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Pancreatic Islet Cell Carcinoma Metastatic to the Eyes
PANCREATIC I S L E T CELL CARCINOMA M E T A S T A T I C T O T H E EYES STEPHEN M. SOLOMON, M.D., AND JAMES R. NICKEL, M.D.
New Orleans, Louisiana ing this admission included the following: complete blood cell count, platelet count, sedimentation rate, urinalysis, serum electrolytes, blood urea nitrogen, bilirubin, serum glutamic oxaloacetic transaminase, lactic dehydrogenase, alkaline phosphatase, thyroxine, sputum culture, sputum cytology, bronchoscopy, chest, skull, and abdominal x-ray fihns, metastatic bone series, intravenous pyelogram, upper gastro intestinal tract series, barium enema, sigmoidoscopy, liver scan, brain scan, electroencephalogram, and glu cose tolerance test. Except for the glucose tolerance test, which confirmed the diagnosis of diabetes mel litus, all of these studies were essentially unremark able and failed to disclose any evidence of a dissemi nated malignancy or location of a primary tumor. However, the patient had a chest x-ray examination three months later that showed an area of radiodensity measuring approximately 3 X 4.5 cm in the posterior left lower lobe. A review of previous chest x-ray films suggested that this density had been pres ent as early as July 1969, at which time it measured approximately 1 cm in size. In view of this slow en largement it was thought that this density might possibly represent a low-grade neoplasm. In June 1972, the patient was hospitalized because of bowel obstruction, dehydration, and severe anemia (hematocrit level of 12%). At that time she was found to have hepatomegaly and an elevated serum amylase. Thereafter her condition rapidly deterio rated. She died in July 1972, approximately one year after the onset of her ocular symptoms and nine months after the discovery of her choroidal lesions.
Islet cell carcinoma of the pancreas has been recognized as a distinct histologic entity for nearly 70 years. 1 This paper presents the clinical and pathologic findings in a case of disseminated pancreatic islet cell carcinoma with metastases to the choroid and ciliary body of both eyes. CASE REPORT
The patient, a white woman, was 73 years old at the time of her death. She had been followed for multiple medical and ophthalmic problems. These in cluded chronic open-angle glaucoma, bilateral cata racts, old pulmonary tuberculosis, diabetes mellitus, hypertensive arteriosclerotic cardiovascular disease, and chronic cholecystitis with cholelithiasis. In July 1971, she presented to the eye clinic com plaining of pain in her left eye. Her visual acuity was 20/40 bilaterally. No ophthalmoscopic abnor malities were noted. In October 1971, she returned to the eye clinic because of rapid loss of vision. At that titne her visual acuity had decreased to 20/200 in each eye. Further examination revealed her eyes to be grossly normal to external examination. The pu pils were miotic secondary to carbachol therapy. Versions and vergences were normal. Applanation tensions were 22 mm Hg in each eye. Slit-lamp ex amination revealed mild nuclear sclerosis and pos terior subcapsular changes, which were believed to be insufficient to explain her markedly decreased vision. Indirect ophthalmoscopic examination re vealed multiple large choroidal elevations in each eye averaging 5 disk diameters in size. Two such lesions were seen in the posterior pole of the right eye and three in the posterior pole of the left eye. These le sions appeared pale gray in color with superimposed pigment epithelial atrophy. Visual field examina tions revealed a bitemporal hemianopsia. On fluorescein angiography the lesions had a mottled appear ance, and areas within them retained the stain for a prolonged period of time. The patient subsequently underwent an extensive medical evaluation culminating in a diagnostic hospitalization in February 1972. At the time of admis sion she was essentially asymptomatic except for her visual complaints and had no significant physical findings. Diagnostic studies obtained before and durFrom the Departments of Ophthalmology and Pathology, U.S. Public Health Service Hospital, New Orleans, Louisiana. Reprint requests to Stephen M. Solomon, M.D., 9340 Edmonston Rd., Greenbelt, MD 20770.
