Case 9 -

Unusual Presentation of Childhood Papillary Thyroid Carcinoma Drs. Josephina C.J. Vermeer-Mens, Vibeke Kuenen-Bouwmeester, and Ronald R. de Krijger Dept. of Pathology, Erasmus MC-Daniel den Hoed Cancer Clinic and Erasmus MC-University Medical Center Rotterdam , The Netherlands

Case History: A 10-year-old boy, complaining of fatigue, presented with multiple bilaterally enlarged neck lymph nodes. Chest X-ray revealed interstitial lung disease, which was confirmed on CT analysis. Because of the clinical suspicion of miliary tuberculosis, a broncho-alveolar lavage was performed. This specimen showed alveolar macrophages, lymphocytes, granulocytes, normal bronchial epithelium, and some groups of atypical epithelial cells that were interpreted as metaplastic epithelium. No micro-organisms were detected. Case 9 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Around the same time fine needle aspiration biopsy was performed on one of the enlarged neck lymph nodes, in the context of the diagnostic work-up. The specimen showed sheets of epithelial cells in a follicular growth pattern and syncytial cell groups with follicles filled with colloid. A diagnosis of metastatic thyroid carcinoma, probably metastatic follicular thyroid carcinoma, was proffered, necessitating thyroid resection. Ultrasound examination of the neck and thyroid showed multiple enlarged lymph nodes and a slightly enlarged right thyroid lobe, which was subsequently confirmed to be a cold nodule on 123I-scintigraphy. Serum thyroglobulin was extremely elevated. Because of the above findings, total thyroidectomy with bilateral lymph node resection were performed, yielding a thyroid of 15 gram with an irregularly enlarged right lobe and several grey-white nodules in both lobes. Microscopically, these nodules corresponded to an infiltrating epithelial tumor composed of follicular structures, but with overlapping nuclei, that were optically clear in many areas. There were rare papillary structures and psammoma bodies, but sclerosis was not a prominent feature. The tumor was diagnosed as the follicular variant of a papillary thyroid carcinoma, 5 cm in largest diameter, showing lymphangio-invasion, and incompletely removed. The bilateral lymph node resection yielded 43 lymph nodes of which 21 at levels 3 to 6 showed metastases. At this stage, the original broncho-alveolar lavage specimen was re-evaluated, and the groups of atypical epithelial cells, originally interpreted as metaplastic were now appreciated as groups of cells originating from the papillary thyroid carcinoma. Also, the "miliary" aspect of the lungs at X-ray and CT was re-appreciated as multiple metastases. Following surgical removal, radioactive 131I ablative therapy (first dose 2960 MBq, second dose 3700 MBq) was installed for his remaining tumor load and thyroid hormone replacement therapy was given. Presently, he is almost 1 year postoperatively and has received 2 doses of ablative therapy with improvement of his thyroglobulin levels, which, however, are still elevated. His general condition is satisfactory. Diagnosis: papillary thyroid carcinoma, follicular variant, metastatic to the lungs General discussion: Thyroid cancer accounts for 1.3% of all malignancies, and papillary thyroid carcinoma (PTC) is the most frequently occurring subtype, representing 80% of cases [1, 2]. Roughly, these figures also apply to the pediatric age group, in which thyroid carcinomas represent 0.5-3.0% of all malignancies, and PTC is the predominant subtype [3]. Within the group of PTC, the latest WHO edition describes no less 15 variants [2]. The importance to recognize several of these variants lies partly in their relationship with prognosis (the tall cell and columnar cell variant are known to be associated with a more aggressive clinical behavior), and partly in their distinction from other thyroid tumors, such as the follicular variant, which in the past has frequently been labelled as a follicular thyroid carcinoma. The quintessence of PTC diagnosis is the nuclear pattern: nuclei are typically enlarged, oval/elongated, and overlapping. In addition, nuclear clearing, grooves and pseudo-inclusions can be appreciated, although the various features