Anaplastic Transformation in Mandibular Metastases of Follicular Variant of Papillary Thyroid Carcinoma: A Case Report and Review of the Literature

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1 552 Available online at Anaplastic Transformation in Mandibular Metastases of Follicular Variant of Papillary Thyroid Carcinoma: A Case Report and Review of the Literature Manju Ambelil, Sadia Sultana, Suvra Roy, and Maria M. Gonzalez Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at Houston-McGovern Medical School, Houston, TX, USA Abstract. Anaplastic transformation of well-differentiated thyroid carcinomas at distant metastatic sites is a rare condition. Most cases described in the literature have occurred in the thyroid or regional lymph nodes. We report a case of anaplastic transformation of the follicular variant of papillary thyroid carcinoma in mandibular metastases. A 76-year-old female presented with a painful and enlarging mandibular mass. She had been treated in the past for the follicular variant of papillary thyroid carcinoma. A palliative hemimandibulectomy was performed. Histology revealed a metastatic papillary thyroid carcinoma, follicular variant, with an unusual finding of solid pleomorphic epithelioid and spindle cell areas, consistent with anaplastic transformation. Key words: Anaplastic transformation, papillary thyroid carcinoma, mandibular metastasis. Introduction The incidence of thyroid cancer has tripled over the past 30 years, with the majority occurring in the past 15 years [1]. The majority of thyroid cancer cases, approximately 85%, are papillary thyroid carcinoma (PTC) which usually tends to be biologically indolent with an excellent prognosis [2]. Among the numerous variants with distinct histopathological features described, conventional or classical PTC is the most common type, followed by the follicular variant of papillary thyroid carcinoma (FVPTC) [3]. Cytologically, FVPTC contains cells that show the nuclear features of PTC, such as ground glass nuclei, nuclear grooves, and overlapping nuclei with or without nuclear inclusions, with a predominant follicular growth pattern. In general, the long-term outcome of both FVPTC and conventional PTC are similar; however, the clinical behavior of FVPTC may be different [4,5]. FVPTC has been reported to have a lower rate of lymph node metastasis and extrathyroidal extension than classical PTC, but a higher rate of lung and bone metastasis [6]. Address correspondence to Manju Ambelil, MD; Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at Houston-McGovern Medical School, 6431 Fannin Street, MSB 2.202, Houston, TX, USA; phone: ; e mail: Manju. Ambelil@uth.tmc.edu Anaplastic transformation is a rare but recognized biologic behavior in differentiated thyroid carcinomas and is associated with an aggressive behavior [7]. The anaplastic transformation may also take place in a metastatic focus, thus supporting the idea that these lesions originate through the dedifferentiation of preexisting well-differentiated cancer [8]. Here, we report a case of a follicular variant of papillary thyroid carcinoma with anaplastic transformation in a mandibular metastasis. Case Report A 76-year-old female presented with increasing left jaw pain for two months and a large fungating mandibular mass in April She had undergone a total thyroidectomy and local excision of a mandibular mass in 2007 for a well differentiated follicular variant of PTC. She had been treated with radioactive iodine-131 until Positron emission tomography scan from an outside hospital in 2008 was suspicious for metastatic disease to the left mandible, spleen, mediastinum and right hilum, although a subsequent iodine scan in 2010 noted only disease in the mandible. Fine-needle aspiration (FNA) of the left mandible in 2011 was positive for metastatic PTC; eventually, the patient was treated with radiotherapy /16/ by the Association of Clinical Scientists, Inc.

