|Ahead of print publication
Thyroid paraganglioma: A case-based systematic review of literature
Pritinanda Mishra, Somanath Padhi, Gayatri Behera
Department of Pathology and Lab Medicine, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India
Department of Pathology and Lab Medicine, All India Institute of Medical Sciences, Bhubaneswar, Odisha
Source of Support: None, Conflict of Interest: None
Thyroid paragangliomas are distinctly rare primary thyroid neoplasms with nearly 75 cases reported worldwide. Due to their similar embryological origin and cytohistomorphology with other thyroid neoplasms, they may pose great diagnostic challenges for pathologists, radiologists, endocrinologists, as well as surgeons leading to unnecessary aggressive therapy. With recent advances in molecular genetics, the prognostic significance of such seemingly innocuous thyroid neoplasms has been better understood. In this manuscript, we describe such a case and present a systematic review of all reported cases till date giving an update on our current knowledge regarding their diagnostic pitfalls, pathology, and molecular genetics.
Keywords: Immunohistochemistry, molecular genetics, thyroid paraganglioma, thyroid tumor, total thyroidectomy
| > Introduction|| |
Extra-adrenal paraganglia, either sympathetic or parasympathetic, are derived from the primitive neural crest cells of the autonomic nervous system. Parasympathetic paragangliomas are almost exclusively present in the head and neck region along the cranial nerves, the arterial vasculature or rarely in orbit and paranasal sinuses. Carotid body tumor is the most common head and neck paraganglioma, followed by glomus jugulare, glomus typanicum, and the vagal paraganglioma. Among the rare anatomic sites of extra-adrenal paraganglioma, thyroid is possibly one of the rarest site constituting <0.1% of all thyroid neoplasms. Since the first description of TPG by Vanmiert in 1964 (then called “chemodectoma”), nearly 75 such cases have been reported around the world over the past five decades, either in the form of sporadic cases or small case series., In view of their rarity and their close embryological resemblance to other common neuroendocrine tumors (NETs), TPG may pose both diagnostic and therapeutic challenges. In this paper, we describe a case of TPG in a middle-aged euthyroid male giving special emphasis on the diagnostic challenges, the molecular and embryological basis and also presenting a systemic review of world literature of all such cases reported till date.
| > Case Presentation|| |
Fine-needle aspiration cytology (FNAC) was sought for a 37-year-old asymptomatic male patient who presented with goiter of 4 years of duration. The physical examination revealed an enlarged, firm to solid, 50 mm × 50 mm nodule involving the right lobe and the isthmus of the thyroid gland that moved with deglutition. There were neither palpable cervical lymph nodes nor any clinical, biochemical, or serological evidence of hypo- or hyper-thyroidism. His family history was negative for any prior thyroid or other endocrine disorders. Doppler ultrasound sonography (USG) of the neck revealed an enlarged right thyroid lobe with a well delineated, solitary hypoechoic nodule measuring 73 mm × 63 mm × 33 mm that involved the lobe and the isthmus without perithyroidal extension. The nodule also had focal cystic areas with increased intra- and peri-nodular vascularity. The left lobe and adjacent isthmus did not show any evidence of calcification or features of Hashimoto's thyroiditis. Head and neck computerized tomography (CT) scan showed a well-defined 45 mm × 34 mm hypodense nodule involving the right lobe and the isthmus of the thyroid gland without any evidence of extracapsular extension. The USG and CT scan findings were more in favor of a “neoplasm,” which was reported as “cold” on 99Tc scan performed elsewhere.
Repeated FNAC from the nodule revealed few follicular epithelial cells in clusters and focal pseudo acinar pattern on a hemorrhagic-colloid mixed background, compatible with the diagnosis of colloid goiter (Bethesda category II). Total thyroidectomy was performed in view of radiological suspicion of a neoplasm. The total thyroidectomy specimen weighed 90 g; the right lobe measured 50 mm × 30 mm × 20 mm, and the left lobe measured 47 mm × 25 mm × 20 mm. On cut section, a 40 mm × 30 mm × 25 mm solid, well encapsulated, firm, grayish-white nodule was seen in the isthmus. The cut surface of the nodule showed no evidence of necrosis or hemorrhage. The histopathological examination of the nodule showed a well-encapsulated neoplasm comprising of nests and trabeculae of round to polygonal cells surrounded by slender vascular septae; thus, giving a Zellballen pattern. Few colloid-filled follicles were seen outside the capsule. The tumor cells had round to ovoid nuclei with fine granular chromatin and small nucleoli in some with moderate amount of granular eosinophilic cytoplasm. There were prominent, thin-walled vascular spaces and areas of hemorrhage [Figure 1]a and [Figure 1]b. On immunohistochemistry (IHC), the neoplastic cells were strongly and diffusely positive for synaptophysin and chromogranin, but negative for pancytokeratin, calcitonin, thyroglobulin, thyroid transcription factor 1 (TTF1), and carcinoembryonic antigen (CEA). S-100 immunostaining highlighted the sustentacular cells focally. The tumor showed a low proliferative activity with a Mib-1 labeling index of <2% [Figure 2]a, [Figure 2]b, [Figure 2]c, [Figure 2]d. Histomorphology, in correlation with IHC findings were consistent with the diagnosis of an intrathyroidal paraganglioma. His postoperative plasma and 24-h urinary catecholamines were within normal limits whereas the radiological evaluation of abdomen and pelvis did not reveal any other evidence suggestive of a syndromic tumor. The patient is presently under close follow-up without any evidence of recurrence or distant metastasis 12 months' postsurgery. In view of financial constraints, the patient refused further molecular work-up.
