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Hepatoma Metastatic to the Orbit
HEPATOMA METASTATIC TO THE ORBIT JANE R. LUBIN, M.D., ARTHUR S. GROVE, JR., M.D., Z. NICHOLAS ZAKOV, M.D., AND DANIEL M. ALBERT, M.D. Boston, Massachusetts
Cases of hepatoma metastatic to the eye are rare. Bock! published the first case report of a hepatocellular carcinoma metastatic to the choroid in 1885. A clinically deep green lesion of the fundus, which looked like hepatoma histologically, was proven chemically to secrete biliverdin. No description of the primary tumor was included. In a second reported case," pathologic examination was not performed. Oatrnan" described a case of a 56-year-old man with a primary liver adenocarcinoma metastatic to the choroid, optic nerve, and sclera. Orbital involvement in this case was presumably by direct extension from the choroidal mass. The involved eye showed a detached retina and secondary glaucoma. Metastases from the liver tumor were also found in the lungs, spleen, kidney, and lymph nodes. The diagnosis was made at autopsy. Taake, Allen, and Straatsma" described a hepatoma metastatic to the choroid with extensive pathologic documentation. Several clinically diagnosed cases of hepatoma metastatic to the orbit have been described. In Mortada's" series of eight cases of orbital metastasis, a 40year-old woman had right proptosis, with a superior rectus metastasis from a bile duct type carcinoma of the liver, with no evidence of tumor by skull x-ray and From the Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts. This study was supported in part by National Institutes of Health Training Grant EY00089-05 (Dr. Lubin). Reprint requests to Daniel M. Albert, M.D., Howe Laboratory of Ophthalmology, Massachusetts Eye and Ear Infirmary, 243 Charles St., Boston, MA 02114. 268
orbital films; therefore, this was probably not an extension from a cerebral metastasis. He gave no histologic confirmation of the diagnosis. jensen," in his Danish study, also stated that he had seen such a case. To date, there have been no published reports of a histologically proven hepatocellular carcinoma metastatic to the orbit. Hepatomas do not occur often in the United States population. Becker? reported the incidence by autopsy studies to be 0.1 to 0.7% of all tumors. High-risk areas of the world include Southeast Asia and the sub-Sahara area. This high incidence is thought to be related to such factors as malnutrition, parasitic infestation, excess iron intake, amebiasis, and most recently, aflatoxin, a fungal product of Aspergillus flavus. However, in the United States, the incidence of hepatoma is clearly related to the intake of alcohol and the presence of cirrhosis, particularly the macronodular variety. Of patients with cirrhosis, 4 to 6% eventually develop hepatoma," and conversely, 85.4% of patients with hepatoma also have cirrhosis. In patients with hemochromatosis (in which cirrhosis eventually develops), the incidence of hepatoma is twice that in patients with cirrhosis only. It was recently noted" that 31.7% of patients with hepatoma also have hepatitis B-associated antigen. Patients with alpha-I antitrypsin deficiency also seem more likely to develop hepatoma than the general population. Only 15 to 25% of liver tumors are of bile duct origin. The rest are of liver parenchymal origin, with variable degrees of anaplastic appearing cells. Hepatoma most commonly metastasizes to the lung (34 of 41), brain (four of 41), and bone (14
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Fig. 1 (Lubin and associates). Left, Initial presentation of the patient, showing right proptosis. Right, View of right proptosis from above.
of 41).10 Recently, a case of hepatocellular carcinoma with metastasis to the jaw was reported, which manifested as a draining sinus.'! We describe herein the case of a man with a history of cirrhosis of the liver and unilateral progressive right proptosis. A diagnosis of hepatocellular carcinoma was made. To the best of our knowledge, this is the first histologically proven case of hepatoma metastatic to the orbit. CASE REPORT A 69-year-old man, born in Georgia, with a history of excessive alcohol intake, tuberculosis treated with isoniazid and ethambutol, and a history of latent syphilis, carne here with slowly progressive right proptosis of three to four months' duration (Fig. 1). The patient had no other complaints. Physical examination revealed an alert man with proptosis of the right eye. The best corrected visual acuity was counting fingers at three feet in both eyes, and no cranial nerve palsies were noted. His neck was supple; no lymphadenopathy was evident. Lungs were clear. Auscultation of the heart revealed a grade 2/6 systolic murmur. His abdomen was soft, with some tenderness in the right upper quadrant, without rebound. The liver edge was palpable 3 ern below the right costal margin, and was firm and nodular. This finding had been unchanged since 1971. His extremities showed minimal clubbing of the fingers. Results of laboratory studies included the following: hemoglobin, 10.8 g/100 rnl, white blood cell count, 19.6 cells/mm", 85% polymorphonuclear leukocytes, one band, five lymphocytes, one monocyte; blood urea nitrogen, 8 mg/loo ml, creatinine, 0.7 mg/IOO ml, blood glucose, 100 mg/l00 ml; total bilirubin, 0.7 mg/l00 ml, direct bilirubin, 0.3 mg/l00 ml; serum glutamic-oxaloacetic transaminase, 24 IU/I; alkaline phosphatase, 30 IU/I; lactic dehydrogenase, 100 lU/I; 5' nucleotidase, 1.7 lUI 100 ml (all within normal limits); total protein, 8.3 g/100 ml; albumin 3..'3 g/IOO ml, globulin slightly high at 5.0 g/IOO ml, calcium and phosphorus, normal. No alpha-fetoprotein was detected in the patient's serum. Orbital ultrasonography (Fig. 2) revealed a superior posterior mass with good sound transmission,
