Primary Spindle Cell Lesions of the Thyroid Gland An Overview

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1 Primary Spindle Cell Lesions of the Thyroid Gland An Overview Giampaolo Papi, MD, 1 Stefania Corrado, MD, 2 and Virginia A. LiVolsi, MD 3 Key Words: Spindle cells; Thyroid; Neoplasm; Papillary thyroid carcinoma; Medullary thyroid carcinoma Abstract Spindle cell lesions of the thyroid gland (T-SCL) are not encountered routinely in clinical practice or in the context of thyroid pathology. They commonly are classified as primary or secondary to metastatic disease. Primary T-SCL can be derived from follicular, C-cell (parafollicular), or mesenchymal components and may be the result of reactive or neoplastic processes, including post fine-needle aspiration spindle cell nodules, Riedel thyroiditis, solitary fibrous tumor, leiomyoma, peripheral nerve sheath tumor, hyalinizing trabecular tumor, spindle epithelial tumor with thymuslike differentiation, follicular dendritic cell tumor, medullary carcinoma, papillary carcinoma, anaplastic carcinoma, sarcoma, squamous cell carcinoma, and carcinoma showing thymus-like differentiation. Because T-SCL may represent the expression of benign and highly malignant neoplasms, distinction among these processes is crucial because it dictates therapy and defines prognosis. The present article reviews the clinical, imaging, pathologic, and immunohistochemical characteristics of primary T-SCL. Spindle cell lesions of the thyroid gland (T-SCL) represent rare entities. They can be of primary thyroid origin or arise secondary to metastatic disease; nevertheless, they may originate from reactive or neoplastic processes. Several proliferations derived from follicular, C-cell (parafollicular), and mesenchymal components may show the morphologic features of T-SCL. Primary T-SCLs include the following entities: post fine-needle aspiration spindle cell nodules of the thyroid (PSCNT), Riedel thyroiditis (RT), solitary fibrous tumor (SFT), muscle cell tumors, peripheral nerve sheath tumors (PNSTs), hyalinizing trabecular tumor (HTT), spindle epithelial tumor with thymus-like differentiation (SETTLE), carcinoma showing thymus-like differentiation (CASTLE), follicular dendritic cell tumor (FDCT), and the spindle cell variants of papillary, medullary, anaplastic, and squamous cell carcinoma. The spindle cell component of primary T-SCLs may vary from focal to extensive, depending on the cellular origin. For example, in most cases of post fine-needle aspiration spindle cell nodules, the nodular proliferation is circumscribed and limited to the central part of the preexisting thyroid lesions submitted to aspiration biopsy. 1 Conversely, in some neoplasms of follicular origin, the cell metaplasia can be so extensive that only the spindle cell component is identified. 2 Because T-SCL may represent the expression of benign and highly malignant neoplasms, distinction among these processes is crucial because it dictates therapy and defines the prognosis for patients. However, T-SCLs present several diagnostic challenges. The interpretation of specimen morphologic features is difficult when it is based solely on cytologic and histologic findings. Indeed, the morphologic and architectural features may lead to the nonspecific Am J Clin Pathol 2005;124(Suppl 1):S95-S123 S95 S95

2 Papi et al / PRIMARY SPINDLE CELL THYROID LESIONS diagnosis of T-SCL, and immunohistochemical staining is required for appropriate classification. The present article reviews the clinical, imaging, pathologic, and immunohistochemical characteristics of primary T-SCLs. Solitary Fibrous Tumor SFT is a rare spindle cell neoplasm, first reported by Klemperer and Rabin 3 in 1931 as a pleural tumor. Subsequently, it has been recognized in multiple organs throughout the body, including liver, 4 parotid gland, 5 female 6,7 and male 8 reproductive systems, urinary bladder, 8 kidney, 9 orbit, 10 auditory canal, 11 mediastinum, 12 peritoneum, 13 breast, 14 gastrointestinal tract, 15 and nervous system. 16,17 Therefore, it is widely accepted that SFT is a ubiquitous neoplasm likely of mesenchymal origin. 18 SFT arising from the thyroid gland (T-SFT) was first described in 1993 by Taccagni et al, 19 who described 3 patients with nodular goiter. Subsequently, another 15 cases have been reported, with an increasing frequency during the last few years. 18,20-27 No cases of SFT of the thyroid have been described in children and adolescents. The youngest patient described with thyroid SFT was 28 years old, 22 and the oldest was 68 years old. 25 No sex predilection was found (female/male ratio, 1:1). Patients usually have a long-standing goiter, slowly increasing in size despite thyrotropin suppression by L-thyroxine therapy. 23 In contrast with occasional observation Image 1 Solitary fibrous tumor of the thyroid gland. The neoplasm is characterized by a proliferation of spindle, fibroblast-like cells (H&E, original magnification 20). of fasting hypoglycemia in subjects with pleural 28,29 and extrapleural SFTs 4,7 due to the paraneoplastic production of insulin-like growth factor, 7 neither laboratory nor clinical signs and symptoms of low glucose plasma levels have been noticed in patients with thyroid SFTs. On examination, the goiter shows a remarkably hard consistency; some patients experience pressure symptoms, such as dysphagia. Pressure symptoms usually are caused by the tumor size at diagnosis, which in most cases exceeds 30 mm in diameter. Indeed, like their extrathyroidal counterparts, 28 SFTs of the thyroid gland usually show large dimensions (nodules up to 97 mm have been reported), 25 have a solid appearance on ultrasound examination, and are cold in thyroid scanning performed using technetium 99m ( 99m Tc) and iodine 131 ( 131 I). 19,20 Usually, fine-needle aspiration (FNA) biopsy does not yield adequate material for a definite cytologic diagnosis because paucicellular smears show few scattered spindle cells and scant colloid. 18,26 The diagnosis of SFT is made by histologic and immunohistochemical examination. Grossly, most T-SFTs appear as large, well-circumscribed, solid, whitish to grayish, seldom tan, lesions. 19,23,25 Microscopically, the neoplasm is characterized by a proliferation of spindle, fibroblast-like cells that often display a haphazard distribution ( patternless pattern) 20,21,24-27 and sometimes infiltrate the surrounding thyroid parenchyma in small fascicles separating the follicles or in nodular structures Image 1. Tumor cells exhibit a weakly eosinophilic cytoplasm; the nuclei show various shapes; round to oval and elongated to spindle-shaped nuclei have been observed: and the nuclei contain finely dispersed chromatin with inconspicuous, sometimes lacking, nucleoli. The degree of tumor cellularity ranges from low to high, and in all cases, a mitotic rate of 4 mitoses or fewer per 10 high-power fields has been recorded. In no case has necrosis or vascular invasion been detected Some tumors may arise in the head and neck and secondarily involve the thyroid. 30,31 By immunohistochemical examination, SFT cells are characterized by staining positively for bcl-2 Image 2, CD34 Image 3, CD99, vimentin, and, rarely, actin. In contrast, SFTs of the thyroid gland do not demonstrate any reaction for epithelial markers such as keratins, thyroglobulin, thyroid transcription factor-1, epithelial membrane antigen (EMA), neuron-specific markers (eg, S-100 protein, neurofilaments, and acetylcholinesterase), neuroendocrine markers (ie, calcitonin, neuron-specific enolase, chromogranin, synaptophysin, and tyrosine hydroxylase), and muscle cell markers (ie, smooth muscle myosin, desmin, and basal lamina components). All reported cases of T-SFT have behaved in a benign manner. The treatment of SFT is surgical excision. S96 S96

3 Image 2 Solitary fibrous tumor of the thyroid gland. Tumor cells stain positively for bcl-2 oncoprotein (bcl-2 stain, original magnification 20). Image 3 Solitary fibrous tumor of the thyroid gland. Tumor cells stain positively for CD34 (CD34, original magnification 40). Riedel Thyroiditis RT is an uncommon form of chronic thyroiditis in which the thyroid gland is replaced by fibrous tissue. Its cause remains obscure, although current evidence suggests that RT might be the local manifestation of a systemic fibrosing disease Clinically, patients with RT usually have a goiter of remarkably hard consistency, often associated with a series of pressure symptoms, mimicking malignancy. In particular, patients may complain of discomfort in the anterior part of the neck, dysphagia, a feeling of suffocation, and, sometimes, dyspnea when lying down Most patients with RT are female (female/male ratio, ~5:1) and are euthyroid, and one third of them have an elevated serum thyrotropin concentration, whereas thyrotoxicosis is a rare finding. 33,38-40 Antibodies against thyroglobulin and thyroperoxidase are elevated (usually at low titers) in 45% to 67% of patients with RT. 39,41,42 Ultrasound may reveal nodular changes or a diffusely hypoechoic gland consistent with thyroiditis. 43 Color power Doppler imaging demonstrates complete absence of vascular flow in areas diagnosed histologically as RT owing to fibrosclerotic changes. 44 Magnetic resonance imaging (MRI) shows a homogeneous image in T 1 - and T 2 -weighted images in RT cases Because tumors and inflammatory lesions of other origins have a different appearance on MRI, this picture should be considered pathognomonic of RT. 44 However, because cytologic examination of FNA biopsy specimens is nondiagnostic in RT cases, histologic confirmation is mandatory for the definitive diagnosis of RT. Indeed, FNA biopsy often yields acellular or paucicellular smears 46,48-52 and fails to demonstrate the perithyroidal extension of the fibroinflammatory process. The histologic diagnosis of RT is made when the following criteria are met 38,39,53 : (1) fibroinflammatory process involving all or a portion of the thyroid gland; (2) evidence of its extension into surrounding tissues, including strap muscles; (3) infiltrates of inflammatory cells without giant cells, lymphoid follicles, oncocytes, or granulomas; (4) evidence of occlusive phlebitis; and (5) absence of neoplasm. In RT, histologic examination shows extensively fibrosing thyroiditis with hyalinization areas. The focal extension of fibrosis, which spreads outside the thyroid capsule and infiltrates the perithyroid muscles, and the presence of vasculitis, resulting from diffuse infiltration of the walls of small and medium-sized veins by lymphocytes and plasma cells, are the distinctive features of RT. The lymphocytic infiltrate is composed of lymphocytes, monocytes, granulocytes, and eosinophils, with no evidence of giant cells, lymph follicles, oncocytes, or granulomas. 42 The inflammatory activity is concentrated almost exclusively on the border between the fibrotic mass and the normal thyroid. Elsewhere within the fibrotic mass, the inflammatory cells are dispersed in a hyalinized matrix where a characteristic spindle-shaped, actin- and vimentin-positive, uniform population of fibroblasts without atypia predominates. 42 Areas of normal thyroid parenchyma usually are observed outside the fibrotic mass. 32 Rarely, the fibroinflammatory process may completely spare 1 lobe. 37 Immunohistochemically, the normal thyroid shows a strong positive stain to thyroglobulin, 54,55 whereas no reaction S97 S97

