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Endocrine Care |
Departments of Endocrinology (A.M.I., G.K., V.F., B.K., J.P.M., A.B.G., G.M.B.), Ophthalmology (R.A.F.W.), Clinical Oncology (P.N.P.), and Nuclear Medicine (K.E.B.), St. Bartholomew’s Hospital, London, United Kingdom EC1A 7BE
Address all correspondence and requests for reprints to: Prof. A. B. Grossman, Department of Endocrinology, St. Bartholomew’s Hospital, London, United Kingdom ECIA 7BE. E-mail: . a.b.grossman{at}qmul.ac.uk
Abstract
Ocular metastases from carcinoid tumors are considered rare. They can be the primary presentation of a carcinoid tumor or develop during the course of the disease. The extent of distant metastases from carcinoid tumors correlates with poor prognosis and survival; early detection of metastasis may change the overall management. Radiopharmaceutical-labeled imaging techniques have been widely applied for the detection and localization of such lesions based on isotope uptake by neuroendocrine tumors. Routine application of these imaging modalities may reveal previously unsuspected lesions and may also be used to help stage the disease and to identify patients who may be treated with radiopharmaceuticals. Of 40 patients with carcinoid tumors reviewed in our department since we started routine scanning, we identified 6 (15%) who demonstrated ocular metastases: 5 with obvious lesions and 1 with presumed metastasis according to the results of nucleotide scanning. All 6 were negative on screening with [123I]meta-iodobenzylguanidine, whereas 3 of 4 who were screened with [111In]octreotide showed positive uptake. All patients responded well to radiotherapy and chemotherapy and did not require surgical treatment. The orbit and its contents appear to be a common site for carcinoid metastasis, and radiopharmaceutical imaging with labeled octreotide is useful in identifying many of these lesions.
CARCINOID TUMORS are mostly low grade neoplasms arising from neuroendocrine cells of the bronchial and gastrointestinal tracts or, more rarely, from other tissues, such as the ovary, larynx, thymus, kidney, prostate, or skin (1, 2). These tumors are characterized by the presence of neurosecretory granules and may be associated with neurosecretory syndromes (1, 2). Although originally thought to be of low malignant potential, clinically evident carcinoid tumors metastasize in 50–75% of patients, the most common sites of metastases being lymph nodes, liver, and bone (1, 2, 3). Carcinoid tumor metastases to the eye and orbit have been reported only rarely (3). Conventional staging imaging techniques, such as computerized tomography (CT) and magnetic resonance (MRI) imaging, as well as more specific techniques, such as fluorescein angiography, have traditionally been used to identify and further characterize such lesions, but over the last decade radiopharmaceutical-labeled imaging techniques have been widely applied to localize carcinoid lesions. These techniques are based on the specific uptake and/or binding of such radiopharmaceuticals (4); their sensitivity in detecting metastatic deposits may be different compared with the other forms of anatomically based imaging, and they can be applied to the initial staging of carcinoid tumors (5).
Meta-iodobenzylguanidine (MIBG) is a catecholamine analog that uses the amine precursor uptake mechanism and may thus be incorporated into vesicles or neurosecretory granules. Radiolabeled MIBG has been shown to possess an approximately 60% sensitivity and specificity in detecting carcinoid tumors (6, 7, 8, 9). Radiolabeled octreotide, a somatostatin analog that binds to somatostatin receptors on the cell membrane, has been shown to be more sensitive than MIBG in detecting carcinoid tumors, although less specific (7, 8, 10). The application of imaging with such peptides has detected previously clinical occult metastases in patients with carcinoid tumors and has been used to identify patients suitable for treatment with [131I]MIBG or, more recently, radiolabeled somatostatin analogs (7).
We have been performing routine imaging with both of these radiopharmaceuticals in patients with carcinoid tumors to identify previously unrecognized lesions, and to select patients who might benefit from treatment with these radiopharmaceuticals (7, 11). We now report six new cases of carcinoid tumors with ocular metastases, two of which were previously unsuspected as they were asymptomatic, whereas one was detectable only by means of radiopharmaceutical imaging. We conclude that ocular metastases are not infrequently found in patients with carcinoid tumors, and that radiopharmaceutical imaging with labeled octreotide is particularly helpful in their identification.