may only be present in parts of the lesion. In recent years, the pathogenesis of PTC has been partly elucidated, with frequent mutations or aberrations in one of three genes that belong to the same intracellular signal transduction pathway: RAS, BRAF, and RET-PTC. Such alterations are mutually exclusive and together they amount to 70% or more of PTC [4]. In addition, these alterations appear to correlate with specific histological variants of PTC and were also shown to be related to a specific pattern of gene expression, as has been investigated by DNA microarray analysis [5]. With regard to the follicular variant of PTC, several recent studies have shown that these tumors, at least in part, contain the same genetic abnormalities as follicular thyroid adenomas and carcinomas, i.e. PAX8-PPARg rearrangements and RAS mutations, but do not show the BRAFV600E mutation, typical for PTC [6]. With regard to treatment for PTC in childhood, there are two options: partial (subtotal) thyroidectomy, in an attempt to decrease the frequency of hypoparathyroidism and laryngeal nerve injury, or total thyroidectomy, allowing early detection and treatment of (pulmonary) metastasis on 131I scanning and decreasing the rate of local and regional recurrence. In both instances cervical lymph node resection is performed, depending on the demonstration of PTC metastases. In cases where pulmonary metastasis is evident, as in our patient, total thyroidectomy is the treatment of choice [7]. The prognosis of PTC is excellent, with overall survival rates of more than 90%. In children, overall survival may actually approach 100%, despite the fact that there is a strong tendency for loco-regional and metastatic spread. In a recently published series of 42 histologically confirmed pediatric cases of PTC, more than half presented with a pT4 tumor (showing extension beyond the thyroid capsule), 95% had lymph node metastases, and 12% (n=5) had distant metastases at presentation. A further 3 patients developed lung metastases during follow-up. Nevertheless, at an average of 189 months follow-up, all 42 patients were alive, with only 2 of them showing signs of persistent disease [8]. References Chu KC, Kramer BS. Cancer patterns in the United States. In Greenwald P, Kramer BS, Weed DL eds. Cancer prevention and control. New York : Marcel Dekker 1995; 37. DeLellis RA, Williams ED. Thyroid and parathyroid tumours: introduction. In DeLellis RA, Lloyd RV, Heitz PhU, Eng C eds. Pathology and Genetics. Tumours of Endocrine Organs. Lyon : IARC Press 2004; 51. Millman B, Pellitteri P. Thyroid carcinomas in children and adolescents. Arch Otolaryngol Head Neck Surg 1995;121:1261-1264. Adeniran AJ, Zhu Z, Gandhi M, Steward DL, Fidler JP, Giordano TJ, Biddinger PW, Nikiforov YE. Correlation between genetic alterations and microscopic features, clinical manifestations, and prognostic characteristics of thyroid papillary carcinomas. Am J Surg Pathol 2006;30:216-222. Giordano TJ, Kuick R, Thomas DG, Misek DE, Vinco M, Sanders D, Zhu Z, Ciampi R, Roh M, Shedden K, Gauger P, Doherty G, Thompson NW, Hanash S, Koenig RJ, Nikiforov YE. Molecular classification of papillary thyroid carcinoma: distinct BRAF, RAS, and RET/PTC mutation-specific gene expression profiles discovered by DNA microarray analysis. Oncogene 2005;24:6646-56. Castro P, Rebocho AP, Soares RJ, Magalhaes J, Roque L, Trovisco V, Vieira de Castro I, Cardoso-de-Oliveira M, Fonseca E, Soares P, Sobrinho-Simoes M. PAX8-PPARgamma rearrangement is frequently detected in the follicular variant of papillary thyroid carcinoma. J Clin Endocrinol Metab 2006;91:213-220. Okada T, Sasaki F, Takahashi H, Taguchi K, Takahashi M, Watanabe K, Itoh T, Ota S, Todo S. Management of childhood and adolescent thyroid carcinoma: long-term follow-up and clinical characteristics. Eur J Pediatr Surg 2006;16:8-13. Collini P, Massimino M, Leite SF, Mattavelli F, Seregni E, Zucchini N, Spreafico F, Ferrari A, Castellani MR, Cantu G, Fossati-Bellani F, Rosai J; Thyroid Cancer Study Group of the Istituto Nazionale Tumori of Milan, Italy.Papillary thyroid carcinoma of childhood and adolescence: a 30-year experience at the Istituto Nazionale Tumori in Milan. Pediatr Blood Cancer 2006;46:300-306.