the underlying primary tumors, and this wide range of manifestations has been the loot, particularly in historical cases, of misdiagnoses and lengthy delays to diagnosis . Even with today's sophisticated diagnostic tools, lack of suspicion and protean presentation can lead to difficulty in properly and efficiently diagnosing orbital metastatic disease . This phenomenon is perhaps fueled by the traditional impotence that ophthalmologists have felt in the lace of metastatic cancer ; why go to great lengths to diagnose a terminal and untreatable condition-, Modern treatment methods, however,

have antiquated this longstanding hopelessness . Lengthy remissions and even apparent cures of metastatic cancers are becoming more and more frequent ; hormonal therapy, advanced cherrtotherapy, and radiotherapy have dramatically altered the outlook for many cancer patients . Ophthalmologists can play a significant role in the diagnosis of metastatic cancer when it involves the eye and orbit . In addition to establishing ills tissue of origin, orbital biopsy cart provide valuable infortnation regarding hormone receptors, information which can guide specific therapy . In this paper we discuss the prevalence, clinical and temporal characteristics, diagnosis, and management of metastatic orbital tumors . To support our clinical impressions, we draw upon the clinical series of one of the authors (R),'" and also tabulate



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Surv Ophthalmol 35 (1) July-August 1990

GOLDBERG ET AL

TABLE I

and an ophthalmologic series will reflect a different

Frequency of Orbital Metastases, as reported 1850-1989 (Known Vs . Occult Primary)

population than a neurosurgical or radiologic study . There is also great variation in the degree of thoroughness with which ocular or orbital involvement is sought . In historical series the tools available for orbital diagnosis were limited . For all these

Nun her of Cases

Years 1850 1920 1940 1960 1980 Total

to to to to to

1919 1939 1959 1979 1989

6 20 35 70 114' 245

Known Primary*

Occult Primary'

1 6 16 35 80

(17%)s (40%) (47%) (50%) (70%)

5 9 17 34 34

(83%)4 (60%) (53%) (50%) (30%)

138

(58%)

99

(42%)

*Cases with positive history of systemic cancer at time of ophthalmic presentation . `Cases with no history of cancer at time of ophthalmic presentation : orbital tumor is presenting sign of systemic cancer . 4 Percentage of cases for which this information was given . "Includes our own series of 38 cases from University of British Columbia . .'

the cases reported in the literature . We will focus on the ophthalmologic similarities that bind this diverse group of tumors together, while trying not to ignore the oncologic peculiarities that distinguish one primary type from another . Although a thorough review of the oncology of the various primary tumors is beyond the scope of this article, emphasis will be placed on those tumors for which there is currently good treatment .

I. Prevalence Orbital metastasis of systemic cancer appears to be increasing in frequency . If we examine the breakdown by decade (Table 1), it is obvious that the number of reports has increased dramatically over the past 20 years . This finding may reflect the overall increase in the volume of medical literature more than it does the frequency of site specific metastatic disease . Nevertheless, the general impression of clinicians who specialize in orbital disorders 9i " p is that metastasis to the orbit is seen more frequently than it was in the past. If this finding is, in fact, true it might represent increased longevity and shifting metastatic patterns in today's cancer patients, whose survival has been extended and immunologic status altered by modern treatment methods . In addition, these patients may be more likely to be aware of, and seek consultation for, ophthalmologic manifestations of their disease. The actual prevalence of orbital metastasis depends on the population studied . Each type of study has its own bias ; a pathologic series will paint a somewhat different picture than a clinical series,

reasons, the true prevalence of orbital metastasis is difficult to determine . A. PREVALENCE OF ORBITAL OR OCULAR METASTASIS IN PATIENTS WITH METASTATIC CANCER One way to look at prevalence is to examine patients with metastatic cancer and determine the prevalence of tumors lodging in the orbit ; of couse, the more exacting the analysis the more metastatic disease found . In a 1944 clinical survey of patients with known metastatic cancer, Godtfredsen H4 suggested that ocular involvement by metastatic disease was rare, occurring in only 6 of 8712 patients or 0 .7% . Albert et al' more recently found 10 cases of orbital or ocular metastasis in 213 clinical cases of metastatic cancer, a prevalence of 4 .7% . These clinical surveys undouhtably missed some clinically occult tumors . In a careful histologic survey of autopsy eyes, Bloch and Gartner2" found a 12% prevalence of metastatic ocular and orbital disease . B . INCIDENCE OF ORBITAL VS . OCULAR METASTASIS Another way to look at the prevalence of orbital metastatic disease is by comparison to intraocular metastases, a differentiation which was not statistically addressed in the studies discussed in the previous section . In large histopathologic series , " .74, "" the ratio of intraocular to orbital metastasis has been found to be in the range of 2 .3 :1-8 : 1 . These high ratios may reflect an acquisition bias in pathology studies ; in a clinical study utilizing modern orbital diagnostic capabilities, Freedman and associates 79 recently found a ratio of 1 .4 :1 . Extrapolating from this figure, taking into account the high prevalence of metastatic cancer, it is likely that orbital metastases are much more common than the small series and case reports in the literature might suggest.? ) C . PREVALENCE OF METASTASIS COMPARED TO OTHER ORBITAL DISEASES Finally, it is clinically useful to examine the prevalence of orbital metastasis among all orbital diseases . Large clinical'' 16 ' 95,200 and radiographic 14 a 220 orbital series have put the proportion of metastatic tumors at 1 .5 - 3 .3% of all orbital cases ; a large pathologic series . . . found a proportion of



TUMORS METASTATIC TO THE ORBIT 2 .5% .

Ifwe consider only orbital neoplasms . the importance of metastasis as a cause of orbital cancer becomes even more apparent . Henderson°' found 56 metastatic I.umors in a clinical series of 552 orbital neoplasms, a proportion of 10% . Analysis of one of the authors' personal series at the University of British Columbia (JR) reveals 38 metastases out of 314 orbital neoplasms, or 12% .

Prostate (8 .3%) Melanoma (5 .2%) G .I . (4 .4%) Renal (3 .2%) Squamous Cell (2 .0%) Lung (11%)

V9%) Breast (42%)

II . Clinical Characteristics Orbital metastases are a heterogeneous group of neoplasms . Their clinical behavior reflects the biology of the parentt tumor and, as we will discuss in later sections, can vary substantially from one pritnary type to the next. On the other hand, they share in common many important clinical characteristi(s and can profitably be examined as a group . Thirty-eight cases of orbital metastasis were seen by one of the authors OR) at the University of British Columbia from 1978 to 1988 ." c' Lymphoma, leukemia, and childhood neuroblastoma were specifically excluded, as were tumors extending into the orbit by direct contiguity from the adjacent sinuses and cranial vault; these tumors are important and common, but are well described in other reviews . Optic nerve involvement via carcinomatous meningitis was also excluded ; this fascinating syndrome indeed causes orbital signs based on metastasis of systemic earlier, 1 ' ° ''` 1V " t ' but the primary locus of the metastatic turner is not in the orbit . In order to augment our own clinical experience, we combined our data with that collected from 207 cases described in the literature ; these cases were selected from 221 case reports as having adequate clinical information for inclusion . In two-thirds (162) of the cases the metastatic nature of the orbital rumor was verified histologically . By no means is this a statistically strenuous analysis ; there is quite obviously a substantial acquisition bias in data assembled from case reports . However, there is still useful information obtained from this database, which is tabulated in 'I-able 2 . A . RELATIVE PREVALENCE OF DIFFERENT PRIMARY TYPES One thing that clearly cannot he determined from combined case reports is the relative prevalence of different types of metastatic disease . A better approximation can be made by combining individual ophthalmologic series, which have a decreased (but not absent) recruitment bias . Fig . 1 presents this data . It is apparent that breast, lung, prostate, and melanoma comprise the largest groups of metastatic cancer ; cases in which the primary tumor could mot be identified also represent a