PATHOLOGIC FINDINGS
An autopsy was performed approximately six hours after death. The pancreas was markedly enlarged (340 g) and contained a large tumor mass. Histologically this tumor was a typical pancreatic islet cell carcinoma (Fig. 1). Metastases were found in the re gional lymph nodes, peritoneum, liver, lungs, kidneys, thyroid, brain, pituitary, and both eyes. The pituitary was markedly enlarged and protruded into the suprasellar region, impinging on the optic chiasm. Microscopi cally the pituitary showed virtually complete replacement by tumor (Fig. 2 ) . Both eyes were removed in their entirety and fixed in formalin. They were of normal size and unremarkable on external examina tion except for an irregular 1.0 X 0.6-cm
806
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+>*
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Fig. 1 (Solomon and Nickel). Islet cell carcinoma in pancreas showing marked nuclear pleomorphism of the malignant cells (hematoxylin and eosin, X440). transillumination defect in the posterior pole of the left eye. On horizontal section the vit reous bodies, retinas, and anterior segments appeared grossly normal except for an un usual whitish gray color of the pars plicata ciliaris of the right eye. Two small slightly elevated whitish-gray nodules, measuring 0.5 cm and 0.2 cm in diameter, were present in the choroid of the right eye near the macula. Four similar nodules ranging from 1.0 cm to 0.4 cm in diameter were found in the choroid of the left eye, the largest corresponding to the transillumination defect. Microscopically, these choroidal nodules proved to be metastatic pancreatic islet cell carcinoma (Fig. 3). They were composed of highly vascular masses of relatively uniform small malignant cells that tended to be ar ranged in compact nests separated by fibrovascular septae. Microscopic foci of meta
static tumor were also found in the ciliary bodies of both eyes (Fig. 4), in the sclera of the left eye, and around several small scleral and choroidal nerves and blood vessels. Other microscopic findings in the eyes included ret inal cystoid degeneration, mild to moderate degenerative changes in the lenses, and many drusen overlying the larger choroidal metastases. DISCUSSION
Intraocular metastatic malignancies have been reported with increasing frequency since Perl's initial report in 1872.2 Recent re view articles have emphasized that, although the eye is a relatively infrequent site of metastasis, it is not as rare as previously thought.3"5 The most common sites of primary tumors are breast and lung.6'7 Numerous other primary sites have been reported in-
808
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N O V E M B E R , 1974
Fig. 2 (Solomon and Nickel). Pancreatic islet cell carcinoma metastatic to pituitary showing a pattern of tumor cell nests separated by nbrovascular septae (hematoxylin and eosin, XlOO).
Fig. 3 (Solomon and Nickel). Left eye. Three large discrete choroidal metastases from a pancreatic islet cell carcinoma. Note the vascularity of the tumor nodules (hema toxylin and"eosin, XS).
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Fig. 4 (Solomon and Nickel). Right eye. Microscopic foci of metastatic pancreatic islet cell carcinoma in the ciliary body (hematoxylin and eosin, XlOO). eluding alimentary tract, thyroid, prostate, ovary, parotid, liver, testis, kidney, uterus, and skin.6'7 Several cases of intraocular metastases from primary pancreatic tumors have also been previously reported. All of these tumors have been adenocarcinomas of the pancreatic exocrine structures or else have not been spec ified as to histologic type.3'4'8'9 To the best of our knowledge, no case of intraocular me tastases from a pancreatic islet cell carcinoma has been previously reported. This is probably due to the relative rarity of this tumor and the fact that it does not usually metastasize out side the abdomen.10'11 The histopathologic findings in our case show that the nodular choroidal lesions seen ophthalmoscopically were in fact metastatic pancreatic islet cell carcinoma. The strikingly persistent retention of dye by the choroidal
metastases, as seen on fluorescein angiography, can probably best be ascribed to their marked vascularity. The patient's initial pre senting symptom of eye pain might have been related to compression of small choroidal and scleral nerves by adjacent foci of metastatic tumor. Her bitemporal hemianopsia was ap parently due to compression of the optic chiasm by a large pituitary metastasis. Al though many islet cell tumors produce insu lin,10"12 the presence of clinical diabetes mellitus in this patient would suggest that her tumor was not of the insulin-producing type. SUMMARY
A 72-year-old white woman presented with eye pain, loss of visual acuity, and bitemporal hemianopsia. She was found to have multiple nodular choroidal lesions in both eyes, readily demonstrable by fluorescein angiography.