2 The patient was subsequently lost to follow- up for two years and presented later with an interval increase in the size of the left mandibular mass. The computed tomography (CT) scan showed a large enhancing heterogeneous partially calcified mass within the left mandibular ramus, which measured 4.7 cm anteroposteriorly x3.8 cm transversely x4.1 cm craniocaudal, with internal necrosis (Figure 1). The mass has increased in size in the transverse dimension with a new extension to involve the proximal aspect of the canal for the inferior alveolar nerve. There was an interval increase in the size of bilateral level IV and level II/level III cervical lymph nodes. She received palliative radiotherapy in late 2014, and was referred to maxillo-facial surgery for consideration of palliative surgery due to increasing jaw pain, dysphagia and left sided facial anesthesia. Materials and Methods Anaplastic Transformation of Follicular Variant of Papillary Thyroid Carcinoma 553 A palliative left hemi-mandibulectomy with reconstruction was performed. Gross examination showed a 5.5x4.5x3.5 cm ulcerated tan- white mass in the mucosa with extension to the underlying bone. Representative tissue sections of the tumor, fixed in 10% buffered formalin, were submitted for paraffin embedding. Results The histopathology evaluation of the H & E stained tissue sections revealed a metastatic follicular variant of PTC (Figure 2 A), composed of small to medium sized, irregularly shaped follicles, with a variable amount of colloid. The cells lining the follicles contain large clear nuclei with grooves and pseudo inclusions (Figure 2B). An unusual finding of solid sheets of tumor cells was noted near the PTC with the involvement of mucosa, bone, and soft tissue. The solid areas were composed of spindle cells and large pleomorphic epithelioid cells with vesicular nuclei and prominent nucleoli (Figure 3 A & B). There were areas of tumor necrosis, and the tumor was present at the margins. These areas were consistent with anaplastic transformation in metastatic PTC. Discussion Anaplastic thyroid carcinoma (ATC) represents the most aggressive extreme of the clinical spectrum of thyroid epithelial neoplasms. It generally has a short survival time with one-year survival rates being reported at 10 20% [9]. A large portion of ATC develops from a pre-existing, incompletely Figure 1. CT scan showing left mandibular ramus mass. treated papillary or follicular thyroid cancers and some develop de novo from a pre-existing goiter. It has been suggested that if an extensive sampling is performed, foci of well-differentiated carcinomas are eventually found in every specimen of ATC [8]. Anaplastic transformation typically occurs within the thyroid gland and the cervical lymph nodes. There are only a few reported cases in the literature where the anaplastic transformation of PTC has occurred in distant metastatic sites including lung, liver, retroperitoneum, breast, shoulder, and submandibular space [7,10-15]. FVPTC is the second most common PTC variant, accounting for % of all PTC cases. Yu et al. [16] described that the long-term outcome of FVPTC is similar to the conventional PTC; however, it has a unique clinical behavior between conventional PTC and follicular thyroid carcinoma. The study showed that FVPTC patients who presented with an extrathyroidal extension or distant metastases had a higher risk of developing diseasespecific mortality than conventional PTC patients with the same presentation, suggesting that FVPTC is not biologically identical to conventional PTC. Li et al. [5] also reported that FVPTC patients with angiolymphatic invasion, extrathyroidal extension, or non-encapsulation had higher rates of distant metastases with a poorer prognosis.

3 554 Figure 2. Histological appearances of the tumor, H & E. (A). Metastatic PTC, follicular variant [100x]; (B). The tumor cells show fine nuclear chromatin and nuclear grooving [400x]. Figure 3. Histological appearances of the anaplastic component, H&E (A). Sheets of pleomorphic epithelioid cells with no architecture [200x]. (B). The malignant cells have abundant eosinophilic cytoplasm, vesicular nuclei and prominent nucleoli [400x]. Metastatic spread of tumors to the jawbones is a rare occurrence, accounting for 1% of all malignant oral tumors [17]. There are only a few reported cases in the literature describing PTC metastasis to the mandible [17-20]. Figure 4. Histologic appearance of the recurrent facial nodule, H&E demonstrates morphology similar to the anaplastic component of the mandibular mass [100x]. Follow up. The patient re-presented after 2 months with enlarging subcutaneous masses along the flap site in the left jaw and left upper neck. FNA and core needle biopsies were obtained from both the facial and neck nodules. The morphologies were similar to the mandibular resection specimen with a predominance of large pleomorphic epithelioid cells (Figure 4). Immunohistochemistry showed positive staining with pan cytokeratin, cam 5.2, p63, CK 5/6, p40, PAX 8 and negative staining

4 Anaplastic Transformation of Follicular Variant of Papillary Thyroid Carcinoma 555 Figure 5. Immunohistochemical features of the recurrent facial nodule. The tumor cells showed diffuse cytoplasmic positivity for pan cytokeratin (A) and nuclear positivity for PAX-8 (B). The tumor cells were negative for thyroglobulin (C) and TTF-1 (D). All photographs at 100x magnification. with TTF-1, thyroglobulin, and S100 (Figures 5A- D). It was reported as a high-grade carcinoma, consistent with metastatic anaplastic thyroid carcinoma, squamoid variant. In conclusion, to the best of our knowledge, this is the first reported case of anaplastic transformation of follicular variant of papillary thyroid carcinoma in a mandibular metastasis. It highlights the potential for aggressive recurrent disease in an indolent malignancy such as papillary carcinoma of the thyroid. Therefore, a thorough sampling of all the specimens to rule out the presence of anaplastic transformation is recommended in patients with a history of thyroid malignancy, including areas of distant metastases. References 1. Davies L, Morris LG, Haymart M, Chen AY, Goldenberg D, Morris J, Ogilvie JB, Terris DJ, Netterville J, Wong RJ, Randolph G; AACE Endocrine SurgeryScientific Committee. American association of clinical endocrinologists and American Ccollege of endocrinology disease state clinical review: The increasing incidence of thyroid cancer. Endocr Pract Jun;21(6): Sipos JA, Mazzaferri EL. Thyroid cancer epidemiology and prognostic variables. Clin Oncol (R Coll Radiol) Aug;22(6): Ozdemir D, Ersoy R, Cuhaci N, Arpaci D, Ersoy EP, Korukluoglu B, Guler G, Cakir B. Classical and follicular variant papillary thyroid carcinoma: comparison of clinical, ultrasonographical, cytological and histopathological features in 444 patients. Endocr Pathol Jun;22(2): Yoon JH, Kwon HJ, Kim EK, Moon HJ, Kwak JY. The follicular variant of papillary thyroid carcinoma: characteristics of preoperative ultrasonography and cytology. Ultrasonography Jul 24.

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