Subjects and Methods
Among all patients with carcinoid tumors seen in the Departments of Clinical Oncology and Endocrinology, St. Bartholomew’s Hospital (London, UK), between 1965 and 2000, 40 patients underwent radiopharmaceutical imaging with either [123I]MIBG or [111In]pentetreotide (7). From this larger series we reviewed the case records of patients with evidence of carcinoid tumors and ocular metastases (4 males and 2 females; median age, 53 yr; range, 20–80 yr). The diagnosis of a carcinoid tumor was based on clinical, biochemical, and histopathological criteria. All 6 patients underwent scintigraphy with [123I]MIBG, and 4 were also imaged with [111In]pentetreotide.
The following clinical and biochemical parameters were recorded, according to our established protocol: symptoms of the carcinoid syndrome (diarrhea, flushing, and/or bronchospasm), weight loss of more than 10%, any symptoms connected with other relevant hormonal secretion and/or associated with any local tumor compressive effect, 24-h urinary 5-hydroxyindoleacetic acid (5-HIAA) excretion, serum and urinary catecholamines, serum 
-fetoprotein, carcinoembryonic antigen, hCGß, gastrointestinal hormones (VIP, pancreatic polypeptide, gastrin, glucagon, somatostatin, and neurotensin), calcitonin, ACTH, and GHRH. All patients had a complete physical examination to identify clinically obvious metastases. The radiological assessment included conventional plain chest radiography, CT, and/or MRI of the abdomen in all patients and, when clinically indicated, CT and/or MRI scanning of the chest, bone, and brain and barium follow-through studies of the bowel. The clinical presentation and course of one of the patients (patient 3, Table 1
), and the results of a formal comparison between the radiopharmaceuticals used for nuclear imaging in some of the patients (patients 1–4), have been the subject of previous reports (7, 11, 12, 13).
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Radioactive labeled MIBG was obtained from a commercial source (Amersham International, Little Chalfont, UK). Between 130–185 MBq [123I]MIBG were injected iv over 30 sec (1 MBq = 27 x 10-3 mCi). Imaging was performed using a large field of view 
-camera (Siemens, Erlangen Germany) set with a 15% window around the photon peak of 159 keV and a parallel hole, low energy, general purpose collimator. Images for 5 x 105 counts were obtained at 10 min, 22 h, and 48 h postinjection covering the head, torso, and thighs, anteriorly and posteriorly. Images were stored on-line in a Hermes Sun workstation (Nuclear Diagnostics, Stockholm, Sweden).
[111In]Diethylenetriamine-pentaacetic acid (DTPA)-labeled pentetreotide scintigraphy (Octreoscan)
An octreotide analog, pentetreotide (Octreoscan 111, Malinckrodt Diagnostica, Petten, The Netherlands), was supplied as a radioactive preparation in single dose ampules. [111In]Pentetreotide was given as a bolus iv injection at a dose up to 120 MBq. Whole body planar images were obtained after 10 min, 4 h, and 21 h. Scanning was performed using a -camera with a large field of view (Orbiter, Siemens) interfaced to an on-line computer (Hermes, Nuclear Diagnostics). Positive scans were identified as those in which uptake of the tracer occurred in areas not normally associated with its accumulation.
Histology
All patients had histological confirmation of carcinoid tumor on tissue obtained from primary lesions or metastases, but in only one patient on tissue obtained directly from the ocular deposit. The tissues from the different patients were fixed in buffered 10% formalin and processed to paraffin wax-embedded blocks. Sections were cut at 3 µm and stained with hematoxylin and eosin, with stains for argyrophilic granules, and with immunochemistry for chromogranin and serotonin. The standard avidin-biotin complex technique was applied to all immunostains (ABC-Vectastain, Vector Laboratories, Inc., Peterborough, UK).
Treatment
Treatment of the primary carcinoid tumor included surgical resection in two patients and conventional external beam radiotherapy in one (Table 1
). Patients with disseminated carcinoid tumors were given chemotherapy with the combination of lomustine and 5-fluorouracil (5-FU) (12, 14) plus external beam radiotherapy to the metastatic lesions. Patients who showed positive uptake to scintigraphy with [123I]MIBG received treatment with [131I]MIBG (patient 2: total dose of 317 mCi, 11.7 GBq, in four doses; patient 6: total dose of 1050 mCi, 38.9 GBq, in six doses) (13), whereas one patient who had a positive octreotide scan received treatment with 90Y-labeled lanreotide (patient 3: total dose of 100 mCi, 3.7 GBq, in four doses).
