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Histochemical Analysis of Breast Carcinoma Metastatic to the Orbit
Histochemical Analysis of Breast Carcinoma Metastatic to the Orbit DAVID M. REIFLER, MD,* PAUL DAVISON, BSt
Abstract: A 62-year-old woman was seen for evaluation of an orbital tumor. Recognition of a relatively rare syndrome of pain, ptosis, and a progressively immobilized globe with enophthalmos suggested the diagnosis of metastatic carcinoma to the left orbit. In this case, this was confirmed by open breast and orbital biopsies, revealing infiltrating lobular breast carcinoma. This is the first reported case where estrogen and progesterone receptors were identified in a metastatic orbital tumor using fluorescent histochemical techniques. This technique was of value in confirming the diagnosis and providing direction for subsequent endocrinologic palliative therapy. [Key words: breast cancer, carcinoembryonic antigen, enophthalmos, estrogen and progesterone receptors, fine-needle aspiration biopsy, fluorescence microscopy, histochemistry, metastatic carcinoma, orbital tumors.] Ophthalmology 93:254-259, 1986
Breast carcinoma is the most commonly identified primary source of carcinoma metastatic to the orbit. I- 5 Orbital metastasis of breast carcinoma may take the form of a diffusely infiltrating scirrhous tumor leading to a classic picture of pain, ptosis, and a progressively immobilized globe with enophthalmos. 2,6 Other protean ophthalmic manifestations of breast carcinoma include an insidious pseudoinflammatory involvement of the ocular adnexa, intracranial metastasis with papilledema, Horner's syndrome, and choroidal tumors. 6 ,7 Metastatic breast carcinoma is frequently susceptible to hormonal manipulation, through surgical ablation of endocrine glands or by pharmacologic hormonal therapy.8 Responsiveness to hormonal manipulation has been correlated with the presence or absence of steroid hormone receptors in breast cancer epithelium. 8- 1O This report describes a unique case of infiltrating lobular breast carcinoma in which both estrogen and progesterone receptors were identified in both the primary tumor and an orbital From the Department of Surgery (Ophthalmology): Michigan State University. Blodgett Memorial Medical Center, Butterworth and Saint Mary's Hospitals. the Western Michigan Ambulatory Surgical Center, and the Department of Pathology.t Blodgett Memorial Medical Center, Grand Rapids. Michigan. Supported in part by a grant from the Cancer Research Fund, Blodgett Memorial Medical Center, Grand Rapids, Michigan. Reprint requests to David M. Reifler, MD, 221 East Paris Medical Building, 1000 East Paris Road SE, Grand Rapids, MI 49506.
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metastasis, using fluorescent steroid histochemical techniques. IO- 12 This case also emphasizes the potential role of the ophthalmologist in the initial diagnosis and management of occult disseminated malignancies.
CASE REPORT A 62-year-old woman was seen in consultation for evaluation of a left orbital tumor. During the previous six months she had become aware of progressively increasing pain in the left orbital region that was associated with left upper lid ptosis and diplopia. Her medical history was negative except for arthritis of the left hip. Previous evaluation by her referring ophthalmologist and a consulting neurosurgeon had disclosed a left orbital tumor, demonstrated by computed tomographic (CT) scan (Fig 1). On examination, the visual acuity was 20/20 in the right eye and 20/80 in the left eye. The left pupil was dilated and showed an afferent defect. There was a mild inferior and temporal displacement of the left globe which showed severely limited ductions, resistance to retropulsion and about 1.5 mm of measured enophthalmos (Fig 2). There was a moderate ptosis of the left upper lid but the blinking mechanism was impaired. Slit-lamp examination revealed central and inferior corneal erosions. Ophthalmoscopic examination disclosed very mild edema of the left optic disc. A-scan and B-scan ultrasonography demonstrated an infiltrating lesion in the superior-medial left orbit that showed relatively poor sound transmission and an irregular orbital fat pattern (Fig 3). Fluorescein angiography demonstrated late staining of the left optic disc.
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Fig 3. B-scan ultrasonogram demonstrating a nonencapsulated mass with relatively poor sound transmission and an irregular orbital fat pattern. Fig 1. A 62-year-old woman with left upper lid ptosis. Enophthalmos with ophthalmoplegia and inferior-temporal displacement of the left globe was present.
Fig 2. Computed tomographic scan demonstrating an infiltrating mass in the medial and superior left orbit.
In view of the clinical, CT and ultrasonographic findings, a general physical examination was performed that revealed a left breast mass and left axillary lymphadenopathy. Subsequent bilateral mammography confirmed probable carcinoma of the left breast. A metastatic work-up included a normal chest roentgenogram, and results of liver function studies were within normal limits. Serum carcinoembryonic antigen (CEA) level was 2.2 ng/ml (normal values, below 2.5 ng/ml). As an outpatient, the patient underwent an open biopsy of the left breast and a fineneedle aspiration biopsy of the left orbital mass was performed at the same time, while the patient was under general anesthesia. The specimens from the orbital aspiration were nondiagnostic as were specimens from a second fine-needle aspiration biopsy, performed subsequently as an office procedure. Following this, the patient was admitted to the hospital where an open left orbital biopsy was performed, utilizing both medial and temporal incisions.