|Figure 1: (a) Colloid filled follicles are seen adjacent to the tumor (H and E, ×100). (b) Round to ovoid cells with granular eosinophilic cytoplasm and Zellballen pattern of arrangement (H and E, ×400)|
Click here to view
|Figure 2: (a) Immunohistochemical staining of paraganglioma showing synaptophysin positivity (IHC, ×100). (b) Tumor cells are immunonegative for thyroid transcription factor 1 immunohistochemical stain, but the adjacent thyroid follicles show nuclear positivity (IHC, ×100). (c) S100 immunohistochemical staining highlighting the sustentacular cells focally (IHC, ×400). (d) Ki-67 (IHC, ×100) showing a low proliferative index|
Click here to view
| > Review of World Literature and Collection of Data|| |
A systematic search of world literature on TPG, over the past 54 years (January 1964–May 2018), was done by using the search engines such as the PubMed, PubMed Central, Medline, and Directory of Open Access Journal databases. Following keywords were used for the literature search: intrathyroidal paraganglioma, thyroid paraganglioma, paraganglioma thyroid, neuroectodermal tumor-thyroid, chemodectoma-thyroid, carotid body tumor thyroid, and primary melanotic paraganglioma of the thyroid. The references of all articles were cross-checked for relevant articles. In 2011, Phitayakorn et al. reported two cases of TPG and reviewed 26 similar cases reported around the world till that time. Since 2011, 28 more articles describing 39 additional cases were reported. Finally, a total of 60 articles describing nearly 75 cases of TPG were found in the world literature till May 2018; and were systematically reviewed in relation to clinical presentation, radiological findings, preoperative FNAC features with their diagnostic pitfalls, frozen section diagnosis, management, histopathology, IHC, molecular genetics (wherever available), and final outcome.
The last two decades have witnessed a dramatic rise in number of TPG being reported worldwide with nearly 60 such cases being reported from 2000 to 2018 till date [Figure 3]. The increased incidence can be attributed to several reasons: first and foremost due to the increased awareness among the patients; the increased number of surgical interventions and a rise in the diagnostic accuracy by technologies such as cellblock preparation, intraoperative frozen consultation, and judicious use of IHC.
| > Presumed Embryogenesis|| |
Thyroid paraganglioma cells are thought to derive from the inferior laryngeal paraganglia. The laryngeal paraganglia are two paired structures, known as the superior and inferior laryngeal paraganglia. It is hypothesized that the TPG takes its origin from the inferior laryngeal paraganglia that is either pulled down by the recurrent laryngeal nerve to lie lateral to thyroid or from the one that is buried inside the thyroid capsule. This common embryologic origin explains why cytologic findings of TPG is often misdiagnosed as other benign and malignant thyroid tumors, such as medullary thyroid carcinoma (MTC), follicular neoplasms, hyalinizing trabecular tumor intrathyroidal parathyroid adenoma, or metastatic NETs.
| > Clinical Presentation|| |
Seventy-six TPG (including the present case) reported till date [Table 1], showed a distinct female predilection (14 [18.4%] males, 62 [81.6%] females, male: female ratio = 1:4.4). With the exception of an isolated case occurring in a 9-year-old child, the rest of the cases were described to occur in adult patients with age ranging from 19 to 78 years (median, 51 years; mean, 50.36 years). The mean age at presentation among female individuals was 49.6 years (range, 9–78 years), with 29.03% (n = 18) presenting before the age of 40 years. Similarly, the mean age at presentation among males was 44.2 years (range, 24–72 years) with 35.7% (n = 5) reported before the age of 40 years. The family history of the paragangliomas was positive in one of the five cases reported by von Dobschuetz et al. This patient had 10 relatives, eight of them were mutation carriers, and six of them had paragangliomas or pheochromocytoma.
