Ocular Pathology for Clinicians Edited by Frederick A. Jakobiec, MD

Metastatic Carcinoid Unresponsive to Radiation Therapy Presenting as a Lacrimal Fossa Mass RICHARD D. DIVINE, MD, RICHARD L. ANDERSON, MD, KARL C. OSSOINIG, MD

Abstract: A case of metastatic carcinoid tumor presenting as a lacrimal fossa mass is described. This appears to be only the fourth case report of metastatic carcinoid to the orbit and the first to include ultrasound evalu­ation. The tumor mass did not regress despite radiation therapy as documented on serial ultrasound examinations. Therapeutic implica­tions of this finding are discussed. Metastatic carcinoid tumors are re­viewed. [Key words: lacrimal tumor, metastatic carcinoid, metastatic or­bital tumor, radiation.] Ophthalmology 89:516-520, 1982

Metastatic carcinoma to the orbit is rare, accounting for only 2-5% of all orbital tumors.1.2 Of these, the majority are secondary to metastatic breast or lung carcinoma. A highly unusual case of carcinoid tumor metastatic to the orbit presenting as a lacrimal fossa mass that did not resolve with radiation therapy is presented. To the authors' knowledge, this is only the fourth case report of carcinoid metastatic to the orbit and the first to include ultrasound evaluation and to document a lack of response to radiation therapy via serial ultrasound examinations.

CASE REPORT

A 70-year-old white woman was first referred to the Orbi­tal Service at the University of Iowa on 11/18/80 with a

From the Orbital and Echography Services, Department of Ophthalmology, University of Iowa Hospitals and Clinics, Iowa City, Iowa.

Supported by grant number 889, awarded by the National Cancer Institute, Department of Health, Education, and Welfare.

Dr. Divine is currently at 2004 Peachtree Road , NW, Atlanta, GA 30367.

Reprint requests to Richard L. Anderson , MD, Department of Ophthalmology, University of Iowa Hospitals and Clinics, Iowa City, IA 52242.

four-week history of painful progressive swelling about the right eye and associated erythema of her eyelids. She had been in her usual state of good health until February 1979 when she underwent a laparotomy for an incomplete bowel obstruction. A carcinoid tumor of her ilium with mesenteric involvement was diagnosed. In addition, she was noted to have bilateral ovarian metastases that were excised. Sub­sequent work-up showed questionable metastatic defects on her liver and bone scans .

Over the ensuing year, she did well save for intermittent bouts of diarrhea that were well controlled on choles­tyramine bid.

In March 1980, she was extensively re-evaluated for metastatic disease. Her liver scan now showed definite per­fusion defects. Her bone scan showed positive uptake over her right humerus and ninth rib. A 24-hour urinary S-hy­droxyindole acetic acid (S'-HIAA) was elevated, for the first time, at 141 mg (NI < 10 mg). Chest x-ray and barium enema revealed no abnormalities.

She was first seen on 11118/80 (Fig I). At that time her vision was 20/20-2 in both eyes. She had 4 mm of right proptosis, and the globe was displaced approximately 3 mm inferiorly and 2 mm nasally. She was orthophoric and had full ductions save for -I limitation to abduction on her af­fected side . There was a palpable mass in the lacrimal fossa. Other than choroidal folds in the superotemporal aspect of her ocular fundus from local mass effect, the rest of her ocular exam was within normal limits . Admission laboratory results including liver function studies were unremarkable. A repeat 24-hour urinary S'-HIAA was markedly elevated at

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DIVINE, et al • OCULAR PATHOLOGY FOR CLINICIANS

Fig 1. Clinical appearance at time of presentation shows several millimeters of right proptosis with inferonasal displacement of the globe secondary to a lacrimal fossa mass. Fig 2. Caldwell view showing decreased transparency of the right

orbit with thinning of the lateral wall.

Fig 3. Left, B-scan echograms displayed at maximum system sensitivity (top) and at 19db under maximum sensitivity (bottom) show tumor (t) next to globe (g) indenting the ocular wall (w) and excavating (-+) the bony orbital wall (b). Right, standardized A-scan echogram at tissue sensitivity (top) shows medium reflectivity, interlaced septa (s), and large angle kappa (K = angle between baseline of echogram and line placed through centers of tumor spikes) indicating strong sound attenuation. At low measuring sensitivity (bottom) surface spike is double­peaked suggesting a capsule (c).