Results
Patient 1
A 75-yr-old man presented with a 4-month history of diplopia and left iliac pain. MRI revealed a left orbital mass, which on histology was shown to be a carcinoid tumor; urinary 5-HIAA levels were normal. Subsequently the patient was referred to this hospital for radiopharmaceutical imaging. Scintigraphy with [123I]MIBG was negative, whereas scintigraphy with [111In]pentetreotide revealed increased uptake in the left orbit (Fig. 1), lungs, and left hilar region. The patient was treated with external beam radiotherapy to the orbital lesion (50 Gy), with a good symptomatic response lasting for the duration of follow-up (1.5 yr). He is currently being considered for treatment with an 90Y-labeled somatostatin analog.
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An 80-yr-old woman presented with a 3-month history of weight loss and flushing. Clinical examination revealed an enlarged and irregular liver; CT scanning of the abdomen confirmed multiple hepatic deposits. Histology of the hepatic lesions was consistent with metastases from a carcinoid tumor. 5-HIAA levels were elevated, and the patient was also found to have Cushing’s syndrome secondary to ectopic ACTH production. Scintigraphy with [123I]MIBG revealed increased hepatic uptake; the patient was treated with four 200-mCi doses of [131I]MIBG over a 2-yr period, with clinical and hormonal improvement and disease stabilization that lasted 3 yr. However, subsequent follow-up revealed abdominal lymph node and skeletal involvement; subsequently, she also developed two obvious firm uninflamed nodules on the conjunctiva of both the right and left lower lids (Fig. 2), synchronous with a similar nodule on her back. This latter lesion was biopsied and confirmed to be a neuroendocrine malignancy. The patient died a few months later.
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A 20-yr-old woman presented with persistent hemoptysis and a left lower lobe lung lesion, which on histology was found to be a bronchial carcinoid tumor; urinary 5-HIAA levels at that time were normal. She was initially treated with left lower lobectomy and postoperative radiotherapy, but 5 yr later she re-presented with symptoms typical of the carcinoid syndrome, hepatic metastases, and elevated 5-HIAA levels; in addition, she was found to have acromegaly secondary to ectopic GHRH secretion. Other aspects of this patients have been described previously (12). She received several courses of chemotherapy with lomustine and 5-fluorouracil, with clinical, hormonal, and objective tumoral responses. However, subsequently she developed blurring of her vision and on clinical examination was found to have bilateral choroidal metastases (one nonpigmented approximately 3 mm lesion just above the optic disc in the right eye, and two lesions of approximately 2 and 3 mm in the lower nasal and upper temporal quadrants of the left eye). She was treated with further chemotherapy, with substantial clinical improvement and regression of the choroidal lesions. During a 30-yr follow-up period she developed multiple metastatic deposits involving the thyroid, heart, ovary, and skeleton and received further courses of chemotherapy. Scintigraphy with [123I]MIBG was negative, but she had positive uptake on scintigraphy with [111In]pentetreotide and received four 25-mCi doses of 90Y-labeled lanreotide. Repeated subsequent clinical examination over 27 yr after initial ocular presentation revealed inactive choroidal lesions (Fig. 3).
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A 40-yr-old man presented with a 1-yr history of flushing and diarrhea and was found to have gross ascites and severe tricuspid regurgitation. Abdominal imaging revealed multiple hepatic deposits and a mass in the right iliac fossa; urinary 5-HIAA levels were grossly elevated, and histology of the hepatic lesions was consistent with metastatic carcinoid tumor. Scintigraphy with [123I]MIBG revealed weak hepatic uptake, precluding further treatment with [131I]MIBG, but scintigraphy with [111In]pentetreotide revealed multiple areas of hepatic uptake as well as uptake in the left orbit (Fig. 4). Ophthalmological examination did not show any ocular signs or evidence of orbital involvement. CT scan of the orbit did not show an obvious orbital lesion. The patient was treated with a combination of lomustine and 5-FU, with temporary symptomatic and hormonal improvement, but died 1 yr after the initial presentation.