|Table 1: Thyroid paraganglioma: A systematic review of seventy-six cases (including the present one) reported worldwide (1964– 2018)|
Click here to view
Clinically, the majority of the patients presented with asymptomatic solitary nodules which ranged in size from 15 to 100 mm and were detected incidentally either by imaging studies or during the physical examination. Pressure-related symptoms such as stridor, dysphagia, dyspnea, and hemoptysis were reported rarely. There was no site predilection for the origin in the thyroid as nearly equal proportion occurred in the left or the right lobe (32 [48.4%] vs. 29 [43.9%], respectively); 5 cases (7.5%) occurred in the isthmus; whereas in the remainder 10 cases (13.2%) the site of origin/localization within the thyroid was not mentioned by the authors. In five cases, there was synchronous carotid body paraganglioma.,,,, In another case, the tumor was accompanied with papillary thyroid carcinoma (PTC), parathyroid adenoma, and bilateral carotid body paragangliomas. With the exception of the case of functional TPG (hypertensive crisis) reported by Skiadas et al., none of the remainder cases had any biochemical evidence of hypo or hyperthyroidism, raised serum calcitonin, CEA, or parathyroid hormone levels; and there was no serological evidence of autoimmune thyroiditis as was evident from negative thyroid peroxidase and antithyroglobulin antibody titers.,, Overall, these tumors in thyroid were clinically indolent with the sole exception of the case reported by Reznick et al., in which the tumor had an aggressive behavior with perithyroidal invasion into surrounding major structures with complete encasement of the right recurrent laryngeal nerve and nodal metastasis. Subsequently, 1 year later, the patient succumbed to her disease exhibiting liver metastasis.
| > Imaging Characteristics|| |
To date, none of the reported cases had been diagnosed accurately as TPG by radiological examinations before surgery. Imaging studies were useful in delineating the size, the intrathyroidal location, and the extrathyroidal extension to adjacent structures. Color Doppler ultrasonography findings consistently revealed a solid thyroid nodule of variable echogenicity (both hypo- to hyperechoic to heterogeneous) associated with intense intra- and perinodular hypervascularity; quite reminiscent of other thyroid neoplasms. In addition, associated calcification and intranodular microcystic changes were also described in some cases, mimicking a malignant tumor., In thyroid scintigraphy, the tumor frequently appeared as “cold nodule,” although “hot nodule” was reported in one case. In contrast-enhanced CT, these tumors were literally similar to that reported from carotid body paragangliomas: intense homogeneous enhancement (due to nodular hypervascularity) with splaying of perinodular vasculature; though heterogeneous enhancement was not uncommon in the presence of internal hemorrhage and/or thrombi. Similarly, on magnetic resonance imaging with contrast, these tumors demonstrated intermediate and heterogeneous signal on T1W and T2W sequences (?). Intense and homogeneous enhancement following the intravenous administration of gadolinium was the last character noted in some of the patients., Most of the thyroid paragangliomas were confined to the thyroid gland with the exception of sporadic reports of extrathyroidal invasion into surrounding structures such as adjacent vessels, nerves, esophagus, trachea, and larynx.,,
| > Pathologic Features|| |
Fine-needle aspiration cytology
The diagnosis of paraganglioma by cytology can be challenging. In view of the proposed embryogenesis (see above), these tumors were commonly misdiagnosed on cytology smears as primary thyroid neoplasms because of the overlapping cytological features. Extensive research of the current literature revealed reports of cytological descriptions and their potential diagnostic pitfalls only in 34 reported cases [Table 1]. Nine (25. %) cases were misdiagnosed as follicular neoplasms; MTC in 8 (22.2%) cases; PTC, carotid body tumor and Bethesda II in 2 (5%) cases each. Five cases (13.5%) were reported as Bethesda III (atypia of undetermined significance); four (10.8%) were diagnosed as Bethesda V; and one case (2.7%) each was misdiagnosed as NET and poorly differentiated epithelial tumor. None of the cases, with the rare exceptions of those reported by Schmit et al. and Çetin et al., yielded an accurate diagnosis. The accurate cytological diagnosis was made on FNAC, supplemented with cell block histology and IHC.,
Aspirate smears from cases of TPG were reported to be variably cellular. The cells were seen dispersed singly as well as in sheets with focal pseudo acinar pattern in a hemorrhagic background. These exhibited diverse cytomorphological patterns ranging from plasmacytoid to epithelial-like to spindled morphology, thus masquerading MTC very closely. The cells had elongated nuclei, fine chromatin, and inconspicuous nucleoli with scant to moderate amount of granular basophilic cytoplasm. Occasional bi-nucleated cells were also reported. Colloid or colloid-like and/or amyloid-like substances described commonly in other primary thyroid neoplasms were not reported in any of these TPG cases. Our case had very poor cytological yield in spite of repeated aspirations; and reported as colloid goiter.