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Fig 4. CAT scan demonstrating a circumscribed mass in the superotemporal aspect of the right orbit.

218 mg (NI < 10 mg). A skull series showed decreased transparency of the right orbit with thinning of the lateral wall (Fig 2). Tomography verified the thinning but showed no erosive changes. A-scan echography revealed a large, oval-shaped, hard, nonvascularized solid tumor with internal septa. The tumor showed medium high reflectivity and strong sound absorption (ie, large angle kappa) a combina-

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tion that, so far, has only been observed in adenoid cystic carcinoma of the lacrimal gland. Its surface was slightly lobulated, encapsulated, and appeared to excavate the bone (Fig 3). A CAT scan verified its location (Fig. 4). The lesion enhanced with contrast.

On 11124/80, an orbitotomy and biopsy were undertaken to rule out the possibility of a lacrimal gland tumor or confirm the presence of metastatic carcinoid. The lesion was seen to protrude anteriorly around the edge of the bony orbit. A biopsy of the mass was taken through the orbital septum. The tumor itself was blue-purple in color and mushy in con­sistency once the capsule had been opened. Frozen section showed a metastatic carcinoid tumor. There appeared to be involvement of the underlying bone that was mottled and spongy. The permanent pathologic specimen showed a char­acteristic pattern for carcinoid and stained positively for argentiffin and argyrophil granules that verified the diagnosis (Fig 5).

The patient was referred to radiation therapy where 4000 rads were given locally over a four-week period at a 6-cm depth via a fixed, appositional field with 18 MeV electrons (20 sessions). Treatment was completed on 119/81.

During and following radiation therapy, she was followed closely with serial echograms that showed no significant change in tumor size (Fig 6). At four months following treat­ment, she continued to have a mass in the lacrimal fossa with 3 mm of right proptosis. Six months later she died of meta­static carcinoid.

Figs SA-C. A, top left, sections show serpiginous ribbons of neoplastic cells. The nuclei are hyperchromatic and uniform. Pleomorphism is minimal (hematoxylin-eosin, x 1(0). B, top right, fontana-Masson stain is positive for argentaffin granules in the neoplastic cells (x 1(0). C, left, grimelius stain is positive for ar­gyrophil granules in the neoplastic cells (x 1(0).

DIVINE, et al • OCULAR PATHOLOGY FOR CLINICIANS

Fig 6. Echogram showing maximum sagittal extension of the tumor in the 10:30 meridian of the orbit. Echograms at tissue sensitivity obtained before (11124/80), during (12116/80, 12/22/80), and after (2/ 17/81, 4/9/81) radiation therapy are displayed on the left (top to bot­tom) and show no significant change in tumor size. Corresponding echograms on the right are recorded at measuring sensitivity.

DISCUSSION

Metastatic carcinoid to the orbit is an extremely rare entity with only three previous case reports in the lit­erature.3 - 5 Despite the fact that carcinoid is the most common endocrine neoplasm of the digestive tract, metastasis tothe orbit rarely occurs. This must be dis-

tinguished from metastasis to the eye, which has been well described. 6- 8

The term carcinoid was first suggested by Obern­dorfer in 1907 to emphasize the malignant appear­ance but benign course of the tumor. Carcinoid is a primary disorder of argentaffin and other serotonin secreting cells. Most carcinoids arise from the gas­trointestinal (GI) tract, although primaries from lung, ovary, and testis have been described. One report of over 3000 cases shows the appendix as the most com­mon site of origin, accounting for over 40% of the tumors.9 The ilium, rectum, and bronchi account for another 12-14% each. Harrison reports that ileocecal primaries (as in this case) account for 80-95% of the tumors. to They are multiple in 15-25% of cases. Most are slow growing and are symptomatic early through local mass effect. Systemic effects appear later sec­ondary to the vasoactive substances that they liberate.