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A 57-yr-old woman with a previous history of hyperparathyroidism and hypergastrinemia in the context of MEN1 syndrome presented with a 1-wk history of reduced visual acuity in the right eye and an infero-temporal quadrantic visual field defect. Clinical examination revealed hepatomegaly, whereas ophthalmoscopy showed a large amelanotic solid lesion superior to the right optic disc with associated subretinal fluid, which was suggestive of amelanotic melanoma (Fig. 5). Histology of the hepatic lesions revealed a metastatic carcinoid tumor; urinary 5-HIAA levels were elevated. Scintigraphy with [123I]MIBG was negative, whereas scintigraphy with [111In]pentetreotide showed uptake in the right orbit, liver, abdomen, and throughout the skeleton. After three courses of chemotherapy with lomustine and 5-FU, there was substantial shrinkage of the hepatic lesions, but no clinical improvement of the ocular lesion. This was therefore treated with a course of external radiotherapy, which resulted in regression of the choroidal metastasis and clinical improvement lasting for the duration of follow-up (3 yr).
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A 45-yr-old man presented with a history of hemoptysis and a pulmonary lesion in the left upper lobe. On histology this was found to be a bronchial carcinoid tumor; urinary 5-HIAA levels were normal. The patient underwent a left upper lobectomy. Six years later he complained of blurring of the vision in his right eye. Clinical examination revealed hepatomegaly and bilateral choroidal lesions, confirmed by MRI scanning (Fig. 6A). Urinary 5-HIAA levels remained normal, but the patient had clinical and biochemical evidence of Cushing’s syndrome secondary to the ectopic ACTH secretion. He was given external radiotherapy (35 cGy) to the right eye, with rapid and sustained improvement of his vision. Subsequent scintigraphy with [123I]MIBG revealed uptake in lungs and liver, but not in the eye. Based on positive [123I]MIBG therapy imaging, he received five 200-mCi doses of [131I]MIBG, with symptomatic and hormonal improvement. A decrease in mean plasma ACTH levels as well as a reduction in the required doses of medical therapy to control Cushing’s syndrome were observed. However, 2 yr later cortisol excess was inadequately controlled with metyrapone and ketoconazole, and he therefore underwent bilateral adrenalectomy. Ophthalmological examination on the most recent follow-up, 6 yr after he received radiotherapy to the orbit, revealed a large flat inactive choroidal lesion in the right eye (Fig. 6B) and normal left fundoscopy.
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Four patients had biochemical evidence of the carcinoid syndrome, and three patients had clinical and biochemical evidence of ectopic hormonal production (two ectopic ACTH and one ectopic GHRH secretion). All six patients underwent scintigraphy with [123I]MIBG, none of whom showed positive uptake in the region of the orbit. Two patients had received treatment before [123I]MIBG scanning: one was [123I]MIBG negative (patient 3), and the other (patient 6) who had strong positive [123I]MIBG uptake in lungs and liver, but not in the eye, had received radiotherapy to the orbit before radiopharmaceutical imaging. Four of the six patients had scintigraphy with [111In]pentetreotide; three of these showed ocular uptake (two in the left and one in the right orbit): all patients except one, patient 3, underwent [111In]pentetreotide scintigraphy before receiving any form of treatment.
Four patients received chemotherapy with the combination of lomustine and 5-FU (patients 3–6). Three patients received chemotherapy only for treatment of ocular metastasis. After this form of treatment there was improvement in the clinical presentation of the choroidal lesions in all patients (patients 3–5); two patients, with major mass effect and visual disturbance (patients 1 and 6), received further external radiotherapy. One patient (patient 2), who showed positive uptake in liver but not in the ocular metastasis, received [131I]MIBG therapy, with hormonal improvement and disease stabilization.
Discussion
Secondary deposits to the uveal tract are considered to be the most common form of intraocular malignancy; similarly, metastatic lesions account for a significant proportion (1–13%) of all orbital masses (3, 15). The primary origin of the great majority of these lesions is breast carcinoma in women and bronchial carcinoma in men (3, 15). Metastases to the uvea from carcinoid tumors represent approximately 2.2% of all uveal metastases (3, 16, 17), whereas metastases to the orbit are thought to be more rare (3, 15, 16, 17, 18). However, considering the relative rarity of carcinoid tumors (2, 19), the prevalence of such uveal and orbital involvement suggests that this is a major site of carcinoid tumor spread. This is particularly evident in our series of 40 unselected patients with carcinoid tumors, in whom 6 (15%) had orbital or uveal metastasis; this especially high proportion may in part be attributed to the high sensitivity of radiopharmaceutical imaging in identifying known or clinically unsuspected lesions (11).