suggesting a cystic orbital tumor or necrotic mass. Best corrected visual acuity was recorded in the chart 25 years ago as 6/60 (20/200) in both eyes (diagnosed as primary optic atrophy), and on recent examination, visual acuity was counting fingers at three feet bilaterally. Fluorescein angiography (Fig. 3) disclosed an area of alternating hyperfluorescence and hypofluorescence, typical of choroidal folds, superotemporal to the disk, without leakage or staining of fluorescein. Computed axial tomography (Fig. 4) revealed a right intraorbital mass, extraconal in location, displacing the globe laterally and inferiorly, without evidence to suggest bone erosion either adjacent to. or distant from, the orbital mass. Supra- and infratentorial regions were normal. Sinus and skull films gave the impression of a soft tissue swelling over the right orbit, with destruction of the medial portion of the orbital rim and increased density in the right frontal sinus. Biopsy of the orbital mass revealed a solid tumor, diagnosed histologically as hepatoma based on the following. the cord-like arrangement of the cells, the basement membrane lining these cords in some areas with poorly defined endothelial cell lining, the abundant granular eosinophilic cytoplasm, and the presence of glycogen granules on PAS stain. Seven years before admission, the patient had had a barium enema that revealed only colonic polyps.
Fig. 2 (Lubin and associates). Orbital ultrasonography reveals superior posterior mass (arrow) having an intraconal location, with good sound transmission.
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Fig. 4 (Lubin and associates). Computed tomography scan showing extraconal mass (arrow) displacing the globe laterally and inferiorly, with no evidence of bone destruction. Fig. 3 (Lubin and associates). Fluorescein angiogram showing choroidal folds superoternporally without leakage or staining of the dye.
Results of an upper gastrointestinal series were negative. Intravenous pyelogram was read as compatible with medullary sponge kidney or papillary necrosis. Also noted was a calyceal diverticulum in the right upper pole. Because of long-standing hepatomegaly and anemia, the patient at that time also had a liver biopsy, which showed portal infiltrates of lymphocytes, occasional plasma cells and macrophages, and a parenchyma with focal hepatic cell necrosis with inflammatory cell infiltrates. In focal areas, the portal zones suggested early fibrosis. These findings are consistent with early Laennec's cirrhosis. No evidence of tumor was found. The patient underwent tests to locate primary tumor. Results of a barium enema and upper gastrointestinal study were negative. Intravenous pyelogram revealed a calcified right upper lobe abnormality, a cold abscess with central calcifications, strongly suggestive of renal tuberculosis, but malignancy could not be eliminated. Liver-spleen scan was consistent with hepatocellular disease, although a few ill-defined filling defects were noted in the right lobe. The spleen was slightly enlarged. Bone scan showed focal areas of increased activity in the femurs (matching areas of destructive lesions on x-ray). No abnormal activity was noted in the skull. Chest x-ray showed fractures of the sixth and eighth ribs, without a history of trauma. The patient developed fever, abdominal pain, nausea, and vomiting. Plain films of the abdomen revealed calcified right upper quadrant stones, and a diagnosis of acute cholecystitis was made. The patient was taken to the operating room for cholecystectomy. Exploratory laparotomy revealed a normal stomach, small bowel and colon, and an enlarged but otherwise normal spleen. The liver was small and contained nodules of hepatic tissue. A 2.5 x 3-cm white nodule was discovered on the underside
of the caudate lobe of the liver. A biopsy specimen was taken of the nodule. A urologic surgeon examined the right upper lobe of the kidney for the possibility of extension of tumor into the liver from this source. The kidney was normal. No biopsy specimen was taken. Histologic sections of the liver biopsy specimen and orbital mass (Figs. 5 and 6) showed similar findings. The wedge of liver tumor showed cells arranged in cords, two to three cells wide. These trabeculae were ill-defined, but in places, a thin basement membrane could be discerned covering the bands of cells. Endothelial cells lined the sinuses. The cells were variable in size, with large, hyperchromatic nuclei, prominent nucleoli, and abundant granular eosinophilic cytoplasm with areas of hyaline material, probably representing Mallory's hyaline.t" No area of normal hepatic parenchyma accompanied the specimen. The orbital
Fig. 5 (Lubin and associates). Liver biopsy showing the characteristic features of hepatoma; cords of atypical parenchymal cells with hyperchromatic nuclei, and abundant granular eosinophilic cytoplasm. Mallory bodies are seen (arrowhead) (hematoxylin and eosin, x470).