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AMERICAN JOURNAL OF OPHTHALMOLOGY
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and orbit in tumors of the eye and adnexa. Int. Oph thalmol. Clin. 2:456, 1962. 4. 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. 5. Ferry, A. P.: Metastatic carcinoma of the eye and ocular adnexa. Int. Ophthalmol. Clin. 7:615, 1967. 6. Reese, A. B.: Tumors of the Eye, 2nd ed. New York, Hoeber, 1964, p. 514. 7. Jensen, O. A.: Metastatic tumours of the eye and orbit. A histopathological analysis of a Danish series. Acta Pathol. Microbiol. Scand. 212(Suppl.) : 201, 1970. ACKNOWLEDGMENTS 8. Ring, H. G.: Pancreatic carcinoma with metas We thank Ramon L. Font, M.D., of the Armed tasis to the optic nerve. Arch. Ophthalmol. 77:798, Forces Institute of Pathology for his comments on 1967. 9. Arisawa, U.: Metastatisches Aderhautkarzinom the ocular pathology; Alfred Hew, Jr., who prosected the autopsy; and Raymond Johnson, who took bei latentem Primartumor. Klin. Monatsbl. Augenheilkd. 17:695, 1914. the photomicrographs. 10. Frantz, V. K.: Tumors of the pancreas. In Firminger, H. I. (ed.) : Atlas of Tumor Pathology. REFERENCES Washington, Armed Forces Institute of Pathology, 1. Fabozzi, S,: Ueber die Histogenese des pri- 1968, fascicle 27. maren Krebses des Pankreas. Beitr. Pathol. Anat. 11. Broder, L. E., and Carter, S. K.: Pancreatic 34:199, 1903. islet cell carcinoma. Ann. Intern. Med. 79:101, 1973. 2. Perl, M.: Contributions to pathology of tumors. 12. Sieracki, J., Marshall, R. B., and Horn, R. C, Virchow's Arch. Pathol. Anat. 56:437, 1872. Jr.: Tumors of the pancreatic islets. Cancer 13 :347, 3. Hart, W. M.: Metastatic carcinoma to the eye 1960. These lesions were thought to be tumor me tastases, but the site of her primary tumor remained undetermined until her death ap proximately one year later. At autopsy she was found to have a disseminated pancreatic islet cell carcinoma with metastases to the regional lymph nodes, peritoneum, liver, lungs, kidneys, thyroid, brain, pituitary, and eyes. Her ocular metastases involved the choroid and ciliary bodies bilaterally.
New Orleans, Louisiana ing this admission included the following: complete blood cell count, platelet count, sedimentation rate, urinalysis, serum electrolytes, blood urea nitrogen, bilirubin, serum glutamic oxaloacetic transaminase, lactic dehydrogenase, alkaline phosphatase, thyroxine, sputum culture, sputum cytology, bronchoscopy, chest, skull, and abdominal x-ray fihns, metastatic bone series, intravenous pyelogram, upper gastro intestinal tract series, barium enema, sigmoidoscopy, liver scan, brain scan, electroencephalogram, and glu cose tolerance test. Except for the glucose tolerance test, which confirmed the diagnosis of diabetes mel litus, all of these studies were essentially unremark able and failed to disclose any evidence of a dissemi nated malignancy or location of a primary tumor. However, the patient had a chest x-ray examination three months later that showed an area of radiodensity measuring approximately 3 X 4.5 cm in the posterior left lower lobe. A review of previous chest x-ray films suggested that this density had been pres ent as early as July 1969, at which time it measured approximately 1 cm in size. In view of this slow en largement it was thought that this density might possibly represent a low-grade neoplasm. In June 1972, the patient was hospitalized because of bowel obstruction, dehydration, and severe anemia (hematocrit level of 12%). At that time she was found to have hepatomegaly and an elevated serum amylase. Thereafter her condition rapidly deterio rated. She died in July 1972, approximately one year after the onset of her ocular symptoms and nine months after the discovery of her choroidal lesions.