PATHOLOGIC FINDINGS BREAST BIOPSY SPECIMEN
Grossly, the tumor was creamy white, poorly circumscribed and indurated. Microscopically (Fig 4), there was diffuse infiltration of small carcinoma cells arranged in a concentric fashion around otherwise normal appearing ducts. Many of the cells were rather bland in appearance,
with pale staining cytoplasm and occasional fine vacuolization. Stains with mucicarmine revealed occasional fine vacuolization. Stains with mucicarmine revealed occasional mucin-staining cells associated with a signet-ring morphology. Small foci oflobular carcinoma in situ were present. The histopathologic diagnosis was infiltrating lobular breast carcinoma. Receptor assays9,10 were performed on a homogenized fresh-frozen portion of the specimen and showed a concentration of estradiol receptor of 42.8 femtomoles/mg cytosol protein (expected values for positive results are greater than 10 femtomoles/mg). The cryostat sections were also studied histochemicallylO-12 and found to be positive for both estrogen and progesterone receptors. The receptor tracers used were fluorochrome conjugates: 17-beta-estradiol-6-carboxymethyl oxime-bovine serum albumin-fluorescein isothiocyanate (estradiol-BSA-FITC) and 1 l-alphahydroxyprogesterone hemisuccinate-bovine serum albumin-tetramethylrhodamine isothiocyanate (progesterone-BSA-TMRITC). After incubation with the tracers, the estrogen-binding sites appeared apple-green, and the progesterone-binding sites showed an orange-red fluorescence when examined with a fluorescence microscope equipped with appropriate filters (Fig 5). ORBITAL FINE-NEEDLE ASPIRAnON BIOPSY
Specimens from both of the fine-needle aspiration biopsy attempts were hypocellular, revealing only a rare cluster of cells including pigment laden macrophage cells and erythrocytes. Although no atypia was noted, the material was considered insufficient for diagnosis. OPEN ORBITAL BIOPSY SPECIMEN
Grossly, the fragments of orbital fat were grayish-yellow in color and firm and gritty in texture. Microscopically (Fig 6), the neoplastic cells were similar in size, architectural arrangement and infiltrative pattern to the neoplastic cells present in the breast. Cryostat sections of the open orbital biopsy specimens were studied for estrogen and progesterone receptors using identical methods to those used for the open breast biopsy 255
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Fig 4. Top, photomicrograph of breast biopsy specimen revealing infiltrating lobular breast carcinoma. Leji, small carcinoma cells locally infiltrating the breast parenchyma (hematoxylin-eosin, original magnification X250). Right, occasional mucinpositive cytoplasmic vacuoles with nuclear displacement giving a "signet-ring" appearance (mucicarmine, original magnification X400). Fig 5. Second row, fluorescence photomicrographs of breast biopsy specimen with cytoplasmic staining in tumor cells for (leji) estrogen receptors (estradiol-BSAFITC, original magnification X250), and (right) progesterone receptors (progesteroneBSA-TMRITC, original magnification X540). Fig 6. Third row, photomicrograph of orbital biopsy specimen revealing small cell malignancy with an infiltrating pattern similar to the primary tumor (see Fig 4) (hematoxylin-eosin, leji, original magnification X I00; right, original magnification X250). Fig 7. Bottom, fluorescence photomicrographs of orbital biopsy specimen with cytoplasmic staining in tumor cells for (leji) estrogen receptors (estradiol-BSA-FITC, original magnification X250) and (right) progesterone receptors (progesterone-BSATMRITC, original magnification X250).
(see above). Again, both the estrogen and progesterone binding sites were delineated by the fluorescent tracers (Fig 7).
SUBSEQUENT COURSE Subsequent evaluation disclosed lytic destructive changes in the region of the left iliac bone, suggestive of 256
additional disseminated metastatic carcinoma. The patient was begun on oral tamoxifen citrate, and she was also given local radiation therapy, using an 18 MEV linear accelerator. Ten MEV photons were employed to treat the left orbit with a total of 4600 rad in divided doses over a four-week period. A total of 4500 rad were also administered to the left pelvis and femur in 18 fractions over 24 days. In addition, daily oral cytoxan and weekly intravenous administration of 5-fluorouracil and methotrexate was instituted.
REIFLER AND DAVISON
Six months following the institution of this therapy, the patient was without pain and ambulating without any difficulty. Best corrected visual acuity improved to 20/20 in the right eye and 20/25 in the left eye. The ductions in the left eye were significantly improved and diplopia was less severe in the primary position, although the patient still preferred to occlude the left lens on her glasses. Both lagophthalmos and levator function on the left side had improved considerably, and this was associated with improvement in the superficial keratopathy. Hertel exophthalmometry measurements showed a slight increase (up to 3 mm) in the left enophthalmos. The papilledema resolved but a dilated and deafferented pupil was still present as was the relative corneal hypesthesia.