Intraoperative frozen section
Frozen section examination is usually not helpful for giving a correct diagnosis during intraoperative consultation. However, in our review, 28 cases in which frozen section was available only two cases were correctly diagnosed as paragangliomas. All the other cases (n = 26, see [Table 1]) were misdiagnosed as primary thyroid neoplasms: medullary (n = 13), follicular neoplasm (n = 6), malignant neoplasm not further classified (n = 2) one case of anaplastic carcinoma and one case of benign neoplasm. The diagnosis of lymphoma, metastasis, and trabecular neoplasm had been also described in the literature. Hence, frozen sections are not recommended in the diagnosis of paraganglioma.
Usually, thyroid paragangliomas are solitary and well circumscribed. The gross appearance of all reported cases is nodular with well-defined borders. Cut surface is solid and fleshy without any evidence of hemorrhage and necrosis. Fibrosis and calcification may be seen. Extrathyroidal extension usually is not seen in TPGs.
Microscopically, thyroid paragangliomas are well delineated with a fibrous capsule. The tumor comprises of neoplastic oval to polygonal cells in nests and trabeculae enclosed by thin delicate fibrovascular septa (so-called “Zellballen” pattern), reminiscent of other NETs. The two types of cells which characterize the tumor include the polygonal chief cells with round to oval nuclei and finely granular cytoplasm and the spindle sustentacular cells with scant cytoplasm. Sudden anisonucleosis is commonly encountered. Nuclear pleomorphism may occasionally be noted, but mitotic figures are scanty. The microscopic features can simulate MTC or a follicular carcinoma and can lead to diagnostic pitfalls. Judicious use of histochemical stains and IHC can prevent an erroneous diagnosis. Dong et al. described a paraganglioma with melanocytic differentiation, in which the melanin pigment was confirmed by Masson Fontana stain.
Immunophenotyping and differential diagnosis
The tumor cells are diffusely positive for neuroendocrine markers such as chromogranin, synaptophysin, neuron-specific enolase but are usually negative for cytokeratin, calcitonin, thyroglobulin, TTF-1, CEA, and parathyroid hormone. Glial fibrillary acidic protein and S100 highlight the sustentacular cells which are located at the periphery of tumor nests. Tyrosine hydroxylase enzyme staining may be supportive of the diagnosis.
Although paragangliomas exhibit distinct morphology and pattern, but the location in the thyroid poses a diagnostic difficulty as it mimics primary neoplasm of the thyroid like, they must be differentiated from MTC, hyalinizing trabecular tumor formerly designated as paraganglioma like adenoma of the thyroid, follicular neoplasms, carcinoid tumors metastasizing to thyroid, and metastatic renal cell carcinoma (RCC). Morphology alone cannot distinguish these entities, thus emphasizing the role of judicious use of IHC in differentiating these lesions as shown in [Table 2].
|Table 2: Immunohistochemistry and differential diagnosis of intrathyroidal paraganglioma|
Click here to view
MTC cells are plasmacytoid to spindloid, arranged in sheets, nests, and trabeculae separated by delicate fibrovascular stroma with extracellular amyloid deposits. In a rare subtype of MTC, the so-called paraganglioma like MTC, a close mimicker of paraganglioma, in which sustentacular cells are also seen, makes the diagnosis even more challenging. IHC can equally be challenging in differentiating these lesions as pure paragangliomas can show immunoreactivity for cytokeratin and calcitonin., However, the case reported by Bockhom et al. as paraganglioma like MTC showed strong immunoreactivity for neuroendocrine markers, cytokeratin, calcitonin, CEA while immunonegative for thyroglobulin and TTF1. Interestingly the spindle and stellate cells showed S100 immunostaining. These cells were intermingled with tumor cells.
Hyalinizing trabecular tumor or paraganglioma-like adenoma of the thyroid can simulate thyroid paraganglioma because of its close histologic resemblance to a NET. They are well-delineated tumors composed of polygonal to columnar cells with elongated nuclei and abundant amount of eosinophilic cytoplasm separated by bands of hyaline material that are negative for Congo Red stain.
Follicular neoplasms are characterized by follicular epithelial cells arranged in microfollicles and solid pattern. Capsular and vascular invasion differentiates follicular adenoma from follicular carcinoma. RCC is the most common extrathyroidal tumor to metastasize to the thyroid. Polygonal cells with clear cytoplasm and distinct cell border arranged in a compact-alveolar or acinar pattern interspersed with intricate, arborizing vasculature are the pathognomonic histological features that characterize RCC.
