Thyroid : a Clinical Case e35

Case report Clin Ter 2013; 164 (1):e35-39. doi: 10.7417/CT.2013.1519

Difficulties in the Diagnosis of Paraganglioma: a Clinical Case P.G. Calò1, M.L. Lai2, E. Guaitoli3, G. Pisano1, P. Favoriti3, A. Nicolosi1, G. Pinna4, S. Sorrenti3

1Department of Surgical Sciences, University of Cagliari; 2A.O.U. Presidio di Monserrato, Cagliari; 3Department of Surgical Sciences, Sapienza, University of Rome; 4Endocrinology, Nuova casa di cura Decimomannu, Cagliari, Italy

Abstract the thyroid capsule (5, 7). With rare exceptions, they are en- docrinologically silent, (4, 8) and the cytological evaluation Thyroid are exceptionally rare tumors and only could be difficult, due to the possible misinterpretation as 35 documented cases have been reported in the literature. We report medullary thyroid carcinomas (MTCs) or other primary or an additional unusual male case of thyroid Paraganglioma associated metastatic thyroid carcinomas (4-7). to a chronic lymphocytic and a papillary microcarcinoma. A with MTCs and follicular A 45-year-old man presented with a solitary . Physi- thyroid neoplasms, should be made using colour flow-dop- cal examination revealed a smooth, well-circumscribed, firm, mobile, pler characteristics, elastosonography or PET and studying painless thyroid nodule in the right lobe measuring 3 cm. Ultrasound molecular markers like the germline activating RET muta- examination showed a 40 mm hypoechoic, non-homogeneous nodule tions documented in 95-98% of hereditary MTCs (8-10). with peri- and intra-nodular vascular flow. An ultrasound-guided fine The first reported thyroid PGL was described by Haegert needle aspiration biopsy was performed showing the presence of in 1974 (11). To our knowledge, only 35 documented cases atypical cells (Thy 3). He underwent a total associated of thyroid PGLs have been reported to date, and in only four to VI level lymphectomy. Histology showed a thyroid Paraganglioma cases male patients were involved (4, 6, 12). Before surgery, associated to a chronic lymphocytic thyroiditis and a papillary micro- only 20 PGLs were submitted to cytological examination carcinoma measuring 0.3 cm in the greatest dimension. (1, 4, 13, 14). Thyroid Paraganglioma is an elusive tumor. It is difficult to Herein we report an additional unusual male case of diagnose and should be included in the differential diagnosis of all thyroid PGL associated to a chronic lymphocytic thyroiditis neuroendocrine tumors of the thyroid, even those arising in men or and a papillary microcarcinoma. behaving in a locally aggressive fashion. Clin Ter 2013; 164(1):e35-39. doi:10.7417/CT.2013.1519 Case report Key words: neuroendocrine tumor, paraganglioma, thyroid neo- plasm A 45-year-old man presented with a solitary, asympto- matic nodule in the right thyroid lobe; the nodule was in- Introduction cidentally discovered by a cervical ultrasound examination performed for other reasons. Paraganglioma (PGL) is an uncommon neoplasm that The patient’s family history revealed colon carcinoma arises from widely dispersed specialized neural crest cells in his dead sister; there was no family history of thyroid that are associated with autonomic ganglia (1-5). The ma- disease. His personal medical history was negative for jority of thyroid tumors are of the differentiated papillary irradiation and he did not have hypertension, flushing, thyroid (PTC) histotype comprising about 90% of all diarrhea or other symptoms related to catecholamines thyroid . The thyroid gland is one of the anatomic hypersecretion. There was no clinical evidence of thyroid sites in which paraganglia are not normally located and dysfunction, with no signs of compression of the adjacent paraganglioma is exceptionally uncommon (1, 2). In the structures or dysphonia. world’s literature only 35 cases of PGL have been reported to Physical examination revealed a smooth, well-circum- date, only 4 of those have been reported in men, it has been scribed, firm, mobile, painless thyroid nodule in the right suggested that PGL occurs predominantly in women (6). lobe measuring 3 cm without palpable cervical lymph no- Thyroid PGLs are thought to arise from the inferior des. The left lobe was unremarkable. Blood pressure was laryngeal paraganglia, which are sometimes situated within normal. Indirect laryngoscopy showed normal mobile vocal