DISCUSSION The diagnosis of orbital metastasis of breast carcinoma may be suspected in women with a known primary and documented evidence of widespread metastases. Because the prior occurrence of breast carcinoma may be quite remote in some cases, a careful history of any previous cancer or surgery should be obtained. Following a thorough clinical examination, orbital ultrasonography and computed tomography should be obtained along with appropriate consultations. Computed tomography greatly facilitates accurate noninvasive characterization and localization of the tumorY As illustrated by this case, the diagnosis of metastatic breast carcinoma should be considered even when there is no history of breast cancer. In this case the diagnosis was strongly suspected in view of the clinical presentation of pain, ptosis, ophthalmoplegia, and enophthalmos combined with the computed tomographic findings of an irregular infiltrating orbital mass. In patients with a history of primary breast carcinoma, ophthalmic signs and symptoms frequently present the first evidence of metastatic disease. 6 Ferry and Font3 found that symptoms of ocular or orbital involvement from breast carcinoma precede recognition of the primary tumor in only about 9% of cases. A remote history of primary breast carcinoma has been found to be far more typical in such cases of orbital metastasis; the average interval between primary and secondary tumors has generally been reported to be about 5 years. 6.14,IS This is in contrast to metastatic lung tumors, where about two-thirds of patients had evidence of ocular or orbital metastasis before the detection of the primary tumor.3 The first reported case of enophthalmic orbital metastasis was given by Lawson in 1910. 16 To date, about 23 additional cases have been cited in the world literature. 2,4,I?-19 Of these, the majority have been metastases from breast carcinoma. The other less frequently encountered primary sites have been the stomach and other abdominal sites,z·17,18 The rather unusual clinical presentation of this patient prompted one of us to analyze the aforementioned cases on the subject of orbital metastasis
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with enophthalmos, and this review was described recently elsewhere. 2o Some oncologists feel that orbital metastasis from breast carcinoma without lymphadenopathy, in the presence of a negative metastatic work-up, is best treated by radiation therapy, without orbital biopsy,z1 However, many authorities believe that a needle biopsy specimen or an open biopsy specimen should be obtained before radiation therapy, to avoid treating patients inappropriately that have an unrelated second disease.? In some cases of metastatic carcinoma to the orbit, microscopic examination for tissue-specific immunologic markers in aspiration 22 or open biopsy specimens23 can specifically confirm the histogenesis of the tumor. In one previously reported case of an orbital metastasis from prostatic carcinoma, the presence of a hormone (androgen) receptor in the tumor cytoplasm was documented. 24 In the case reported herein, two attempts at fine-needle aspiration biopsy were nondiagnostic. In retrospect, the negative results are not surprising. A negative fine-needle aspiration biopsy has been noted to be particularly characteristic of tumors with a predominantly fibrous matrix where intercellular cohesion is strong and cellularity is diminished,zs The scirrhous nature of most orbital tumors that produce enophthalmos has been emphasized by Henderson2 and substantiated by others. 2o In cases of suspected orbital metastasis with enophthalmos, an orbital fine-needle aspiration biopsy should probably be bypassed for more definitive procedures. Although orbital fine-needle biopsy has a low rate of complications, selection of patients is still advisable. For example, the accuracy rate of orbital fine-needle aspiration biopsy is about half that achieved when patients are carefully selected. 26,2? Some authors have recommended a large bore-needle biopsy (16-18 -gauge) in patients who are debilitated to the point that general anesthesia is inadvisable.? The large boreneedle can obtain a cylinder of tissue that is readily processed by paraffin embedding rather than cytologic techniques. In this case, however, an open orbital biopsy was subsequently chosen. In the evaluation of orbital tumors, many authorities proceed directly to an open orbital biopsy, particularly in cases of presumed primary lesions. 26 Fine-needle aspiration biopsy precludes a comprehensive determination of certain cell surface markers (as in lymphoid lesions) or useful ultrastructural information obtainable only through electron microscopy.26,28 Using open orbital biopsies and assay techniques on homogenized tissue, Bullock and Yanes6 were first able to demonstrate the presence estrogen receptor in three patients with breast carcinoma metastatic to the orbit. This assay, which was performed on the primary tumor in this case, involves the addition of radioactive estradiol to 1 ml of homogenized fresh-frozen tissue. The presence of estradiol and progesterone receptors have not been previously demonstrated in an orbital metastasis using fluorescent histochemical methods on freshfrozen tissue. Unlike the earlier studies on orbital metastatic lesions,6 both estrogen and progesterone receptors were identified. Based on the results of this case and other 257
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histochemical studies of primary and metastatic breast tumors, 10, II it would seem that fluorescent histochemical study of cryostat sections is a useful method of documenting the presence or absence of estrogen and progesterone receptors in orbital metastasis from breast carcinoma. It should be noted that a variety of techniques have been developed to analyze steroid hormone receptors in breast neoplasms. 29 These methods have taken the form of either of tissue assays or histochemical demonstration (Table 1).29,30 Among these techniques, the use of monoclonal antibodies may have greater sensitivity since these antibodies can bind to sites already occupied by steroid hormone and to partially denatured sites. 29 However, new histochemical receptor assays remain to be further validated against standard quantitative assays.30 The accepted standard assays have utilized either sucrose density gradient sedimentation or dextran-coated charcoal. 29 Other ancillary tests, such as the serial measurement of serum carcinoembryonic antigen (CEA), have been applied in cases of metastatic breast carcinoma6 and other types of carcinoma. 31 In cases of breast carcinoma, however, this test is less useful than studies of steroid hormone receptors and, as demonstrated by this case, serum levels of CEA may be normal. Approximately 50 to 60% of women with breast tumors containing estrogen receptor respond objectively to endocrine therapy, while less than 15% of women with breast tumors lacking estrogen receptor have a favorable objective response.9 Tumors, either primary or metastatic, showing the highest estrogen receptor content have the highest regression rates with endocrine therapy.8 The response rate increases to 78% of patients with breast tumors containing receptors for both estrogen and progesterone. 8,9 The presence of estrogen receptors in breast cancers has been generally accepted as a predictor of extended diseasefree survival. 32- 34 Progesterone receptor analysis has also been found to be of predictive value in cases of breast carcinoma. In the early stages of breast cancer, Clark et al 35 found that the measurement of progesterone receptor levels had an even greater predictive value for disease-free survival than estrogen receptors. Gross et al 36 found that when progesterone receptors were initially present but subsequently absent, there was a poorer survival than when the presence of progesterone receptors was retained. However, Raemaekers et al 34 failed to confirm any independent predictive value of progesterone receptor status, either in the initial biopsy specimen or in sequential biopsy analyses. In summary, when a disseminated malignancy presents initially with symptoms in the orbital region, the ophthalmologist is in a unique position to make the correct diagnosis and to expediently refer the patient for further evaluation and treatment. As illustrated by this case, special laboratory studies can be used as an aid in the diagnosis and management of disseminated cancer. Although the fluorescent histochemical demonstration of hormone receptors was highlighted in this report, the availability of other methods should also be considered in the course
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Table 1. Steroid Hormone Receptors: Methods of Analysis Quantitative assays Sucrose density gradient (SDR) analysis Dextran-coated charcoal (DCC) assays Monoclonal antibody assays Enzyme-linked immunochemical assay (EIA) Immunoradiometric assay (IRMA) Histochemical methods Fluorescein-coupled estradiol Estradiol antibody with fluorescent second antibody Steroid-albumin fluorescein Peroxidase-antiperoxidase (PAP) method Avidin-biotin-complex (ABC) method
of diagnostic evaluation. Finally, the unreliability of fineneedle aspiration biopsy in cases of suspected scirrhous orbital metastasis should be recognized. In such cases, particularly in the presence of enophthalmos and ophthalmoplegia, it is reasonable to proceed directly to an open orbital biopsy in order to confirm the pathologic diagnosis.