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Fig. 6 (Lubin and associates). Orbital biopsy showing the same features seen in Figure 5, but with somewhat more anaplastic appearing cells, more marked and atypical. Areas of basement membrane with endothelial cell lining can be seen (arrowhead) (Masson trichrome, x470). specimen showed more bizarre, variably sized cells than the liver nodule. More atypical mitoses were noted. Trabeculae were even less well defined, and there were only traces of basement membrane, with little evidence of an endothelial lining. Periodic acid-Schiff staining revealed the presence of glycogen granules. No bile staining was seen on either specimen, and there was no calcification of stroma. Electron microscopy was done on the orbital tumor, which showed abundant glycogen, mitochondria, and endoplasmic reticulum in the cytoplasm, and the presence of poorly defined basement membrane-lined sinuses with endothelial cells, confirming the diagnosis of hepatoma. Palliative radiotherapy only was given. The patient received 3,000 rads in two weeks to the right orbit. No chemotherapy was given at the patient's request. The orbital mass regressed significantly after completion of the course of radiotherapy.
DISCUSSION Although brain metastases from hepatocellular carcinoma are relatively common and this tumor tends to metastasize to the flat bones of the jaw and skull, this case is unusual because it metastasized to the orbit. No evidence could be found by computed axial tomography scan, bone scan, or orbital roentgenography that this orbital mass originated from a bone metastasis. Erosion around the orbital rim was thought to be secondary to the expanding nature of the lesion. Although no histologically proven cases of this nature appear in published reports, we have re-
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cently heard of a similar case from Houston, Texas, with exophthalmos as the initial symptom of a hepatoma (Richard T. May, M.D., personal communication, May 1978). Metastasis of tumors to the orbit occurs much less frequently than metastasis to the globe. Pathologic series by Hart.P jensen," and Bloch and Cartner'" have confirmed the clinical observation that the incidence of involvement of metastatic carcinoma to the orbit is one-fifth that of metastatic carcinoma to the eye. In his survey of published reports, Rose1 5 found only 51 reports of metastatic carcinoma to the orbit before 1965. Since 1950, 61 patients with metastases to the orbit and eyelid have been described.t" In contrast, by 1936, Lemoine and Mclseod!? had already found 230 reports of patients with carcinoma metastatic to the eye. From another point of view, metastatic carcinoma rarely appears as an expanding lesion of the orbit producing exophthalmos. In his series of 230 consecutive patients with exophthalmos, MOSS18 found only one patient who had a metastatic carcinoma to the orbit. Silva'" reported a similar series of 300 consecutive patients with clinical exophthalmos. When surgical biopsy specimens were taken only seven of them had metastatic carcinoma (incidence = 2.3%). Reese,2o in a series of 877 consecutive cases of orbital neoplasms, found 29 to be metastatic in nature (incidence = 3%). Henderson-! reported from the Mayo Clinic series (1948 to 1966) a total of 32 metastatic carcinomas among 465 orbital tumors (incidence = 7%). In 1953, Ingalls 22 had 216 patients with tumors (and pseudotumors) of the orbit, and found three to be of metastatic origin. Spaeth,23 in a statistical analysis of 170 cases of ocular malignancy, included four patients with ocular metastasis from distant primaries. Recently, Font and F erry24 studied 227 cases of carcinoma
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metastatic to the eye and adnexae from the Armed Forces Institute of Pathology files, and among these cases, found 28 that were metastatic to the orbit. The ratio of ocular to orbital involvement was 7:1 (or an incidence of 12%). Most authors agree 6,16.24 that the most frequent sites of origin for metastatic carcinoma to the eye and ocular adnexae include the following: (1) breast, and (2) lung, with genitourinary tract and gastrointestinal tract also common primary sites. However, a wide range of primary tumors may metastasize to the eye. The eye or orbit may not infrequently be the first site of malignant