Evaluation of Metastatic Cancer to the

Eye

Carcinoembryonic Antigen and Gamma Glutamyl Transpeptidase Joseph B. Michelson, MD;

Norman T.

Felberg, PhD; Jerry

\s=b\Plasma carcinoembryonic antigen (CEA) and gamma glutamyl transpeptidase (GTP) were studied in 24 patients with

cancer

metastatic to the uveal tract.

Eighty-three percent demonstrated elevated CEA levels, while only 36% (49 of 135 patients) with primary uveal melashowed elevated levels. While none of the uveal melanoma patients had a CEA value greater than 10 ng/ml, 58% (14) of the patients with metastatic tumors to the uvea had values greater than 10 ng/ml. Forty-six percent (11) of patients with metastatic tumors to the uvea demonstrated elevated GTP levels that correlated with documentation of liver metastases. Ninety-two percent of the patients with metastatic cancer to the uvea had either an elevated CEA or GTP level. When used together, plasma CEA and GTP levels appear to be helpful in differentiating metastatic tumors to the uvea from primary uveal melanomas. These assays also appear to be useful in determining tumor burden and concurrent hepatic involvement in patients with metastatic tumors to the uvea. noma

(Arch Ophthalmol 95:692-694, 1977)

A.

Shields, MD

One

of the most perplexing diagnostic problems in ophthalmology is the patient who presents with an amelanotic mass in the fundus for which the differential diagnosis includes amelanotic choroidal melanoma, metastatic cancer from an occult primary malignancy, and choroidal hemangioma.1 While the radioactive phosphorus uptake test is useful in discriminating between benign and malignant intraocular lesions, it can-

not differentiate between

primary

a

melanoma and a metastatic cancer to the choroid.-:| We recently reported a patient with colorectal adenocarcinoma metastatic to the choroid in whom an elevated plasma carcinoernbryonic antigen (CEA) level suggested the diagnosis, and whose choroidal tumor demonstrated a positive stain for CEA by an immunohistologic technique.' We subsequently demonstrated that over one half of patients with uveal melanoma have a normal CEA, and suggested that CEA might be of benefit in differentiating metastatic lesions to the uvea from primary uveal melanomas,1 but the number of patients with metastatic lesions was too small'' to be statisti-

for publication Oct 20, 1976. From the Department of Molecular Biology of the Research Institute (Drs Michelson and Felberg), and the Oncology Unit of the Retina Service (Dr Shields), Wills Eye Hospital and Research Institute, Philadelphia. Reprint requests to The Research Institute, Wills Eye Hospital, 1601 Spring Garden Street, Philadelphia, PA 19130 (Dr Felberg).

Accepted

'

cally significant.

Table 1.—CEA Distribution in Patients With Metastatic Cancer to the

Eye

% Patients With CEA levels _A_

0-2.5

2.6-50

5.1-10.0

>

10.0

ng/ml _Primary Site_No._ng/ml*_ng/ml_ng/ml Colorectal adenocarcinoma_4_0_0_0_100 Lung

cancer

4

0

0

25

75

Carcinomatosis 0 100 (unknown primary)_2_0_0 Breast Cutaneous melanoma_1_0_100_0_0 Metastatic cancers from all 10.3 Uveal melanoma 63.7 25.9 0 135t

cancer_13_30.8_15^4_1^4_38.5

sites_24_167_12J5_]2S_58.3

"Normal range." flncludes 56 patients described previously by Michelson

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et al 1976.''

Table 2.-GTP Level Distributions in Patients With Metastatic Tumors to the Eye* GTP level

Normalt

Elevated

7

1

1

8 P< .01

No liver métastases

Documented

liver métastases -

9.9199

*ln addition, follow up was lost on three Patients with elevated levels and four patients with normal levels. tin this laboratory, GTP values greater than 20 "J are considered elevated. (Normal control 10.3 ± 4.1 IU, 93.3% less than 20 IU) values -

o z

< tu

O

Table 3.—Incidence of Liver Métastases in Patients With Metastatic Cancer to the Eye.

Primary Slte

No.

Liver

Mor-

Metastasis»

talltyt

Colorectal adenocarcinoma

Lung cancer

Unknown

4_50% 4_75% 2

100%

10

75% 100%

100%

20

30 40 50

TIME

Breast_13_38%_0%

w

105

(DAYS)

Cutaneous

melanoma

All sites

1_100%

24

100% 42%

54%

"As detected by elevated GTP levels or patient

history.

tPercent patients deceased at Paper submitted for publication.

the time this

Chaimoff et al" recently demonstrated that an elevated gammaglu-

tamyl transpeptidase (GTP) level,

in

the absence of jaundice, suggests the

Presence of liver métastases. Munjal et alT suggest that GTP and other liver function enzymes, as well as CEA, are valuable collectively in increasing the accuracy of diagnosis in those patients w¡th liver metastasis from colorectal, 'ung, and breast carcinomas. Steele et alK and Cooper et al" have shown that elevated GTP levels indicate liver •ivolvement prior to clinical confirmation in patients with colorectal adenocarcinoma. This study describes the value of combined plasma CEA and GTP levels ln 24 patients whose first clinical Manifestation of metastatic disease •nvolved the uveal tract. METHOD