Other

. Fig

1. Prevalence of various primary types, in (ombined series . `Other" includes : neurohlastoma (1 .6'X) ; testicle (1 .2%) ; adrenal pancreas, and thyroid (0 .8%) each) ; bile duct, carcinoid, fibrosarcoma, choroidal melanoma, ovary, parotid, and uterus (0 .4%) each) . References : Albert 1967, 4 Bulloch 1980, 3 ' Font 1976, ' F[icedman 1987,'` I lenderson 1980x' loosen 1970,''" Kennedy 1984, 1'2[ Rootman 1989,," Shields 1988 .'`10

significant proportion . These combined series are a mixture of clinical and pathologic sources ; thus, they do not reflect the distribution of primary tumors metastatic to the orbit as well as would a large, careful, autopsy series . For example, metastatic lung cancer, which has a fulminant course and typically metastasizes to the orbit when the patient is already quite ill systemically . will be underrepresented in a clinical series compared to breast cancer which runs a slower course and is more likely to be present in a patient who is able to ambulate to the ophthalmologist's office . Regardless, the breakdown in Fig . I should be representative of the mixture that might . present to an ophthalmologist . B . LATERALIZATION Several authors have suggested that systemic tumors metastasize preferentially to the left orb it"°3,"2 .11" The vascular architecture of the carotid system, with the left common carotid arising directly from the aorta, has been offered as an explanation fbr this ."" More recent papers have disputed the idea of left-side preference .'' " 191 '1 he cumulated data from these 245 cases challenge the assertion of left-side predilection (Table 2) and actually suggests a right-side preference, although this is not statistically significant (Chi Squared Test, P = .05) . For cases in which laterality was listed, 116 (5(3%e) of cases were right-sided, compared to 95 (43%) involving the left orbit Seventeen (7% .) of cases were bilateral .



TABLE

2

Clinical Charactensit of Orbital Metastasis, by Primary Site Side

Breast' Prostate" Melanoma` Kidney (renal cell)" Carcinoide Gl t lung" Thyroid" Unknown' Wilms' Melanoma Choroidk _10 Pancreas'Liver (hepatoma) 1 61 .26 Uterus Adrenal""' Bladder 1M10 .107 Parotid 46 ' 182 Seminoma 16' 17"" Bile duct 4U Cervixti 7 Fibrous HistiocyteY02 Gall Bladder"' 159 Mesothelioma Ovary Peritoneum 156 184 I'heochromocytoma Squamous cell lip Sympathoblastoma 46 Vagina 10s Sarcoma" 5,ns,ln5

Right

Sex

Age*

Left

Bilat

Male

Female

Total

59 70 45 57 64 51 58 49 76 2 62 45 68 52 55 70 55 27 69 73 47 40 34 86 56 33 38 21 41 31

20 17 13 5 1 5 5 2 3 2 3 4 1 1 0 1 1 1 0 1 l 0 1 0 1 11 1 1 0 4

26 25 II 11 6 4 4 7 2 1 1 0 2 2 2 1 1 1 1 0 0 1 0 1 0 0 0 0 0 5

10 1 0 I 3 I 0 0 0 1 0 0 0 0 0 0 0 0

0 44 17 12 1 6 6 2 4 4 0 3 3 0 1 1 1 2 1 0 1 1 1 0 0 0 1 1 0 9

67 0 7 4 10 5 3 7 1 1 4 1 0 3 1 1 1 0 0 1 0 0 0 1 1 1 0 0 1 0

67 44 24 17 11 11 9 9 5 5 4 4 3 3 2 2 2 2 1 1 1 1 1 1 1 1 1 1 I 10

56

95

116

17

123

118

245

Fibrosarcoma Liposarcoma l 65 Ostcosarcoma Osteofibrosarconla" 6 Reticulosarconla 3-0 All

* .Average References : 69 .76.82,110 .114 .181,135.140,142,143,146.I49,153,156,158,162,166 .180,194. aB reast :''3,9.12.19,14 .19,2u,26,27,.31,37 .39 .47,48 .5.3, .54 21'2,217 .32, :43,81 .58,89,9494 .9&119 .122 R3 .`.27,129,148 .164 .183,18.5,188.2U4,208,2i6,218 bPl'ostate :17 .18,2I 2229,31 .64,66.74,105 .137,155,295 .213 :2,15,30,36,43,44 M el anoma .106 .107,120 .125,140 .17L174 .196 .20&211,219 dK l(I ney :7.24 .4852,u6,100 .75 .80 .91 .92,102,132 .178.189 `Cardinold :'15' 60 tG1 :50 .62,134,110,152,156.167 .187 4Lung:"8'43 .N3.6470 .133,215 l . 12 s. .5a 97, I 03.128 . 54.214 'Thyroid 7 .59 'Unknown :' 1 W ilms: 6 .11 .78 .87,157 k (:horoidal Melanoma : 49 .77,161,192 47 .138 .221 'li ivcr : (This data also includes 38 cases seen at University of British Columbia .) 85

C . LOCALIZATION

CT, radiographic, surgical and autopsy findings allows us to make a more detailed analysis of the localization of orbital metastasis, which is depicted graphically in Fig . 2 . Although the superior orbit is

Previous authors have suggested that the superior and medial orbit is the most common physical location for orbital metastasis . 71 '07 Font and Ferry 75 found no quadrant to be preferred . Combining the

a common site, these data suggest that the lateral

location data from the assembled cases - based on

orbit is actually the most common quadrant

4

for

TUMORS METASTATIC TO THE ORBIT metastatic tumors . It is difficult to determine with certainty the principal tissue destination of orbital metastases . Often by the time localizing studies (primarily CT scans) are performed, the tumor mass has grown to involve bone, muscle, fat, and other orbital tissues . In most cases, though, a reasonable assumption can be made as to the primary tissue destination of orbital metastasis . This information, tabulated in Table 3, provides an opportunity to compare the metastatic patterns of different primary tumors . Fhe overall ratio of tissue destination shows bone and fat to be more common than muscle in a ratio of 2 :2 : 1 . However, different primary tumor types demonstrate distinct preferences for certain tissues . Prostate carcinoma has a strong tendency to metastasize to hone (bone : fat : muscle 4 : 1 :0), whereas breast carcinoma has a tendency to localize in orbital fiat and muscle (ratio 1 :3 : 2) . Melanoma had the strongest preference for muscle (ratio 1 :4 :4) of all the primary tumors . Thyroid carcinomas are also known to metastasize to bone, although the total numbers are small (Table 2) When metastatic tumor enlarges the extraocular muscle discretely, without other orbital involvement, sorting through the differential diagnosis can ; 1i7196207 this presentation was dehe challenging scribed in seven of the reviewed cases, including four cases of metastatic breast carcinoma .2 11 .21176, A IIs, The differential diagnosis of discrete extraocular muscle enlargement includes Graves' disease, myositis ('"pseudounnor" ), lymphoma and other primary neoplasms, arteriovenous malformation, carotid cavernous fistula, acromegaly, amyloidosis, trichinosis . and cysticercosis .

Fig. 2 .

Localization of orbital metastasis ((ombined case

reports) .

in patients with known primary tumors . However, an inadequate history will often leave undiscovered this vital hit of information : for reasons of denial, embarrassment, forgetfulness, or lack of association (some primary tumors may have been diagnosed 20 years prior to orbital metastasis), patients often neglect to disclose a history of known cancers . A history of previous cancer should be diligently pursued in any patient with an undiagnosed orbital tumor . In a significant proportion of orbital metastases, on the other hand, the orbital tumor is the presenting sign of systemic cancer (occult primary) .''''" "c`"' .',°," :` In 42%% of the combined cases the orbital symptoms and signs preceded the diagnosis of the primary tumor . This proportion varies greatly among different tumor types, as seen in Fig . 3 . Analysis of reported cases over time reveals a striking reversal in the tendency for metastatic cancer to first present as an orbital tumor ('fable 1) : in earlier reports, orbital presentation of systemic metastasis was more common than primary tumor presentation, but the presentations are of equal fre-

D . TIMING OF METASTASIS : KNOWN VS . OCCULT PRIMARY The majority ofnietastati( orbital tumors present

FABLE 3 Rout' lAtrailzatinn, by Prernmy Site Tissue Localization : Number of Cases Primary Site

Bone

All types* Rrcast Lung Prostate GI Renal Melanoma

55 (39c9.)' 4 (149i) 1 (33%r) 22 (79%) 4 (449.) 3 (509.) 2

Fat 54 12 2 5 3 2

(l2%c)

*Includes additional unlisted primary types . - Cumulative percentages for each primary type .