spread, and ocular symptoms occasionally precede the diagnosis of primary tumor. In 60% (17 of 28) of cases in Font and Ferry's series,24 orbital symptoms preceded the symptoms of the primary lesion. This was also true in our case. Font and Ferry'" found immediate symptoms of orbital metastasis of carcinoma, in order of frequency, to include the following: exophthalmos, 75%; pain, 29%; decreased vision, 29%; periorbital swelling, 25%; a visible mass, 21%; and ophthalmoplegia and diplopia, 18%. They found no preponderance of either left- or right-sided orbital metastases. Of the eye and adnexae, the orbit is the second most frequent site of involvement by metastatic carcinoma (after the posterior segment of the eye).24 The orbital muscles are the usual site,2S and less commonly, the orbital bones. SUMMARY
A 69-year-old man with a history of cirrhosis of the liver had unilateral progressive proptosis without jaundice, abdominal pain, or gastrointestinal symptoms. Results of laboratory and radiographic studies were also normal. Orbital biopsy revealed hepatocellular carcinoma. Although hepatocellular carcinoma
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has often been shown to metastasize to the brain and often to the flat bones of the skull, to the best of our know ledge, this is the first histologically proven case of hepatoma metastatic to the orbit. REFERENCES 1. Bock, E.: Ueber einen sarckomartigen biliverdin enthaltenden tumor der choroidea. Virchow's Arch. [Pathol. Anat.] 91:442, 1883. 2. Kaemerer, G.: Metastatischer Aderhautskrebs bei primaren Krebs der Leber. Korrespondensblatt der arztlichen ver Thuringen 27:62, 1898. 3. Oatman, E. L.: Metastatic carcinoma of the choroid. Am. J. Med. Sci. 151:375, 1903. 4. Taake, W. H., Allen, R. A., and Straatsma, B. R.: Metastasis of a hepatoma to the choroid. Am. J. Ophthalmol. 56:208, 1963. 5. Mortada, A.: Roentgenography in orbital metastases with exophthalmos. Am. J. Ophthalmol. 65:48, 1968. 6. Jensen, O. A.: Metastatic tumors of the eye and orbit. A histopathological analysis of a Danish series. Acta Pathol. Microbiol. Scand. (Suppl.) 212: 201,1970. 7. Becker, F.: Hepatoma. Nature's tumor model. Am. J. Pathol. 74:179,1974. 8. Anderson, W. A. D., and Kissane, J. M.: Pathology. St. Louis, C. V. Mosby Co., 1977, pp. 1412-1417. 9. Balasegaramm, M.: Management of primary liver cell carcinoma. Am. J. Surg. 130:33, 1975. 10. El-Demeni, A. A., Huros, A. B., Goldsmith, H., and Foote, F. W.: Primary malignant tumors of the liver. Cancer 27:7, 1971. 11. Muldoon, C. J.: A hepatocarcinoma with osseous metastases. J. Laryngol. Otol. 88:891, 1974. 12. Smetana, C., Cyorkey, F., Cyorkey, P., and Busch, H.: Studies on nucleoli and cytoplasmic fibrillar bodies of human hepatocellular carcinomas. Cancer Res. 32:925, 1972. 13. Hart, W. M.: Metastatic carcinoma to the eye and orbit. Int. Ophthalmol. Clin. 2:465, 1962. 14. Bloch, R. S., and Gartner, S.: The incidence of ocular metastatic carcinoma. Arch. Ophthalrnol. 85: 673, 1971. 15. Rose, A. M.: Die orbita als Absiedlungsort von Mahgnomen. Klin. Monastbl. Augenheilkd. 147:857, 1965. 16. Albert, D. M., Rubenstein, R. A., and Scheie, H. G.: Tumor metastasis to the eye. 1. Incidence in 213 adult patients with generalized malignancy. Am. J. Ophthalmol. 63:723, 1967. 17. Lemoine, A. N., and McLeod, J.: Bilateral metastatic carcinoma of the choroid. Successful roentgen treatment of one eye. Arch. Ophthalmol. 16:804, 1936. 18. Moss, H. M.: Expanding lesions of the orbit. A clinical study of 230 consecutive cases. Am. J. Ophthalmol. 54:761, 1962.
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19. Silva, D.: Orbital tumors. Am. J. Ophthalmol, 65:318, 1968. 20. Reese, A. B.: Tumors of the Eye, 3rd ed. New York, Harper and Row, 1976, pp. 529-536. 21. Henderson, T. W.: Orbital Tumors. Philadelphia, W. B. Saunders Co., 1973, pp. 474-494. 22. Ingalls, R. B.: Tumors of the Orbit. Springfield, Charles C Thomas, 1953, p. 410. 23. Spaeth, E. B.: Ocular tumors. Arch. Ophthalmol. 46:421, 1951.
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24. Font, R. L., and Ferry, A. P.: Carcinoma metastatic to the eye and orbit. Cancer 38: 1326, 1976. 25. Bedford, P. D., and Daniel, P. M.: Discrete carcinomatous metastases in the extrinsic ocular muscles. A case of carcinoma of the breast with exophthalmic ophthalmoplegia. Am. J. Ophthalmol. 49:723, 1960.