Correspondence: Prof. Salvatore Sorrenti. Department of Surgical Sciences, Sapienza, University of Rome, Italy. Viale Regina Elena, 324, 00161 Rome, Italy. Tel./Fax: +39-0649972448. E-mail: [email protected]

Copyright © Società Editrice Universo (SEU) e36 P.G. Calò, et al. folds. Hormone dosages (TSH, FT3, FT4 and ) were within normal ranges and anti-peroxidase and anti- antibodies were undetectable. Ultrasound examination showed a 40 mm hypoechoic, non-homogeneous nodule in the right thyroid lobe with remarkable peri- and intra-nodular vascular flow; neither nodules in the left lobe nor neck enlargement were evident. A 99mTc thyroid scan showed a “cold” no- dule in the right lobe, which corresponded to the palpable lump. An ultrasound-guided fine needle aspiration biopsy was performed showing the presence of atypical cells (Thy 3), organized in rare solid nests of cells with mild cytologic atypia allowing the diagnosis of “indeterminated follicular lesion” (Fig. 1). He underwent a total thyroidectomy asso- Fig. 1. Fine needle aspiration biopsy: presence of atypical cells (Thy ciated to VI level lymphectomy because the intraoperative 3), organized in rare solid nests of cells with mild cytologic atypia al- aspect suggested a thyroid carcinoma. Surgery was very lowing the diagnosis of “indeterminated follicular lesion”. HE 400x. difficult, due to the presence of a firm neoplasm that spread outside the thyroid capsule, adhering to the surrounding neck structures, in particular to right laryngeal recurrent nerve and trachea. The thyroid gland seemed “easy to bleed” and Histology showed a relatively well circumscribed tumor, surgical excision plans could not be clearly identified but measuring 3 cm in diameter, which did not exhibit a cap- the laryngeal recurrent nerves and the parathyroid glands sule and spread beyond the thyroid capsule. The neoplasm were seen and preserved. There were no postoperative was composed of sheets and solid nests of cells, negative complications. at immunohistochemistry for thyroglobulin, calcitonin,

Fig. 2. Histological examination: panel A:HE 40X, panel B: S-100 100X, panel C: Thyroglobulin 40X, panel D: Chromogranin 10X, panel E: 40X. Thyroid Paraganglioma: a Clinical Case e37