Although most of the paragangliomas are considered sporadic, to date, approximately 30% to 40% are associated with at least 14 known susceptibility genes (MEN1, NF1, RET, von Hippel–Lindau [VHL], SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, EGLN1, HIF2A, KIF1Bb, and MAX). Up to 30% of all head and neck paragangliomas are hereditary and are associated with different tumor syndromes. Major hereditary disorders associated with paraganglioma are multiple endocrine neoplasia (MEN), VHL disease, neurofibromatosis, and familial paraganglioma syndromes 1-5. The paraganglioma syndromes caused by mutations of the succinate dehydrogenase (SDH) genes make up most of the familial cases. Paraganglioma 1 is associated with mutation of the succinate dehydrogenase complex, subunit D gene (SDHD); paraganglioma 2 with mutation of the SDH5/SDHAF2 gene; paraganglioma 3 with mutation of the SDHC gene; paraganglioma 4 with mutation of the SDHB gene; and paraganglioma 5 with mutation of the SDHA gene.
SDH complex has 4 subunits encoded by 4 SDH genes (SDHA, SDHB, SDHC, and SDHD) and play a crucial part in Kreb cycle as part of the mitochondrial complex II in the aerobic electron transport of the respiratory chain. Mitochondrial complex II is a tumor suppressor gene, the loss of which leads to the overexpression of several hypoxia-inducible genes that result in the proliferation of paraganglia. SDHD and SDHB mutation carriers are associated with synchronous development of multiple head and neck paragangliomas and pheochromocytomas. The risk for the development of malignancy is significantly higher in patients with SDHB mutations, compared with patients with SDHC and SDHD mutations or those with sporadic tumors. A surrogate marker for some of the familial paraganglioma syndromes caused by SDH mutations is the loss of SDHB immunoexpression. A negative SDHB staining indicates the presence of a mutation and a positive staining indicates the absence of mutation. The immunohistochemical stain for SDHB has also provided prognostic data because of the high rate of malignancy associated with SDHB-driven paragangliomas.
In our review, 18% of TPG (n = 14) had genetic testing. Seven cases were negative for RET and SDH mutation,,,, whereas in one study there were no reported results. Costinean et al. in 2012 first described a number of homozygous and heterozygous single nucleotide polymorphism in the B, C, and D subunits of SDH genes in TPG. A large series of PGs from various sites of the body identified germline mutation in the SDH genes particularly in the subunit D and B. They observed that patients with mutation carriers were younger, had an aggressive course and frequently presented with multiple or malignant PGs. von Dobschuetz et al. reported SDH mutations in 4 out of their 5 cases of TPG (SDHB in 2 and SDHA in 2). The youngest patient having SDHB mutation developed metachronous bilateral phaeochromocytoma. Zantour et al. identified a heterozygous germline mutation in exon 4 of the SDHB gene in a young patient without any apparent family history of PG. On a clinical basis, the patient had a high risk of recurrence and was monitored regularly. [Table 3] summarizes the molecular genetics in thyroid paragangliomas reported in the literature.
|Table 3: Molecular genetics in thyroid paragangliomas reported in the literature|
Click here to view
Treatment and prognosis
The initial modality of treatment is surgical excision. Depending on the size, multifocality, extent of involvement options ranges from subtotal hemithyroidectomy to total thyroidectomy. There have been no reports of local recurrence following complete excision of the tumor. The role of radiotherapy is unknown, and only three cases,, are documented.
Nearly 60 articles,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, were reviewed describing nearly 75 cases of intra thyroidal paraganglioma, pertaining to clinical presentation, radiological findings, preoperative FNAC features with their diagnostic pitfalls, frozen section diagnosis, management, histopathology, IHC, molecular genetics (wherever available), and final outcome, which is possibly the largest review on thyroid paragangliomas.
| > Conclusion|| |
Thyroid paragangliomas are extremely rare primary neoplasms associated with a benign and indolent biological behavior. From a pathologist's perspective, they can be a great morphological mimicker of common thyroid neoplasms such as MTC, follicular neoplasm, as well as metastasis. Preoperative cytodiagnosis can be both challenging as well as misleading. Familiarity among all regarding this tumor with judicious use of IHC should lead to the correct diagnosis and avoid unnecessary aggressive therapy. The active surveillance for multicentric tumors and/or metastasis as well as triaging patients and their family members for optimal genetic testing with immunohistochemical stains for the loss of SDHB and SDHA proteins is recommended. Finally, because these tumors are known to develop late metastasis and are associated with unpredictable behavior, a long-term clinical follow-up is prudent.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Zantour B, Guilhaume B, Tissier F, Louvel A, Jeunemaitre X, Gimenez-Roqueplo AP, et al.