Islet cell carcinoma of the pancreas has been recognized as a distinct histologic entity for nearly 70 years. 1 This paper presents the clinical and pathologic findings in a case of disseminated pancreatic islet cell carcinoma with metastases to the choroid and ciliary body of both eyes. CASE REPORT
The patient, a white woman, was 73 years old at the time of her death. She had been followed for multiple medical and ophthalmic problems. These in cluded chronic open-angle glaucoma, bilateral cata racts, old pulmonary tuberculosis, diabetes mellitus, hypertensive arteriosclerotic cardiovascular disease, and chronic cholecystitis with cholelithiasis. In July 1971, she presented to the eye clinic com plaining of pain in her left eye. Her visual acuity was 20/40 bilaterally. No ophthalmoscopic abnor malities were noted. In October 1971, she returned to the eye clinic because of rapid loss of vision. At that titne her visual acuity had decreased to 20/200 in each eye. Further examination revealed her eyes to be grossly normal to external examination. The pu pils were miotic secondary to carbachol therapy. Versions and vergences were normal. Applanation tensions were 22 mm Hg in each eye. Slit-lamp ex amination revealed mild nuclear sclerosis and pos terior subcapsular changes, which were believed to be insufficient to explain her markedly decreased vision. Indirect ophthalmoscopic examination re vealed multiple large choroidal elevations in each eye averaging 5 disk diameters in size. Two such lesions were seen in the posterior pole of the right eye and three in the posterior pole of the left eye. These le sions appeared pale gray in color with superimposed pigment epithelial atrophy. Visual field examina tions revealed a bitemporal hemianopsia. On fluorescein angiography the lesions had a mottled appear ance, and areas within them retained the stain for a prolonged period of time. The patient subsequently underwent an extensive medical evaluation culminating in a diagnostic hospitalization in February 1972. At the time of admis sion she was essentially asymptomatic except for her visual complaints and had no significant physical findings. Diagnostic studies obtained before and durFrom the Departments of Ophthalmology and Pathology, U.S. Public Health Service Hospital, New Orleans, Louisiana. Reprint requests to Stephen M. Solomon, M.D., 9340 Edmonston Rd., Greenbelt, MD 20770.
PATHOLOGIC FINDINGS
An autopsy was performed approximately six hours after death. The pancreas was markedly enlarged (340 g) and contained a large tumor mass. Histologically this tumor was a typical pancreatic islet cell carcinoma (Fig. 1). Metastases were found in the re gional lymph nodes, peritoneum, liver, lungs, kidneys, thyroid, brain, pituitary, and both eyes. The pituitary was markedly enlarged and protruded into the suprasellar region, impinging on the optic chiasm. Microscopi cally the pituitary showed virtually complete replacement by tumor (Fig. 2 ) . Both eyes were removed in their entirety and fixed in formalin. They were of normal size and unremarkable on external examina tion except for an irregular 1.0 X 0.6-cm
806
VOL. 78, NO. 5
■^ *'•
METASTATIC ISLET CELL CARCINOMA
Slim
+>*
807
mr^J*Z
Fig. 1 (Solomon and Nickel). Islet cell carcinoma in pancreas showing marked nuclear pleomorphism of the malignant cells (hematoxylin and eosin, X440). transillumination defect in the posterior pole of the left eye. On horizontal section the vit reous bodies, retinas, and anterior segments appeared grossly normal except for an un usual whitish gray color of the pars plicata ciliaris of the right eye. Two small slightly elevated whitish-gray nodules, measuring 0.5 cm and 0.2 cm in diameter, were present in the choroid of the right eye near the macula. Four similar nodules ranging from 1.0 cm to 0.4 cm in diameter were found in the choroid of the left eye, the largest corresponding to the transillumination defect. Microscopically, these choroidal nodules proved to be metastatic pancreatic islet cell carcinoma (Fig. 3). They were composed of highly vascular masses of relatively uniform small malignant cells that tended to be ar ranged in compact nests separated by fibrovascular septae. Microscopic foci of meta
static tumor were also found in the ciliary bodies of both eyes (Fig. 4), in the sclera of the left eye, and around several small scleral and choroidal nerves and blood vessels. Other microscopic findings in the eyes included ret inal cystoid degeneration, mild to moderate degenerative changes in the lenses, and many drusen overlying the larger choroidal metastases. DISCUSSION
Intraocular metastatic malignancies have been reported with increasing frequency since Perl's initial report in 1872.2 Recent re view articles have emphasized that, although the eye is a relatively infrequent site of metastasis, it is not as rare as previously thought.3"5 The most common sites of primary tumors are breast and lung.6'7 Numerous other primary sites have been reported in-
808
AMERICAN JOURNAL OF OPHTHALMOLOGY
N O V E M B E R , 1974
Fig. 2 (Solomon and Nickel). Pancreatic islet cell carcinoma metastatic to pituitary showing a pattern of tumor cell nests separated by nbrovascular septae (hematoxylin and eosin, XlOO).