TTF1 and positive for chromogranin, synaptophysin, NSE; hyalinizing trabecular adenoma and medullary carcinoma, S-100 was focally expressed (Fig. 2). On the basis of these especially when it exhibits a nesting pattern of growth (1, findings the final diagnosis of PGL was made. A chronic 7, 13, 16, 19). Particularly, it is important to differentiate lymphocytic thyroiditis and a papillary microcarcinoma thyroid PGLs from medullary cancer, especially because measuring 0.3 cm in the greatest dimension were also of the treatment and prognostic implications. In contrast to found. The were not involved. The most medullary thyroid cancers, PGLs stain negative for patient was discharged on the second postoperative day and cytokeratin, CEA and CT (4). substitutive treatment with L-thyroxine was undertaken. He FNAB- Tg protein and FNAB- Tg mRNA /FNAB- CT is alive and well without evidence of recurrent disease 18 mRNA can be helpful in cases in which cytology resulted months after surgery. inadequate or when the cytological diagnosis is inconsistent with patient’s clinical parameters. FNAB-C, Tg/CT mRNA and Tg protein determination Discussion in the fine-needle washout are safe in the diagnosis of me- dullary thyroid carcinoma (20-23). Thyroid PGLs are exceptionally rare tumors and, to our Our case stained positive for S-100 and synaptophysin knowledge, only 35 documented cases have been reported and negative for thyroglobulin, calcitonin, TTF1, P63 and in the literature (7, 13); nevertheless, in the head and neck CEA, leading to the diagnosis of thyroid PGL. region PGLs arising from the carotid body and larynx are It has been demonstrated that PGLs are generally benign not so uncommon, very often occurring also near the thyroid lesions, but the occurrence of malignant PGLs has also been (1, 2). Etiology of such an unusual finding is unclear. In fact, reported (1, 18). The differential diagnosis between benign paraganglia are not normally present in the thyroid gland; and malignant PGL is difficult and cellular criteria for the most prevailing point of view is that during embryoge- malignancy have not been defined yet (1). The criteria for nesis inferior laryngeal paraganglia is being occasionally malignancy include , necrosis, uniform cytological incorporated into the gland, where it gives rise to thyroid atypia and vascular invasion (1, 12, 13). Unlike malignant PGL (1, 2, 4, 12, 15). neoplasms elsewhere, local infiltration is not indicative of All the reported cases occurred in females, with the malignancy (1, 14). Several authors suggest that there are exception of four males, and the majority were between 40 no histological differences between benign and malignant and 60 years of age (range 9-73) (3, 7, 13, 15-17). Our case PGLs the only diagnostic criterion in favor of malignancy is the first case in which PGL was associated to a chronic being the presence of local recurrence or distant metastases lymphocytic thyroiditis and a papillary microcarcinoma. (1, 7). Local tumor recurrence of TP has not been reported, The available data on the clinical presentation of the world’s which further emphasizes the importance of primary surgical cases of PGL are given in Table 1 (6). treatment of these locally aggressive tumors. Primary thyroid PGLs occurred in 4 cases in literature Total thyroidectomy or thyroid lobectomy (if tumor is in association with a synchronous or metachronous carotid confined to a single thyroid lobe) are the preferred treatment body tumor (3, 12, 13). Thyroid PGL was primarily diagno- options and generally can be considered to be curative (3, 7, sed as a thyroid mass (22/32) or cold nodule (6/32) (6). 12, 13). Elective neck dissection is not indicated (3, 7, 13, In the present case, the surgeon did not observe any 15), but in some cases, such as our patient, the presence of relationship between the tumor and the carotid vessel and, atypical cells at cytology and the intraoperative aspect of the despite great difficulty, he was able to dissect the tumor from neoplasm can lead to perform a VI level lymphectomy. If the the ipsilateral recurrent laryngeal nerve. preoperative diagnosis was correctly made, a right lobec- Thyroid PGLs are usually asymptomatic ( 3, 5, 7), rarely tomy could be a correct approach. Moreover, the unknown functional (4), and manifest themselves as a mass in the associated chronic lymphocytic thyroiditis and papillary neck (15). No cases of thyroid PGL associated with multiple micro-carcinoma suggested that the total thyroidectomy endocrine neoplasia have been reported to date. was finally the best treatment. Preoperative diagnosis of thyroid PGL has been difficult The prognosis of primary thyroid PGL appears to be in all the cases reported, including our own. Intranodular favorable, provided that surgical excision is complete (13). and perinodular blood flow in thyroid PGLs is detected by Aggressive local extension is not a predictor of recurrence color Doppler imaging and no hot nodules were ever been or distant metastasis (4, 12). reported at thyroid scan in contrast to our case (4) . The Benign head and neck paragangliomas have a 5-year sur- cytological findings have been reported to be frequently in- vival of 95%, while malignant paragangliomas are estimated conclusive (1, 4, 13, 14) (Tab. 1) and, in some cases revealed to have a 5-year survival rate of 43.3% (6, 24). atypia which misdiagnosed PGL with thyroid malignancy In all reported cases there was no evidence of recurrence (1, 18, 19). In the case reported, the correct diagnosis was or metastatic disease following surgical excision (1, 3, 4, 12, not clinically suspected preoperatively, also because of the 13, 19, 25). Metastasis or deaths have not been reported in absence of specific symptoms or signs of PGL. In addition, association with these tumors. Our patient is alive without fine needle aspiration suggested the possibility of a mali- recurrent disease 18 months after surgery. gnant thyroid tumor. In conclusion, thyroid PGL is an elusive tumor, which is The diagnosis of thyroid PGL may be extremely difficult difficult to diagnose both preoperatively and postoperatively on a purely morphological basis, and immunohistochemistry and which should be included in the differential diagnosis of is essential to show the difference from other types of tumors all neuroendocrine tumors of the thyroid, even those arising (5). Differential diagnosis includes two main entities, namely in men or behaving in a locally aggressive fashion. e38 P.G. Calò, et al.