Athyroid nodule revealing a paraganglioma in a patient with a new germline mutation in the succinate dehydrogenase B gene. Eur J Endocrinol 2004;151:433-8.
Phitayakorn R, Faquin W, Wei N, Barbesino G, Stephen AE. Thyroid-associated paragangliomas. Thyroid 2011;21:725-733.
Feghaly J, Astras G, Loizou M, Panayiotou G, Mooradian A. Primary paraganglioma of thyroid gland: Clinical and immunohistochemical analysis with a literature review. Eur Med J 2016;1:101-6.
Pelizzo MR, Conti C, Pennelli G, Bellan E, Cook GJ, Wong KK, et al.
Thyroid paraganglioma: Our experience and systematic review of the literature on a rare tumor. Am J Clin Oncol 2018;41:416-23.
Vanmiert PJ. The treatment of chemodectomas by radiotherapy. Proc R Soc Med 1964;57:946-51.
Massaioli N, Balbo G, Fausone G, Negro D. Endothyroid (non-chromaffin) branchiomeric paraganglioma. Description of a clinical case. Minerva Chir 1979;34:867-74.
von Dobschuetz E, Leijon H, Schalin-Jäntti C, Schiavi F, Brauckhoff M, Peczkowska M, et al.
Aregistry-based study of thyroid paraganglioma: Histological and genetic characteristics. Endocr Relat Cancer 2015;22:191-204.
Haegert DG, Wang NS, Farrer PA, Seemayer TA, Thelmo W. Non-chromaffin paragangliomatosis manifesting as a cold thyroid nodule. Am J Clin Pathol 1974;61:561-70.
Cayot F, Bastien H, Justrabo E, Mottot C, Cuisenier J, Bruchon Y, et al.
Multiple paragangliomas of the neck localized in the thyroid region. Papillary thyroid cancer associated with parathyroid adenoma. Sem Hop 1982;58:2004-7.
Hughes JH, El-Mofty S, Sessions D, Liapis H. Primary intrathyroidal paraganglioma with metachronous carotid body tumor: Report of a case and review of the literature. Pathol Res Pract 1997;193:791-6.
Mohyuddin N, Ferrer K, Patel U. Malignant paraganglioma of the thyroid gland with synchronous bilateral carotid body tumors. Ear Nose Throat J 2013;92:E20-3.
Skiadas PK, Kakavoulis TN, Gikonti IJ. Normalisation of blood pressure and heart rate after excision of a thyroid paraganglioma. Eur J Surg 2001;167:392-4.
Yano Y, Nagahama M, Sugino K, Ito K, Kameyama K, Ito K, et al.
Paraganglioma of the thyroid: Report of a male case with ultrasonographic imagings, cytologic, histologic, and immunohistochemical features. Thyroid 2007;17:575-8.
Kronz JD, Argani P, Udelsman R, Silverberg L, Westra WH. Paraganglioma of the thyroid: Two cases that clarify and expand the clinical spectrum. Head Neck 2000;22:621-5.
Ferri E, Manconi R, Armato E, Ianniello F. Primary paraganglioma of thyroid gland: A clinicopathologic and immunohistochemical study with review of the literature. Acta Otorhinolaryngol Ital 2009;29:97-102.
Reznick D, Scharpf J, Doshi K, Siperstein A, Berber E, Chute D, et al
. Malignant primary paraganglioma of the thyroid gland: The first reported case. AACE Clin Case Rep 2016;2:e70-5.
Yu BH, Sheng WQ, Wang J. Primary paraganglioma of thyroid gland: A clinicopathologic and immunohistochemical analysis of three cases with a review of the literature. Head Neck Pathol 2013;7:373-80.
Foppiani L, Marugo A, Del Monte P, Sartini G, Bandelloni R, Marugo M, et al.
Thyroid paraganglioma manifesting as hot toxic nodule. J Endocrinol Invest 2005;28:479-80.
Rim Z, Rim B, Houda C, Souheil J, Najeh B, Ghazi B, et al
. Paraganglioma of the carotid body: Report of 26 patients and review of the literature. Egypt J Ear Nose Throat Allied Sci 2015;16:19-23.
Armstrong MJ, Chiosea SI, Carty SE, Hodak SP, Yip L. Thyroid paragangliomas are locally aggressive. Thyroid 2012;22:88-93.