8

(39%) (41%) (67%) (17%) (33%) (33c/) (47%)

Diffuse

Muscle 25 7 1

1 1 7

(18%) (24%) (4%c) (11%) (17(7,) (41%)

6 6

(4°7d (2t'7)

I

(I i%)



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Surv Ophthalmol 35 (1) July-August 1990

N-24

GOLDBERG ET AL

Known Primary : Positive history of cancer

∎ Occult Primary: Orbital tumor first sign of cancer

N-BO

N-42

N-9

N-12

N-9

N=10 N=17

N-9

100 y Qh y

st U w

1

75-

50CC

3 01

25-

I

I

s~eo~a~ez~oz Az3~fe ~,yo,Cf a

Fig . 3 .

,pooh ~ 6,

a'

Site of Primary Tumor Ratio of occult primary to known primary in orbital metastasis (combined case reports) .

quency in reports from 1960 to 1980 . In reports since 1980 (including our own series of cases) only 28% of metastatic tumors presented first as orbital masses. Thus, there is an increasing tendency to diagnose the primary tumor before it presents as an orbital metastasis ; this is likely a reflection of increasing clinical awareness and diagnostic acumen regarding primary cancers . The fact that in more than a quarter of cases systemic metastatic cancer will manifest first as an orbital process places an important . diagnostic burden on the ophthalmologist. who will be the first physician to evaluate these patients . A high suspicion of metastatic disease combined with a certain amount of diagnostic acumen may help lead to an earlier diagnosis of systemic cancer, which, in this age of improved treatment and even occasional cures for metastatic cancer, has profound implications for the patient . E. TEMPORAL CHARACTERISTICS The average survival for all cases was 9 .3 months (median actuarial survival 6 .4 months) ; this is consistent with recent reported series . 75,79,97,190 As one might expect, the survival has increased in recent reports, illustrated in Fig . 4, which plots both diagnosis of primary malignancy and survival on a time line with time = 0 representing the rime of presentation to the ophthalmologist . We have already pointed out that in most cases, the primary tumor is diagnosed before the patient presents with an orbital tumor . The average time of diagnosis of the primary cancer was 31 months before ophthalmologic presentation . As expected, more recent reports are

characterized by a longer mean interval from primary tumor diagnosis to ophthalmologic presentation (Fig . 4), reflecting increasingly sophisticated methods of diagnosing the primary cancer . These global statistics underemphasize the striking diversity of temporal course among the different types of primary tumors, a diversity that reflects the biology of these cancers . An informative derivation is presented in Fig . 5 . Here we have again plotted on a time line for each type the average time of primary tumor diagnosis and the average survival. On the one extreme, tumors like breast and carcinoid have a drawn-out temporal course : the tumor is typically diagnosed long before the patient presents to the ophthalmologist, and survival following orbital metastasis is also relatively prolonged, often measured in years instead of months . Breast cancer is well known for lengthy delay from diagnosis of the primary to the appearance of metastasis, and this is reflected in our own combined series with an average delay of three years . Another tumor with a drawn-out temporal course is thyroid carcinoma . In our combined cases, an average of live years passed from the time of diagnosis of primary thyroid cancer until the appearance of orbital metastasis (the longest interval among all primary types in our series), and average survival following ophthalmic presentation was 42 months . Thyroid cancer is challenging because of the potential difficulty in accurately diagnosing the primary malignancy . If careful sectioning of the excised thyroid mass is not performed, the area of malignant follicular (or less likely papillary) cells may be overlooked . This may account for cases in



TUMORS METASTATIC TO THE ORBIT

Time of Diagnosis of Primary Tumor

-

120 - 60

\

-24

7

I

Survival (Mean)

-12 -6

1

24

-

60

120

MONTHS (Ophthalmic presentation = 0 months)

Fig . 4.

Temporal characteristics of orbital metastasis by year of case report (combined case reports) .

I

Time of Diagnosis of Primary Tumor

I

Survival (Median)

MONTHS (Ophthalmic presentation

0 months)

Fig_ 5 . Temporal characteristics of orbital metastasis by tumor of origin (combined case reports) . Small ticks indicate individual cases .



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Surv Ophthalmol 35 (]),July-August 1990

which apparently benign tumors have been noted to metastasize 5 7,1°' Melanoma is somewhat intermediate . The tendency of cutaneous melanoma to demonstrate long delay from onset of primary tumor to first appearance of metastasis is well known, with cases of latency up to 46 years on record . 17' However, once metastasis has occurred, the disease is rapidly progressive . Our cases reflected these tendencies, with a long delay from diagnosis of the primary cancer until orbital presentation (almost two years, on average), but with a short survival time once the metastatic disease had manifest . On the other extreme are tumors such as lung and gut, with a fulminant course . These tumors are diagnosed shortly before or sometimes after orbital presentation, and run a rapidly progressive course with survival typically less than six months following ophthalmologic presentation . Because these cancers metastasize early, patients may present with orbital findings and systemic wasting before their primary cancer has been diagnosed . 'thus, they have gained the reputation as "silent" primaries . F. OTHER CONCURRENT METASTASES We would expect other organs to be involved with cancer in patients with orbital metastases . Henderson found that 51 of 55 (91%) orbital metastases were accompanied by metastases to other sites . Tabulation of our combined cases reveals that in Ill cases (47%) concurrent metastasis in other sites was noted, including 14 cases with concurrent metastasis to the choroid . Of course, whether one finds metastasis in other sites depends on how hard one looks, so this figure is undoubtably lower than the true prevalence of concurrent metastasis . In reality, it is probable that few orbital metastases are truly solitary, despite the clinical inability to demonstrate other concurrent metastases . The only exceptions might be in cases of metastatic carcinoid tumor and renal cell carcinoma . Carcinoids arise from neuroendocrine precursor cells in the gut or bronchi, are very slow growing, and survival as long as 15 years following ocular or orbital metastasis has been described . 1Ry 175 Clinically, solitary orbital metastases of carcinoid primary may be for practical purposes truly isolated, and this combined with the excellent prognosis for lengthy survival has led many authors to recommend surgical extirpation of isolated carcinoid metastases .75 .ns, "' Renal cell carcinoma may also present with solitary metastases . Isolated metastatic tumors of renal cell carcinoma have been managed surgically elsewhere in the body 17," with a 35% 5-year survival (which is comparable to the survival of patients without detectable metastases,) and occasional cures have been

TABLE 4 Presenting Symptom and Signs

Number of Cases (Percent)* Reported

symptoms

Diplopia Proptosis Pain Decreased Vision Blepharoptosis Mass

81 (38%) 76(35%) 50(23%) 44(20%) 35(16%) 28 (13%)

Observed Signs

Proptosis 138(64%) Motility Disturbance 125(58%) 58 (27%0) Palpable Mass Blepharoptosis 45(21%) Decreased Vision 48(22%) 39 (18%0) Displacement Chcmosis 32(15%) Enophthalmos 22(10%) Disk Edema 17 (8%) Retinal Folds or Striac 9 (4%) Parasthesia 7 (3%) Pulsation 3 (1 .5%) *Percent of all cases for which signs or symptoms were listed . reported, G. SYMPTOMS AND SIGNS As a group, among orbital neoplasia, metastases have a relatively rapid onset of symptoms ; the average duration of symptoms (until presentation) for the cases reviewed was 3 .6 months, with lung, pancreas, and melanoma tending toward a more precipitous onset (respectively 1 .4, 0 .8, and 1 .3 months), and breast and thyroid characterized by a longer average duration of symptoms (5 .5 and 16 months) . Proptosis and motility disturbances are the most common presenting symptoms and signs (Table 4) . Motility disturbance out of proportion to the degree of proptosis can occur and is somewhat characteristic of orbital metastasis ." Pain is not infrequent, occurring in 23% of cases for which symptoms were listed . It may be present early in the course, in contrast to other tumors for which pain is typically a late symptom . The single exception to this is tumors that invade by contiguity, where pain or paresthesia are the most frequent early symptoms . A palpable mass was noted in 27% of cases . Blepharoptosis and decreased vision were also common signs and symptoms ; both are multifactorial (ptosis, for example, can be caused by edema, mechanical, neurogenic, and myogenic factors) . Pulsation is an unusual but interesting sign of metastatic tumor . Most often this is secondary to destruction of orbital bone leading to transmission of brain pulsation, but vas-