OPHTHALMIC MINIATURE
The enemy were so frightened when they saw me, that they leaped out of their ships and swam to shore; I then took my tackling, and fastening a hook to the hole at the prow of each, I tied all the cords together at the end. While I was thus employed, the enemy discharged several thousand arrows, many of which stuck in my hands and face; and, besides the excessive smart, gave much disturbance in my work. My greatest apprehension was for mine eyes, which I should have infallibly lost, if I had not suddenly thought of an expedient. I kept, among other little necessities, a pair of spectacles, in a private pocket which, as I observed before, had escaped the Emperor's searchers. These I took out, and fastened as strongly as I could upon my nose, and thus armed, went on boldly with my work, in spite of the enemy's arrows, many of which struck against the glasses of my spectacles, but without any effect other than a little to discompose them. ]ohnathan Swift, A Voyage To Lilliput
Cases of hepatoma metastatic to the eye are rare. Bock! published the first case report of a hepatocellular carcinoma metastatic to the choroid in 1885. A clinically deep green lesion of the fundus, which looked like hepatoma histologically, was proven chemically to secrete biliverdin. No description of the primary tumor was included. In a second reported case," pathologic examination was not performed. Oatrnan" described a case of a 56-year-old man with a primary liver adenocarcinoma metastatic to the choroid, optic nerve, and sclera. Orbital involvement in this case was presumably by direct extension from the choroidal mass. The involved eye showed a detached retina and secondary glaucoma. Metastases from the liver tumor were also found in the lungs, spleen, kidney, and lymph nodes. The diagnosis was made at autopsy. Taake, Allen, and Straatsma" described a hepatoma metastatic to the choroid with extensive pathologic documentation. Several clinically diagnosed cases of hepatoma metastatic to the orbit have been described. In Mortada's" series of eight cases of orbital metastasis, a 40year-old woman had right proptosis, with a superior rectus metastasis from a bile duct type carcinoma of the liver, with no evidence of tumor by skull x-ray and From the Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts. This study was supported in part by National Institutes of Health Training Grant EY00089-05 (Dr. Lubin). Reprint requests to Daniel M. Albert, M.D., Howe Laboratory of Ophthalmology, Massachusetts Eye and Ear Infirmary, 243 Charles St., Boston, MA 02114. 268
orbital films; therefore, this was probably not an extension from a cerebral metastasis. He gave no histologic confirmation of the diagnosis. jensen," in his Danish study, also stated that he had seen such a case. To date, there have been no published reports of a histologically proven hepatocellular carcinoma metastatic to the orbit. Hepatomas do not occur often in the United States population. Becker? reported the incidence by autopsy studies to be 0.1 to 0.7% of all tumors. High-risk areas of the world include Southeast Asia and the sub-Sahara area. This high incidence is thought to be related to such factors as malnutrition, parasitic infestation, excess iron intake, amebiasis, and most recently, aflatoxin, a fungal product of Aspergillus flavus. However, in the United States, the incidence of hepatoma is clearly related to the intake of alcohol and the presence of cirrhosis, particularly the macronodular variety. Of patients with cirrhosis, 4 to 6% eventually develop hepatoma," and conversely, 85.4% of patients with hepatoma also have cirrhosis. In patients with hemochromatosis (in which cirrhosis eventually develops), the incidence of hepatoma is twice that in patients with cirrhosis only. It was recently noted" that 31.7% of patients with hepatoma also have hepatitis B-associated antigen. Patients with alpha-I antitrypsin deficiency also seem more likely to develop hepatoma than the general population. Only 15 to 25% of liver tumors are of bile duct origin. The rest are of liver parenchymal origin, with variable degrees of anaplastic appearing cells. Hepatoma most commonly metastasizes to the lung (34 of 41), brain (four of 41), and bone (14
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Fig. 1 (Lubin and associates). Left, Initial presentation of the patient, showing right proptosis. Right, View of right proptosis from above.
of 41).10 Recently, a case of hepatocellular carcinoma with metastasis to the jaw was reported, which manifested as a draining sinus.'! We describe herein the case of a man with a history of cirrhosis of the liver and unilateral progressive right proptosis. A diagnosis of hepatocellular carcinoma was made. To the best of our knowledge, this is the first histologically proven case of hepatoma metastatic to the orbit. CASE REPORT A 69-year-old man, born in Georgia, with a history of excessive alcohol intake, tuberculosis treated with isoniazid and ethambutol, and a history of latent syphilis, carne here with slowly progressive right proptosis of three to four months' duration (Fig. 1). The patient had no other complaints. Physical examination revealed an alert man with proptosis of the right eye. The best corrected visual acuity was counting fingers at three feet in both eyes, and no cranial nerve palsies were noted. His neck was supple; no lymphadenopathy was evident. Lungs were clear. Auscultation of the heart revealed a grade 2/6 systolic murmur. His abdomen was soft, with some tenderness in the right upper quadrant, without rebound. The liver edge was palpable 3 ern below the right costal margin, and was firm and nodular. This finding had been unchanged since 1971. His extremities showed minimal clubbing of the fingers. Results of laboratory studies included the following: hemoglobin, 10.8 g/100 rnl, white blood cell count, 19.6 cells/mm", 85% polymorphonuclear leukocytes, one band, five lymphocytes, one monocyte; blood urea nitrogen, 8 mg/loo ml, creatinine, 0.7 mg/IOO ml, blood glucose, 100 mg/l00 ml; total bilirubin, 0.7 mg/l00 ml, direct bilirubin, 0.3 mg/l00 ml; serum glutamic-oxaloacetic transaminase, 24 IU/I; alkaline phosphatase, 30 IU/I; lactic dehydrogenase, 100 lU/I; 5' nucleotidase, 1.7 lUI 100 ml (all within normal limits); total protein, 8.3 g/100 ml; albumin 3..'3 g/IOO ml, globulin slightly high at 5.0 g/IOO ml, calcium and phosphorus, normal. No alpha-fetoprotein was detected in the patient's serum. Orbital ultrasonography (Fig. 2) revealed a superior posterior mass with good sound transmission,