4 Papi et al / PRIMARY SPINDLE CELL THYROID LESIONS to thyroglobulin staining is detected in RT areas. Staining for eosinophil granule major basic protein shows tissue eosinophilia in the early stage of RT; in contrast, eosinophilia is absent in patients with long-standing disease. 56 RT is a benign disease, which often is self-limiting, and, therefore, no treatment is needed in most cases. L-Thyroxine substitution should be given in cases of hypothyroidism. When tracheal or esophageal compressive symptoms develop or malignancy is to be excluded, surgical treatment is mandatory. To relieve obstructive symptoms, some authors have advocated the use of corticosteroids (mainly prednisone) and, more recently, tamoxifen or a combination of both. 67 Hyalinizing Trabecular Tumor HTT is a tumor of follicular origin with a trabecular pattern of growth and marked intratrabecular hyalinization (World Health Organization [WHO] classification, 2004). 68 Synonyms include hyalinizing trabecular adenoma and paraganglioma-like adenoma of the thyroid gland. This neoplasm was first described in the medical literature by Zipkin 69 in 1905, Masson 70 in 1922, and Ward et al 71 in It ultimately was defined in 1987 by Carney et al 72 as a benign, encapsulated, follicular-derived neoplasm composed of elongated cells arranged around capillaries in a background of hyaline and occasionally calcified extracellular matrix. Thirteen cases in their original series were reported as having peculiar morphologic features, including encapsulation, trabeculae, or solid nests of medium to large follicular cells and markedly hyalinized stroma. HTT mimics medullary carcinoma and paraganglioma, as well as papillary thyroid carcinoma. Bronner et al 73 suggested the term paraganglioma-like adenoma of the thyroid (or PLAT) because of the peculiar arrangement of tumor cells around vessels. In the series by Carney et al, 72 the clinical behavior of HTT was invariably benign, and because of this evidence, the authors considered the term adenoma appropriate for this entity. Subsequently, a few cases of HTT with metastases, capsular, and/or vascular invasion have been reported These reports argued against the initial definition of HTT as a benign entity and its categorization as a distinct tumor of the thyroid. The main problem is the differential diagnosis between HTT and papillary carcinoma. Indeed, both exhibit the same microscopic features, such as psammoma bodies, nuclear grooves, and pseudoinclusions. 72 They are of thyroid follicular epithelial origin and, therefore, express thyroglobulin. Nevertheless, several authors reported the concurrent presence, in the same patient, of HTT and Hashimoto thyroiditis 80,81 or papillary carcinoma. 55 Hence, Li et al 82 classified thyroid lesions that showed hyalinization and trabecular architecture into 4 groups: hyalinizing trabecular adenoma in normal thyroid, hyalinizing trabecular adenoma-like changes associated with nodular hyperplasia or lymphocytic thyroiditis, hyalinizing trabecular carcinoma with capsular and/or vascular invasion, and focal hyalinizing trabecular adenoma-like changes associated with papillary carcinoma. A number of authors have hypothesized that HTT and papillary thyroid carcinoma (PTC) are related and may share a similar pathogenesis. Fonseca et al 83 observed that there were no differences in the expression of stratified epithelialtype cytokeratins in their series of HTT and papillary carcinoma. Conversely, Hirokawa et al 84 did not confirm this evidence in their series: HTT did not show reactivity for cytokeratin (CK)19 and high-molecular-weight cytokeratin, whereas papillary carcinoma was strongly positive for these markers. Papotti et al 85 demonstrated the occurrence of ret/ptc rearrangements in about 30% of HTTs of the thyroid gland, and because these rearrangements are peculiar to papillary carcinoma, they concluded that HTT represents a variant of papillary carcinoma characterized by prominent hyalinized stroma and a trabecular growth pattern. Similarly, Cheung et al 74 detected the presence of ret/ptc rearrangements in 6 of 8 patients with HTT using reverse transcription polymerase chain reaction with Southern hybridization and immunohistochemical analysis. However, it should be emphasized that recent studies have shown ret/ptc rearrangements in lymphocytic thyroiditis 86 and in benign follicular tumors. 87 Therefore, these findings do not constitute definitive evidence that HTT and papillary carcinoma are of similar origin, and the histogenesis of HTT remains controversial. HTT is a rare tumor that uncommonly occurs in people younger than 30 years and shows a marked female predilection. 81 It manifests as a single, usually slow-growing mass in the anterior part of the neck. Some patients have a concurrent multinodular goiter or diffuse enlargement of the thyroid gland due to concurrent lymphocytic thyroiditis. Most subjects are euthyroid; thyroid dysfunction is rare and is the consequence of coexistent thyroiditis or toxic nodular goiter. Ultrasound examination detects a hypoechoic nodule that sometimes exhibits hyperechoic spots reflecting the presence of psammoma bodies. Thyroid scan shows a cold area in all HTT cases. The FNA biopsy specimen often is interpreted as papillary carcinoma because of the nuclear features in the tumor. Aspirates range from slightly to moderately cellular, and cells are arranged in irregular aggregates or singly dispersed. In some areas, a curvilinear or whorled arrangement of tumor cells, often associated with amorphous hyalineappearing material resembling amyloid, is seen. HTT cells S98 S98

5 are spindle shaped or, less frequently, oval. Nuclei are large and elongated, often featuring grooves and pseudoinclusions Occasionally, psammoma bodies may be found. Casey et al 92 reviewed the cytologic material from 29 cases of HTT. The smears, which were uniformly bloody, featured cells in cohesive aggregates radially oriented around hyaline material, less frequently, singly. Papanicolaou stain clearly demonstrated intranuclear cytoplasmic inclusions, nuclear grooves, and nuclear overlapping in the majority of cases. Rapid Romanowsky stained smears highlighted the hyaline material (metachromatic), perinuclear clearing, and cytoplasmic bodies. The authors concluded that the combination of a bloody background, radially oriented cohesive cells with abundant cytoplasm, nuclei with frequent cytoplasmic inclusions and grooves, and the presence of hyaline should suggest the diagnosis of HTT. Kuma et al 93 compared the cytologic features of 16 HTT cases with those of 20 papillary carcinomas. The nuclear grooves were a common finding in both tumors, with an incidence of 81.8% in HTT and 100% in papillary carcinoma cases. With respect to papillary carcinoma, distinctive features peculiar to HTT were the following: vague, curved nuclear palisading; radiating arrangement surrounding hyaline material; elongated cells; cell processes; ill-defined cell border; faintly stained and filamentous cytoplasm; yellow bodies; hyaline material in the background; lack of papillary architecture; and sheet-like arrangement. Grossly, HTT presents as a single, solid, encapsulated or circumscribed neoplasm displaying a homogeneous, lobulated cut surface with a yellow tinge and occasional gross calcifications. Histologic examination shows a neoplasm composed of spindle-shaped cells arranged in nests and trabeculae within a delicately hyalinized fibrovascular stroma. Most lesions are encapsulated, but occasionally tumor capsular invasion with infiltration into adjacent normal thyroid and even lymph node metastases have been reported. 74 Tumor cells have an abundant hyaline, acidophilic to amphophilic cytoplasm and distinct cell borders. Scattered cytoplasmic yellow bodies are a common finding. Nuclei contain prominent grooves and cytoplasmic pseudoinclusions and small nucleoli. Occasional mitotic figures are detected. Furthermore, psammoma bodies may be evident. Immunohistochemical examination reveals that HTT cells are strongly reactive for thyroglobulin, thyroid transcription factor (TTF)-1, and MIB-1 and negative for calcitonin Discrepant results have been obtained with CK19 and highmolecular-weight CKs. 83,84 Some HTTs are reported to stain for RET/PTC oncoprotein 74,85 and galectin Treatment of HTT is controversial. 97 This neoplasm behaves in a benign manner in almost all cases, and, therefore, it initially was named trabecular hyalinizing adenoma. 72 Because occasional cases with capsular and/or vascular invasion and lymph node metastases have been reported, and the term hyalinizing trabecular carcinoma has been used to define them, a noncommittal diagnosis of hyalinizing trabecular tumor rather than adenoma has been favored during recent years. However, the nature of the reported malignant HTT cases is still debated; some authors believe that at least some of them were papillary carcinomas with HTT-like foci rather than true HTTs. 97,98 The same authors also believe that pure HTTs (ie, not associated with papillary carcinoma) are neoplasms of very low, if any, malignant potential 88 and should be treated as such, that is, by partial thyroidectomy only. Papillary Thyroid Carcinoma PTC is a malignant tumor of the thyroid gland characterized by follicular cell differentiation and peculiar nuclear features. PTC constitutes at least 80% of all thyroid malignancy and, therefore, is the most common malignant tumor of the thyroid gland. 54,55,89,99 The cause of PTC is related to the mutation of oncogenes specifically involved in the tumorigenesis occurring in thyroid follicular cells. It has been demonstrated that chromosomal rearrangements of receptor tyrosine kinase genes (ret and TRK) represent the most common structural genetic alterations in PTC. Somatic rearrangements of the ret gene, known as ret/ptc, have been detected in PTC These rearrangements result in tyrosine kinase activation and translocation of the fusion protein to the cytoplasm. To date, a family of 5 fusion proteins, RET/PTC1 through RET/PTC5, have been documented, which are the result of the transposition of a cellular gene adjacent to the tyrosine kinase domain of RET. RET/PTC1 is expressed more frequently by sporadic PTC 110 ; RET/PTC3 and RET/PTC5 are found more commonly in solid and radiation-induced PTCs, especially in children exposed to the Chernobyl nuclear reactor accident; and RET/PTC2 and RET/PTC4 are variably implicated in sporadic and radiation-induced PTC. Chromosomal rearrangements involving the TRK gene originating from the fusion of the tyrosine kinase domain of TRK on chromosome 1q22 to the 5 terminal sequence of the tropomyosin (TPM3), predominating in radiation-induced PTC; the TPR gene, also located on 1q; or the TFG gene on chromosome are found in some cases. Activating point ras gene mutations have been described in a few PTCs, 111 whereas BRAF gene point mutations at nucleotide position 1796 have been documented in up to 70% of PTC cases. 112 The ret/ptc, ras, and BRAF all encode proteins that act along the same intracellular signaling pathway, leading to the activation of the MAPK (mitogen activated protein kinase) cascade, and S99 S99