Identifying metastases in patients with carcinoid tumors is important prognostically, as their presence is associated with a much poorer 5-yr survival (<50%, compared with the 70% survival of those without metastases) (2). However, this may often be difficult using conventional imaging techniques, such as ultrasonography, CT, and MRI (20). Successful localization of primary and/or metastatic carcinoid tumors has been achieved using scintigraphy with [123I]MIBG (9) and [111In]pentetreotide (21). Imaging with radiolabeled somatostatin analogs demonstrates an overall sensitivity of 72–87% for detecting carcinoid lesions, although the specificity of the technique varies (20, 22, 23). Scintigraphy with somatostatin analogs has led to the identification of unknown primary or metastatic carcinoid tumors and is particularly useful in identifying orbital lesions (7, 22). Imaging with [123I]MIBG shows a sensitivity of 60–70% in identifying carcinoid lesions (22, 23). In addition, the presence of significant uptake identifies patients who can be treated with these radiopharmaceuticals (7).
In our series only one patient had histological confirmation of the ocular lesion; however, the other patients had a prior history of a carcinoid tumor, developed typical features of the carcinoid syndrome and ectopic hormone production, and had histological confirmation of metastasis from the carcinoid tumor in other sites, and three had somatostatin-avid tumor in the orbital region. Three patients had choroidal deposits, where biopsy is associated with a high risk of hemorrhage, with the potential complication of rendering the patient blind. The response to treatment further distinguishes carcinoid metastasis from other ocular neoplastic lesions; in all of our patients the ocular lesions responded well to chemotherapy and radiotherapy. Of particular interest is patient 6, in whom a provisional diagnosis of melanoma was made. In this patient complete regression of the ocular lesion and ocular signs after radiotherapy rendered this diagnosis improbable, as melanomas are typically radioresistant. In our series, because the clinical picture, biochemical investigations, and imaging all supported the diagnosis of metastasis from a carcinoid tumor, it was considered unethical to biopsy the ocular lesion, particularly in view of the high risk of complications.
Very few reports, mostly individual case histories, have demonstrated the usefulness of radiopharmaceuticals in the diagnosis of disseminated carcinoid or other neuroendocrine tumors to the orbit and/or the uvea (15, 24). In our series we demonstrated previously unknown ocular metastases in two of the six patients through the use of radiopharmaceutical-labeled imaging, in particular, imaging with [111In]pentetreotide. None of our patients with ocular metastases had a positive [123I]MIBG scan, although an orbital metastasis secondary to a carcinoid tumor with positive uptake on scintigraphy with [131I]MIBG has also been described (15). Previous studies analyzing carcinoid tumors, including large numbers of patients, have failed to demonstrate such a high prevalence of ocular involvement, although this becomes more apparent with the use of more sensitive diagnostic modalities, such as radiopharmaceutical imaging, and longer follow-up intervals (1, 2, 3, 17). Formal comparisons have shown that scintigraphy with somatostatin analogs detects more lesions than scintigraphy with [123I]MIBG in patients with carcinoid tumors, although occasionally there may be complementary areas of uptake (7, 8). Our experience would suggest that the routine use of scintigraphy with [111In]pentetreotide is useful for initial staging of patients with carcinoid tumors, particularly as this form of imaging is more sensitive than [123I]MIBG and will also detect the great majority of previously unsuspected lesions detected on scintigraphy with [123I]MIBG (7, 25). Scintigraphy with [123I]MIBG can be used to identify patients who can be treated with [131I]MIBG, whereas a positive [111In]pentetreotide scan identifies patients who can be treated with 90Y-labeled somatostatin analogs and is associated with an overall more favorable prognosis (7, 11).