Tabella 1. World’s cases of Thyroid Paraganglioma.

Sex Age FNA Treatment Armstrong J. et al. F 67 ND TT Armstrong J. et al. M 40 Completion TT Armstrong J. et al. M 60 NA TT Van Miert F 63 Drill biopsy = chemodectoma Irradiation Haegert et al. F 36 Carotid body tumor L hemi-thyroidectomy Massaioli et al. F 9 NA ST Banner et al. F 36 NA Surgical resection Buss et al. F 50 NA L hemi-thyroidectomy Cayot et al. F 58 NA TT Olofsson et al. F 44 Poorly differ. epith. tumor L Lobectomy, trach Mitsudo et al F 50 Susp for malig tumor, poss MTC TT+segmental trach de Vries and Watson F 43 ND L Lobectomy Brownlee and Shockley F 27 NA R lobectomy Hughes et al. F 31 NA L Lobectomy LaGuette et al. F 56 NA R lobectomy +isthmus LaGuette et al. F 64 NA L Lobectomy+isthmus LaGuette et al. F 55 NA Completion TT Bizollon et al. F 48 NA NA Tiong et al. F 52 Susp cytological features Completion TT Kronz et al. M 55 Susp for MTC L Lobectomy+isthmus Kronz et al. F 52 ND L hemi-thyroidectomy,tracheostomy Napolitano et al. F 47 NA TT Skiadas et al. F 54 Suggest malig, poss PTC TT Vera-Cruz et al. F 32 MTC R lobectomy Vodovnik F 46 Atypia R lobectomy +isthmus Corrado et al. F 46 ND R lobectomy Zantour et al. F 32 Susp MTC TT Foppiani F 51 ND TT Yano et al. M 24 Susp Foll Thy Neo R lobectomy Ashraf et al. F 40 MTC Surgical resection Ferri et al. F 63 Atypia R lobectomy Poggioli et al. F 36 NA TT Erem et al. F 58 NA R lobectomy +isthmus+partial L Lobectomy Phitayakorn et al. F 41 Susp for MTC Surgical resection Phitayakorn et al. F 73 Foll Neo R lobectomy Ca: Carcinoma; Differ: Differentiated; Epit: Epithelial; Foll: Follicolar; L: Left; Malig: Malignant; MTC: Medullary Thryroid Carcinoma; NA: Not Available; ND: Not Diagnostic, Neo: Neoplasm; Poss: Possible; R: Right; ST: Subtotal Thyroidectomy; Susp: Suspicious; Trach: Trachea; TT: Total Thyroidectomy. Thyroid Paraganglioma: a Clinical Case e39

