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Carcinoids are a heterogeneous group of tumours believed to arise from enteroendocrine cells scattered primarily throughout the gastrointestinal tract, but these tumours are also found at other sites such as the lungs. Although the term carcinoid underscores the benign nature of the tumour with an indolent course, its potential for metastasis is widely recognised.1,2 The most frequent sites for metastasis include the lymph nodes, liver, and bone.2 Metastasis to the eye and orbit is rare. Gastrointestinal carcinoids tend to metastasise to the orbit while bronchial carcinoids have the propensity to metastasise to the uvea.2,3 The interval between diagnosis of the primary tumour and the recognition of ocular or orbital metastasis varies. The longest reported interval is 24 years for intraocular metastasis, and 15 years for orbital metastasis.1,4 We report on a patient with metastatic carcinoid to the uvea occurring 43 years after excision of the primary bronchial carcinoid and confirmed by histological and immunohistochemical tests, and we propose a mechanism for such delayed metastasis.
A 65 year old white woman was found to have a superiorly located choroidal mass in the right eye and an inferonasal elevated mass in the left eye on routine examination. Medical history is significant for the diagnosis in 1958 of bronchial adenoma, presently known as bronchial carcinoid. The patient underwent lung surgery, details of which are unavailable. She denies any history of smoking. The bronchial carcinoid recurred in 1965 and a right lower lobectomy was performed. The histopathological diagnosis was bronchial adenoma, cylindroid type, with metastasis to the peribronchial lymph node of the basilar segments.
On initial examination, visual acuity was 20/25 in each eye. Fundus examination of the right eye revealed a lightly pigmented dome-shaped golden brown mass at the 12 o’clock position involving the pars plana ciliaris and peripheral choroid. Echography revealed a solid ciliary body and peripheral choroidal mass lesion located superiorly with an elevation of 4 mm and a base diameter of 8 mm. Internal reflectivity was medium to high, with a moderately irregular internal structure. The left fundus revealed an inferonasal non-pigmented orange-reddish choroidal lesion with overlying subretinal fluid and calcification (Fig 1). Echography of this lesion showed an elevation of 2.2 mm and a base diameter of 7 mm with medium internal reflectivity.
The metastatic examination included magnetic resonance imaging of the brain, computed axial tomography of the chest, abdomen and pelvis, positron emission tomography scan, and mammography. It did not show any evidence of metastasis. Clinical diagnosis in the left eye was choroidal haemangioma versus naevus. Differential diagnoses in the right eye included ciliary body-peripheral choroidal melanoma, retinal pigment epithelium (RPE) adenoma, adenocarcinoma, and metastatic lesion. The patient underwent an iridocyclectomy with peripheral choroidectomy in the right eye.
The gross specimen consisted of an oval-shaped dark mass measuring 10 × 9 mm. Microscopic examination revealed a well circumscribed mass within the ciliary body and peripheral choroid with morphological evidence of infiltrating cells with trabecular, tubular, cord-like, or rosette-like patterns (Fig 2A). These cells showed moderate amounts of cytoplasm containing uniform nuclei displaying granular material. Distinct nucleoli were noted and occasional mitotic figures were detected. The tumour stroma also showed prominent vascularity. Immunohistochemical studies were positive for neuron specific enolase, synaptophysin (Fig 2B), chromogranin (Fig 2C), and CD 57. They were focal positive for neuroendocrine, weak positive for non-squamous keratin, variable for vasointestinal polypeptide, and negative for serotonin. Occasional tumour cells stained for Ki-67 but were negative for p53 and thyroid transcription factor (TTF-1). Upon electron microscope examination, the formalin fixed tissue showed tumour cells displaying electron dense intracytoplasmic granules measuring 100–125 nm. Electron lucent space and a membrane surround these central electron dense granules5 (Fig 2D). The histopathological diagnosis was metastatic carcinoid, involving ciliary body and peripheral choroid.
Notwithstanding their metastatic potential, carcinoids are compatible with long term survival2 (as attested by our patient’s case). To our knowledge, the 43 year interval between diagnosis of the patient’s primary tumour and recognition of uveal metastasis is the longest interval reported to date. Low immunoreactivity to Ki-67 and non-reactivity to p53 may possibly explain the indolent course of this tumour and its metastasis many years after the resection of the original tumour. Ki-67 is a DNA binding nuclear protein that is expressed in proliferating cells but not in quiescent cells. It is regarded as a fractional measure of tissue and tumour growth.6 P53, a tumour suppressor gene, is the most commonly mutated gene in tumours; its functional inactivation can bring about abnormal cell proliferation. Occasional staining of the patient’s tumour to Ki-67 and the negative staining of the tumour to p53, as well as its histologically well circumscribed appearance, demonstrate low proliferative activity and low aggressiveness. These biological factors may have played a part in the delayed metastasis of the patient’s tumour.
TTF-1 is a nuclear transcription factor primarily expressed in the lungs and thyroid. Its expression may be useful in determining the site of origin of a metastatic neuroendocrine tumour.7 However, expression of TTF-1 in primary or metastatic pulmonary carcinoids varies anywhere from completely negative8 to 44%9 to a high of 80%.7 Despite a clinical history of the primary tumour arising from the bronchus, the patient’s metastatic lesion like those reported by Fabbro et al8 exhibited no staining to TTF-1. Likewise, the tumour’s histological trabecular pattern and negative serotonin staining favour the bronchus as its site of origin.
Although bilateral ocular involvement suggests the diagnosis of a metastatic process, the 43 year long interval since resection of the bronchial carcinoid led to the clinical impression of uveal melanoma. Consequently, this case suggests that carcinoid tumours can metastasise as much as four decades after removal of the primary tumour. The prognosis for metastatic uveal tumour is generally poor; uveal carcinoids, however, are compatible with long term survival.2 Consequently, awareness and recognition of carcinoid’s delayed metastatic potential can translate to maximisation of the patient’s visual, systemic, and overall prognosis.
We thank Dr James D Sanchez, medical oncologist, Southwest Cancer Clinic, Las Vegas Nevada.
Supported in part by grant no EY03040 from the National Institutes of Health and the Research to Prevent Blindness Inc, New York, NY, USA.