TUMORS METASTATIC TO THE ORBIT

9

cular metastases, particularly of thyroid and renal origin, can demonstrate intrinsic pulsation due to high internal blood flow ." "7 io6,107 .128,172 A significant and frequently overlooked sign is enophthalmos (seen in 22 cases, or 10% of cases for which signs and symptoms were described) . Metastatic breast cancer is by far the most likely to presentn with enophthalmos (comprising 18 of the 22 cases, or 82%), but gastrointestinal (GI) (two cases) and lung bone case) are among other metastatic tumors, including prostate, which occasionally present with enophthalmos . 'I he potential etiologies of enophthalmos arc varied :" Probably the most important mechanism, particularly in the set.ting of metastatic breast carcinoma, is contraction of fibroblasts in the diffuse scirrhous orbital tumor leading to posterior traction and tethering of the globe . 51 " 7 "" Another potential mechanism of enophthalmos in these cases is destruction of the bony walls of the orbit, resulting in a "biologic orbital decompression" with consequent enophthalmos . H. A SIMPLIFICATION : SYNDROMES OF PRESENTATION Although the tabulation of signs and symptoms is helpful, it does not by itself provide a clinical framework with which to evaluate and categorize the diverse group of patients with orbital metastases . In analyzing our own series, we found that the clinical presentations tend to break down into five generalized types . In order of frequency, they are: Mass : Primary mass effect, either palpable (anterior) or causing axial or nonaxial displacement of the globe . Infiltrative: Diffuse or localized infiltration of orbital tissues characterized by diplopia, enophthalmos, limitation of eye movements or frozen globe, and a firm orbit (increased resistance to retrodisplacement.) Functional : Decrease in cranial nerve function (11, I11, IV, V, V I) out of proportion to mass or infiltration . Inflammatory : Acute or subacute onset of inflammatory signs and symptoms including pain, chcmosis, injection, pain on eve movements, erythema, lid swelling . Silent : No orbital or symptoms . These syndromes are best illustrated by representative cases .

Fig . 6 . Case I : Syndrome of presentation - Mass . Top : Clinical appearance, with proptosis and displacement of the right globe . A right tarsorrhapy has been performed . The temporalis fussa is full on the right (arrowhead) ; a funs mass is palpable in this region . Bottom : CT scan reveals right lateral orbital mass with involvement of the right temporal and middle cranial fbssa . There is irregular hyperostosis of the greater wing of the sphenoid (asterisk) .

1 . Mass Presentation (Case 1) An 80-year-old male presented with a two-week history of right periorbital pain and proptosis . His past history was notable for prostatic adenocarcinoma diagnosed two years previously, with metastasis to the right parotid gland discovered eight months

2 . Infiltrative Presentation (Case 2) A 67-year-old female presented with a twomonth history of her left eye "getting smaller ." There was no history of diplopia, pain or decreased vision . Her past history was significant for infiltrating lobular carcinoma of the breast diagnosed four

prior to ophthalmologic presentation . On examination, 9 man of right proptosis was noted, with medial and inferior displacement of the globe . There was a palpable fullness in the right temporalis fossa (Fig . 6A)_ In addition, ductions were globally reduced oil the right, with virtually absent abduction, suggesting a sixth nerve palsy . Corneal hypesthesia was elicited . Funduscopic examination revealed bilateral uveal metastases . A CI' scan demonstrated an enhancing mass in the lateral right orbit, associated with irregular hyperostosis of the greater - wing of the sphenoid (Fig. 6B) . The clinical diagnosis was metastatic prostate carcinoma to the right orbit . The patient underwent radiation therapy to the right orbit, but was lost to follow-up .

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Fig. 7 . Case 2 : Syndrome of presentation - Infiltrative . Top: Clinical appearance, with 2 mm enophthalmos ofthe left globe . Bottom: CT scan with contrast demonstrates an

Fig. 8 . Case 3 : Syndrome of presentation - Functional . Top : Clinical appearance, with complete right ptosis and mild periorbital edema . Bottom: CT scan with contrast

enhancing lesion diffusely filling the left orbit, encasing the optic nerve .

demonstrates an enhancing mass in the right orbital apex.

Fig. 9. Case 4 : Syndrome of presentation - Inflammatory . Top left: Clinical appearance, with periorbital erythema and brawny induration on the left . Bottom : CT scan

with contrast demonstrates diffuse orbital opacification with scleral enhancement as seen in idiopathic orbital inflammatory syndrome . Right: Orbital biopsy demonstrates poorly differentiated adenocarcinoma . (H&E, original magnification 40X .)

TUMORS METASTATIC TO THE ORBIT years previously, with abdominal metastases discovered two years previously . On examination, she exhibited 2 ram of left enophthalmos and 3 mm of left upper eyelid ptosis (Fig . 7A) . Ductions of the left eye showed global limitation, particularly in upgaze . The orbit was firm to palpation . The clinical diagnosis was breast cancer metastatic to the orbit . CT scan (Fig. 7B) demonstrated an enhancing lesion diffusely filling the left orbit, encasing the optic nerve . No biopsy was perforated . The patient followed a rapidly progressive downhill course, and died of complications of diffuse systemic metastatic breast carcinoma three months following ophthalmologic presentation . 3 . Functional Presentation (Case 3) An 81-year- old female presented with a two-day history of painless loss of vision in the right eye, associated with "puffiness" of the eyelids . There was no history of known systemic cancer, although her history was positive for undiagnosed GI bleeding . On examination, there was evidence of a complete right orbital apex syndrome, with light perception vision, absent extraocular movements, ptosis, fixed pupil, and dense corneal hypesthesia (Fig . 8A) . CT scan (Fig . 8B) demonstrated all enhancing mass in the right orbital apex . A course of radiotherapy to the right orbit was begun, but the patient deteriorated rapidly and died within one month with diffuse metastatic disease . No site of origin was identified ; autopsy was not performed . 4. Inflammatory Presentation (Case 4) A 50-year-old female with a history of alcohol abuse was transferred lrom another hospital with the diagnosis of acute left orbital cellulitis associated with several weeks of left orbital pain . There was no history of previous cancer . On examination, the patient was confused . The left periorbita was erythematous and indurated (Fig . 9A) . The globe was froten . and the conjunctiva was injected and chemotic .

I ntraocular examination was normal . An orbital CT scan revealed "shaggy" anterior orbital opacilication on the left with scleral enhancement (Fig . 9B) . An orbital biopsy was performed under local anaesthesia, and histologic examination revealed poorly differentiated adenocarcinoma (Fig . 9(1) . The diagnosis of metastatic tumor to the orbit was made . Before any further diagnostic or therapeutic measures could be taken, the patient deteriorated rapidly and died six days following admission . At autopsy, widespread metastases were discovered and the primary site was found to be pancreatic . 5 . Silent Presentation The category of the silent presentation includes cases that have no orbital signs or symptoms, some of which are discovered serendipitously - for example, on a GI scan performed for some other reason, or during etmdeation or other unrelated orbital surgety . 6 . Discussion The syndromes are rarely pure in their presentation . For example, a patient with proptosis from an orbital mass will not uncommonly develop nmtilitydisturbances due to mechanical eflects on the extraocular muscles or to infiltrative neural involvement, as demonstrated in Case 1 . Flowever, the overall pattern is clear in the majority of cases ; in our own series, one dominant presentation was apparent in 24 of 38 cases (63%) and in the remainder, a main syndrome of presentation could be determined, accompanied by one or more secondary syndromes . In 193 (84%) of the case reports, enough clinical information was provided to categorize the case into one of the four syndromes . Although this assignment of historical cases is artificial, the tabulated data provides a general sense of the relative frequency of these different presentations (Table 5) . It is apparent that with the exception of breast

1ABLY 5 Syndrome

of

Orbital entalion, Pre, by Primary Sile

Syndrome of Presentation : Number of Cases lold trativc Functional 1 nflatmnat ory -

Mass Primary Type All "I vpes* 127 (669t) -i 45 (24)'0) Breast 23 (4599 25 (50%) 5 (71 01e) 1 (11%) Lung Prostate 25 (76%) 4 (12%a) I (6%) Melanoma 14 (82%/) G1 3 (38%) 5 (62%) Renal 9 (82%) 2 (18%) . *tnchrdes additional unlisted primary types iGumufative percentages for each primary type .