6 Papi et al / PRIMARY SPINDLE CELL THYROID LESIONS they cooperate to induce the development of papillary carcinoma. 113 PTC usually affects young patients, although it may occur in all decades of life. Clinically, it usually manifests as a slow-growing, firm mass. Most cases are not clinically evident (mainly, microcarcinomas) and are detected incidentally during neck ultrasound performed for nonthyroidal diseases (eg, carotid artery Doppler imaging) or histologic examination of thyroidectomy specimens from operations performed for disorders unrelated to papillary carcinoma. 114,115 Ito et al 116 observed 162 patients with papillary microcarcinomas without surgery. During the follow-up period, more than 70% of tumors did not change or decreased in size compared with the size at diagnosis; 10.2% enlarged by more than 10 mm; and lymph node metastases in the lateral compartments appeared in only 1.2% of cases. On the other hand, PTC shows a marked tendency to metastasize via lymphatics. In the aforementioned study by Ito et al, patients underwent thyroidectomy plus lymphadenectomy, and neck lymph node metastases were found in 50% of cases. Another characteristic of PTC is its tendency to manifest as multicentric tumors. The cause of multifocality in PTCs is a matter of debate among pathologists. Indeed, some authors agree that it represents intraglandular metastases of the same PTC, and a monoclonal origin of such lesions has been shown. 117 In contrast, Apel et al 118 and Sugg et al 119 demonstrated an independent origin of different PTCs located in the same gland. Ultrasound reveals PTC as a solid, hypoechoic, and hypervascularized mass with undefined margins, often containing microcalcifications The 99m Tc and 131 I scans display a cold area. The following histopathologic variants of PTC, disclosing peculiar growth patterns and cell types, have been identified: follicular variant, macrofollicular variant, oncocytic variant, clear cell variant, diffuse sclerosing variant, tall cell variant, solid variant, PTC with focal insular component, morular-cribriform variant, columnar cell variant, spindle cell variant, and follicular variant with spindle mesenchymallike areas. Because the aim of this article is to describe T- SCLs, only the cytologic, pathologic, and immunohistochemical aspects of the morular-cribriform, columnar cell, and spindle cell variants will be reviewed. The term cribriform-morular variant of PTC (CMVPTC) was proposed by Cameselle-Teijeiro and Chan 123 in 1999 to designate a PTC characterized by focal papillary architecture, cribriform structures, solid and spindle cell areas, and squamous morules. In 1994, Harach et al 124 described 4 PTC cases with the same characteristics of CMVPTC in association with familial adenomatous polyposis (FAP). The association between FAP and CMVPTC was confirmed in 1998 in a study by Perrier et al. 125 CMVPTC mainly affects young women (usually younger than 30 years) and occur both with FAP and as a sporadic form. 123,126 Patients with FAP and CMVPTC show typical germline mutations of the adenomatous polyposis coli (APC) gene that is located in the 5q21 region. 127 However, Cameselle-Teijeiro et al 126 reported a case of CMVPTC with a somatic but not germline mutation of the APC gene. In any case, whenever a CMVPTC is encountered, FAP should be ruled out. The neoplasm may be solitary or multifocal. 123,124 FNA biopsy usually yields highly cellular smears composed of round to spindle-shaped cells with abundant, dense cytoplasm containing vacuoles. 128 The nuclei are slightly enlarged and round to oval, with finely granular chromatin and indistinct nucleoli. Frequent intranuclear creases, grooves, and cytoplasmic invaginations (pseudoinclusions) are seen. 126,129 Morules with peculiar nuclear clearing and a cribriform pattern without colloid are a distinctive cytologic feature of CMVPTC. 129 Histologic examination reveals that the tumor is encapsulated in most cases, partially divided into lobules by a sclerotic septum. It is composed of a combination of follicular, tubular, solid, trabecular, spindle cell, cribriform, and morular patterns of growth merging with one another Image 4 and Image 5. The tumor cells demonstrate nuclear clearing, grooves, and intranuclear cytoplasmic pseudoinclusions. Typical whorl structures (so-called morules), Image 4 Papillary thyroid carcinoma. The neoplasm demonstrates a predominantly infiltrative pattern of growth, with single spindle-shaped cells; in the lower part of the field, tumor cells growing in a papillary architecture and organized in a cribriform structure are evident (H&E, original magnification 20). S100 S100

7 Image 5 Papillary thyroid carcinoma (neck lymph node metastasis). Tall columnar tumor cells showing eosinophilic cytoplasm and clear nuclei with grooves and pseudoinclusions and forming elongated papillary structures (H&E, original magnification 20). composed of neoplastic cells with oval to spindle-shaped nuclei, also are present. Vascular invasion and mitotic figures usually are absent. Rarely, capsular invasion may be detected. 129 Cameselle-Teijeiro and Chan 123 clearly defined the histologic characteristics peculiar to CMVPTC: encapsulation or circumscription, a distinctive cribriform pattern of growth, the presence of follicles usually devoid of colloid, papillary formations, tall cells with abundant, oxyphilic cytoplasm and frequent pseudostratification, spindle cells, hyperchromatic nuclei showing grooving and pseudoinclusions, and morular metaplasia with peculiar nuclear clearing. Immunohistochemically, the tumor cells of CMVPTC show positivity for thyroglobulin, TTF-1, EMA, cytokeratins, vimentin, estrogen and progesterone receptors, bcl-2, and retinoblastoma proteins. 123 The prognosis of CMVPTC does not differ from that of classic PTC, which is invariably excellent (10-year survival rate, near 98%). Therefore, it is crucial to distinguish it from the aggressive variants of PTC, mainly tall cell and columnar cell variants. The columnar cell variant of PTC (CCVPTC) was first described by Evans 130 in CCVPTC exhibits the architecture of PTC, but a tall columnar epithelium and pronounced nuclear stratification in association with mixed papillary, complex glandular and cribriform patterns with solid foci of spindle cells are unique features of this tumor. 54,131 The neoplasm is made up entirely of a solid spindle cell pattern; sometimes, a columnar-cell pattern is present focally. 130 LiVolsi 54 described the prominent subnuclear vacuolization, resembling early secretory endometrium, as a distinctive finding in CCVPTC. Like classical PTC, tumor cells are immunoreactive to thyroglobulin and TTF-1. The differential diagnosis between CCVPTC and the tall cell variant of PTC relies on a more pronounced degree of nuclear stratification exhibited in the former. As the tall variant of PTC, CCVPTC behaves in an aggressive manner, showing extrathyroidal extension, regional (Image 5) and distant metastasis, and a fatal outcome. 130 However, in the absence of capsular invasion and extrathyroidal extension, a better outcome has been described. 131,132 Recently, Woenckhaus et al 133 reported a case of PTC in a 32-year-old woman characterized by an overwhelming abundance of spindle cellular proliferation and designated it spindle cell variant of papillary thyroid carcinoma. Grossly, the tumor appeared as a solid, encapsulated, white-yellow, solitary mass. Microscopic examination revealed an encapsulated lesion predominantly composed of spindle cells arranged in bundles having a mesenchymal appearance. A minimal follicular component was present. The cell cytoplasm was clear or eosinophilic with indistinct cellular borders; the nuclei were large, oval, slightly indented, and optically clear and displayed rare pseudoinclusions. Vascular and capsular invasion and necrosis were absent. Immunohistochemically, the spindle cell and follicular cell components were positive, the latter more strongly, for thyroglobulin, AE1/AE3, CAM 5.2, vimentin, and bcl-2. Immunostaining with calcitonin, chromogranin A, synaptophysin, smooth muscle actin, HHF35, CD34, HMB-45, and p53 was negative. The authors concluded that this tumor represented a metaplastic variant of PTC. Similarly, Carcangiu 134 reported the case of a 31-yearold woman with a 43-mm mass in the left thyroid lobe. Light microscopy revealed all characteristics of the follicular variant of PTC, but also spindle mesenchymal-like areas. The spindle cell component of the tumor was arranged in fascicles and resembled mesenchymal cells. However, in contrast with lesions of mesenchymal origin, the spindle cell component of this neoplasm was immunoreactive for thyroglobulin and cytokeratin, suggesting mesenchymal-like metaplasia of thyrocytes. Carcangiu 134 designated this entity, which behaved in a favorable manner, as papillary carcinoma, follicular variant, with spindle mesenchymal-like areas. Finally, Vergilio et al 2 described 10 cases of spindle cell proliferations of the thyroid arising in association with papillary carcinoma (7 cases) or follicular adenoma (3 cases). The female/male ratio was 4:1; patient age ranged from 25 to 71 years. The lesions were wholly or at least partly encapsulated and varied in size from 3 to more than 30 mm. The spindle cells, constituting 1% to 95% of the tumor, grew with a diffuse or nodular pattern and had eosinophilic cytoplasm with indistinct cellular borders and thin, elongated or plump, S101 S101

