The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 11 5303-5307
Copyright © 2004 by The Endocrine Society
Choroidal and Skin Metastases from Papillary Thyroid Cancer: Case and a Review of the Literature
Anca M. Avram,
Robert Gielczyk,
Lyndon Su,
Andrew K. Vine and
James C. Sisson
Division of Nuclear Medicine, Department of Radiology (A.M.A., J.C.S.), Division of Dermatology (R.G., L.S.), and Department of Ophthalmology and Visual Sciences (A.K.V.), Kellogg Eye Center, University of Michigan Medical Center, Ann Arbor, Michigan 48109
Address all correspondence and requests for reprints to: Dr. James C. Sisson, University of Michigan Medical Center, 1500 East Medical Center Drive, UH B1G 505D, Ann Arbor, Michigan 48109-0028. E-mail: jsisson{at}med.umich.edu.
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Abstract
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A patient with widely metastatic papillary thyroid cancer who had been previously treated with 131I and external beam radiation presented with purple nodular lesions on his face and scalp. On biopsy, the nodules were papillary carcinoma with cells that stained for thyroglobulin. Subsequently he developed decreased left eye visual acuity, and fundoscopy revealed lesions typical of choroidal metastases. Dermal and choroidal metastases of papillary thyroid carcinoma are both rare. However, the significance of these clinical manifestations may be overlooked and ignored unless the diagnosis is considered. New skin nodules or visual acuity decline in a patient with papillary thyroid cancer may represent manifestations of distant metastatic disease and should prompt thorough evaluation with dermatological examination and fundoscopy. Choroidal and skin metastases have almost always occurred in patients with advanced disease, but initial presentation with these lesions is possible, and in such instances a thorough search for additional sites of metastatic disease is recommended. Occasionally such metastases may respond to 131I therapy or external beam radiation.
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Introduction
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PAPILLARY THYROID CARCINOMAS (PTC) usually manifest slow progression. Distant metastases occur in about 10% of patients, who can still survive for many years (1). Most distant metastases appear in lung and bone (1). Deposits of PTC in the eye or skin are distinctly uncommon. We describe a patient with PTC who developed, over a period of months, metastatic foci in multiple dermal sites and in the choroid of each eye.
In a review of the literature we found reports of 19 cases of skin metastases (2) and four cases of choroidal metastases from PTC (3, 4, 5, 6), but only one patient had been described with deposits in both skin and choroid (5). These metastases have almost always appeared in patients with advanced disease. The patient described here presented with dermal and choroidal lesions in the setting of widespread PTC. Patients presenting with new skin lesions or abrupt decrease in visual acuity should be thoroughly evaluated. Appraisal of the entire skin, biopsy of suspicious lesions, and application of thyroglobulin immunostain will readily provide the diagnosis. After abrupt changes in visual acuity, fundoscopic examination and ocular ultrasound by an ophthalmologist are recommended for identification and monitoring of choroidal metastatic deposits. The dermatological and choroidal tumors may respond to 131I therapy. At a minimum, knowledge of metastases will aid in understanding the clinical features of these lesions by physician and patient.
The case was reviewed by the University of Michigan institutional review board and was given clearance for publication.
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Case Reports
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At the age of 63 yr, the man presented with a solitary, right thyroid nodule associated with right cervical lymphadenopathy. Right lobectomy and isthmusectomy were followed by 131I treatment (unknown dose). The excised tissue was 7.5 x 4 x 2.5 cm and largely composed of papillary carcinoma exhibiting capsular and angiolymphatic invasion; in addition, a 2-cm right jugulodigastric lymph node metastasis with angiolymphatic invasion was removed. At the time of the initial surgery, bone scan, chest x-ray, and laboratory data were said to be normal, and there was no indication of distant metastases. In retrospect, he was considered to have advanced disease according to two staging systems: MACIS stage 4 (score, 8.29) (7) and TNM stage III (8).
After surgery and 131I treatment, the patient was treated with levothyroxine (0.1 mg daily). His thyroglobulin levels, initially low (<4 ng/ml; TSH, 0.3 mU/liter), increased during the follow-up period concurrent with disease recurrence (Fig. 1
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Fifteen years after the initial diagnosis and treatment, he developed a right paratracheal mass, mediastinal adenopathy, and multiple pulmonary nodules; cytology from fine needle aspiration of a dominant lung nodule was consistent with PTC and stained for thyroglobulin (January 2000). Upon withdrawal of T4, his thyroglobulin rose to 8450 ng/ml. A second 131I treatment (dose unknown) was followed by external beam radiation therapy to his neck and mediastinum. After external beam radiation therapy, an esophageal stricture developed, and the patient required a temporary gastrostomy tube for nutrition. In the following years (June 2000 to November 2003), his thyroglobulin levels continued to rise during T4 suppressive therapy, indicating increasing tumor burden, which was also apparent in an enlarging right paratracheal mass and increased number and size of the pulmonary nodules (Fig. 2).
Seventeen years (October 2002) after the initial diagnosis, the patient noted a purple nodule on his left cheek. Biopsied tissue was interpreted as carcinoma; the cells stained for thyroglobulin. Subsequently, he developed several similar lesions on his scalp and right temple (Fig. 3).