9 (5%) I (2 0k) 1 (14'7) `i (9% .)

9 2

(5(I (4!i

t CM) 2 (12' •t



12

Surv Ophthalmol 35 (1) July-August 1990

and GI origin, the most common syndrome of presentation is a mass, with proptosis or displacement the predominant signs . Pain, inflammation, and secondary motility disturbance are often present as well . Second in frequency is the infiltrative pattern, characterized by restricted motility and enophthalmos . Notably, in cases of breast primary, the infiltrative syndrome of presentation was most common ; this finding is consistent with the aforementioned tendency for metastatic breast carcinoma, particularly of the scirrhous type, to present with enophthalmos and motility disturbance . The infiltrative pattern can also be seen in GI, prostate, lung, and other primaries, as noted in relation to enophthalmos .'I'he infiltrative pattern represents a diagnostic challenge ; these patients may be misdiagnosed or unrecognized for long periods of time, and may masquerade as, for example, acquired retraction syndrome, 127 essential facial hemiatrophy, 1R0 or cranial nerve palsies . An interesting syndrome of presentation may be seen with seminoma, which can, rarely, present with bilateral nonspecific inflammatory or Graves' The etiology of the exlike orbitopathy .'36•" 1,203 ophthalmos is not known ; it is not related to direct orbital metastasis, as demonstrated by autopsy in one case, 136 and has shown regression in response to steroids or excision of the primary tumor . An endocrine mechanism has been postulated, and two of the three reported cases were associated with an elevated serum HCG (Human Chorionic Gonadotropin), but no direct link has been established . Direct orbital metastasis of seminoma must he carefully excluded in these cases ."='i9 I. MISDIAGNOSIS : DIAGNOSTIC PITFALLS Misdiagnosis and lengthy delay in diagnosis are common in metastatic cancer to the orbit. We have already discussed several of the reasons for this : lack of suspicion, protean clinical manifestations, and difficulty in obtaining a complete history with regard to previous cancer . In 20 cases (6 of our personal cases), an initial misdiagnosis was mentioned . The tabulation of these misdiagnoses broken down by syndrome of presentation (Table 6) is revealing . The most common misdiagnoses - cellulitis, myositis, endophthalmitis and idiopathic orbital inflammatory syndrome ("inflammatory pseudotumor") - occurred in tumors with an inflammatory syndrome of presentation . The clinician does not automatically consider an orbital metastasis in a patient who presents with a "hot" orbit and, indeed, this differential diagnosis properly resides fairly low down on the list . However, in our series, eleven cases presented in this fashion and all eleven were initially misdiag-

GOLDBERG ET AL nosed . The key point in properly diagnosing metastatic tumor in a patient masquerading as cellulitis or idiopathic orbital inflammatory syndrome is a history of previous cancer, which should alert the clinician to the possibility of metastasis . In some patients, though, the inflamed orbit will be the first sign of cancer and a negative history will be obtained. From a clinical point of view, features that will suggest orbital metastasis are a firm orbit associated with a brawny induration and a progressive (usually over weeks) unrelenting course dominated by these features along with infiltrative phenomena . The diagnostic challenge of the infiltrative syndrome of presentation has already been discussed . Other common misdiagnoses were in patients with a functional syndrome of presentation : myasthenialike motility disturbance, sixth nerve palsy, and orbital apex syndrome can have multiple etiologies and, again, a careful history is the best diagnostic tool in arriving at the correct diagnosis . The remaining misdiagnoses reflect the lengthy differential diagnosis of orbital masses, and although history, examination, and special diagnostic studies will often narrow the likely possibilities, biopsy is required in the majority of cases to definitively establish the diagnosis of metastatic disease .

III . Diagnostic Modalities A. PHYSICAL EXAMINATION The details of our routine ophthalmologic and

TABLE 6 Misdiagnoses of Orbital Misdiagnoses Inflarn natory presentation Pseudotumoriss 5 ""s

Cellulitis"s .215 Idiopathic inflammation 149 Endophthalmitis' J 4 Myositis5 ° Allergy"

Functional presentation

Myasthenia gravis 39,1 "7,196 Sixth nerve palsy" Orbital apex syndrome 95

Metastasis

Number of Cases 11

4 3 1 1 I I

3 1 1

Infiltrative presentation

Idiopathic orbital fibrosis" Dysthyroid ophthalmopathy'L

t

I 1

Mass presentation

Lacrimal gland tumorszs 6,60 Mucocele Meningioma 1 N 3 Chocolate cyst 159

5

6

3 1 I I

TUMORS METASTATIC TO THE ORBIT orbital examination have been published elsewhere ;"' they are the cornerstone of evaluation of the orbital metastasis . A general physical examination is indispensable in patients with known or suspected metastatic disease . Breast and prostate primaries in adults, for example, and abdominal neuroblastoma in children, can often be readily detected on physical examination . On our service and in reported cases 11" the diagnosis of orbital metastasis has been confirmed by diagnosis of the primary lesion during the initial visit to the ophthalmologist . B . LABORATORY TESTS Both nonspecific and specific laboratory tests are available to help in the diagnostic workup of patients suspected of harboring orbital metastasis . A nonspecific test that can be useful in the differential diagnosis of an orbital mass of suspected metastatic origin is the carcinoembryonic : antigen (C:EA) . The CFA may be elevated in patients with metastatic cancer, and the degree of elevation may relate to total tumor load . For example, Bullock s " found that elevated CEAwas specific for metastasis in his series of 42 patients with proptosis ; however, it was not very sensitive, since only 5 of l3 cases with metastatic orbital tumors had CEA levels that were significantly elevated (greater than 5 nglrnl) . Tlierefore a negative test may not rule out metastatic disease . Specific tests can be useful in tumors which elaborate a measurable substance into the bloodstream . Of the tumors that frequently metastasize to the orbit, prostate cancer [producing prostatic acid phosphatase (PAP)) 10f and seminoma [producing human chorionic gonadotropin (HCG)]'s``'ts elaborate specific substances which can be measured for diagnosis, staging, or treatment follow-tip . Carcinoid tumors may elaborate 5-HIAA into the urine, particularly in the presence of hepatic metastases and in association with the carcinoid syndrome (flushing, diarrhea, lacrimation, conjunctival injection, and other vasornotor instabilities), which usually implies a significant tumor load .''' A general evaluation for other metastases is important in diagnosis and staging of patients . After a confirmation by tissue diagnosis of the metastases general evaluation is best accomplished by an oncologist so that a careful directed investigation based on the nature of the primary lesion is carried out . C . COMPUTED TOMOGRAPHY Computed tomography (CT) is the practical standard for the diagnosis of orbital disease, and nretastatic tumors are no exception . C'f not only allows localization of the tumor within the orbit, but can also provide important clues regarding tissue char-

F, 75-year-old female with no known history of cancer presented with proptosis and inferior displacement of the left globe . CT scan with contrast demonstrates a 2 x 2 cm discrete mass in the superior orbit . Tissue obtained from orbital biopsy was suggestive of metastatic oat cell carcinoma from lung .

acteristics .~"` 'I' he C' I' findings in metastatic orbital tumors run a wide gamut, but can be simplified into four basic categories : Mass (Figs . 8B, 10) : Intraorbital discrete solid mass, typically well defined and mildly contrast-enhancing . May involve or be associated with orbital structures such as bone, muscle, lacrimal gland . Indents rather than invades the globe . Calcification very unusual, as is cystic appearance (denoting central necrosis .) Diffuse (Figs . 7B, 11): Diffuse mildly enhancing involvement of orbital tissues, with blurring ofborders and obscuration of normal orbital structures . Enophthalrnos may be apparent . Borer (Figs . 6B, 12) : Primarily bone involvement ;

(metastatic pancreatic carcinoma) . CT I] . (as scan reveals a contrast enhancing mass diffusely filling the left orbit, encasing the optic nerve . Note blurring of borders and obscuration of details of normal orbital structures .