ACKNOWLEDGMENTS Drs. Mark Moleski, Lynn Hedeman and Willard Stawski participated in the diagnostic evaluation of the patient. Drs. Anna Broecker, Martin Cloherty and Dale Kessler examined the pathologic specimens. Mike Brown proofread the manuscript. The authors gratefully acknowledge their contributions.
REFERENCES 1. Bloch RS, Gartner S. The incidence of ocular metastatic carcinoma. Arch Ophthalmol1971; 85:673-5. 2. Henderson JW. Orbital Tumors. Philadelphia: WB Saunders, 1973; 473. 3. Ferry AP, Font RL. Carcinoma metastatic to the eye and orbit. I. A clinicopathologic study of 227 cases. Arch Ophthalmol 1974; 92:27686. 4. Font RL, Ferry AP. Carcinoma metastatic to the eye and orbit. III. A clinicopathologic study of 28 cases metastatic to the orbit. Cancer 1976; 38:1326-35. 5. Gartner S. Metastatic carcinoma to the eye and adnexa. In: Duane TO, ed. Clinical Ophthalmology. Hagerstown: Harper & Row, 1978; Volume 5, Chapter 34. 6. Bullock JD, Yanes B. Ophthalmic manifestations of metastatic breast cancer. Ophthalmology 1980; 87:961-72. 7. Mottow·Uppa L, Jakobiec FA. Iwamoto T. Pseudoinfiammatory met· astatic breast carcinoma of the orbit and lids. Ophthalmology 1981 ; 88:575-80. 8. Osborne CK, Yochmowitz MG, Knight WA III, McGuire WL. The value of estrogen and progesterone receptors in the treatment of breast cancer. Cancer 1980; 46:2884-8. 9. Wittliff JL. Steroid·hormone receptors in breast cancer. Cancer 1984;
53:630-43. 10. Pertschuk LP, Tobin EH, Tanapat P, et al. Histochemical analyses of
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11. 12. 13.
14. 15. 16. 17. 18.
19. 20. 21. 22.
23.
24.
steroid hormone receptors in breast and prostatic carcinoma. J Histochem Cytochem 1980; 28:799-810. Lee SH. Cancer cell estrogen receptor of human mammary carcinoma. Cancer 1979; 44:1-12. Lee SH. Cellular estrogen and progesterone receptors in mammary carcinoma. Am J Clin Patho11980; 73:323-9. Hesselink JR, Davis KR, Weber AL, et al. Radiological evaluation of orbital metastases, with emphasis on computed tomography. Radiology 1980; 137:363-6. Hutchison OS, Smith TR. Ocular and orbital metastatic carcinoma. Ann Ophthalmol 1979; 11 :869-73. Castro PA, Albert OM, Wang WJ, Ni C. Tumors metastatic to the eye and adnexa. Int Ophthalmol Clin 1982; 22(3):189-223. Lawson A. Secondary contracting scirrhus of orbit. Trans Ophthalmol Soc UK 1910; 30:236-7. Larmande A, Rossazza C. Metastases orbitaires enophthalmiantes. Ophthalmologica 1979; 179:25-31. Barroche G, Gehin P, Salmon 0, et al. Enophthalmie-ophtalmoplegie par metastase orbitaire d'un carcinome mammaire. Rev Otoneuroophtalmol1979; 51 :447-53. Cline RA, Rootman J. Enophthalmos: a clinical review. Ophthalmology 1984; 91 :229-37. Reifler OM. Orbital metastasis with enophthalmos; a review of the literature. Henry Ford Hosp Med J, in press. Sidrys L. Letter to the editor. Ophthalmology 1981; 88:379. Reifler OM, Kini SR, liu 0, littleton RH. Orbital metastasis from prostatic carcinoma; identification by immunocytology. Arch Ophthalmol1984; 102:292-5. Winkler CF, Goodman GK, Eiferman RA, Yam LT. Orbital metastasis from prostatic carcinoma; identification by an immunoperoxidase technique. Arch Ophthalmol1981; 99:1406-8. Carriere VM, Karcioglu ZA, Apple OJ, Insler MS. A case of prostate carcinoma with bilateral orbital metastases and the review of the literature. Ophthalmology 1982; 89:402-6.