Plasma CEA

assays

were

performed by

the indirect and direct method, employing the CEA assay kit, which utilizes the

Serial CEA and GTP values for patients with metastatic cancers to the choroid. Open symbols—CEA values; closed symbols—GTP values. Squares—patient 1, breast cancer métastases; circles—patient 2, metastatic adenocarcinoma from an unknown primary source. Normal values are less than 2.5 mg/nl for CEA and less than 20 IU for SGTP.

Hansen zirconyl phosphate gel technique."' The GTP was assayed by the method of Szasz." All patients were referred to the Oncology Unit of the Retina Service, Wills Eye Hospital, and had a thorough ocular evaluation by one of the authors (J.A.S.). Patients were evaluated for liver metastases by one or more of the following: liver chemistries (alkaline phosphatase, SGPT, SGOT, and LDH), technetium Tc 99m liver scans, laparotomy, or post mortem examination.

RESULTS Of the 24 patients with metastatic tumors to the uvea, the primary site of the malignancy was as follows: breast (13); colorectal (4); lung (4); cutaneous melanoma (1); and unknown (2). For comparison, 135 uveal melanoma patients (including 56 from Michelson et al " ) were included. Plasma CEA values for these patients are presented in Table 1. Twenty (83%) of the patients with métastases to the uvea had elevated

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plasma CEA levels, in marked contrast to patients with primary uveal melanomas where only 36% had

elevated values. The distribution of patients with CEA values greater than 10 ng/ml shows a clear distinction between primary uveal melanoma (0%) and patients with metastases from all sites to the uveal tract (58%). Only four (17%) of the patients with métastases had normal CEA values, and all of these had primary breast cancer. There were 17 patients with metastatic tumor to the uvea whose clinical evaluation was sufficient to determine whether or not hepatic involvement was present (Table 2). Of the nine patients with liver métastases, eight had elevated GTP levels. Of eight patients who failed to demonstrate liver métastases, only one had elevated GTP levels, and this patient had breast cancer with CEA levels greater than 5,000 ng/ml, suggestive

of massive systemic involvement. The patient with liver involvement and normal GTP levels had breast cancer metastasis to bone, a palpable epigastric mass, and elevated alkaline phosphatase, SGOT and SGPT levels. When both CEA and GTP assays were used in combination, 22 (92%) of the patients with metastatic cancer to the eye had elevated levels in one or both tests. Of the two patients not detected by either test, one patient was a 28-year-old woman, who developed an intraocular lesion following bilateral breast cancer; the other a 66year-old woman patient with breast cancer metastatic to the eye alone. Neither patient showed liver metastases or other involvement, and both remain well following radiation therapy to the intraocular metastasis. Previous studies show the value of employing GTP as an aid in detecting liver métastases in patients with colorectal adenocarcinoma." ' " Our study confirms this view and adds further insight into the metastatic process. The Figure shows the development of elevated GTP levels in two patients. As CEA and GTP levels rose, LDH, alkaline phosphatase, and SGOT were also found to rise in one patient indicating progressive liver involvement.

COMMENT This study has indicated that plasma CEA and GTP levels may be of diagnostic and prognostic help in

patients

with

tumors to the

presumed metastatic Although inflam-

uvea.

mations of entodermal tissues (ulcerative colitis, pancreatitis, cirrhosis, etc) may yield CEA levels between 2.5 ng/ ml and 5 ng/ml, levels exceeding 10 ng/ml are more indicative of a cancerous process.'-'" Patients with metastatic disease from either breast or lung carcinoma are those most frequently seen by the ophthalmologist." While CEA may not be significantly elevated in breast and lung cancer patients until considerable distant tumor spread has occurred,'-'"'-'7 it is at this stage of metastasis that the patient consults the ophthalmologist. Nearly two thirds of the patients with metastasis in our series presented with CEA values greater than 10

ng/ml,

as

expected

widely

in

disseminated disease.1'' Prior to metastatic spread, patients with breast or lung carcinoma have lower CEA distributions than found in our

group.1"'--''"'"

The CEA levels could not be correlated with the degree of intraocular involvement with metastatic breast disease but may suggest the degree of spread to CEA synthesizing organs such as the liver. Our data show 58.3% of the patients with metastatic cancer to the eye had values greater than 10.0 ng/ml. However, no patients with primary uveal melanomas had values greater than 10.0 ng/ml. In patients with an intraocular tumor, a CEA value greater than 10 ng/ml suggests

Carcinoembryonic antigen (CEA) positive static adenocarcinoma of the choroid. Ophthalmol 93:794-796, 1975. 5. Michelson JB,

meta-

Arch

Felberg NT, Shields

Carcinoembryonic antigen:

JA: Its role in the evalua-

tion of intraocular malignant tumors. Arch

Ophthalmol 94:414-416,

1976. 6. Chaimoff C, Wolloch Y, Eichhorn F, et al: Gamma glutamyl transpeptidase as an aid in the

This investigation was supported in part Iff Public Health Service training «rant EY-00084 (J.H.M.), by Academic Career Development Award 5K07 EY-00032 (N.T.K.), Blomedlc« Research support grant FR5510, and The Retin* Research and Development Foundation of I''1'''

adelphia.