14

Surv Oplithalmol 35 (1) July-August 1990

GOLDBERG ET AL bone 9 and thyroid metastases commonly cause an osteolytic response . 9712K Magnetic resonance imaging (M RI) provides similar and in some ways superior anatomic inforination, including direct saggital images . As we learn more about this promising modality, the ability to obtain data regarding tissue characteristics may substantially augment our diagnostic capabilitics .s' . ' 60 ' 89 For example, signal intensity on T2weighted images is helpful in distinguishing idiopathic orbital inflammatory tumor (low intensity) from lymphoma or metastasis (high it tensit y ) . I'0

An S2-year-old male with no history of previous cancer presented with proptosis and displacement of the right globe associated with deep orbital pain . CT scan reveals a soft tissue mass involving the orbit and middle cranial fossa (arrow) . with irregular bony destruction of the lateral orbital wall and sphenoid . Tissue obtained at orbital biopsy revealed poorly differentiated metastatic carcinoma ; no primary site was identified despite extensive systemic work up . Fig . 12 .

may be hyperostotic (osteoblastic) or hypostotic (osteolytic) ; moth-eaten appearance of bone may be present in either type . Large areas of bone destruction may be present_ All lesions should be assessed using appropriate bone settings on CT . Muscle (Fig . 13) : Enlargement of one or more extraocular muscles, may appear smooth or have nodular reticulated herders infiltrating adjacent We have already pointed out the tendency for certain primary tumors to show stereotyped metastatic patterns with regard to destination tissue, so it should not be surprising that similar patterns emerge when we tabulate these CT categories by primary tumor type (Table 7) . We see that the most common CT presentation is a mass, followed by bone involvement. Breast carcinoma tends to favor mass and muscle, prostate carcinoma strongly tends towards bony involvement, and melanoma has the highest affinity for muscle . Diffuse involvement presents one of the most challenging differential diagnoses ; this pattern was seen in breast (four cases), CI (one case), and pancreas (one case, Case 4 above) primaries . We did not subcategorize bony involvement into hyperostotic and lytic groups, but it should he realized that prostate, thyroid, renal and other cancers that metastasize to bone can produce either type of bony response with corresponding hypo-or hyperdense changes on CT . Prostate carcinoma particularly tends to produce a hyperostotic, or osteoblastic response with increased density and thickness of

D . NEEDLE BIOPSY One of the best orbital applications of needle biopsy is in the setting of suspected metastatic tumors .' 22 When it is successful, it can save the patient the expense and risk of open biopsy . If an adequate specimen can be obtained, hormone receptor and surface antigen studies for tissue source identification can be performed directly on the tissue fragment recovered from the needle - for example, in cases of metastatic prostate carcinoma . "9 .164 I n sclerosing lesions, such as scirrhous breast and gut metastases, needle biopsy tends to produce "dry taps" with little or no tissue retrieval . In our own series of cases, seven needle biopsies were performed and four of the seven were unsuccessful because of lack of tissue ; three "dry taps" were in metastatic breast carcinoma and the remaining inadequate specimen was in a case of CI primary . Of the ten needle biopsies reported in the combined case reports,'f •~-''Ffi 74 121 12RI3QI35 .164,lti6,19i eight were successful ; it is possible that some additional unsuc-

A 64-year-old female with a two-year history of cutaneous melanoma presented with diplopia, restricted extraocular movements, and chemosis . C I- scan with contrast reveals an inhomogenous mass associated with, and indistinguishable from, the right lateral rectus muscle . A bony defect is noted in the lateral orbital wall (arrowhead) . Fig . 13 .

TUMORS METASTATIC TO THE ORBIT

15 TABLE 7

CT Presentation, St Primly Site

CT Presentation : Number of Cases Mass Muscle All types* 46 (58%) 7 (9%) Breast 9 (60%) 2(13%) Lung 2 (100%) Prostate 15(65%) 8 (35%) GI ](20%) 3 (60%) Renal 2 (66(X ) 1 (33%) Melanoma I (14%) 3 (43%) 3 (43%) *Includes additional unlisted primary types . tcunu lative percentages for each primary type . Bone 20(25%)f

cessful needle biopsies went unreported . The two reported unsuccessful needle biopsies were in cases of breast metastasis . E . PATHOLOGIC TECHNIQUES The overwhelming majority of metastases are poorly differentiated or "round cell" tumors ; thus, diagnosis may and often does require special histochemical, immunohistochemical and electronmicroscopic techniques ."' Further, in the case of hormonally responsive tumors, steroid receptor studies on the biopsy tissue are important from a therapeutic point of view . If there is a likely diagnosis of metastasis the surgeon should be aware of - this, discuss the case with die pathologist in advance, and provide an adequate amount of nontraumatized fresh tissue so that the appropriate receptor or immunohistochemical studies can be carried out . I he range of typical histologic features, variants and specific distinguishing features of the common orbital metastasis are outlined in Table 8 . The field of imnumohistochemistry is a rapidly evolving one with the development of a broader range of specific monoclonal antibodies that identify tissue of origin . Careful, delicate handling and appropriate transmission of an adequate biopsy are critical responsibilities of the ophthalmic surgeon .

IV. Treatment It is a serious mistake to assume that once metastatic cancer has been diagnosed, the situation is hopeless . Although it is true that, as a group, these patients have a short expected life span, there are many cancers for which excellent treatment exists (and the list of treatable tumors continues to expand) . Longterm survivals are not unheard of : live patients survived five years or more after ophthalmic presentation (Fig . 5) . Even in the case of tumors for which no direct treatment is available, patients with troubling symptoms, such as decreased vision

Diffuse 6 (87) 1(27 17,) 1 (20 01 .)

or pain, can often gain dramatic, if usually temporary, relief through the use of orbital radiotherapy or chemotherapy . To a person with a limited number of weeks or months of life remaining, the ability to maintain visual function is profoundly important . This is an area of medicine in which the axiom to provide continued function and comfort is paramount-The principal modalities of treatment used in the therapy of patients with metastatic cancer are radiotherapy, hormonal therapy, chemotherapy and surgical therapy . The divers(- clinical behaviors and treatments of the common metastatic tumors to the orbit are summarized in Table 9 . A . RADIOTHERAPY Radiotherapy has proven extremely useful in the treatment of orbital metastasis . Typically, a total of 3000-4000 rad (30 to 40 Gy) is given in divided doses over a week or two . Drarnatic improvement in orbital signs and symptoms, including recovery of vision when impairment is secondary to orbital mass effect, is not uncommon . In published series (which include patients with lymphoma and leukemia), the success rate has been reported to be 70-90%- 839('' 11 Even in metastatic carcinoid tumors, which are traditionally considered to be fairly radioresistant, b"" success with orbital radiotherapy has been reported"' 92,179 In the combined case reports and our own series, 64 patients had orbital radiotherapy as part of their treatment ; of 44 patients for whom the results of radiotherapy were discussed, 32 (73%) improved, 8 (18%a) had no response, and 2 (5%) worsened following radiotherapy . Radiotherapy for orbital metastasis is generally associated with few complications, particularly if care is taken with dosing, field placement, and shielding of the globe . . . "' Complications are possi-



TABLE S Histologic, Histoc hemical and Electron-Microscopic Features of Orbital Metastases Distinguishing Features Histology Tumor Type

Usual

Immunehistochemical

Electron Microscopic

Mucin Papillary Systemic CEA Anaplastic PAS-positive cenMucinous tral "target" Histiocytoid : intracytoplasmic lumen, cicatricial Lobular carcinoma

Estrogen recepfor Breast tumor assoc . antigens and products

Mucous (as evideuced by secretory granules) Intracytoplasmic lumens No features are specific

Mucin (in adenMa .) Carcinoid : Gremelius positive (argyrophilic)

Neuron-specific enolase (in neuroendocrime oat cell group) Serotonin and other specific monoclonals for varying secretory products

Electron-dense secretory granules in carciuoid oat cell group Mucin (in adenocarcinoma) cytoplasmic inelusions

Variants

Histochemical

Breast

Adenocarcinoma

Lung

Undifferentiated Oat Cell oat cell (± carMay show necrocinoid) sis with DNA in vessel wall and Squamous carcinoma calcospherites Adenocarcinoma Mixed