Schmit GD, Gorman B, van Heerden JA, Gharib H. Inferior laryngeal paraganglioma mimicking a primary thyroid tumor. Endocr Pract 2006;12:432-5.
Çetin Ş, Kir G, Yilmaz M. Thyroid paraganglioma diagnosed by fine-needle aspiration biopsy, correlated with histopathological findings: Report of a case. Diagn Cytopathol 2016;44:643-7.
Zhang W, Policarpio-Nicolas ML. Aspiration cytology of primary thyroid paraganglioma. Diagn Cytopathol 2015;43:838-43.
Navaratne L, Mathew RG, Kousparos G, McCombe A. The management of locally invasive primary thyroid paraganglioma: A case report and review of the literature. Head Neck Pathol 2017;11:139-45.
Lee SM, Policarpio-Nicolas ML. Thyroid paraganglioma. Arch Pathol Lab Med 2015;139:1062-7.
Dong YJ, Zhang ZW, Wang Z, Wang XY, Tian ZZ, Zhang XS, et al.
Primary melanotic paraganglioma of thyroid gland: Report of a rare case with clinicopathologic and immunohistochemical analysis and a literature review. Clin Med Insights Pathol 2017;10:1-5.
Tischler AS, Pacak K, Eisenhofer G. The adrenal medulla and extra-adrenal paraganglia: Then and now. Endocr Pathol 2014;25:49-58.
Bockhorn M, Sheu SY, Frilling A, Molmenti E, Schmid KW, Broelsch CE, et al.
Paraganglioma-like medullary thyroid carcinoma: A rare entity. Thyroid 2005;15:1363-7.
Johnson TL, Zarbo RJ, Lloyd RV, Crissman JD. Paragangliomas of the head and neck: Immunohistochemical neuroendocrine and intermediate filament typing. Mod Pathol 1988;1:216-23.
Sneige N, Mackay B, Ordonez NG, Batsakis JG. Laryngeal paraganglioma. Report of two tumors with immunohistochemical and ultrastructural analysis. Arch Otolaryngol 1983;109:113-7.
Dahia PL, Ross KN, Wright ME, Hayashida CY, Santagata S, Barontini M, et al.
AHIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. PLoS Genet 2005;1:72-80.
González Poggioli N, López Amado M, Pimentel MT. Paraganglioma of the thyroid gland: A rare entity. Endocr Pathol 2009;20:62-5.
Yu X, Wang Y, Wang P, Ji CH, Miao CD, Zheng S, et al.
Primary thyroid paraganglioma mimicking medullary thyroid carcinoma: A case report. Oncol Lett 2015;10:1000-2.
Waise S, Jogai S. Thyroid paraganglioma. Diagn Histopathol 2018;24:124-5.
Castelblanco E, Gallel P, Ros S, Gatius S, Valls J, De-Cubas AA, et al.
Thyroid paraganglioma. Report of 3 cases and description of an immunohistochemical profile useful in the differential diagnosis with medullary thyroid carcinoma, based on complementary DNA array results. Hum Pathol 2012;43:1103-12.
Costinean S, Balatti V, Bottoni A, Old M, Croce C, Wakely PE Jr., et al.
Primary intrathyroidal paraganglioma: Histopathology and novel molecular alterations. Hum Pathol 2012;43:2371-5.
Burnichon N, Rohmer V, Amar L, Herman P, Leboulleux S, Darrouzet V, et al.
The succinate dehydrogenase genetic testing in a large prospective series of patients with paragangliomas. J Clin Endocrinol Metab 2009;94:2817-27.
Kay S, Montague JW, Dodd RW. Nonchromaffin paraganglioma (chemodectoma) of thyroid region. Cancer 1975;36:582-5.
Banner B, Morecki R, Eviatar A. Chemodectoma in the mid-thyroid region. J Otolaryngol 1979;8:271-3.
Buss DH, Marshall RB, Baird FG, Myers RT. Paraganglioma of the thyroid gland. Am J Surg Pathol 1980;4:589-93.
Olofsson J, Gröntoft O, Sökjer H, Risberg B. Paraganglioma involving the larynx. ORL J Otorhinolaryngol Relat Spec 1984;46:57-65.
Mitsudo SM, Grajower MM, Balbi H, Silver C. Malignant paraganglioma of the thyroid gland. Arch Pathol Lab Med 1987;111:378-80.
de Vries EJ, Watson CG. Paraganglioma of the thyroid. Head Neck 1989;11:462-5.
Brownlee RE, Shockley WW. Thyroid paraganglioma. Ann Otol Rhinol Laryngol 1992;101:293-9.