Fig. 3 (Solomon and Nickel). Left eye. Three large discrete choroidal metastases from a pancreatic islet cell carcinoma. Note the vascularity of the tumor nodules (hema toxylin and"eosin, XS).
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Fig. 4 (Solomon and Nickel). Right eye. Microscopic foci of metastatic pancreatic islet cell carcinoma in the ciliary body (hematoxylin and eosin, XlOO). eluding alimentary tract, thyroid, prostate, ovary, parotid, liver, testis, kidney, uterus, and skin.6'7 Several cases of intraocular metastases from primary pancreatic tumors have also been previously reported. All of these tumors have been adenocarcinomas of the pancreatic exocrine structures or else have not been spec ified as to histologic type.3'4'8'9 To the best of our knowledge, no case of intraocular me tastases from a pancreatic islet cell carcinoma has been previously reported. This is probably due to the relative rarity of this tumor and the fact that it does not usually metastasize out side the abdomen.10'11 The histopathologic findings in our case show that the nodular choroidal lesions seen ophthalmoscopically were in fact metastatic pancreatic islet cell carcinoma. The strikingly persistent retention of dye by the choroidal
metastases, as seen on fluorescein angiography, can probably best be ascribed to their marked vascularity. The patient's initial pre senting symptom of eye pain might have been related to compression of small choroidal and scleral nerves by adjacent foci of metastatic tumor. Her bitemporal hemianopsia was ap parently due to compression of the optic chiasm by a large pituitary metastasis. Al though many islet cell tumors produce insu lin,10"12 the presence of clinical diabetes mellitus in this patient would suggest that her tumor was not of the insulin-producing type. SUMMARY
A 72-year-old white woman presented with eye pain, loss of visual acuity, and bitemporal hemianopsia. She was found to have multiple nodular choroidal lesions in both eyes, readily demonstrable by fluorescein angiography.
810
AMERICAN JOURNAL OF OPHTHALMOLOGY
NOVEMBER, 1974
and orbit in tumors of the eye and adnexa. Int. Oph thalmol. Clin. 2:456, 1962. 4. 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. 5. Ferry, A. P.: Metastatic carcinoma of the eye and ocular adnexa. Int. Ophthalmol. Clin. 7:615, 1967. 6. Reese, A. B.: Tumors of the Eye, 2nd ed. New York, Hoeber, 1964, p. 514. 7. Jensen, O. A.: Metastatic tumours of the eye and orbit. A histopathological analysis of a Danish series. Acta Pathol. Microbiol. Scand. 212(Suppl.) : 201, 1970. ACKNOWLEDGMENTS 8. Ring, H. G.: Pancreatic carcinoma with metas We thank Ramon L. Font, M.D., of the Armed tasis to the optic nerve. Arch. Ophthalmol. 77:798, Forces Institute of Pathology for his comments on 1967. 9. Arisawa, U.: Metastatisches Aderhautkarzinom the ocular pathology; Alfred Hew, Jr., who prosected the autopsy; and Raymond Johnson, who took bei latentem Primartumor. Klin. Monatsbl. Augenheilkd. 17:695, 1914. the photomicrographs. 10. Frantz, V. K.: Tumors of the pancreas. In Firminger, H. I. (ed.) : Atlas of Tumor Pathology. REFERENCES Washington, Armed Forces Institute of Pathology, 1. Fabozzi, S,: Ueber die Histogenese des pri- 1968, fascicle 27. maren Krebses des Pankreas. Beitr. Pathol. Anat. 11. Broder, L. E., and Carter, S. K.: Pancreatic 34:199, 1903. islet cell carcinoma. Ann. Intern. Med. 79:101, 1973. 2. Perl, M.: Contributions to pathology of tumors. 12. Sieracki, J., Marshall, R. B., and Horn, R. C, Virchow's Arch. Pathol. Anat. 56:437, 1872. Jr.: Tumors of the pancreatic islets. Cancer 13 :347, 3. Hart, W. M.: Metastatic carcinoma to the eye 1960. These lesions were thought to be tumor me tastases, but the site of her primary tumor remained undetermined until her death ap proximately one year later. At autopsy she was found to have a disseminated pancreatic islet cell carcinoma with metastases to the regional lymph nodes, peritoneum, liver, lungs, kidneys, thyroid, brain, pituitary, and eyes. Her ocular metastases involved the choroid and ciliary bodies bilaterally.