8 Papi et al / PRIMARY SPINDLE CELL THYROID LESIONS oblong nuclei with finely granular chromatin and subtle nucleoli. Immunohistochemical examination revealed that the spindle cells stained positively with thyroglobulin and, less commonly, with keratin, whereas they were not stained by calcitonin and rarely stained for smooth muscle actin (only 1 case). Such an immunohistochemical profile, with a positive reaction to thyroglobulin in all cases, loss of cytokeratin immunoreactivity in several cases, and demonstration of positive staining with smooth muscle actin in 1 case, suggested that these spindle cell proliferations may represent metaplastic transformation of thyroid follicular epithelium. The cases reported by Woenckhaus et al, 133 Vergilio et al, 2 and Carcangiu 134 are believed to be the result of metaplastic transformation of follicular epithelium. Transition from differentiated epithelial cells to mesenchymal cells with changing patterns of expression of intermediate filaments has been described for several cell culture systems. 135,136 Greenburg and Hay 137 examined the changes in cytoskeletal expression during the transformation of thyroid epithelium to mesenchyme in rat thyroid cells grown in type I collagen matrix. They found that the highly differentiated epithelium that expressed cytokeratin changed into a vimentin cytoskeleton and lost thyroglobulin expression during epithelial-mesenchymal transformation in normal thyroid epithelium. The persistence of cytokeratin in the cytoplasm of the newly formed mesenchyme-like cells is the result of their origin from thyrocytes because there is no keratin expression in mesenchymal cells surrounding the follicles in situ. Herrmann and Trevor 138 showed that cells isolated from papillary carcinoma and follicular adenoma, when maintained in cell culture, undergo an epithelialmesenchymal transition, assuming fibroblastoid morphologic features and exhibiting reactivity with antibodies to cytokeratin, thyroglobulin, and vimentin. It is very important to distinguish metaplastic proliferations from aggressive malignant neoplasms of mesenchymal origin, owing to their completely different biologic behavior. Medullary Thyroid Carcinoma Medullary thyroid carcinoma (MTC) is a malignant tumor of the thyroid gland that arises from the neural crest derived parafollicular C cells, as first suggested by Williams in In 1973, Wolfe et al 140 described C-cell hyperplasia (CCH) in the vicinity of familial MTC and identified it as a precursor of heritable MTC. Currently, more than 30 years following the discovery by Wolfe et al, 140 there is no uniform definition of CCH. The term CCH refers to 2 pathologic conditions with different neoplastic potential: neoplastic and reactive. Neoplastic represents the precursor lesion of heritable MTC, whereas reactive is associated with autoimmune thyroiditis, aging, hypergastrinemia, and hypercalcemia related and unrelated to hyperparathyroidism and is adjacent to tumors of follicular origin According to Wolfe et al, 140 the normal C cells are arranged singly, whereas multiple large clusters of C cells characterize the hyperplasia. Other authors have suggested the presence of more than 20 cells to indicate hyperplasia and fewer than 5 cells to suggest absence of hyperplasia. 143,148 LiVolsi et al 148 and LiVolsi 149 suggested that 2 to 5 C cells with more than 50 cells per low-power field indicate hyperplasia. Bigner et al 150 defined CCH as a condition with more than 6 C cells per thyroid follicle. Albores-Saavedra and Krueger 151 defined reactive CCH as a condition characterized by at least 50 normal-appearing C cells per low-power field in areas of high C-cell concentration. Some authors have shown that immunostains for a polysialic acid component of a neural adhesion molecule can distinguish primary from secondary CCH. 152 MTC represents approximately 5% of all thyroid neoplasms. 153 It is sporadic in about 80% of patients and familial in the remaining 20%. 154,155 It has been demonstrated that distinct germline mutations in the ret proto-oncogene, which encodes a transmembrane receptor with cytoplasmic tyrosine kinase activity, are associated with the dominantly inherited cancer syndromes multiple endocrine neoplasia (MEN) types 2A and 2B and familial medullary thyroid carcinoma (FMTC), all sharing MTC as part of the disease phenotype. 155 MEN2A (or Sipple syndrome) consists of MTC, CCH, adrenal pheochromocytoma, adrenal medullary hyperplasia, and parathyroid hyperplasia (in about 20% of cases). 150,156,157 Conversely, MEN2B is characterized by MTC, CCH, pheochromocytoma, adrenal medullary hyperplasia, mucosal neuromas, gastrointestinal ganglioneuromas, and musculoskeletal abnormalities Finally, in FMTC, MTC occurs alone in families with the ret proto-oncogene mutation. In 1993, Gardner et al, 162 using genetic linkage studies, mapped MEN2 loci to a small interval on chromosome 10q11.2. In the same year, Mulligan et al 163 identified missense mutations on the ret proto-oncogene in 20 of 23 MEN2A families. In MEN2A, mutations occur in 1 of 5 cysteine codons in exons 10 and 11. In 1994, Hofstra et al 164 demonstrated a mutation in codon 918 (exon 16) of the gene in MEN2B that resulted in a substitution of threonine for methionine in the tyrosine kinase domain of the RET protein. Such a point mutation has been identified in 95% of cases of MEN2B. 165,166 Two additional novel mutations involving codon 768 (exon 13) and codon 804 (exon 14) have been found in cases of FMTC. 165, Subsequently, mutations in the ret proto-oncogene have been identified in more than 90% of the families with MEN2, which can be S102 S102

9 used as a screening tool to diagnose and identify asymptomatic family members with this syndrome. 167,171 Sporadic MTC also can exhibit ret mutations in the tumors. It has been demonstrated that these mutations may affect the prognosis. 167,171 The most common mutations in sporadic cases are seen in codon 918; the less common mutations involve cysteine codons and codons 768 and MTC was first reported by Hazard et al 175 in These authors described 21 cases of a peculiar type of thyroid carcinoma that had a solid nonfollicular histologic pattern, the presence of amyloid in the stroma, and a high incidence of lymph node metastasis. 175 Several years earlier, Horn 176 reported 7 cases of thyroid carcinoma with amyloid and termed it solid carcinoma of the thyroid. Hazard et al 175 suggested the name medullary (solid) thyroid carcinoma for this new entity. They thought that the term solid used alone might result in confusion with anaplastic carcinoma that also has a solid pattern of growth; on the other hand, the term medullary, commonly used to define a histologically solid type of tumor, might indicate a soft tissue tumor, which MTC is not. Therefore, they compromised, and used both terms, solid and medullary, to characterize the tumor. Familial forms of MTC usually affect younger patients than those affected by sporadic MTC. In particular, CCH and microcarcinomas are detectable in young children with MEN2B (younger than 3 years). Patients with sporadic MTC who are younger than 40 years have been described occasionally. 177 A slight female predilection has been shown in sporadic cases. Clinically, MTC appears as one or more firm, painless thyroid nodules. 178 Cervical lymph node and distant metastases are detected in 50% and 15% of patients, respectively. 54,55,89,154 Ultrasound examination usually shows a hypoechoic mass with undefined margins that may be solitary or part of a multinodular goiter; in some cases, the thyroid gland may appear as diffusely hypoechoic as the result of concurrent chronic thyroiditis. 144 Sonography also is useful to detect metastatic involvement of the neck lymph nodes. Thyroid function test results are within the normal range in patients with MTC; however, when Hashimoto thyroiditis, diagnosed by elevated antithyroglobulin and antithyroperoxidase antibody titers and typical ultrasound features, is concomitantly present, hypothyroidism may develop. An association between CCH and chronic thyroiditis has been documented. 144,145 Guyetant et al 144 reported the occurrence of CCH in 20% of patients with Hashimoto thyroiditis. Recently, Karanikas et al 179 reported autoimmune thyroiditis in 25% of hypercalcitoninemic patients with and without nodular goiter. In 1 case in this series, Hashimoto thyroiditis coexisted with a micro-mtc, which was recognized only by presurgical calcitonin measurement. Niccoli et al 180 found that 50% of cases of MTC had histologic features of thyroiditis. Also, other authors have suggested a possible correlation among chronic thyroiditis, CCH, and thyroid carcinoma. 181,182 At present, no conclusive data are available concerning an etiologic relationship between chronic thyroiditis and MTC. The measurement of the plasma calcitonin concentrations is a useful diagnostic tool in the evaluation of patients with MTC. Meyer and Abdel-Bari 183 and Bussolati et al 184 first documented calcitonin production in tumor cells, in 1968 and 1969, respectively. It has been demonstrated that elevated basal and pentagastrin-stimulated calcitonin levels identify almost 100% of MTCs, even at the stage of microcarcinoma Nevertheless, basal calcitonin measurement has a low specificity in the detection of cases of MTC because benign nodules; differentiated thyroid cancer; nonthyroidal diseases, including sepsis, renal failure, and neuroendocrine tumors; and even exercise have been associated with increased serum calcitonin concentrations ,188 It is of interest that patients with MTC with larger nodules showed higher basal calcitonin values. A close correlation of tumor volume and preoperative calcitonin levels also was recorded for patients with MTC by Sheuba et al. 189 This finding may be related to the greater calcitonin-secreting cellular mass that composes large nodules compared with small ones. FNA cytology is able to distinguish benign from malignant nodules in most patients with MTC; however, falsenegative reports are not uncommon. In contrast with basal calcitonin measurement, cytologic examination shows low sensitivity and high specificity (close to 100% in most studies) in the diagnosis of MTC. 177,180,187,190,191 The cytologic diagnosis of MTC is based on the following findings: hypercellular smears with noncohesive cells; pleomorphic population of spindle, plasmacytoid, round, oval, polyhedral, and triangular cells; intracytoplasmic red granules; round to oval, hyperchromatic, often eccentric nuclei with coarsely granular chromatin; absence of follicles or papillary structures; and amyloid deposits (which appear deep green on Papanicolaou staining and display an apple-green birefringence when stained with Congo red) When aspirates demonstrate all of the aforementioned features, the cytologic diagnosis of MTC is not difficult. However, rarely, tumor cells are monomorphic and exhibit carrot-shaped nuclei, elongated cytoplasmic processes, cytoplasmic nippling, numerous intracytoplasmic vacuoles resembling grape cells, nuclear budding, mast cell like granules, and a Burkitt lymphoma appearance. 192 In these cases, the cytologic diagnosis of MTC is difficult, and the smears may be misinterpreted as sarcoma, plasmacytoma, S103 S103