References 14. Vodovnik A. Fine Needle Aspiration Cytology of Primary Thyroid Paraganglioma. Report of a Case with Cytolo- 1. Corrado S, Montanini V, De Gaetani C, et al. Primary para- gic, Histologic and Immunohistochemical Features and ganglioma of the thyroid gland. J Endocrinol Invest 2004; Differential Diagnostic Considerations. Acta Cytol 2002; 27:788-92 46:1133-7 2. Gonzàlez Poggioli N, Lòpez Amado M, Yebra Pimentel MT. 15. Brownlee RE, Shockley WW. Thyroid paraganglioma. Ann Paraganglioma of the Thyroid Gland: A Rare Entity. Endocr Otol Rhinol Laryngol 1992; 101:293-9 Pathol 2009; 20:62-5 16. Hughes JH, El-Mofty S, Sessions D, et al. Primary Intra- 3. Tiong HY, White SA, Roop L, et al. Paraganglioma – an thyroidal Paraganglioma with Metachronous Carotid Body unusual solitary nodule of the thyroid. Eur J Surg Oncol Tumor: Report of a Case and Review of the Literature. Pathol 2000; 26:720-1 Res Pract 1997; 193:791-6 4. Yano Y, Nagahama M, Sugino K, et al. Paraganglioma of 17. LaGuette J, Matias-Guiu X, Rosai J. Thyroid Paraganglioma: the Thyroid: Report of a Male Case with Ultrasonographic A Clinicopathologic and Immunohistochemical Study of Imagings, Cytologic, Histologic, and Immunohistochemical Three Cases. Am J Surg Pathol 1997; 21:748-53 Features. Thyroid 2007; 17:575-8 18. Mitsudo SM, Grajower MM, Balbi H, et al. Malignant Para- 5. Zantour B, Guilhaume B, Tissier F, et al. A thyroid nodule ganglioma of the Thyroid Gland. Arch Pathol Lab Med 1987; revealing a paraganglioma in a patient with a new germline 111:378-80 mutation in the succinate dehydrogenase B gene. Eur J En- 19. Napolitano L, Francomano F, Angelucci D, et al. Thyroid docrinol 2004; 151:433-8 paraganglioma: report of a case and review of the literature. 6. Armstrong MJ, Chiosea SI, Carty SE, et al. Thyroid para- Ann Ital Chir 2000; 71:511-3 gangliomas are locally aggressive. Thyroid 2012; 22:88-93 20. Sohn YM, Kim MJ, Kim EK, et al. Diagnostic performance 7. Erem C, Kocak M, Nuhoglu İ, et al. Primary thyroid paragan- of thyroglobulin value in indeterminate range in fine needle glioma presenting with double thyroid nodule: a case report. aspiration washout fluid from lymph nodes of thyroid cancer. Endocr 2009; 36:368-71 Yonsei Med J 2012; 53:126-131 8. Sorrenti S, Guaitoli E, Catania A, et al. Surgical strategies in 21. Baldini E, Sorrenti S, Catania A, et al. Diagnostic utility of patients with medullary thyroid carcinoma. Clin Ter 2012; thyroglobulin measurement in the fine needle aspirates from 163:e303-6 cervical lymph nodes: a case report. G Chir 2012; 33:387- 9. Cantisani V, Ulisse S, Guaitoli E, et al. Q-Elastography in the 91 Presurgical Diagnosis of Thyroid Nodules with Indeterminate 22. Ulisse S, Baldini E, Sorrenti S, et al. High expression of the Cytology. PLoS One 2012; 7:e50725 urokinase plasminogen activator and its cognate receptor 10. Trimboli P, Ulisse S, D’Alò M, et al. Analysis of clinical, ul- associates with advanced stages and reduced disease-free trasound and colour flow-Doppler characteristics in predicting interval in papillary thyroid carcinoma. J Clin Endocrinol malignancy in follicular thyroid neoplasms. Clin Endocrinol Metab 2011; 96:504-8 2008; 69:342-4 23. Ulisse S, Baldini E, Sorrenti S, et al. In papillary thyroid 11. Haegert DG, Wang NS, Farrer PA, et al. Non-chromaffin carcinoma BRAFV600E is associated with increased expres- paragangliomatosis manifesting as a cold thyroid nodule. sion of the urokinase plasminogen activator and its cognate Am J Clin Pathol 1974; 61:561-70 receptor, but not with disease-free interval. Clin Endocrinol 12. Kronz JD, Argani P, Udelsman R, et al. Paraganglioma of 2012; 77:780-6 the thyroid: two cases that clarify and expand the clinical 24. Feng N, Zhang WY, Wu XT. Clinicopathological analysis of spectrum. Head Neck 2000; 22:621-5 paraganglioma with literature review. World J Gastroenterol 13. Ferri E, Manconi R, Armato E, et al. Primary paraganglioma 2009; 15:3003-08 of thyroid gland: a clinicopathologic and immunohistochemi- 25. Skiadas PK, Kakavoulis TN, Gikonti IJ. Normalisation of cal study with review of the literature. Acta Otorhinolaryngol Blood Pressure and Heart Rate after Excision of a Thyroid Ital 2009; 29:97-102 Paraganglioma. Eur J Surg 2001; 167:392-4