suggesting a cystic orbital tumor or necrotic mass. Best corrected visual acuity was recorded in the chart 25 years ago as 6/60 (20/200) in both eyes (diagnosed as primary optic atrophy), and on recent examination, visual acuity was counting fingers at three feet bilaterally. Fluorescein angiography (Fig. 3) disclosed an area of alternating hyperfluorescence and hypofluorescence, typical of choroidal folds, superotemporal to the disk, without leakage or staining of fluorescein. Computed axial tomography (Fig. 4) revealed a right intraorbital mass, extraconal in location, displacing the globe laterally and inferiorly, without evidence to suggest bone erosion either adjacent to. or distant from, the orbital mass. Supra- and infratentorial regions were normal. Sinus and skull films gave the impression of a soft tissue swelling over the right orbit, with destruction of the medial portion of the orbital rim and increased density in the right frontal sinus. Biopsy of the orbital mass revealed a solid tumor, diagnosed histologically as hepatoma based on the following. the cord-like arrangement of the cells, the basement membrane lining these cords in some areas with poorly defined endothelial cell lining, the abundant granular eosinophilic cytoplasm, and the presence of glycogen granules on PAS stain. Seven years before admission, the patient had had a barium enema that revealed only colonic polyps.
Fig. 2 (Lubin and associates). Orbital ultrasonography reveals superior posterior mass (arrow) having an intraconal location, with good sound transmission.
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Fig. 4 (Lubin and associates). Computed tomography scan showing extraconal mass (arrow) displacing the globe laterally and inferiorly, with no evidence of bone destruction. Fig. 3 (Lubin and associates). Fluorescein angiogram showing choroidal folds superoternporally without leakage or staining of the dye.
Results of an upper gastrointestinal series were negative. Intravenous pyelogram was read as compatible with medullary sponge kidney or papillary necrosis. Also noted was a calyceal diverticulum in the right upper pole. Because of long-standing hepatomegaly and anemia, the patient at that time also had a liver biopsy, which showed portal infiltrates of lymphocytes, occasional plasma cells and macrophages, and a parenchyma with focal hepatic cell necrosis with inflammatory cell infiltrates. In focal areas, the portal zones suggested early fibrosis. These findings are consistent with early Laennec's cirrhosis. No evidence of tumor was found. The patient underwent tests to locate primary tumor. Results of a barium enema and upper gastrointestinal study were negative. Intravenous pyelogram revealed a calcified right upper lobe abnormality, a cold abscess with central calcifications, strongly suggestive of renal tuberculosis, but malignancy could not be eliminated. Liver-spleen scan was consistent with hepatocellular disease, although a few ill-defined filling defects were noted in the right lobe. The spleen was slightly enlarged. Bone scan showed focal areas of increased activity in the femurs (matching areas of destructive lesions on x-ray). No abnormal activity was noted in the skull. Chest x-ray showed fractures of the sixth and eighth ribs, without a history of trauma. The patient developed fever, abdominal pain, nausea, and vomiting. Plain films of the abdomen revealed calcified right upper quadrant stones, and a diagnosis of acute cholecystitis was made. The patient was taken to the operating room for cholecystectomy. Exploratory laparotomy revealed a normal stomach, small bowel and colon, and an enlarged but otherwise normal spleen. The liver was small and contained nodules of hepatic tissue. A 2.5 x 3-cm white nodule was discovered on the underside
of the caudate lobe of the liver. A biopsy specimen was taken of the nodule. A urologic surgeon examined the right upper lobe of the kidney for the possibility of extension of tumor into the liver from this source. The kidney was normal. No biopsy specimen was taken. Histologic sections of the liver biopsy specimen and orbital mass (Figs. 5 and 6) showed similar findings. The wedge of liver tumor showed cells arranged in cords, two to three cells wide. These trabeculae were ill-defined, but in places, a thin basement membrane could be discerned covering the bands of cells. Endothelial cells lined the sinuses. The cells were variable in size, with large, hyperchromatic nuclei, prominent nucleoli, and abundant granular eosinophilic cytoplasm with areas of hyaline material, probably representing Mallory's hyaline.t" No area of normal hepatic parenchyma accompanied the specimen. The orbital
Fig. 5 (Lubin and associates). Liver biopsy showing the characteristic features of hepatoma; cords of atypical parenchymal cells with hyperchromatic nuclei, and abundant granular eosinophilic cytoplasm. Mallory bodies are seen (arrowhead) (hematoxylin and eosin, x470).