10 Papi et al / PRIMARY SPINDLE CELL THYROID LESIONS Image 6 Medullary thyroid carcinoma. Spindle-shaped tumor cells grow in a trabecular pattern within amyloid deposits (H&E, original magnification 20). Image 7 Medullary thyroid carcinoma. Detail of Image 6 (H&E, original magnification 20). or Burkitt lymphoma. Sometimes, the cell population has a bizarre appearance and numerous mitoses are seen, resembling anaplastic carcinoma. Recently, a case of MTC with intracytoplasmic lumina was reported; the tumor cells had intracytoplasmic lumina containing sparse microvilli and abundant granular material with dense, round bodies on ultrastructural sections. 198 Grossly, the sporadic tumors usually are solitary lesions, whereas the familial tumors are multiple and involve both lobes. 54,55,89,98 They are located at the site of the highest C- cell concentration, ie, the lateral upper two thirds of the gland, 54,55,89,98 and are white-gray to tan and well circumscribed but not encapsulated. Light microscopy might reveal various growth patterns, and MTC might mimic other thyroid tumors. 199 The characteristic features are sheets, nests, and/or trabeculae of polygonal, round, or spindle cells Image 6 and Image 7. A dense, collagenous or hyalinized material containing amyloid deposits usually separates the tumor cell nests. Tumor cells have round to oval, small nuclei with finely granular chromatin, inconspicuous nucleoli, and scant mitotic figures. The cytoplasm is granular and eosinophilic to amphophilic, with ill-defined margins. Necrosis and hemorrhage are rare, whereas lymphatic and vascular invasion are common. Owing to the quite variable histopathologic appearance of MTC, several MTC variants have been identified: papillary or pseudopapillary, 200,201 glandular (tubular or follicular), 202 giant cell, 203 spindle cell, 204 small cell, 205,206 paraganglioma-like, 207 oncocytic cell, 208,209 clear cell, 210 angiosarcoma-like, 211 squamous cell, 208 melaninproducing, 212 and amphicrine. 213 The diagnosis of MTC always should be supported by immunohistochemical analysis. Calcitonin Image 8 and calcitonin gene-related peptide represent the most sensitive markers for the neoplasm, although they are not specific because they also can be found in endocrine tumors of nonthyroid origin (eg, islet cell tumors and intestinal neuroendocrine carcinomas). 214,215 All MTCs stain with calcitonin gene-related peptide; in contrast, about 1.5% of MTC cases are not stained by calcitonin. 216,217 MTC cells also are immunoreactive for cytokeratins, neuron-specific Image 8 Medullary thyroid carcinoma. Tumor cells stain positively for calcitonin (calcitonin, original magnification 40). S104 S104

11 Image 9 Medullary thyroid carcinoma. Tumor cells stain positively for carcinoembryonic antigen (carcinoembryonic antigen, original magnification 40). Image 10 Medullary thyroid carcinoma. Tumor cells stain positively for chromogranin A (chromogranin A, original magnification 40). enolase, synaptophysin, carcinoembryonic antigen (CEA) Image 9, and chromogranin A Image 10, whereas they are not stained by thyroglobulin. In some familial MTC cases, S-100 protein antibody stains sustentacular cells occurring at the periphery of the tumor cell nests. 217,218 MTC is more aggressive than papillary and follicular thyroid carcinomas; the survival rate at 10 years is 40% to 50% and is strongly dependent on tumor stage at diagnosis. 219,220 It has been clearly demonstrated that when the neoplasm is confined to the thyroid and thyroidectomy with dissection of the central lymph node compartment is performed, the chance of definitive cure is high (about 75%- 80%). 221,222 Hence, early detection of MTC is crucial. Post Fine-Needle Aspiration Spindle Cell Nodules of the Thyroid PSCNT is a reactive spindle cell lesion, recently recognized in patients who had previously undergone an FNA biopsy of thyroid nodules. 1 Spindle cell proliferations following surgical procedures and occurring also in extrathyroidal body sites, such as nodular fasciitis, proliferative fasciitis, inflammatory pseudotumor, and postoperative spindle cell nodule, have been reported In 1984, Proppe et al 226 described the first 8 patients who developed spindle cell nodules of the genitourinary tract after surgery. Subsequently, other cases, mainly limited to the lower genitourinary tract, have been documented. In 1999, Baloch and coworkers 1 first described 10 cases of PSCNT, 7 women and 3 men aged 49 to 74 years. The interval between the biopsy and surgical excision ranged from 2 weeks to 2 months, and the spindle cell proliferation occurred in benign and malignant thyroid nodules. The size of PSCNT ranged from 3 to 10 mm (mean, 5.6 mm; median, 5.5 mm). PSCNTs were not encapsulated and were located mostly in the center of preexisting thyroid nodules. Light microscopy revealed that the lesion was composed of intersecting bundles of plump spindle cells with elongated nuclei with vesicular chromatin, inconspicuous nucleoli, and illdefined cytoplasmic borders. Furthermore, small thin-walled vessels and a mixed inflammatory infiltrate constituted mainly of histiocytes, few lymphocytes, and hemosiderinladen macrophages were found. The degree of cellularity ranged from mild, with irregular foci of collagen deposition with focal hyalinization (seen in only 2 cases), to exuberant, and such variability may be related to the temporal relationship between the FNA and the following surgery, the size of biopsy needle, and an undetermined host response. Immunohistochemical examination showed diffuse cytoplasmic reactivity of the spindle cell component against smooth muscle actin; conversely, the lesion failed to react with cytokeratin. The histiocytic marker CD68 stained the macrophage component in all cases. These immunohistochemical features support the histologic evidence of the myofibroblastic origin of the spindle cell component. 229 PSCNTs are benign entities. Some cases of PSCNT may mimic sarcoma owing to their high cellularity and plump spindle cells with enlarged nuclei; however, low mitotic rate, relative circumscription, lack of cell pleomorphism, a history of FNA biopsy, and immunohistochemical results should lead to the correct diagnosis. S105 S105

12 Papi et al / PRIMARY SPINDLE CELL THYROID LESIONS Smooth Muscle Tumors Smooth muscle tumors (SMTs) are benign (leiomyoma) or malignant (leiomyosarcoma) neoplasms arising from smooth muscle cells. Primary and secondary SMTs of the thyroid gland are exceedingly rare. Metastases to the thyroid of leiomyosarcomas originating from the leg, 230,231 pulmonary artery, 232 and uterus 233 have been documented. Because they are clinically, pathologically, and immunohistochemically indistinguishable from primary SMTs, the diagnosis of thyroid metastases of SMT is based only on a known history of leiomyosarcoma in an extrathyroidal site. To our knowledge, 5 cases of primary leiomyoma and 11 cases of primary leiomyosarcoma of the thyroid gland have been reported. Some authors have postulated that the site of origin of primary thyroid SMT is represented by the smooth muscle walled vessels in the capsule of the gland. 239,246 Although the cause and risk factors related to SMT are unknown, Tulbah et al 241 reported a case of Epstein-Barr virus associated leiomyosarcoma in a child with congenital immunodeficiency. This tumor expressed large amounts of Epstein-Barr virus messenger RNA, similar to that seen in pediatric SMTs associated with AIDS and/or after organ transplantation. Leiomyoma usually affects younger patients than does leiomyosarcoma, which occurs predominantly during the sixth and seventh decades of life. Benign SMTs of the thyroid have been documented most often in female subjects (female/male ratio, 4:1), probably owing to the well-known expression of estrogen receptor proteins by these tumors 246 ; conversely, their malignant counterparts do not demonstrate a sex predilection. Both tumors manifest clinically with an indolent mass in 1 thyroid lobe, growing slowly in the cases of leiomyoma and rapidly enlarging in patients with leiomyosarcoma. Patients with leiomyosarcoma frequently complain of pressure symptoms, mainly tracheal obstruction. 240 Thyroid function test results were normal in all patients with thyroid SMT. Ultrasound examination of the thyroid gland detected a hypoechoic mass 239 that appeared as a cold nodule on scintigraphy. 237 Takayama et al 239 described the radiologic findings in a case of leiomyosarcoma. Computed tomography showed a low-density mass with calcification and necrosis invading the thyroid cartilage. Magnetic resonance examination revealed the tumor as an isointense mass, enhancing after gadolinium administration, on T 1 - weighted images and a mass of intermediate signal on T 2 - weighted images. Cytologic examination of FNA biopsy specimens from malignant SMT revealed a variable number of atypical spindle cells. The differential diagnosis with the spindle cell variant of anaplastic carcinoma usually is difficult on a cytologic basis. The spindle cell variant of medullary carcinoma may be ruled out by normal plasma calcitonin concentrations. 185,186 Grossly, SMT appears as a well-circumscribed mass of huge dimensions. Leiomyosarcomas tend to be larger and softer than leiomyomas and show a tendency for tumor necrosis, hemorrhage, and cystic degeneration ,242 Histologic examination discloses intersecting fascicles of spindle-shaped smooth muscle cells clearly related to vessel walls. Tumor cells have slightly hyperchromatic, blunt-ended nuclei located in the central part of cytoplasm, occasionally adjacent to cytoplasmic vacuoles. In leiomyosarcoma, a high degree of nuclear atypia, high mitotic rate, abundant necrosis, and prominent vascular and capsular invasion are detected. Immunohistochemically, benign and malignant SMT cells are reactive for vimentin, smooth muscle actin, musclespecific actin, smooth muscle myosin, basal lamina components (including laminin and type IV collagen), and desmin, whereas they are not stained by thyroglobulin, cytokeratin, chromogranin, and calcitonin. 238,243,245 Leiomyomas invariably behave as benign tumors and usually are cured by lobectomy or partial thyroidectomy only. In contrast, leiomyosarcomas are highly aggressive neoplasms, associated with a poor outcome despite radical therapeutic interventions. Thompson et al 236 studied 5 cases of SMT, 1 leiomyoma and 4 leiomyosarcomas. The patient with leiomyoma was alive, without evidence of local or distant recurrence 11 years after initial diagnosis; of the patients with leiomyosarcoma, 3 had a survival time less than 2 years, and 1 was alive with multiple lung metastases at the 10-month follow-up. Peripheral Nerve Sheath Tumors PNSTs are benign (neurilemoma or schwannoma) or malignant (malignant peripheral nerve sheath tumor [MPNST]) neoplasms arising from sympathetic or parasympathetic nerves. PNSTs may develop in any body site. Although nearly half appear in the head and neck region, they are located most commonly in the temporal bone and upper cervical region. Some cases of PNST arising from nerves located in the perithyroid region also have been described, 247,248 mimicking a primary thyroid neoplasm. Furthermore, secondary localization to the thyroid of extrathyroidal MPNSTs has been documented. 249 Primary PNSTs of the thyroid gland are exceedingly rare. To date, 17 cases (16 adults and one 12-year-old girl) have been reported The postulated origin includes the Schwann cells in the neural sheath of the cervical plexus innervating the thyroid or the sensory nerves. 263,269 Association with medium to large nerves located close to the thyroid capsule has been shown. 263 Generally, clinical S106 S106