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25. Kennerdell JS, Dekker A, Johnson BL, Dubois PJ. Fine-needle aspiration biopsy; its use in orbital tumors. Arch Ophthalmol 1979; 97: 1315-7. 26. Krohel GB, Tobin DR, Chavis RM. Inaccuracy of fine needle aspiration biopsy. Ophthalmology 1985; 92:666-70. 27. Kennerdell JS, Siamovits TL, Dekker A, Johnson Bl. Orbital fine-needle aspiration biopsy. Am J Ophthalmol1985; 99:547-51. 28. Jakobiec FA, Iwamoto T, Knowles OM II. Ocular adnexal lymphoid tumors, correlative ultrastructural and immunologic marker studies. Arch Ophthalmol1982; 100:84-98. 29. Mirecki OM, Jordan VC. Steroid hormone receptors and human breast cancer. Lab Med 1985; 16:287-94. 30. DeSombre ER, Carbone PP, Jensen EV, et aI. Steroid receptors in breast cancer. N Engl J Med 1979; 301: 1011-2. 31. Hansen HJ, Snyder JJ, Miller E, et al. Carcinoembryonic antigen (CEA) assay; a laboratory adjunct in the diagnosis and management of cancer. Hum Patho11974; 5:139-47. 32. Knight WA III, livingston RB, Gregory EJ, McGuire Wl. Estrogen receptor as an independent prognostic factor for early recurrence in breast cancer. Cancer Res 1977; 37:4669-71. 33. Hubay CA, Pearson OH, Marshall JS, et al. Adjuvant therapy of stage II breast cancer: 48-month follow·up of a prospective randomized clinical trial. Breast Cancer Res Treat 1981; 1:77-82. 34. Raemaekers JM, Beex LV, Koenders AJ, et al. Concordance and discordance of estrogen and progesterone receptor content in sequential biopsies of patients with advanced breast cancer: relation to survival. Eur J Cancer Clin Oncol 1984; 20:1011-8. 35. Clark GM, McGuire WL, Hubay CA, et al. Progesterone receptors as a prognostic factor in stage II breast cancer. N Engl J Med 1983; 309:1343-7. 36. Gross GE, Clark GM, Chamness GC, McGuire Wl. Multiple progesterone receptor assays in human breast cancer. Cancer Res 1984; 44:836-40.
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Abstract: A 62-year-old woman was seen for evaluation of an orbital tumor. Recognition of a relatively rare syndrome of pain, ptosis, and a progressively immobilized globe with enophthalmos suggested the diagnosis of metastatic carcinoma to the left orbit. In this case, this was confirmed by open breast and orbital biopsies, revealing infiltrating lobular breast carcinoma. This is the first reported case where estrogen and progesterone receptors were identified in a metastatic orbital tumor using fluorescent histochemical techniques. This technique was of value in confirming the diagnosis and providing direction for subsequent endocrinologic palliative therapy. [Key words: breast cancer, carcinoembryonic antigen, enophthalmos, estrogen and progesterone receptors, fine-needle aspiration biopsy, fluorescence microscopy, histochemistry, metastatic carcinoma, orbital tumors.] Ophthalmology 93:254-259, 1986
Breast carcinoma is the most commonly identified primary source of carcinoma metastatic to the orbit. I- 5 Orbital metastasis of breast carcinoma may take the form of a diffusely infiltrating scirrhous tumor leading to a classic picture of pain, ptosis, and a progressively immobilized globe with enophthalmos. 2,6 Other protean ophthalmic manifestations of breast carcinoma include an insidious pseudoinflammatory involvement of the ocular adnexa, intracranial metastasis with papilledema, Horner's syndrome, and choroidal tumors. 6 ,7 Metastatic breast carcinoma is frequently susceptible to hormonal manipulation, through surgical ablation of endocrine glands or by pharmacologic hormonal therapy.8 Responsiveness to hormonal manipulation has been correlated with the presence or absence of steroid hormone receptors in breast cancer epithelium. 8- 1O This report describes a unique case of infiltrating lobular breast carcinoma in which both estrogen and progesterone receptors were identified in both the primary tumor and an orbital From the Department of Surgery (Ophthalmology): Michigan State University. Blodgett Memorial Medical Center, Butterworth and Saint Mary's Hospitals. the Western Michigan Ambulatory Surgical Center, and the Department of Pathology.t Blodgett Memorial Medical Center, Grand Rapids. Michigan. Supported in part by a grant from the Cancer Research Fund, Blodgett Memorial Medical Center, Grand Rapids, Michigan. Reprint requests to David M. Reifler, MD, 221 East Paris Medical Building, 1000 East Paris Road SE, Grand Rapids, MI 49506.
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metastasis, using fluorescent steroid histochemical techniques. IO- 12 This case also emphasizes the potential role of the ophthalmologist in the initial diagnosis and management of occult disseminated malignancies.
CASE REPORT A 62-year-old woman was seen in consultation for evaluation of a left orbital tumor. During the previous six months she had become aware of progressively increasing pain in the left orbital region that was associated with left upper lid ptosis and diplopia. Her medical history was negative except for arthritis of the left hip. Previous evaluation by her referring ophthalmologist and a consulting neurosurgeon had disclosed a left orbital tumor, demonstrated by computed tomographic (CT) scan (Fig 1). On examination, the visual acuity was 20/20 in the right eye and 20/80 in the left eye. The left pupil was dilated and showed an afferent defect. There was a mild inferior and temporal displacement of the left globe which showed severely limited ductions, resistance to retropulsion and about 1.5 mm of measured enophthalmos (Fig 2). There was a moderate ptosis of the left upper lid but the blinking mechanism was impaired. Slit-lamp examination revealed central and inferior corneal erosions. Ophthalmoscopic examination disclosed very mild edema of the left optic disc. A-scan and B-scan ultrasonography demonstrated an infiltrating lesion in the superior-medial left orbit that showed relatively poor sound transmission and an irregular orbital fat pattern (Fig 3). Fluorescein angiography demonstrated late staining of the left optic disc.