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FIG. 3. Cutaneous metastases of PTC. A 1.5-cm nodule on the left cheek is well circumscribed, with an intact overlying epidermis, and has characteristic red-purple coloration. The patient reported no adverse symptoms, such as tenderness, bleeding, or pruritus.
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A biopsy was also obtained of the nodule on the right temple. This showed a dermal tumor composed of collapsed and open glands in a fibrous stroma, consistent with metastatic adenocarcinoma. Immunostaining revealed the presence of thyroglobulin within glandular cells and lumens, confirming the diagnosis of metastatic thyroid carcinoma (Fig. 4).
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FIG. 4. Thyroglobulin immunostain confirms the presence of thyroglobulin throughout the glandular metastatic tumor cells and within the luminal colloid material.
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In March 2003, the patient experienced an abrupt decrease in left eye vision. Fundoscopic examination of the eye detected a choroidal lesion typical of an ocular metastasis (Fig. 5).
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FIG. 5. Left eye showed a 2 x 3 disk diameter and 1.5 mm in height metastasis in the superior macula and a second 3 x 3 disk diameter and 2.0 mm in height lesion in the superior peripheral retina.
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In May 2003, T4 treatment was withdrawn in preparation for 131I therapy. His thyroglobulin rose to 10281 ng/ml, and his diagnostic and posttherapy scans portrayed multiple foci of radioactivity in his right neck and in bilateral pulmonary nodules, but none in the dermal lesions or in the region of his eyes. On sequential images over several days, an intense concentration of radioiodine was seen in the right frontal region characteristic of a metastasis, but his skull x-ray and head computed tomography scan failed to reveal any abnormality in the region; there were no bony or brain metastases. He then was treated with 3.0 GBq 131I, a dose restricted by a retention of 63% of 131I in his body at 48 h, possibly arising from renal insufficiency (creatinine, 2.1 mg/dl); images of the therapeutic dose showed the same abnormalities as seen with the diagnostic images of 131I. After 131I therapy, the patient reported improvement of his left eye vision. Six months later, fundoscopic examination revealed bilateral choroidal metastatic deposits, but at that point all lesions lacked a vascular appearance, and there was no evidence of subretinal fluid accumulation; thus, the lesions were considered inactive. The relationship between improvement in vision and 131I therapy may be coincidental.
Ten months after 131I therapy, the patient’s left eye vision deteriorated again, and fundoscopy revealed progression of the superior macular lesion, now measuring 3.5 x 3.5 disk diameters. Fluorescein angiogram showed extensive leakage of fluorescein at the level of retinal pigment epithelium, consistent with active, progressive metastatic disease. T4 was again withdrawn for 6 wk in preparation for radioiodine treatment; during the ensuing hypothyroidism, his metastatic skin disease progressed, with occurrence of multiple new lesions on face and skull (right jaw, right lip, right temple, and right occipital area) and enlargement of the previously noted lesions; his thyroglobulin rose to 17,423 ng/ml (TSH, 130 mU/liter). He then was treated with 3.7 GBq 131I. His diagnostic and posttherapy 131I scans portrayed, in addition to the previously described foci in the skull, neck, and lungs, a new focus of activity in the left pelvis, most likely representing an iliac bone metastasis (Fig. 6). The choroidal lesions have since become stable.
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FIG. 6. Whole body scan obtained 48 h after administration of 3700 MBq 131I portrays multiple foci of abnormal uptake: a, right frontal focus; b, paratracheal tumor; c, small foci in the lungs; d, physiological activity in the stomach; and e, focus in left iliac bone.
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Discussion
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Our patient exemplifies the widespread metastatic dissemination of PTC. Diagnosis of dermal metastases was established by histology of PTC with thyroglobulin-containing cells. Diagnosis of choroidal metastasis from thyroid carcinoma was based on typical ophthalmoscopic and ultrasonographic appearance of choroidal metastases and medical history of metastatic thyroid carcinoma, which is his only neoplasm. The dermal and choroidal metastases appeared after there was hematogenous dissemination of tumor to lungs and probably to bone (the focus of radioactivity in his frontal region was probably a very early bone metastasis).
PTC is often multifocal and commonly metastasizes to regional lymph nodes (in 40% of cases). Sites of distant metastases from PTC are the lung (49%), bone (25%), lung and bone (15%), and central nervous system (12%) (1). Other unusual sites of distant metastasis are the liver, kidneys, and adrenal glands. Metastases to the eye and skin are unusual from well differentiated thyroid cancer. The literature reported 42 cases of skin metastases, for which the primary thyroid tumor was PTC in 57% and follicular thyroid carcinoma in 42% (2).