13 presentation of schwannoma is a slow-growing thyroid nodule. Curiously, it has been noted that PNST tends to occur prevalently in the right lobe of the thyroid 262 ; however, rare cases involving the left thyroid lobe have been reported. 268 Most patients deny pressure symptoms, 262,268 and physical examination usually shows a mobile, nontender mass in the anterior part of the neck. Conversely, MPNST 266 causes dyspnea due to tracheal compression and deviation, dysphagia due to esophageal invasion, and dysphonia due to recurrent laryngeal nerve paralysis. The results of thyroid function tests are within the normal range. Ultrasound examination of schwannomas shows a hypoechoic mass, 268 whereas computed tomography scanning demonstrates a well-circumscribed, homogeneous area of low density. 267 In contrast, in MPNST, computed tomography images reveal an inhomogeneous, low-density mass, showing tracheal compression and invasion of perithyroid soft tissues. 263,264,266 Thyroid scanning using iodine or technetium demonstrates a cold nodule. 267 FNA biopsy usually is not helpful in the diagnosis of PNST because it usually yields material composed of scattered spindle cells in a bloody background. In 1 case, inflammatory cells with hemosiderin, consistent with an inflammatory or degenerative process, were seen. 267 Grossly, the neoplasm is a gray to tan mass frequently showing cystic degeneration. Tumor size ranges up to 7 cm in greatest dimension. Histologic examination of schwannoma shows an encapsulated neoplasm exhibiting 2 patterns, designated as Antoni A and Antoni B areas. Antoni A, which represents the main, if not unique, component in most PNST cases, is composed of interlacing fascicles of spindle cells arranged in a palisading or organoid manner (Verocay bodies). Antoni B displays a population of tumor cells separated by abundant, edematous, fluid-forming cystic spaces. Mitoses usually are absent, and no vascular invasion is detected. MPNST, the malignant counterpart of schwannoma, is a highly aggressive neoplasm that destroys the surrounding thyroid parenchyma and invades perithyroid soft tissues. The tumor is characterized by marked cellularity, high mitotic activity, abundant necrosis, and exuberant vascular invasion. The plump and almost epithelioid appearance of the cells surrounding the vessels and areas of necrosis with irregular borders and palisading at the edges are typical features of such malignancy. Two cases of the triton variant of MPNST, typically characterized by rhabdomyoblastic differentiation, have been observed in the thyroid. 259,260 Granular cell tumors of the thyroid are also reported. 270,271 Immunohistochemical examination shows strong reactivity of PNST cells against S-100 protein and vimentin, 272 whereas no reactivity for thyroglobulin, TTF-1, cytokeratin, chromogranin, calcitonin, actin, or desmin is detected. Thyroidectomy should be performed in all PNST cases to make the correct diagnosis. In the presence of schwannoma, the operation should be limited to lobectomy, whereas total thyroidectomy, including radical neck dissection, is required in some cases of MPNST. 259 Thyroid schwannoma behaved as a benign neoplasm in all reported cases. In contrast, in most patients with MPNST, the prognosis was similar to that of undifferentiated carcinoma despite surgery and postsurgical irradiation and chemotherapy. 263,264,266,269 Spindle Epithelial Tumor With Thymuslike Differentiation According to the recently published WHO classification of tumors of endocrine organs, SETTLE is a rare, malignant tumor of the thyroid characterized by lobulated architecture and biphasic cellular composition featuring spindle-shaped epithelial cells that merge into glandular cells. 68 Synonyms are the following: thyroid spindle cell tumor with mucinous cysts, 273 malignant teratoma, 274,275 and thymoma of the thyroid gland. 276 In 1991, Chan and Rosai 277 formally characterized SETTLE as a tumor of neck derived from ectopic thymus or branchial pouch remnants. Some histologic features, such as incomplete lobulation, perivascular spaces, biphasic epithelioid/epithelial and spindle cell populations, cysts and cleft-like spaces, and rare, thin epithelial ribbons suggest thymic differentiation. However, the origin of SETTLE from the thymus has been debated by some authors 278 based on negative immunostaining of tumor cells for CD20, 273 a B-cell marker expressed in the epithelial cells in a proportion of spindle cell thymomas, 279 and CD5, 280,281 a leukocyte marker expressed by several thymic carcinomas, and owing to recent demonstration of ras gene mutations in thyroid SETTLEs 278 that have not been reported in thymic epithelial tumors. Furthermore, terminal deoxynucleotidyl transferase positive immature lymphocytes peculiar to thymomas 282 have not been demonstrated in SETTLE. In the few cases reported, the ages of patients with SETTLE range from 4 to 59 years, but the tumor occurs predominantly in children, adolescents, and young adults. 283,284 Indeed, only 1 adult, a 59-year-old man, has been described with the neoplasm. 280 Moreover, a slight male predominance (male/female ratio, 1.5:1) has been observed. 274, ,280 Clinically, the neoplasm usually manifests as a firm, smooth mass in 1 thyroid lobe present for a variable duration; less commonly, all of the gland is enlarged, of hard consistency, and without palpable nodules, mimicking thyroiditis. 276,277,285,286 Rarely, neck lymph node S107 S107

14 Papi et al / PRIMARY SPINDLE CELL THYROID LESIONS enlargement, a rapidly growing thyroid mass, and tracheal compression are present. The results of thyroid function tests and, when performed, calcitonin and CEA levels, were within the normal range in all patients. Thyroid ultrasound showed a clearly demarcated, solid nodule, except for a few cases in which no nodularity was found and a diffusely hypoechoic structure typical for autoimmune thyroiditis was detected. 285,286 The tumors appear cold scintigraphically and display heterogeneous solid and cystic densities on computed tomography scan. FNA biopsy is seldom diagnostic for SETTLE because this neoplasm is very rare, not often considered, and easily confused with other entities (eg, spindle cell variants of medullary, papillary, and anaplastic thyroid carcinoma and thymoma). Only 2 cases of SETTLE were diagnosed correctly by cytologic examination 285,287 ; in 1 case, the aspirate was interpreted initially as synovial sarcoma. 288 The smears usually contain numerous clusters of spindle cells that grow dissociated or in groups or aggregates. Besides the spindle cell component, an epithelioid/epithelial cell type may be seen in the aspirates as well. Some authors 285 suggest that in an appropriate clinical setting, smears showing a biphasic epithelioid and spindle cell population, especially if admixed squamous, mucinous, and respiratory epithelial cells are observed, may be diagnostic of SETTLE. In any case, spindle cells represent the prominent cell type. They have distinct cell borders and scant cytoplasm, with uniform, elongated, and cigar-shaped nuclei containing fine and dispersed chromatin and small and indistinct nucleoli. In the background, abundant red extracellular material in the form of fine dust-like granules and irregular patches is present in Giemsa-stained smears. When immunocytochemical analysis was performed, 285 spindle and epithelioid cells demonstrated a positive reaction to pancytokeratin; conversely, staining for thyroglobulin, calcitonin, and CEA was negative in both cell types. Grossly, an encapsulated, partially circumscribed, or infiltrative nodule is demonstrated. The cut surface usually is firm, grayish, and vaguely lobulated, with a slightly gritty, whorled appearance. Histologic examination reveals a highly cellular neoplasm, demonstrating a lobulated pattern of growth. Lobules of neoplastic tissue are separated by irregular thin and thick fibrous septa, and some of them are dense, some reticular, and others cystic. In cystic lobules, cleft or empty spaces lined by epithelial cells with focal irregular papillary structures may be seen. The tumor compresses the thyroid parenchyma beyond the capsule, often invading the surrounding normal thyroid tissue. In most cases, the neoplasm is composed of a biphasic epithelioid and spindle cell population, but monophasic variants of SETTLE, including neoplasms exclusively composed of spindle cells or glandular structures, have been reported. 286 Spindle cells show faintly eosinophilic cytoplasm and elongated or oval nuclei with fine chromatin and inconspicuous nucleoli. Epithelial cells are cuboidal to columnar and sometimes mucinous or ciliated. They are organized in tubulopapillary structures and cysts and are intermingled with spindle cells or localized within fibrous bands. Foci of abrupt squamous differentiation within a spindle cell background may be found. Rarely, clear, epithelial ribbons in a sclerotic stroma, similar to those detected in hamartomatous thymoma, are seen. 285 Vascular invasion may be present. Mitotic figures, necrosis, and atypia usually are absent; however, Kirby et al 287 reported a case of SETTLE in a 29-year-old man showing numerous mitotic figures and focal necrosis. Immunohistochemically, the spindle and glandular cells are strongly and diffusely positive for cytokeratins. In some cases, the spindle cell component also demonstrates a diffusely positive reaction against vimentin and α-smooth muscle actin and patchy positivity for muscle-specific actin, EMA, and neuron-specific enolase. Both cell populations are negative for thyroglobulin, calcitonin, chromogranin A, synaptophysin, S-100 protein, CEA, CD20, and CD5. Electron microscopic examination of the spindle cells demonstrated prominent cytoplasmic tonofilaments, desmosomes, and basal lamina consistent with an epithelial cell origin. DNA content analysis by flow cytometry revealed DNA diploidy. 284 Thyroidectomy always should be performed in patients with SETTLE to obtain a definite histologic diagnosis. The extension of surgery may vary from lobectomy to total thyroidectomy and depends on the involvement of one or both thyroid lobes, respectively, by nodular disease. Neither 131 I ablation therapy nor follow-up based on serum thyroglobulin during L-thyroxine suppression therapy is indicated because the neoplasm does not originate from thyroid follicular cells. Although SETTLE is considered a tumor with lowgrade malignant potential, aggressive behavior has been reported in some cases. Indeed, in most patients, the neoplasm grows slowly and may cause lymph node and pulmonary metastases some years after diagnosis; despite the occurrence of metastasis, long-term survival usually is observed after thyroidectomy. Nevertheless, Kloboves- Predovnik et al 285 described a patient who developed metastatic disease a few months after diagnosis. In their review of SETTLE, Cheuk et al 280 demonstrated that the overall metastatic rate increased from 33% in patients with a follow-up of less than 5 years to 71% for patients followed up for more than 5 years. S108 S108