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Fig 3. B-scan ultrasonogram demonstrating a nonencapsulated mass with relatively poor sound transmission and an irregular orbital fat pattern. Fig 1. A 62-year-old woman with left upper lid ptosis. Enophthalmos with ophthalmoplegia and inferior-temporal displacement of the left globe was present.
Fig 2. Computed tomographic scan demonstrating an infiltrating mass in the medial and superior left orbit.
In view of the clinical, CT and ultrasonographic findings, a general physical examination was performed that revealed a left breast mass and left axillary lymphadenopathy. Subsequent bilateral mammography confirmed probable carcinoma of the left breast. A metastatic work-up included a normal chest roentgenogram, and results of liver function studies were within normal limits. Serum carcinoembryonic antigen (CEA) level was 2.2 ng/ml (normal values, below 2.5 ng/ml). As an outpatient, the patient underwent an open biopsy of the left breast and a fineneedle aspiration biopsy of the left orbital mass was performed at the same time, while the patient was under general anesthesia. The specimens from the orbital aspiration were nondiagnostic as were specimens from a second fine-needle aspiration biopsy, performed subsequently as an office procedure. Following this, the patient was admitted to the hospital where an open left orbital biopsy was performed, utilizing both medial and temporal incisions.
PATHOLOGIC FINDINGS BREAST BIOPSY SPECIMEN
Grossly, the tumor was creamy white, poorly circumscribed and indurated. Microscopically (Fig 4), there was diffuse infiltration of small carcinoma cells arranged in a concentric fashion around otherwise normal appearing ducts. Many of the cells were rather bland in appearance,
with pale staining cytoplasm and occasional fine vacuolization. Stains with mucicarmine revealed occasional fine vacuolization. Stains with mucicarmine revealed occasional mucin-staining cells associated with a signet-ring morphology. Small foci oflobular carcinoma in situ were present. The histopathologic diagnosis was infiltrating lobular breast carcinoma. Receptor assays9,10 were performed on a homogenized fresh-frozen portion of the specimen and showed a concentration of estradiol receptor of 42.8 femtomoles/mg cytosol protein (expected values for positive results are greater than 10 femtomoles/mg). The cryostat sections were also studied histochemicallylO-12 and found to be positive for both estrogen and progesterone receptors. The receptor tracers used were fluorochrome conjugates: 17-beta-estradiol-6-carboxymethyl oxime-bovine serum albumin-fluorescein isothiocyanate (estradiol-BSA-FITC) and 1 l-alphahydroxyprogesterone hemisuccinate-bovine serum albumin-tetramethylrhodamine isothiocyanate (progesterone-BSA-TMRITC). After incubation with the tracers, the estrogen-binding sites appeared apple-green, and the progesterone-binding sites showed an orange-red fluorescence when examined with a fluorescence microscope equipped with appropriate filters (Fig 5). ORBITAL FINE-NEEDLE ASPIRAnON BIOPSY
Specimens from both of the fine-needle aspiration biopsy attempts were hypocellular, revealing only a rare cluster of cells including pigment laden macrophage cells and erythrocytes. Although no atypia was noted, the material was considered insufficient for diagnosis. OPEN ORBITAL BIOPSY SPECIMEN
Grossly, the fragments of orbital fat were grayish-yellow in color and firm and gritty in texture. Microscopically (Fig 6), the neoplastic cells were similar in size, architectural arrangement and infiltrative pattern to the neoplastic cells present in the breast. Cryostat sections of the open orbital biopsy specimens were studied for estrogen and progesterone receptors using identical methods to those used for the open breast biopsy 255
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Fig 4. Top, photomicrograph of breast biopsy specimen revealing infiltrating lobular breast carcinoma. Leji, small carcinoma cells locally infiltrating the breast parenchyma (hematoxylin-eosin, original magnification X250). Right, occasional mucinpositive cytoplasmic vacuoles with nuclear displacement giving a "signet-ring" appearance (mucicarmine, original magnification X400). Fig 5. Second row, fluorescence photomicrographs of breast biopsy specimen with cytoplasmic staining in tumor cells for (leji) estrogen receptors (estradiol-BSAFITC, original magnification X250), and (right) progesterone receptors (progesteroneBSA-TMRITC, original magnification X540). Fig 6. Third row, photomicrograph of orbital biopsy specimen revealing small cell malignancy with an infiltrating pattern similar to the primary tumor (see Fig 4) (hematoxylin-eosin, leji, original magnification X I00; right, original magnification X250). Fig 7. Bottom, fluorescence photomicrographs of orbital biopsy specimen with cytoplasmic staining in tumor cells for (leji) estrogen receptors (estradiol-BSA-FITC, original magnification X250) and (right) progesterone receptors (progesterone-BSATMRITC, original magnification X250).
(see above). Again, both the estrogen and progesterone binding sites were delineated by the fluorescent tracers (Fig 7).
SUBSEQUENT COURSE Subsequent evaluation disclosed lytic destructive changes in the region of the left iliac bone, suggestive of 256
additional disseminated metastatic carcinoma. The patient was begun on oral tamoxifen citrate, and she was also given local radiation therapy, using an 18 MEV linear accelerator. Ten MEV photons were employed to treat the left orbit with a total of 4600 rad in divided doses over a four-week period. A total of 4500 rad were also administered to the left pelvis and femur in 18 fractions over 24 days. In addition, daily oral cytoxan and weekly intravenous administration of 5-fluorouracil and methotrexate was instituted.