The CEA assays

t

were

performed by J-f'

Vandevoorde, PhD, and Connie Smith of

Hop kits

man-LaRoche, Inc. The CEA-Roche assay were provided by J. Synder of Holl'ma"' LaRoche, Inc, and Ruth Grevious provided secretarial aid.

References 1. Shields JA: The differential diagnosis of choroidal melanomas, in Peyman GA, et al (eds): Symposium on Intraocular Tumors. New York, Appleton, to be published. 2. Shields JA, Hagler WS, Federman JL, et al: The significance of the 32P uptake test in the diagnosis of posterior uveal melanomas. Trans Am Acad Ophthalmol Otolaryngol 79:297-306, 1975. 3. Shields JA, McDonald PR: Improvements in the diagnosis of posterior uveal melanoma. Arch Ophthalmol 91:259-264, 1974. 4. Michelson JB, Felberg NT, Shields, JA, et al:

that the lesion is a metastasis. Table 3 provides information on the metastatic process. When a patient presents with ocular métastases from an adenocarcinoma of the gastrointestinal tract (colorectal and unknown) or lung cancer, there is a good probability of hepatic involvement. Twothirds of the women presenting with breast cancer metastatic to the eye, however, have no liver métastases and no other clinically detectable lesions, suggesting that the choroid may be a favored site for the métastases from the breast. This information has obvious significance in determining survival of such patients. As seen in Table 3, there is a direct relationship between elevated GTP levels and mortality in these patients. The combined use of the CEA and GTP assays in evaluating the patient with an intraocular tumor is of value in (a) discriminating between primary amelanotic melanoma and metastatic tumor to the uvea, (b) evaluating the extent of tumor burden, (c) detecting secondary invasion to the liver, and hence (d) prognosis.

diagnosis of liver metastases. Israel Med Sci 11:781-784, 1975. 7. Munjal D, Chawla PL, Lokich JJ, et al: Carcinoembryonic antigen and phosphohexose isomerase, gamma glutamyl transpeptidase and lactate dehydrogenase levels in patients with and J

without liver metastases. Cancer 37:1800-1807, 1976. 8. Steele L, Cooper EH, Mackay AM, et al: Combination of carcinoembryonic antigen and gamma glutamyl transpeptidase in the study of the evolution of colorectal cancer. Br J Cancer 30:319-324, 1975. 9. Cooper EH, Turner R, Steele L, et al: The contribution of serum enzymes and carcinoembryonic antigen to the early diagnosis of metastatic colorectal cancer. Br J Cancer 31:111-117, 1975. 10. Hansen HJ, Lance KP, Krupey J: Demonstration of an ion-sensitive antigenic site on

carcinoembryonic antigen using Zirconyl phosphate gel. Clin Res 19:143, 1971.

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11. Szasz G: A kinetic photometric method for gamma glutamyl transpeptidase. Clin Chem 15:124-136, 1969. 12. Martin EW Jr, Kibbey WE, DiVecchia L, et al. Carcinoembryonic antigen, clinical and historical aspects. Cancer 37:62-81, 1976. 13. McCartney WH, Hoffer PB: Carcinoembryonic antigen assay in hepatic metastases detection. JAMA 236:1023-1027, 1976. 14. Ferry AP, Font FL: Carcinoma metastatic to the eye and orbit. Arch Ophthalmol 92:276-286, 1974. 15. Hansen JH, Snyder JJ, et al: Carcinoembryonic antigen (CEA) assay: A laboratory adjunct in the diagnosis and management of cancer. Human Pathol 5:139-147, 1974. 16. Vincent RG, Chu TM: antigen in patients with carcinoma of the lung. Thorac Cardiovasc Surg 66:320-328, 1973. 17. Reynoso G, Chu FM, Holyoke JM, et al: Carcinoembryonic antigen in patients with different cancers. JAMA 220:361-365, 1972. serum

Carcinoembryonic J

Evaluation of metastatic cancer to the eye. Carcinoembryonic antigen and gamma glutamyl transpeptidase.

Evaluation of Metastatic Cancer to the Eye Carcinoembryonic Antigen and Gamma Glutamyl Transpeptidase Joseph B. Michelson, MD; Norman T. Felberg,...
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