15 Carcinoma Showing Thymus-like Differentiation CASTLE is a carcinoma of the thyroid gland with architectural resemblance to thymic epithelial tumors (WHO classification, 2004). 68 Synonyms are lymphoepitheliomalike carcinoma of the thyroid gland, intrathyroid epithelial thymoma, and primary thyroid thymoma. CASTLE is a rare tumor; only 22 cases have been reported. 277, Most cases are localized within the thyroid gland, but the neoplasm occasionally may arise in the perithyroid soft tissues of the neck. The origin of neoplastic cells in CASTLE has not been demonstrated completely. The prevailing view is that it arises from remnants in the thyroid gland or perithyroidal tissue of the branchial pouch capable of thymic differentiation. This hypothesis is supported by the following evidence: (1) Ectopic thymic tissue has been found in the vicinity of the tumor in some cases of CASTLE. 289 (2) The neoplasm, or some areas surrounding the neoplasm, often demonstrates a true thymic differentiation, with Hassall corpuscles, lymphoepithelial-like structures, and mature lymphocyte infiltration in the stroma. 295,296 (3) Positive staining of tumor cell with immunohistochemical markers associated with thymic carcinoma, such as bcl-2, mcl-1, and CD5, has been found. 291,292,294 In 1998, Dorfman et al 292 examined 5 cases of CASTLE and 5 cases of thyroid carcinoma with squamous differentiation for immunoreactivity against an anti-cd5 antibody reactive in fixed, paraffin-embedded tissue specimens with microwave antigen retrieval. All cases of CASTLE showed positive CD5 immunoreactivity, including foci of lymph node and lung metastases. In contrast, none of the cases of thyroid carcinoma with squamous differentiation was immunoreactive for CD5. This study supported the thymic derivation of CASTLE and confirmed the results of a previous study. 291 CASTLE affects adults, mainly middle-aged, with a slight female predominance (female/male ratio, 1.3:1). Patients have a painless, slow-growing thyroid mass and often complain of pressure symptoms, like hoarseness and dysphagia. In about one third of cases, lymph node enlargement consistent with metastatic disease is detected at initial examination. 277 Ahuja et al 293 performed a detailed study of imaging features in a patient with CASTLE. The tumor was located in the neck, posterior to the neurovascular bundle, entirely separated from the thyroid gland, extending from just below the left submandibular gland to the left supraclavicular fossa. Ultrasound revealed that the neoplasm had a lobulated outline and was solid and hypoechoic with a heterogeneous echo pattern, displaying moderate vascularity on color flow images. Computed tomography revealed soft tissue density with no evidence of calcification, and the mass enhanced after administration of contrast medium. A clear plane was evident between the tumor and the thyroid gland. MRI revealed an isointense mass on T 1 - weighted sequences, enhanced only moderately with a central, irregular nonenhancing area after injection of contrast material, and the mass was hyperintense on T 2 - weighted sequences. On thyroid scan, the tumor invariably appeared as a cold nodule. Cytologic examination of FNA biopsy performed on SETTLE nodules usually misses the right diagnosis, and the neoplasm often is misinterpreted as a spindle cell lesion of other derivation, such as medullary or anaplastic thyroid carcinoma (ATC). 296 Grossly, the tumor shows a yellowish gray cut surface and well-demarcated borders. Light microscopy reveals that the neoplasm is separated into lobules by scattered, fibrous trabeculae, resembling thymomas and thymic carcinomas. Islands of tumor cells are variably sized and penetrated by delicate vessels. The neoplasm is composed of squamoid and focally spindle-shaped cells with lightly eosinophilic cytoplasm and oval, pale to vesicular nuclei containing small distinct nucleoli. Focal keratin pearls occasionally may be seen. The tumor islands and stroma are infiltrated by numerous small lymphocytes and plasma cells. Thymus-like tissue with Hassall corpuscles sometimes is found adjacent to the tumor cells. On immunohistochemical examination, tumor cells stain positively with cytokeratin, CD5, bcl-2, and mcl-1 and lymphocytes demonstrate positive staining for the T- cell markers and MIC 2 (CD99) and a negative immunoreaction for B-cell markers. Positive immunostaining for CD5 is particularly important to support the diagnosis of CASTLE over other entities, such as undifferentiated thyroid carcinoma, squamous cell carcinoma (SCC), and metastatic lymphoepithelioma-like carcinoma. CASTLE should be differentiated from the aforementioned entities because these lesions are associated with an aggressive clinical course. Indeed, CASTLE is considered a tumor with a low-grade malignant potential, although aggressive behavior has been reported occasionally. 298 Conversely, undifferentiated thyroid carcinoma, SCC, and metastatic lymphoepithelioma-like carcinoma result in a rapidly fatal outcome. Roka et al 297 recently reviewed all 22 reported cases of CASTLE. Seventeen patients (77%) had unknown or involved lymph nodes, whereas no lymph node involvement was observed in the other 5 subjects (23%). In 6 patients, only local recurrence developed; in 3, distant recurrence developed; and 2 had local and distant recurrence. When S109 S109

16 Papi et al / PRIMARY SPINDLE CELL THYROID LESIONS treated by surgery and irradiation, patients with lymph node metastases experienced local recurrence less frequently than patients treated by surgery alone. Four subjects with recurrent tumors were treated with radiotherapy and chemotherapy, and a variable response was obtained. Follicular Dendritic Cell Tumor FDCT is a rare neoplasm composed of cells showing morphologic and phenotypic features of follicular dendritic cells (WHO classification, 2004). 68 This tumor arises from follicular dendritic cells that are located in primary and secondary lymphoid follicles and have an important role in the immune response as antigenpresenting cells for the B-cell compartment. 299 Owing to its rarity, FDCT probably is underrecognized by clinicians and pathologists. The most common sites of origin of the neoplasm are cervical lymph nodes, although it also occurs in extranodal head and neck sites, such as tonsils, pharynx, parapharyngeal soft tissue, palate, and parotid gland. 300,301 In 1999, Galati et al 302 described the only case reported of dendritic cell sarcoma of the thyroid. This adult patient had a painless mass in the neck in association with a lesion in the thyroid. After reviewing 34 cases of head and neck FDCT, Vargas et al 300 reported a mean age of 38 years (range, years) without a sex predominance (a roughly equal number of males and females). Grossly, FDCTs appear as tan-gray, well-circumscribed masses. Light microscopy reveals a relatively uniform population of oval to spindle cells arranged in diffuse, fascicular, and vaguely whorled growth patterns. The tumor cells display an eosinophilic cytoplasm and round to ovoid, vesicular nuclei with focal atypia and prominent nucleoli. A variable number of small lymphocytes, dispersed between the tumor cells, with focal prominent perivascular cuffing, usually is found. Scattered multinucleated giant cells also may be present. Foci of necrosis are rarely seen. Mitotic rates vary from case to case, from low to high. Immunohistochemical examination is crucial for the diagnosis. 303 Tumor cells are diffusely immunoreactive for CD21, CD23, CD35, vimentin, and EMA; variably positive for S-100 protein and CD68; and sometimes focally positive for CD45 and CD20; in contrast, they are not stained by actin, myeloperoxidase, ALK-1, CD1a, CD3, CD5, CD30, HMB-45, desmin, actin, thyroglobulin, or low-molecularweight cytokeratins. Lymphocytic population shows a mixed T- and B-cell phenotype. The treatment of FDCT is based mainly on surgical excision of the neoplasm, eventually followed by chemotherapy (eg, CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone]) and/or radiation therapy. The response to treatment is variable. In the review of 34 FDCT cases performed by Vargas et al, 300 after the primary treatment (surgery alone or in association with chemotherapy or radiotherapy), 12 patients had no evidence of disease, whereas 5 had incurable disease. Of 13 patients in whom recurrence developed (10 locally, 3 distally), 2 died, 4 had no evidence of disease after secondary treatment, 6 were alive with disease, and 1 was lost to follow-up. In the thyroid FDCT reported by Galati et al, 302 histologic examination revealed metastatic localization of the tumor in 4 of 17 surgically removed cervical lymph nodes. Therefore, although originally considered a low-grade malignancy, FDCT demonstrates a high recurrence rate and significant metastatic potential 304 and should be considered and treated as a moderately aggressive head and neck tumor. 300 Anaplastic (Undifferentiated) Thyroid Carcinoma ATC represents the most aggressive tumor of the thyroid gland, one that is almost invariably associated with a fatal outcome. 54, ATC accounts for 5% to 10% of all thyroid cancers and typically occurs in elderly people (mean age in the mid-60s) and has a female predominance. Most cases of ATC show evidence of a preexisting differentiated (mainly, papillary carcinoma) or poorly differentiated thyroid carcinoma in cytologic and histologic samples. 54,310, Recently, Quiros et al 317 studied 8 ATCs for BRAF and ras mutations, ret/ptc rearrangements, and p53 mutation. BRAF was mutated in 5 of the 8 ATCs tested. Histologic examination revealed that 4 of these 5 BRAF-mutated ATCs contained a PTC component, suggesting they may be derived from BRAF-mutated PTC. Analysis of the ras mutation revealed only an H-ras mutation at codon 11. Immunohistochemical analysis of RET/PTC rearrangements revealed no positive staining of RET in any of the 8 ATCs, suggesting that these ATCs are not derived from ret/ptc-rearranged PTC. In contrast, p53 was detected in the nuclei of 5 of 5 BRAF-mutated ATCs. p53 staining was present only in anaplastic thyroid tumor cells, not in neighboring papillary thyroid tumor cells. The authors concluded that many ATCs with papillary components are derived from BRAF-mutated PTC, with the addition of a p53 mutation. Such findings support the current view that ATC originates from the dedifferentiation of tumor cells derived from thyroid follicular epithelium. Indeed, the morphologic appearance of ATC cells is that of a poorly differentiated neoplasm because it is characterized by the presence of polygonal, giant, and spindle cells in variable proportions. Furthermore, despite its derivation from thyroid follicular S110 S110