There were six reported cases presenting with choroidal involvement (Table 1). The primary tumor was PTC in four cases (3, 4, 5, 6), and follicular thyroid carcinoma (9) and clear cell carcinoma with positive thyroglobulin immunostaining (10) in one case each. There was only one patient who displayed both skin and choroidal metastases (5). In this case, the primary tumor was a 3.5-cm tall cell variant papillary carcinoma, and the patient presented 4 yr after primary treatment (total thyroidectomy and modified neck dissection, followed by 131I therapy) with widespread metastatic disease involving the skeleton, lung (micronodular lesions), brain, nodular scalp lesions, and left choroid (leading to sudden partial loss of vision). Bilateral choroidal involvement has not been described previously; despite widespread disease with metastatic foci to the lungs (macronodular lesions), mediastinal lymph nodes, multiple skin nodules on the face and scalp, and bone lesions, our patient exhibited no evidence of brain metastasis. Skin and eye involvement in well differentiated thyroid cancer usually occurred in the setting of widely disseminated metastatic disease. Most patients had evidence of nodal, lung, and bone metastases, but initial presentation with choroidal metastasis (one case) (6) or skin metastasis (four cases) is possible (2), leading to the discovery of occult thyroid cancer upon total thyroidectomy.
Dermal lesions typically present as slowly growing erythematous or purple plaques or nodules, usually on the scalp, face, or neck. The scalp is the most common site, being involved in approximately two thirds of cases (11). The lesions may be solitary or multiple and are almost always asymptomatic. Ulceration is not common. The presence of dermal metastases portends a poor prognosis, because visceral metastatic disease is almost invariably present. Thus, median survival after diagnosis of cutaneous metastases is 19 months (11). Biopsy of suspected lesions will readily provide the diagnosis, as it did in our patient.
The choroid is the vascular pigmented tissue layer between the sclera and the retina of embryonic origin in neural crest cells (ectoderm). The choroid nourishes the outer retina and a portion of the optic nerve. Blood flow in the choroid is very high, with an oxygen concentration in the venous compartment that is only a few percent less than that in the arterial compartment. The most common primary sites of metastatic carcinoma to the choroid are the breast and lung in female and male patients, respectively. Although choroidal metastases from thyroid cancer have been rarely reported, probably rigorous searches for these lesions are uncommon. Therapy with 131I, although unlikely to cure the metastatic deposits, may be followed by improvement of vision and may decrease the size of the lesions (3). In the case of non-131I-avid tumors, as demonstrated by negative 131I whole body scan, ocular external beam radiation remains a therapeutic option (4).
In our patient, the dermal involvement appeared to worsen temporarily after the withdrawal of T4. Prolonged TSH stimulation resulting from T4 withdrawal may lead to accelerated progression of metastatic lesions, with important clinical consequences, especially for patients with brain and choroidal metastases. Administration of 131I therapy after recombinant human TSH stimulation should be considered to minimize tumor progression and clinical sequelae.
It is now well recognized that most neoplasms consist of several tumor cell populations that vary in growth rates, karyotype, and production of growth factors and stimulators of angiogenesis (12). Formation of metastatic foci results from selection of an aggressive subpopulation of tumor cells out of the primary tumor. The metastatic cascade starts with progressive proliferation in the primary tumor, development of central tumor hypoxia, leading to initiation of angiogenesis and tumor vascularization. As the tumor grows, there are continued genetic alterations in the tumor cell population, resulting in the selection of tumor cell clones with distinct growth advantage and invasive phenotype. These cells detach from the primary tumor, invade the newly formed tumor vessels, and gain access to the systemic circulation. The tumor cell emboli are trapped in the microcirculation of distant organs, extravasate from the vascular or lymphatic compartment, and, after evading the immune response, proliferate in response to local paracrine growth factors.
In the case of our patient, gradual tumor growth and metastases involving initially mediastinal lymph nodes and lung and subsequent development of skin, choroid, and bone metastatic deposits suggest that the biological behavior of the carcinoma evolved through several steps of clonal selection, resulting in the proliferation of more aggressive tumor cell types. The propensity of thyroid cancer skin metastases to localize to the upper body is documented in the majority of cases (2, 11) and may relate to local vascular factors essential for the highly complex nature of metastasis formation (initial tumor recruitment of local vasculature, followed by angiogenic switch: the tumor establishes its own vascular network through the secretion of various angiogenic factors and the removal or suppression of angiogenesis inhibitors). The rich dermal capillary network of the scalp, face, and chest as well as the choroid may initially trap the tumor cell emboli from the circulation and then provide the environment for successful formation of metastatic foci.
Metastatic thyroid carcinoma may be a diagnostic challenge. Many tumors cannot be detected by scintigraphic or radiological techniques; thus, clinical evaluations continue to have an important role. The presence of new dermal lesions in a patient with a history of thyroid cancer should lead to a full examination of the skin for cutaneous nodules that may be metastases and to diagnosis by biopsy and histological examination with thyroglobulin immunostaining. Abrupt changes in visual acuity should prompt an evaluation by an ophthalmologist acquainted with ocular metastases and the use of ocular ultrasound, if necessary, for detection of choroidal metastatic deposits. The possible association of dermal and choroidal metastases should be borne in mind, and the finding of one should lead to a search for the other. Although treatments may not provide much benefit, understanding the clinical manifestations determines the overall management of the patient.
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Footnotes
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Abbreviation: PTC, Papillary thyroid cancer.
Received April 23, 2004.
Accepted August 2, 2004.
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References
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Abstract
Introduction