LaGuette J, Matias-Guiu X, Rosai J. Thyroid paraganglioma: A clinicopathologic and immunohistochemical study of three cases. Am J Surg Pathol 1997;21:748-53.
Bizollon MH, Darreye G, Berger N. Thyroid paraganglioma: Report of a case. Ann Pathol 1997;17:416-8.
Tiong HY, White SA, Roop L, Furness PN, Nicholson ML. Paraganglioma-an unusual solitary nodule of the thyroid. Eur J Surg Oncol 2000;26:720-1.
Napolitano L, Francomano F, Angelucci D, Napolitano AM. Thyroid paraganglioma: Report of a case and review of the literature. Ann Ital Chir 2000;71:511-3.
Vera-Cruz P, Zagalo C, Felix A, Pratas S, Rosa Santos J. Paraganglioma tiroideo. Caso clinico. Thyrosis Paraganglioma. Case Report. Rev Chil Anat 2001;19:331.
Vodovnik A. Fine needle aspiration cytology of primary thyroid paraganglioma. Report of a case with cytologic, histologic and immunohistochemical features and differential diagnostic considerations. Acta Cytol 2002;46:1133-7.
Hinojar AG, Prieto JR, Muñoz E, Hinojar AA. Relapsing paraganglioma of the inferior laryngeal paraganglion: Case report and review of the literature. Head Neck 2002;24:95-102.
Corrado S, Montanini V, De Gaetani C, Borghi F, Papi G. Primary paraganglioma of the thyroid gland. J Endocrinol Invest 2004;27:788-92.
Ashraf MJ, Azarpira N, Vasei M, Tavakol MH, Khademi B. Thyroid paraganglioma: Diagnostic pitfall in fine needle aspiration biopsy. Acta Cytol 2008;52:745-7.
Erem C, Kocak M, Nuhoglu İ, Cobanoglu U, Ucuncu O, Okatan BK, et al.
Primary thyroid paraganglioma presenting with double thyroid nodule: A case report. Endocrine 2009;36:368-71.
Mun KS, Pailoor J, Chan KS, Pillay B. Extra-adrenal paraganglioma: Presentation in three uncommon locations. Malays J Pathol 2009;31:57-61.
Basu S, Viswanathan S. Primary paraganglioma of thyroid presenting as solitary thyroid mass. J Cancer Res Ther 2011;7:385-7.
Tatar C, Karsidag T, Tuzun S. Tiroid bezinde paraganglioma [Paraganglioma of the thyroid gland]. Med Bull Haseki Haseki Tip Bulteni 2012;50:110-2.
Sedlak A. Malignant paraganglioma of the thyroid gland: A case study. Case Report J 2015. [In press].
Evankovich J, Dedhia RC, Bastaki JM, Tublin M, Johnson JT. Primary sclerosing paraganglioma of the thyroid gland: A case report. Ann Otol Rhinol Laryngol 2012;121:510-5.
Akhtar K, Sen Ray P, Ahmad SS, Sherwani RK. Paraganglioma of the thyroid gland: Cytologists' enigma. BMJ Case Rep 2013;2013. pii: bcr2013009518.
Calò PG, Lai ML, Guaitoli E, Pisano G, Favoriti P, Nicolosi A, et al.
Difficulties in the diagnosis of thyroid paraganglioma: A clinical case. Clin Ter 2013;164:e35-9.
Filipovic A, Vuckovic L, Pejakov L. Paraganglioma of the thyroid gland: A case report. Vojnosanit Pregl 2014; 71:875-8.
Taweevisit M, Bunyayothin W, Thorner PS. Thyroid paraganglioma: “Naked” nuclei as a clue to diagnosis on imprint cytology. Endocr Pathol 2015;26:232-8.
Ozpek A, Kir G, Tolan HK, Yucel M, Tekesin K, Bas G, et al
. Thyroid paraganglioma: An extremely rare tumor of the thyroid. Ann Clin Case Rep 2016;1:1188.
Aydoǧan Bİ, Dizbay Sak S, Güllü S. Cervical paraganglioma mimicking thyroid nodule: A rare clinical case. Case Rep Endocrinol 2016;2016:8527279.
Sangtian J, Evasovich MR, Harindhanavudhi T. A rarity in a common disease: Thyroid paraganglioma. Am J Med 2017;130:e133-5.
Gill M, Roychoudhury AK, Thukral S, Gupta A, Bansal N. Primary paraganglioma of the thyroid gland – A rare case report. J Clin Diagn Res 2017;11:15-6.
Nguyen NA, Peter I, Levay B, Andi J, Polgar C, Nagy ZT. Thyroid gland paraganglioma: Report of a case and review of the literature. Int J Clin Exp Med 2017;10:16703-8.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]