Neuroblastoma

Round cell neoplasm

Occasionally Wright's rosettes

Prostate

Tubuloalveolar adenocarcinoma

Undifferentiated

With or without mucin (usually without)

GI

Varies : adenocarcinoma columnar

Acinar Papillary Mutinous (t mucin) Positive signet ring

Mucin Systemic CEA positive

Columnar Brush border with luminal aspect Terminal cytoplasmic filimentary webs

Kidney (Renal carcinoma) (Hypernephroma)

Clear cell adenocarcinoma (± granular)

Mixed Granular Clear

Lipid : usually present

Abundant glycogen with lipid inclusions

Melanoma

Amelanotic epithclioid cells

Thyroid

Adenocarcinoma (follicular)

Varied types : Follicular Papillary Medullary (spindle component)

Carcinoid

Abundant granular cytoplasm and nuclear stippling

Commonly solid May be tubular, acinar, or rossette-like

Seminoma

Large pale syncytial cells with lymphocytes

Ewing's sarcoma

Round cell neoplasm

Neurosecretory granules, neurotubles ± axons

With or without fontana

Prostate-specific antigen Prostatic acid phosphatase

HMB45 5-100 protein positive

Premelanosomes

Calcitonin

Neurosecretory granules (in medullary)

Lipid may be present Argyrophilic (Lung) Argentaf in (GI)

Chromogranin Neuron-specific enolasc

Neurosecretory granules

PAS-positive, diastasesensitive glycogen

Cytogenetics : Glycogen translocation (chromosomes I I and 22)



TABLE 9 Summary: Characteristics of Common Primary 'l ypes

Clinical Characteristics Breast Enophthalmos, infiltrative pattern of presentation

Long latency, may metastasize many years after primary cancer discovered

Diagnosis C'I : Bone, muscle involved ; may be dill fuse infiltration Needle biopsy typically unsuccessful

Treatment Hormonal therapy Radiotherapy

Hormone receptors (estrogen, progesterone) on fresh biopsy tissue

lung Short latency, often "silent" primary (CXR may be normal)

Radiotherapy Chemotherapy (oat cell)

Rapid progression of symptoms Patient often systemically ill, survival is poor Prostate Older patient

May have pain Long survival possible

Melanoma Long latency, may metastasize many years after primary skin cancer discovered

CT : Bony involvement, often hyperostotic

Hormonal therapy

Needle biopsy useful ; can often use special immunohistologic stains on needle biopsy specimen

Orchiectomy

C1 : often involves muscle

Radiotherapy

Radiotherapy

Chemotherapy

Short survival after metastatic disease develops Gl Radiotherapy

Short latency, may be "silent" primary May have infiltrative syndrome of presentation Thyroid Primary thyroid tumor may have been read as "benign"

CT : Bone involvement, may he osteolytic

Radiotherapy Radioactive iodine

Long latency ; long survival May have pulsation Carcinoid Long latency ; long survival

May have carcinoid syndrome Potentially isolated metastasis Renal Varied ; may lie fultninant or latent

CT : typically well-defined mass

Radiotherapy

Urinary 5-HIAA may be elevated, especially with liver involvement

Surgical excision if isolated

Radiotherapy

May have pulsation Senrinona Young males

Radiotherapy (very radiosensitive)

Nonmetastatic prooptosis Pancreas Fulminant onset, short survival

Radiotherapy



18

GOLDBERG ET AL

Surv Ophthalmol 35 (1) July-August 1990

ble, however ; Mortada' 4N noted a 50% occurrence of cataract in 13 patients undergoing radiotherapy for orbital metastasis . As patients treated for orbital metastatic cancer continue to survive longer, we may begin to observe more ocular radiation complications . Still, because of its ability to ameliorate symptoms of otherwise untreatable orbital tumors, radiation therapy remains the mainstay of the treatment of orbital metastatic disease . B . HORMONAL THERAPY Certain cancers originating in organs that participate in hormonal axes have on their cell surfaces hormone receptors, and if these cancers remain fairly well differentiated, they may show a modulation of growth in response to therapeutic hormonal manipulation . The primary examples in the orbit are metastatic prostate and breast carcinoma . The presence of hormone receptors on the surface of these tumors can be detected and measured in the laboratory with adequate specimens of fresh tissue ; here the orbital surgeon can play a vital role by obtaining an adequate tissue specimen . Excellent results have been obtained with hormonal therapy of prostate and breast carcinoma metastatic to the orbit; particularly in the case of prostate carcinoma, virtual reversal of orbital symptoms and occasional longterm survival have been reported (Fig . 14) . 9.45 12 Diethylstilbestrol (DES), with or without orchiecmmy, has been the mainstay of hormonal therapy for prostate cancer since the 1950s ; more recently, specific luteinizing hormonereleasing hormone (LHRH) agonists have been introduced which may avoid the feminizing side effects of DES or orchiectomy . 109 The LHRH agonists do riot seem to offer improved palliation or survival over DES, however,' 09 and they are associated with an initial testosterone surge and tumor growth period of several weeks duration . This contraindicates their use in compressive spinal cord lesions and, therefore, presumably in compressive orbital apex lesions as well . Metastatic breast carcinoma is temporarily responsive to hormonal manipulation in the majority of cases ."' The importance of screening for estrogen receptors on tissue biopsy is illustrated by McGuire et al, who found that 55-60% of metastatic breast tumors with positive estrogen receptor (ER) are responsive to endocrine therapy ."' T he presence of progesterone receptor (PgR) adds even greater predictive value ."' C. CHEMOTHERAPY With the advent of more aggressive and specific chemotherapeutic protocols, chemotherapy for metastatic disease has become increasingly impor-

tant . Of the common metastases to the orbit, small cell carcinoma of the lung and neuroblastoma arc particularly chemosensitive . Chemotherapy often plays an important adjunctive role in palliative therapy of orbital metastases . D . SURGERY In general, patients with metastatic orbital tumors arc not candidates for therapeutic surgical intervention . Their disease is systemic, and radical surgery cannot offer a cure . Furthermore, radiotherapy and in some cases hormonal therapy offer alternative treatment modalities which often provide significant palliation . There are cases for which surgery is indicated . Metastatic carcinoid tumors are sometimes so slowly growing that for practical purposes they are isolated tumors . In these cases, excision of the metastatic tumor (along with the primary, if it can be found and safely excised) can provide longterm relief of symptoms and perhaps improved survival . Renal cell carcinoma may also present with solitary metastases 149 ' Y06 and although the prognosis is still rather poor, surgical excision may be indicated for apparently isolated orbital metastases . Some ntetastatic tumors produce intolerable symptoms, such as pain or gross proptosis ; if radiotherapy, chemotherapy or other medical approaches are unsuccessful at relieving symptoms, then surgical debulking may be indicated for palliation, despite the poor prognosis for survival .

V . Oncologic Considerations A. ORGAN SPECIFIC METASTASIS Throughout this review, we have touched on one of the most fascinating issues of cancer biology, the phenomenon of organ-specific metastasis . Why does breast carcinoma dominate orbital metastasis, while other common cancers, particularly of GI origin, are much less frequently observed at this site? What accounts for the tendency for tissue specific metastasis - for example, prostate to bone or melanoma to muscle? What causes breast carcinoma to lodge frequently in the choroid, when neuroblastoma, 5 Ewing's sarcoma"' and prostate metastases seem to lodge instead in the orbit? Three hypotheses have been advanced as explanations for organ specific metastasis : mechanical, seed and soil, and specific tumor cell adherence .'' 324 The mechanical theory ascribes organ specific metastasis to variations of blood flow and capillary sieving due to vascular architecture, phenomena said to explain left-sided dominance of orbital metastases . The seed and soil theory and the specific tumor cell adherence theory are similar in

TUMORS METASTATIC TO THE ORBIT

IU

Top left : A 65-year-old male with no previous history ofcancer presented with epiphora, ptosis, proptosis and displacement of the left globe, and a palpable mass in the left medial orbit . Top right: Coronal CT scan with c'onthast rcveals an anterior medial orbital mass surrounding the left globe . Orbital biopsy revealed adenocarcinoma . A large prostate gland was discovered on physical examination, and prostaticm biopsy revealed po o rly differentiated adenocarcinoma . Bottom : Clinical diethylstilbesterol . appearance following treatment Orbital mass is non palpable and ocular symptoms have largely resolved Current lollowup is 7 Nears, and the patient remains free of clinical reunrenca Fig. 14 .