REIFLER AND DAVISON
Six months following the institution of this therapy, the patient was without pain and ambulating without any difficulty. Best corrected visual acuity improved to 20/20 in the right eye and 20/25 in the left eye. The ductions in the left eye were significantly improved and diplopia was less severe in the primary position, although the patient still preferred to occlude the left lens on her glasses. Both lagophthalmos and levator function on the left side had improved considerably, and this was associated with improvement in the superficial keratopathy. Hertel exophthalmometry measurements showed a slight increase (up to 3 mm) in the left enophthalmos. The papilledema resolved but a dilated and deafferented pupil was still present as was the relative corneal hypesthesia.
DISCUSSION The diagnosis of orbital metastasis of breast carcinoma may be suspected in women with a known primary and documented evidence of widespread metastases. Because the prior occurrence of breast carcinoma may be quite remote in some cases, a careful history of any previous cancer or surgery should be obtained. Following a thorough clinical examination, orbital ultrasonography and computed tomography should be obtained along with appropriate consultations. Computed tomography greatly facilitates accurate noninvasive characterization and localization of the tumorY As illustrated by this case, the diagnosis of metastatic breast carcinoma should be considered even when there is no history of breast cancer. In this case the diagnosis was strongly suspected in view of the clinical presentation of pain, ptosis, ophthalmoplegia, and enophthalmos combined with the computed tomographic findings of an irregular infiltrating orbital mass. In patients with a history of primary breast carcinoma, ophthalmic signs and symptoms frequently present the first evidence of metastatic disease. 6 Ferry and Font3 found that symptoms of ocular or orbital involvement from breast carcinoma precede recognition of the primary tumor in only about 9% of cases. A remote history of primary breast carcinoma has been found to be far more typical in such cases of orbital metastasis; the average interval between primary and secondary tumors has generally been reported to be about 5 years. 6.14,IS This is in contrast to metastatic lung tumors, where about two-thirds of patients had evidence of ocular or orbital metastasis before the detection of the primary tumor.3 The first reported case of enophthalmic orbital metastasis was given by Lawson in 1910. 16 To date, about 23 additional cases have been cited in the world literature. 2,4,I?-19 Of these, the majority have been metastases from breast carcinoma. The other less frequently encountered primary sites have been the stomach and other abdominal sites,z·17,18 The rather unusual clinical presentation of this patient prompted one of us to analyze the aforementioned cases on the subject of orbital metastasis
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with enophthalmos, and this review was described recently elsewhere. 2o Some oncologists feel that orbital metastasis from breast carcinoma without lymphadenopathy, in the presence of a negative metastatic work-up, is best treated by radiation therapy, without orbital biopsy,z1 However, many authorities believe that a needle biopsy specimen or an open biopsy specimen should be obtained before radiation therapy, to avoid treating patients inappropriately that have an unrelated second disease.? In some cases of metastatic carcinoma to the orbit, microscopic examination for tissue-specific immunologic markers in aspiration 22 or open biopsy specimens23 can specifically confirm the histogenesis of the tumor. In one previously reported case of an orbital metastasis from prostatic carcinoma, the presence of a hormone (androgen) receptor in the tumor cytoplasm was documented. 24 In the case reported herein, two attempts at fine-needle aspiration biopsy were nondiagnostic. In retrospect, the negative results are not surprising. A negative fine-needle aspiration biopsy has been noted to be particularly characteristic of tumors with a predominantly fibrous matrix where intercellular cohesion is strong and cellularity is diminished,zs The scirrhous nature of most orbital tumors that produce enophthalmos has been emphasized by Henderson2 and substantiated by others. 2o In cases of suspected orbital metastasis with enophthalmos, an orbital fine-needle aspiration biopsy should probably be bypassed for more definitive procedures. Although orbital fine-needle biopsy has a low rate of complications, selection of patients is still advisable. For example, the accuracy rate of orbital fine-needle aspiration biopsy is about half that achieved when patients are carefully selected. 26,2? Some authors have recommended a large bore-needle biopsy (16-18 -gauge) in patients who are debilitated to the point that general anesthesia is inadvisable.? The large boreneedle can obtain a cylinder of tissue that is readily processed by paraffin embedding rather than cytologic techniques. In this case, however, an open orbital biopsy was subsequently chosen. In the evaluation of orbital tumors, many authorities proceed directly to an open orbital biopsy, particularly in cases of presumed primary lesions. 26 Fine-needle aspiration biopsy precludes a comprehensive determination of certain cell surface markers (as in lymphoid lesions) or useful ultrastructural information obtainable only through electron microscopy.26,28 Using open orbital biopsies and assay techniques on homogenized tissue, Bullock and Yanes6 were first able to demonstrate the presence estrogen receptor in three patients with breast carcinoma metastatic to the orbit. This assay, which was performed on the primary tumor in this case, involves the addition of radioactive estradiol to 1 ml of homogenized fresh-frozen tissue. The presence of estradiol and progesterone receptors have not been previously demonstrated in an orbital metastasis using fluorescent histochemical methods on freshfrozen tissue. Unlike the earlier studies on orbital metastatic lesions,6 both estrogen and progesterone receptors were identified. Based on the results of this case and other 257