It is interesting that carcinoids arising from different sites characteristically behave as different tumors: ap­pendical tumors rarely metastasize and have a five­year survival rate of 99%; bronchial carcinoids occa­sionally metastasize and have a survival rate of 87%; tumors of the ileocecum, colon, and stomach fre­quently metastasize to liver, regional nodes, and bone and have a five-year mortality of 50%. 9 In addition, the various tumor sites appear to secrete different vasoac­tive substances: intestinal carcinoids secrete serotonin while bronchial and gastric carcinoids secrete 5'-HTP, a serotonin precursor. to

It is important to differentiate between carcinoid tumor and carcinoid syndrome. One may have the tumor, but need not have the clinical syndrome. The syndrome is characterized by paroxysmal vasomotor disturbances (cutaneous flushing, salivation, lacrima­tion, tachycardia), GI symptoms (cramps, diarrhea, borborygmi), respiratory complaints (wheezing, dys­pnea), and cardiac changes (endocardial fibrosis). The symptoms originally were felt to be caused by the high levels of circulating serotonin. More recently it has become evictent that the symptom complex is second­ary to a complicated interaction of various released kinins, histamine, and vasoactive substances in addi­tion to serotonin.

Ophthalmic manifestations of the syndrome have recently been reviewed by Wong and MelmonY They described a pronounced injection of the bulbar con­junctiva associated with marked lacrimation and periorbital edema in 16 patients with known carcinoid tumor when challenged with an epinephrine bolus. In addition, they found retinal arterial vasoconstriction with sludging, a precipitous decrease in ophthalmic artery pressure, and retinal pigment clumping in many.

It is interesting that the syndrome is usually a late finding in the disease process and is usually associated with metastatic liver disease. A healthy liver will nor­mally detoxify vasoactive substances presented from the venous circulation and therefore protect the sys­temic arterial circulation from its side effects. It is not until the liver has been compromised and no longer is

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able to detoxify sufficiently these substances that the syndrome presents. This is not true, however, for bronchial carcinoids that secrete serotonin precursors directly into the arterial circulation.

The case here is typical in that the patient had an ileocecal primary presenting as intermittent bowel obstructions secondary to mass effect. She had slow­ly progressive disease and probable metastatic liver and bone involvement. She only developed the full­blown carcinoid syndrome as her liver presumably became more damaged. It is most unusual that she developed a metastatic orbital lesion as part of her disease process.

This case is informative in that it is the first time that orbital ultrasound has been described on this tumor. A-mode ultrasound demonstrated a well-outlined, oval-shaped, hard, non vascularized solid tumor with internal septa. This physical make-up was verified on pathologic examination of the specimen. More cases are needed, however, to further evaluate whether these findings are characteristic for this tumor.

This case is also interesting in that serial ultrasound measurements allowed the investigators to demon­strate quantitatively insignificant tumor shrinkage de­spite radiation therapy. The effectiveness of radiation therapy for carcinoid tumors is anecdotal and remains unproven. There are several isolated case reports where radiation was felt to be of benefit. Gaitan-Gaitan et al controlled five of ten patients with inoperable abdominal carcinoid tumor with total abdominal ir­radiation. 12 Rush et al reduced proptosis and relieved ocular symptoms within two months of delivering 3,500 rads of radioactive cobalt to the orbit of a patient with metastatic carcinoid from the colon.5 This treat­ment modality, however, remains controversial. Curi­ously, no mention of radiation therapy for carcinoid tumors is made in the standard radiation therapy textbooks .13.14 In this case, serial ultrasonic mea­surements demonstrated no change in tumor size de­spite treatment with 4000 rads to the involved area four months earlier. It is stressed that radiation therapy may not be the treatment of choice for all cases of carcinoid tumor, that radiation response is unpredicta-

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ble, and that surgical debulking at the time of biopsy may be indicated despite the possible later use of radi­ation.

ACKNOWLEDGMENTS

The authors would like to acknowledge gratefully Jane Duwa who typed this manuscript and John Fratkin who pro­vided the pathologic evaluation.

REFERENCES

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3. Honrubia FM, Davis WH, Moore MK, Elliot JH. Carcinoid syndrome with bilateral orbital metastases. Am J Ophthalmol 1971; 72:1118-21.

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13. Fletcher GH: Textbook of Radiotherapy, 3rd ed. Philadelphia: Lea and Febiger, 1980.

14. Moss WT, Brand WN, Battifora H. Radiation Oncology; Ratio­nale, Technique, Results, 5th ed. St Louis: CV Mosby, 1979.