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Fig. 6 (Lubin and associates). Orbital biopsy showing the same features seen in Figure 5, but with somewhat more anaplastic appearing cells, more marked and atypical. Areas of basement membrane with endothelial cell lining can be seen (arrowhead) (Masson trichrome, x470). specimen showed more bizarre, variably sized cells than the liver nodule. More atypical mitoses were noted. Trabeculae were even less well defined, and there were only traces of basement membrane, with little evidence of an endothelial lining. Periodic acid-Schiff staining revealed the presence of glycogen granules. No bile staining was seen on either specimen, and there was no calcification of stroma. Electron microscopy was done on the orbital tumor, which showed abundant glycogen, mitochondria, and endoplasmic reticulum in the cytoplasm, and the presence of poorly defined basement membrane-lined sinuses with endothelial cells, confirming the diagnosis of hepatoma. Palliative radiotherapy only was given. The patient received 3,000 rads in two weeks to the right orbit. No chemotherapy was given at the patient's request. The orbital mass regressed significantly after completion of the course of radiotherapy.
DISCUSSION Although brain metastases from hepatocellular carcinoma are relatively common and this tumor tends to metastasize to the flat bones of the jaw and skull, this case is unusual because it metastasized to the orbit. No evidence could be found by computed axial tomography scan, bone scan, or orbital roentgenography that this orbital mass originated from a bone metastasis. Erosion around the orbital rim was thought to be secondary to the expanding nature of the lesion. Although no histologically proven cases of this nature appear in published reports, we have re-
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cently heard of a similar case from Houston, Texas, with exophthalmos as the initial symptom of a hepatoma (Richard T. May, M.D., personal communication, May 1978). Metastasis of tumors to the orbit occurs much less frequently than metastasis to the globe. Pathologic series by Hart.P jensen," and Bloch and Cartner'" have confirmed the clinical observation that the incidence of involvement of metastatic carcinoma to the orbit is one-fifth that of metastatic carcinoma to the eye. In his survey of published reports, Rose1 5 found only 51 reports of metastatic carcinoma to the orbit before 1965. Since 1950, 61 patients with metastases to the orbit and eyelid have been described.t" In contrast, by 1936, Lemoine and Mclseod!? had already found 230 reports of patients with carcinoma metastatic to the eye. From another point of view, metastatic carcinoma rarely appears as an expanding lesion of the orbit producing exophthalmos. In his series of 230 consecutive patients with exophthalmos, MOSS18 found only one patient who had a metastatic carcinoma to the orbit. Silva'" reported a similar series of 300 consecutive patients with clinical exophthalmos. When surgical biopsy specimens were taken only seven of them had metastatic carcinoma (incidence = 2.3%). Reese,2o in a series of 877 consecutive cases of orbital neoplasms, found 29 to be metastatic in nature (incidence = 3%). Henderson-! reported from the Mayo Clinic series (1948 to 1966) a total of 32 metastatic carcinomas among 465 orbital tumors (incidence = 7%). In 1953, Ingalls 22 had 216 patients with tumors (and pseudotumors) of the orbit, and found three to be of metastatic origin. Spaeth,23 in a statistical analysis of 170 cases of ocular malignancy, included four patients with ocular metastasis from distant primaries. Recently, Font and F erry24 studied 227 cases of carcinoma
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metastatic to the eye and adnexae from the Armed Forces Institute of Pathology files, and among these cases, found 28 that were metastatic to the orbit. The ratio of ocular to orbital involvement was 7:1 (or an incidence of 12%). Most authors agree 6,16.24 that the most frequent sites of origin for metastatic carcinoma to the eye and ocular adnexae include the following: (1) breast, and (2) lung, with genitourinary tract and gastrointestinal tract also common primary sites. However, a wide range of primary tumors may metastasize to the eye. The eye or orbit may not infrequently be the first site of malignant spread, and ocular symptoms occasionally precede the diagnosis of primary tumor. In 60% (17 of 28) of cases in Font and Ferry's series,24 orbital symptoms preceded the symptoms of the primary lesion. This was also true in our case. Font and Ferry'" found immediate symptoms of orbital metastasis of carcinoma, in order of frequency, to include the following: exophthalmos, 75%; pain, 29%; decreased vision, 29%; periorbital swelling, 25%; a visible mass, 21%; and ophthalmoplegia and diplopia, 18%. They found no preponderance of either left- or right-sided orbital metastases. Of the eye and adnexae, the orbit is the second most frequent site of involvement by metastatic carcinoma (after the posterior segment of the eye).24 The orbital muscles are the usual site,2S and less commonly, the orbital bones. SUMMARY