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histochemical studies of primary and metastatic breast tumors, 10, II it would seem that fluorescent histochemical study of cryostat sections is a useful method of documenting the presence or absence of estrogen and progesterone receptors in orbital metastasis from breast carcinoma. It should be noted that a variety of techniques have been developed to analyze steroid hormone receptors in breast neoplasms. 29 These methods have taken the form of either of tissue assays or histochemical demonstration (Table 1).29,30 Among these techniques, the use of monoclonal antibodies may have greater sensitivity since these antibodies can bind to sites already occupied by steroid hormone and to partially denatured sites. 29 However, new histochemical receptor assays remain to be further validated against standard quantitative assays.30 The accepted standard assays have utilized either sucrose density gradient sedimentation or dextran-coated charcoal. 29 Other ancillary tests, such as the serial measurement of serum carcinoembryonic antigen (CEA), have been applied in cases of metastatic breast carcinoma6 and other types of carcinoma. 31 In cases of breast carcinoma, however, this test is less useful than studies of steroid hormone receptors and, as demonstrated by this case, serum levels of CEA may be normal. Approximately 50 to 60% of women with breast tumors containing estrogen receptor respond objectively to endocrine therapy, while less than 15% of women with breast tumors lacking estrogen receptor have a favorable objective response.9 Tumors, either primary or metastatic, showing the highest estrogen receptor content have the highest regression rates with endocrine therapy.8 The response rate increases to 78% of patients with breast tumors containing receptors for both estrogen and progesterone. 8,9 The presence of estrogen receptors in breast cancers has been generally accepted as a predictor of extended diseasefree survival. 32- 34 Progesterone receptor analysis has also been found to be of predictive value in cases of breast carcinoma. In the early stages of breast cancer, Clark et al 35 found that the measurement of progesterone receptor levels had an even greater predictive value for disease-free survival than estrogen receptors. Gross et al 36 found that when progesterone receptors were initially present but subsequently absent, there was a poorer survival than when the presence of progesterone receptors was retained. However, Raemaekers et al 34 failed to confirm any independent predictive value of progesterone receptor status, either in the initial biopsy specimen or in sequential biopsy analyses. In summary, when a disseminated malignancy presents initially with symptoms in the orbital region, the ophthalmologist is in a unique position to make the correct diagnosis and to expediently refer the patient for further evaluation and treatment. As illustrated by this case, special laboratory studies can be used as an aid in the diagnosis and management of disseminated cancer. Although the fluorescent histochemical demonstration of hormone receptors was highlighted in this report, the availability of other methods should also be considered in the course
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Table 1. Steroid Hormone Receptors: Methods of Analysis Quantitative assays Sucrose density gradient (SDR) analysis Dextran-coated charcoal (DCC) assays Monoclonal antibody assays Enzyme-linked immunochemical assay (EIA) Immunoradiometric assay (IRMA) Histochemical methods Fluorescein-coupled estradiol Estradiol antibody with fluorescent second antibody Steroid-albumin fluorescein Peroxidase-antiperoxidase (PAP) method Avidin-biotin-complex (ABC) method
of diagnostic evaluation. Finally, the unreliability of fineneedle aspiration biopsy in cases of suspected scirrhous orbital metastasis should be recognized. In such cases, particularly in the presence of enophthalmos and ophthalmoplegia, it is reasonable to proceed directly to an open orbital biopsy in order to confirm the pathologic diagnosis.
ACKNOWLEDGMENTS Drs. Mark Moleski, Lynn Hedeman and Willard Stawski participated in the diagnostic evaluation of the patient. Drs. Anna Broecker, Martin Cloherty and Dale Kessler examined the pathologic specimens. Mike Brown proofread the manuscript. The authors gratefully acknowledge their contributions.
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25. Kennerdell JS, Dekker A, Johnson BL, Dubois PJ. Fine-needle aspiration biopsy; its use in orbital tumors. Arch Ophthalmol 1979; 97: 1315-7. 26. Krohel GB, Tobin DR, Chavis RM. Inaccuracy of fine needle aspiration biopsy. Ophthalmology 1985; 92:666-70. 27. Kennerdell JS, Siamovits TL, Dekker A, Johnson Bl. Orbital fine-needle aspiration biopsy. Am J Ophthalmol1985; 99:547-51. 28. Jakobiec FA, Iwamoto T, Knowles OM II. Ocular adnexal lymphoid tumors, correlative ultrastructural and immunologic marker studies. Arch Ophthalmol1982; 100:84-98. 29. Mirecki OM, Jordan VC. Steroid hormone receptors and human breast cancer. Lab Med 1985; 16:287-94. 30. DeSombre ER, Carbone PP, Jensen EV, et aI. Steroid receptors in breast cancer. N Engl J Med 1979; 301: 1011-2. 31. Hansen HJ, Snyder JJ, Miller E, et al. Carcinoembryonic antigen (CEA) assay; a laboratory adjunct in the diagnosis and management of cancer. Hum Patho11974; 5:139-47. 32. Knight WA III, livingston RB, Gregory EJ, McGuire Wl. Estrogen receptor as an independent prognostic factor for early recurrence in breast cancer. Cancer Res 1977; 37:4669-71. 33. Hubay CA, Pearson OH, Marshall JS, et al. Adjuvant therapy of stage II breast cancer: 48-month follow·up of a prospective randomized clinical trial. Breast Cancer Res Treat 1981; 1:77-82. 34. Raemaekers JM, Beex LV, Koenders AJ, et al. Concordance and discordance of estrogen and progesterone receptor content in sequential biopsies of patients with advanced breast cancer: relation to survival. Eur J Cancer Clin Oncol 1984; 20:1011-8. 35. Clark GM, McGuire WL, Hubay CA, et al. Progesterone receptors as a prognostic factor in stage II breast cancer. N Engl J Med 1983; 309:1343-7. 36. Gross GE, Clark GM, Chamness GC, McGuire Wl. Multiple progesterone receptor assays in human breast cancer. Cancer Res 1984; 44:836-40.
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