Classically, the diagnosis of ocular metastases is mainly suspected on the basis of the history of carcinoid tumor, other evidence of systemic metastases, and typical clinical features (3, 17). However, previous evidence of a carcinoid tumor is present in only 44–70% of such patients, whereas patients with primary orbital carcinoid tumors have also been described (3, 26); one of these patients was followed-up for 15 yr without developing any evidence of another extraorbital primary site (26). The differential diagnosis of an amelanotic choroidal mass includes amelanotic malignant melanoma, metastatic neuroblastoma, small cell bronchogenic carcinoma, and paraganglioma (3). In our series, an ocular presentation represented the first clinical sign of metastatic carcinoid tumor in one patient, whereas in another patient with MEN1 the ocular metastasis lead to the discovery of other secondaries in the liver, although the primary was never found. In the remaining four patients, features of the carcinoid syndrome preceded the discovery of ocular involvement.
Exact data regarding survival after the diagnosis of ocular metastatic carcinoid tumor are absent, but some patients have survived for longer than the average in the presence of other noncarcinoid primary tumors (27, 28, 29). Carcinoid tumors are mostly low grade neoplasms, and patients may have prolonged survival despite dissemination; therefore, maintaining quality of life by providing early diagnosis and effective treatment to prevent visual deterioration and early involvement in palliative therapeutic programs, may be as important as the primary treatment (30, 31). In addition, the increasing number of investigative procedures and therapeutic options for both diagnosis and treatment of carcinoid tumors is best dealt with by a multidisciplinary approach (31). Although primary orbital tumors require total surgical excision (16), metastases to the uvea and the orbit are associated with widespread disease, in which case other therapeutic modalities appear to be more appropriate (2). The generally accepted treatment of orbital metastatic disease is with irradiation and/or chemotherapy (16). Although occasionally ocular metastases from carcinoid tumors can be relatively radioresistant (28, 32), external beam irradiation is nevertheless an effective and noninvasive tool in selected cases (24, 29, 33). Such radiotherapy is particularly useful for single and symptomatic lesions. However, the particular advantage of radiopharmaceuticals is that they can be used to treat disseminated lesions in a variety of sites, and the dose may be repeated as required. Regression of choroidal metastases after chemotherapy has also been described (28). One case of successfully treated choroidal metastases from a bronchial carcinoid with xenon arc photocoagulation and proton beam irradiation has also been reported (34). In our patients the combination of chemotherapy with external beam radiotherapy was associated with symptomatic improvement and stabilization of the lesions with minimal adverse effects. In addition, the presence of radiopharmaceutical uptake suggests the possibility of treatment with such analogs, although there are no long-term data on the efficacy of such treatment or its safety in patients with orbital masses. It is therefore our current policy to perform in all patients with carcinoid tumors scintigraphy with 111In-labeled octreotide. In the presence of positive orbital uptake, formal ophthalmological assessment is performed, whereas patients who do not demonstrate such an uptake are followed-up by regular fundoscopy. The value of follow-up scintigraphy with 111In-labeled octreotide needs to be assessed.
In summary, metastases to the eye and the orbit were demonstrated in 15% of our patients with carcinoid tumors. The ability of radiopharmaceutical imaging, particularly labeled octreotide, to demonstrate disseminated disease and identify previously unsuspected lesions can be used for staging of the disease and may improve the quality of life by the early diagnosis and treatment of such lesions. External radiotherapy, with or without adjuvant systemic chemotherapy, is an effective tool in treating patients with metastatic ocular carcinoid tumors, whereas treatment with radiopharmaceuticals has yet to be assessed.
Acknowledgments
Footnotes
Abbreviations: CT, Computerized tomography; DTPA, diethylenetriamine-pentaacetic acid; 5-FU, 5-fluorouracil; 5-HIAA, 5-hydroxyindoleacetic acid; MIBG, meta-iodobenzylguanidine; MRI, magnetic resonance imaging.
Received September 25, 2001.
Accepted December 31, 2001.
References
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  A. F. Scarsbrook, A. Ganeshan, J. Statham, R. V. Thakker, A. Weaver, D. Talbot, P. Boardman, K. M. Bradley, F. V. Gleeson, and R. R. Phillips Anatomic and Functional Imaging of Metastatic Carcinoid Tumors RadioGraphics, March 1, 2007; 27(2): 455 - 477. [Abstract] [Full Text] [PDF]
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 G. A. Kaltsas, G. M. Besser, and A. B. Grossman The Diagnosis and Medical Management of Advanced Neuroendocrine Tumors Endocr. Rev., June 1, 2004; 25(3): 458 - 511. [Abstract] [Full Text] [PDF]
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