A 69-year-old man with a history of cirrhosis of the liver had unilateral progressive proptosis without jaundice, abdominal pain, or gastrointestinal symptoms. Results of laboratory and radiographic studies were also normal. Orbital biopsy revealed hepatocellular carcinoma. Although hepatocellular carcinoma
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has often been shown to metastasize to the brain and often to the flat bones of the skull, to the best of our know ledge, this is the first histologically proven case of hepatoma metastatic to the orbit. REFERENCES 1. Bock, E.: Ueber einen sarckomartigen biliverdin enthaltenden tumor der choroidea. Virchow's Arch. [Pathol. Anat.] 91:442, 1883. 2. Kaemerer, G.: Metastatischer Aderhautskrebs bei primaren Krebs der Leber. Korrespondensblatt der arztlichen ver Thuringen 27:62, 1898. 3. Oatman, E. L.: Metastatic carcinoma of the choroid. Am. J. Med. Sci. 151:375, 1903. 4. Taake, W. H., Allen, R. A., and Straatsma, B. R.: Metastasis of a hepatoma to the choroid. Am. J. Ophthalmol. 56:208, 1963. 5. Mortada, A.: Roentgenography in orbital metastases with exophthalmos. Am. J. Ophthalmol. 65:48, 1968. 6. Jensen, O. A.: Metastatic tumors of the eye and orbit. A histopathological analysis of a Danish series. Acta Pathol. Microbiol. Scand. (Suppl.) 212: 201,1970. 7. Becker, F.: Hepatoma. Nature's tumor model. Am. J. Pathol. 74:179,1974. 8. Anderson, W. A. D., and Kissane, J. M.: Pathology. St. Louis, C. V. Mosby Co., 1977, pp. 1412-1417. 9. Balasegaramm, M.: Management of primary liver cell carcinoma. Am. J. Surg. 130:33, 1975. 10. El-Demeni, A. A., Huros, A. B., Goldsmith, H., and Foote, F. W.: Primary malignant tumors of the liver. Cancer 27:7, 1971. 11. Muldoon, C. J.: A hepatocarcinoma with osseous metastases. J. Laryngol. Otol. 88:891, 1974. 12. Smetana, C., Cyorkey, F., Cyorkey, P., and Busch, H.: Studies on nucleoli and cytoplasmic fibrillar bodies of human hepatocellular carcinomas. Cancer Res. 32:925, 1972. 13. Hart, W. M.: Metastatic carcinoma to the eye and orbit. Int. Ophthalmol. Clin. 2:465, 1962. 14. Bloch, R. S., and Gartner, S.: The incidence of ocular metastatic carcinoma. Arch. Ophthalrnol. 85: 673, 1971. 15. Rose, A. M.: Die orbita als Absiedlungsort von Mahgnomen. Klin. Monastbl. Augenheilkd. 147:857, 1965. 16. Albert, D. M., Rubenstein, R. A., and Scheie, H. G.: Tumor metastasis to the eye. 1. Incidence in 213 adult patients with generalized malignancy. Am. J. Ophthalmol. 63:723, 1967. 17. Lemoine, A. N., and McLeod, J.: Bilateral metastatic carcinoma of the choroid. Successful roentgen treatment of one eye. Arch. Ophthalmol. 16:804, 1936. 18. Moss, H. M.: Expanding lesions of the orbit. A clinical study of 230 consecutive cases. Am. J. Ophthalmol. 54:761, 1962.
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19. Silva, D.: Orbital tumors. Am. J. Ophthalmol, 65:318, 1968. 20. Reese, A. B.: Tumors of the Eye, 3rd ed. New York, Harper and Row, 1976, pp. 529-536. 21. Henderson, T. W.: Orbital Tumors. Philadelphia, W. B. Saunders Co., 1973, pp. 474-494. 22. Ingalls, R. B.: Tumors of the Orbit. Springfield, Charles C Thomas, 1953, p. 410. 23. Spaeth, E. B.: Ocular tumors. Arch. Ophthalmol. 46:421, 1951.
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24. Font, R. L., and Ferry, A. P.: Carcinoma metastatic to the eye and orbit. Cancer 38: 1326, 1976. 25. Bedford, P. D., and Daniel, P. M.: Discrete carcinomatous metastases in the extrinsic ocular muscles. A case of carcinoma of the breast with exophthalmic ophthalmoplegia. Am. J. Ophthalmol. 49:723, 1960.
OPHTHALMIC MINIATURE
The enemy were so frightened when they saw me, that they leaped out of their ships and swam to shore; I then took my tackling, and fastening a hook to the hole at the prow of each, I tied all the cords together at the end. While I was thus employed, the enemy discharged several thousand arrows, many of which stuck in my hands and face; and, besides the excessive smart, gave much disturbance in my work. My greatest apprehension was for mine eyes, which I should have infallibly lost, if I had not suddenly thought of an expedient. I kept, among other little necessities, a pair of spectacles, in a private pocket which, as I observed before, had escaped the Emperor's searchers. These I took out, and fastened as strongly as I could upon my nose, and thus armed, went on boldly with my work, in spite of the enemy's arrows, many of which struck against the glasses of my spectacles, but without any effect other than a little to discompose them. ]ohnathan Swift, A Voyage To Lilliput