with

that they hypothesize tumor cell-host tissue interactions of the mic oenvironment and of cell surface antigens, respectively, as the primary factors accounting for organ specific metastasis . A reccn review 121 documents experimental data regarding organ-specific metastasis, including recent characterization of surface carbohydrates, which may be the locus of host tissue-tumor cell recognition . It is likely that all three hypothesized mechanisms are responsible in some combination for organ or sit(, specific metastasis . B . METASTATIC CANCER OF UNKNOWN ORIGIN An important group of orbital metastases are those in patients with unknown primaries [11dc of the patients in the combined series (Fig . I)] . In large series with meLastatic cancer of unknown oilgin,"""'" over half the patients remained undiagnosed despite extensive investigations, and even autopsy was unsuccessful at diagnosing the primary As cancer in about 10`,'b to 30% of cases .' o , I- ' might be predicted, the tumors that are typically silent' -- metastasizing early in (heir course Comprise the majority of these unknown primaries ; 1 '11

",

lung, stomach, colon, pancreas, thyroid and ovarian cancers are common causes of( ryptic metastases .'"' Diagnostic efforts in this difficult group of patients ate best directed toward ruling out as efficiently as possible those cancers fill which there is reasonably effective treatment palliation .' °" Breast, prostate and endometrial cancers have the potential for successful palliation with hormonal therapy . Germ cell tumors, ivntphomas and leukemias can sometimes be virtually' cured with couabination therapy . Ovarian and small cell lung cancers have curative potential, and thyroid and pancreatic tumors can he successfully palliated . :1 thoughtfully directed oncologic workup can investigate these possibilities, while minimizing the need for timeconsuming, painful and potentially invasive tests in these patients, for whom the limited time remaining is of great importance . of

Vt . Summary Orbital tnetastase .s are a heterogenous group of neoplasms whose clinical behavior reflects to a large extent the biology of the underlying primary cancer and can be divided into four basic svudromes including ; mass, infiltrative, functional and inilam-



20

Surv Ophrhalmol 35 (1) ,July-August 1990

matory presentations ('Cable 5) . The clinical presentations of metastatic tumors are diverse, but some general trends help differentiate them from other orbital tumors . A history of cancer may be obtainable (sometimes requiring considerable diligence), but in many cases, the orbital symptoms are the first manifestation of systemic cancer . The onset of symptoms is typically rapid, unrelenting and progressive over a few weeks or months . Motility disturbance is common, sometimes out of proportion to the degree of proptosis . Pain, when present, often occurs early in the clinical course . Breast and other scirrhous carcinomas can present with a diagnostically challenging infiltrative syndrome, characterized by enophthalmos and limitation of eye movements ; these signs are easily overlooked or misinterpreted . Investigative goals include identification of the orbital tumor as a metastasis, and when possible without undue hardship to the patient, diagnosis of the underlying primary cancer . The ophthalmologist can play a role not only in the former, utilizing advanced imaging and needle or open biopsies where necessary, but in the latter by facilitating special histologic studies on orbital tissue . A multidisciplinary approach, with cooperation between the ophthalmologist, family doctor, pathologist, and oncologist is essential in proper diagnosis and management of this challenging group of patients . Treatment from an ophthalmologic standpoint includes preservation of vision and relief of pain . Radiotherapy and hormonal therapy can often achieve these goals, sometimes dramatically . Radical surgery is contraindicated except in extreme cases for palliative debulking, or in cases of unusual tumors such as carcinoid and renal carcinoma, which may have isolated metastases and offer potential for longterm cure via surgical excision . It is important to avoid a hopeless or helpless attitude ; with modern treatments, patients with metastatic cancer are surviving longer and virtual cures are occasionally possible . Even in patients with limited survival, preservation of vision has a dramatic impact on the quality of life . An awareness of the typical presentations of metastatic cancer to the orbit combined with a certain amount of clinical vigilance and diagnostic acumen can reward the clinician with some of the most satisfying patients and grate-

ful families encountered in the practice of ophthalmology .

References 1 . Abdalla Ml, Ghaly AF, Hosni F : Liposarcoma with orbital metastases : case report . Br j Ophihalmol 50:426428, 1966 2 . Adelstein FF., Schmidt W : Subre una metastasis tumoral (Melanoma cutanco maligno) en los musculos extrinsecos del cjo . Arch Soc Oftalmol Hisp Am 28 :752-756, 1968

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22

Surv Ophthalmol 35 (1) July-August 1990

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24

Surv Ophthalmol 3 .5 (1) July-August 1990

cell carcinoma- j Ural 111:836-838, 197.5 207 . '1 rukel SL, MUSK : Recognition and differential diagnosis of enlarged extraocular muscles in computed tomography . Am f Ophthalmol 87503-512, 1979 208 . Usui T, Ishibe T, Nihira H : Orbital metastasis from prostatic carcinoma . Br] Urol 47 :458, 1975 209. Van Arnam CE, Fine M : Orbital metastasis of renal carcinoma . Arch Ophthalmol 57:694-701, 1957 210. Van Buskirk EL : Adenoma of pancreas with orbital metastasis . Am J Ophthalmol 48 :107, 1959 211 . van Duyse U, Marbaix: Metastase ethmoido-orhitaire d'hypernephrome latent . Arch Ophiatmol 39:396-409, 1922 212 . Vancea P, Balan R : Metastatisches Adeno-Karzinom der Orhita . Klin Monatsbl Augneheilkd 142:308-314, 1963 213 . Vida LO, Binder PS : Simtiitaneous metastasis of skin melanoma to the eye and orbit . Ann Ophthalmol 10:431-433, 1978 214 . Vraher F, Zahn KZ : Metastasis of a malignant adenoma of the thyroid to the orbit . Ceskasloverw'ka OfMlmof 8: 140-145, 1952 215 . Whyte AM : Bronchogenie carcinoma metastasizing to the orbit. A case report . ./ Maxillofac Surg 6 :277-280, 1978 216. Winkler CF, Goodman GK, Eiferman RA, et al : Orbital metastasis from prostatic carcinoma : identification by an imnmnoperoxidase technique . Arch Ophthalmol 99:14061408, 1981 217 . Wintersteiner H : Kin pall von Augennmskelmetastasen nach Carcinoma ntamtnae . Min Monaisbl Augenheilkd 37: 331-338, 1899 218. Wolter JR, Hendrix RC : Osteoblastic prostate carcinoma metastatic to the orbit . Am f Ophihalmol 92:648-651, 1981 219. Woody JH, Geeraets WJ : Orbital metastasis of renal cell carcinoma . Eye Ear Nose Throat Man 45:90-93, 1966 220. Zizmor J, Fasano CV, Smith B, et al : Roentgenographic diagnosis of unilateral exophthalmos . JAMA 197 :343-346, 1966 221 . %uhler MA, Rivera R, Lane M : Hepatoma presenting as a retro-orbital metastasis . Confer 48:1883-1885, 1981

GOLDBERG ET AL C.

Prevalence of metastasis compared to other orbital diseases II . Clinical characteristics A. Relative prevalence of different primary types B . Lateralization C . Localization D . Timing of metastasis : known vs . occult primary E . Temporal characteristics F . Other concurrent metastases G . Symptoms and signs H . A simplification : syndromes of presentation . Mass presentation 1 2 . Infiltrative presentation 3 . Functional presentation 4 . Inflammatory presentation 5 . Silent presentation 6 . Discussion 1 . Misdiagnosis : Diagnostic pitfalls III . Diagnostic Modalities A. Physical examination B . Laboratory tests C . Computed tomography D . Needle biopsy E . Pathologic techniques IV . Treatment A . Radiotherapy B . Hormonal Therapy C . Chemotherapy D . Surgery V . Oncologic considerations A . Organ specific metastasis B . Metastatic cancer of unknown origin VI . Summary

Outline I . Prevalence A . Prevalence of orbital or ocular metastasis in patients with metastatic cancer B . Prevalence of orbital vs . ocular metastasis

Reprint requests to Robert A . Goldberg, MD, Jules Stein Eye Institute, Los Angeles, CA 90024-1771 .