17 cells, the neoplasm sometimes demonstrates a negative immunoreaction with epithelial markers, and further immunohistochemical studies must be performed to definitely distinguish it from other tumors with similar morphologic features. Thus, the diagnosis of ATC is not always obvious. Clinically, the tumor manifests with the rapid onset of a hard, fixed thyroid mass, often accompanied by weight loss, compression symptoms such as dysphagia and dyspnea, and dysphonia due to paralysis of recurrent nerves. In up to 80% of patients, this rapid growth occurs in preexisting benign or malignant thyroid lesions. Extrathyroidal involvement is frequent at the time of the initial examination, with early secondary localization of the neoplasm to cervical lymph nodes and lungs. FNA biopsy usually yields abundant material composed of a pleomorphic population of cells in a necrotic background. However, not infrequently, necrosis and hemorrhage are so abundant that the sample results in inadequate material. For example, Luze et al 318 reported 12% of ATC samples containing only necrotic material. The tumor cells are represented by numerous bizarre, oval to spindle-shaped, dyscohesive elements showing anisocytosis, anisonucleosis, and irregular nuclei Image 11. In some cases, a population of multinucleated, osteoclast-like giant cells with hyperchromatic nuclei and inconspicuous cytoplasm is predominant (osteoclastoma-like ATC). 319 Occasionally, a dry material is obtained from the aspirate, and the smears contain a few bland-looking spindle cells and lymphocytes dispersed in a background of fibrous tissue, resembling RT. This variant of Image 11 Anaplastic thyroid carcinoma. Fine-needle aspiration biopsy specimen. Giant and spindle cells exhibiting scanty cytoplasm and bizarre, hyperchromatic nuclei are evident (Papanicolaou, original magnification 100). ATC has been designated the paucicellular variant of ATC. 54,320,321 Us-Krasovec et al 322 retrospectively analyzed the fineneedle aspirates of 113 cases diagnosed as ATC at their institution. Overall, 94.7% of cases were considered diagnostic of malignancy, 2.7% were suggestive of malignancy, and 2.7% were nondiagnostic. Of the cases classified cytologically as malignant, a diagnosis of ATC was made correctly in 84.1%; in 5.6%, a moderately or poorly differentiated thyroid carcinoma was suspected; in 1.9%, the diagnosis of SCC was given; in 1.9%, differentiation between ATC and a soft tissue tumor or MTC was not possible; and in 5.6%, a malignant tumor of otherwise unspecified origin was diagnosed. Eighty-three representative cases were reviewed and separated into 3 distinct morphologic groups according to the predominant cell type: pleomorphic cell (including round, polygonal, and spindle-shaped cells), round cell, and spindle cell. In the pleomorphic cell group, samples contained numerous malignant cells covering a wide range of sizes, from small to gigantic. Rarely, giant osteoclast-like cells and giant foreign body type cells were detected. The cytoplasm was scant to moderate, basophilic, and frequently well delineated. The nuclei were round, oval, irregular, or sometimes bizarre and hyperchromatic, with small, large, or gigantic, round or irregularly shaped, and rarely multiple nucleoli. Mitoses were seen frequently. In the round cell group, tumor cells demonstrated a plasmacytoid appearance in some cases and grew mostly dissociated, showing marked anisocytosis and anisonucleosis. The cytoplasm was moderate to abundant, basophilic, and well delineated, occasionally containing phagocytized leukocytes. The nuclei were round and irregular and sometimes also bizarre, with small to very large nucleoli. In the series by Us-Krasovec et al, 322 the spindle cell population was the most rare. Only 1 sample was highly cellular and 2 were moderately cellular, whereas the remaining 4 showed few cells embedded in tissue fragments. Also, Schneider and Frable 323 found a minority of cells showing spindle features in ATC aspirates. The cytoplasm was moderate, pale, basophilic, and well-delineated. Many naked nuclei were present, with an indented nuclear membrane, coarse chromatin, and rare nucleoli. Grossly, ATC exhibits a large, fleshy cut surface with areas of hemorrhage and necrosis Image 12. The neoplasm infiltrates and destroys surrounding soft tissues and adjacent structures, including lymph nodes, larynx, pharynx, trachea, and esophagus. Histologic examination of ATC demonstrates a widely invasive tumor composed of different cell types, including spindle, giant, epithelioid, squamoid, and osteoclast-like cells, that are present in variable proportions Image 13. The cytologic features are the same as reviewed previously for S111 S111

18 Papi et al / PRIMARY SPINDLE CELL THYROID LESIONS Image 12 Anaplastic thyroid carcinoma. Gross findings. The thyroid gland is infiltrated by a huge mass displaying areas of hemorrhage and necrosis. ATC. Neoplastic cells may be arranged in a fascicular, solid, or storiform pattern, replacing and entrapping the surrounding follicular parenchyma of the thyroid and invading the perithyroid tissues. In all ATC cases, abundant coagulative necrosis, a high mitotic rate, and extensive vascular invasion are evident. From the morphologic viewpoint, tumors composed predominantly or exclusively of spindle cells usually are indistinguishable from sarcoma and should be differentiated from fibrosarcoma, malignant fibrous histiocytoma, hemangio-pericytoma, and angiosarcoma or rhabdomyosarcoma Immunohistochemical analysis showing a positive reaction for keratins favors the diagnosis of an epithelial malignancy. However, cases of ATC with true rhabdomyosarcomatous differentiation have been reported, demonstrating only a few, scattered, weakly positive cells immunoreactive for epithelial markers and strong and generalized positivity for vimentin, actin, desmin, and myoglobin. 327 Other histologic variants include the osteoclastoma-like variant, the paucicellular variant, and the lymphoepithelioma-like variant. Osteoclastoma-like anaplastic carcinoma is composed of numerous osteoclast-like, multinucleated giant cells with granular cytoplasm mixed with oval to spindle-shaped cells. 319,328 The paucicellular variant is a tumor predominated by acellular fibrous or infracted tissue with central dystrophic calcification and hypocellular foci comprising mildly atypical spindle cells intermingled with collagen and small lymphocytes. 54,320,321 The lymphoepithelioma-like variant is composed, on the one hand, of syncytial sheets of epithelial cells with large vesicular nuclei, prominent Image 13 Anaplastic thyroid carcinoma. Histologic examination shows an undifferentiated tumor composed of different cell types, including spindle, giant, epithelioid, and squamoid cells present in variable proportions (H&E, original magnification 100). nucleoli, and high mitotic activity, and on the other hand of an abundant lymphoid infiltrate surrounding and invading the cell sheets. This ATC variant resembles nasopharyngeal lymphoepithelioma; however, no evidence of Epstein-Barr virus infection was detected. 329 The immunohistochemical profile of ATC is protean. Immunoreactivity for cytokeratin is present in 40% to 100% of cases depending on epitope retrieval procedures and the antibody used. 305,326,330,331 Tumor cells also are immunoreactive for EMA in 30% to 50% of cases and to p53, 317,331 whereas CEA is rarely expressed. Typically, ATC cells do not stain with thyroglobulin, calcitonin, TTF-1, or RET/PTC oncoprotein 317,330,331 ; sometimes a positive reaction to thyroglobulin is detected within rare nonneoplastic thyroid follicular cells entrapped in the tumor. In all but occasional cases of rhabdomyosarcomatoid differentiation of neoplastic cells, 327 ATC does not stain with muscular and vascular markers. In particular, the following markers are useful for distinguishing ATC from other tumors with similar morphologic features as follows: from rhabdomyosarcoma and leiomyosarcoma, desmin, actin, and Myo-D1; from angiosarcoma, factor VIII related antigen, CD31, and CD34; from melanoma, S-100 protein and HMB-45; and from large cell lymphoma, CD45. The prognosis for patients with ATC is poor. The overall 5-year survival rate ranges from 0% to 14%, and the median survival is 2.5 to 6 months. 332 When surgical resection is possible owing to the evidence of clear excision planes, thyroidectomy should be performed to relieve obstructive symptoms. Patients who undergo complete surgical resection S112 S112