Carcinoma showing thymus-like differentiation of the thyroid (CASTLE)

Carcinoma showing thymus-like differentiation (CASTLE) is a rare intrathyroidal neoplasm, probably arising from ectopic thymus or branchial pouch remnants. The tumor was first reported by Miyauchi et al. [1].The clinical and pathological features of this tumor were classified by Chan et al. [2] into 4 groups: ectopic hamartomatous thymoma, ectopic cervical thymoma, spindle ephithelial tumor with thymic-like differentiation (SETTLE), and carcinoma showing thymus-like differentiation (CASTLE). Recently, CASTLE has been designated as an independent clinicopathologic entity of thyroid tumors in the most recent edition of the World Health Organization classification of tumors of endocrine organs[3].To our knowledge, less than 100 cases of CASTLE have been reported in the literature, 45 cases of which (including one of the authors’ patient) have been identified in China. We report a new case of this entity and suggest recommendations for diagnosis.     

Tumors of the neck showing thymic or related branchial pouch differentiation: a unifying concept

A number of rare tumors occurring in the soft tissues of the neck and the thyroid gland, reported in the literature under a variety of designations, show complete to partial histologic resemblance to the fetal, mature, or involuted thymus and mediastinal thymomas. This family of tumors spans a range of histologic appearances and behaviors from completely benign lesions to metastasizing malignant tumors. After reviewing the previously reported and new cases, we have been able to delineate four reasonably well-defined clinicopathologic entities within this spectrum. On the benign end is "ectopic hamartomatous thymoma," which occurs in the soft tissues of the lower neck. It is characterized by spindle epithelial cells, solid or cystic epithelial islands, and adipose cells which intermingle haphazardly to impart a hamartomatous quality. In the middle of the spectrum are the ectopic cervical thymomas which are usually benign, but can sometimes be locally invasive and can exceptionally metastasize. They are histologically identical to mediastinal thymomas, and residual ectopic thymus is not uncommonly identifiable in the periphery of the tumor. On the malignant end are tumors we have designated as "spindle epithelial tumor with thymus-like differentiation" (SETTLE) and "carcinoma showing thymus-like differentiation" (CASTLE). Tumors of the SETTLE type occur in the thyroid gland of young patients, and are highly cellular tumors comprised of compact bundles of long spindle epithelial cells which merge with tubulopapillary structures and/or mucinous glands. Tumors of the CASTLE type are histologically similar to thymic carcinoma of the lymphoepithelioma or squamous cell variety. We postulate that this family of tumors arises either from ectopic thymus or remnants of branchial pouches which retain the potential to differentiate along the thymic line.     

Fine-needle aspiration biopsy of monophasic variant of spindle epithelial tumor with thymus-like differentiation of the thyroid: report of one case and review of the literature

Spindle epithelial tumor with thymus-like differentiation (SETTLE) is a rare biphasic tumor of the thyroid with approximately 20 well-documented cases reported in the English literature. Although a monophasic variant of SETTLE is conceivable, the majority of the reported cases were truly biphasic tumors. A minimal amount of epithelial component was present in the reported cases of so-called spindle-cell predominant SETTLE. Here, we report an apparently monophasic case of SETTLE in a 16-yr-old girl, in which no epithelial cells were identified in either fine-needle aspiration biopsy (FNAB) or the subsequent hemithyroidectomy specimen. The FNAB smears were moderately cellular and composed of single and loosely grouped spindle cells with homogenous metachromatic material, which could be mistaken as amyloid, erroneously suggesting medullary thyroid carcinoma. The compact nodules of uniform spindle cells in histology sections raised the possibility of monophasic synovial sarcoma. The spindle cells stained positive for both cytokeratin and vimentin, but were negative for thyroglobulin and calcitonin as well as neuroendocrine markers, confirming the diagnosis of SETTLE.     

甲状腺呈胸腺样分化癌病理观察

目的 探讨甲状腺呈胸腺样分化癌（CASTLE）的病理特征、诊断及鉴别诊断。方法 分析2例甲状腺CASTLE的临床表现,对标本进行病理学和免疫组织化学（EnVision^TM法）染色观察。结果 大体检查肿瘤呈质硬灰白色略旱分叶状肿块。光镜下肿瘤组织呈轮廓清楚的巢状,巢间可见丰富的促结缔组织增生性间质。肿瘤细胞呈多边形或梭形,胞质轻度嗜酸,核卵圆形,呈空泡状,有清楚的小核仁,核异型性较轻,核分裂象1～2／10HPF。免疫组织化学肿瘤细胞表达CD5及CD117。结论 CASTLE是一种少见的甲状腺恶性肿瘤,有一定的病理学特征。应与甲状腺未分化癌、甲状腺鳞状细胞癌、转移性淋巴上皮瘤样癌及滤泡树突细胞肉瘤等鉴别。免疫组织化学CD5等标记对鉴别诊断有帮助。     

Spindle epithelial tumor with thymus-like differentiation of thyroid gland: report of two cases with follow-up

Spindle epithelial tumor with thymus-like differentiation (SETTLE) is a rare malignant thyroid tumor showing thymic or related branchial pouch differentiation. The tumors are composed predominantly of spindle cells along with focal epithelial component and ductular formations. SETTLE occurs in young patients, with indolent growth and a tendency to develop delayed blood-borne metastases. We herein report two cases of SETTLE with a follow-up period of 64 months and 30 months, respectively.     

Cytologic diagnosis of “CASTLE” of thyroid gland: Report of a case with histologic correlation

We report on the cytologic and histologic features of a rare form of lymphoepithelioma-like carcinoma of the thyroid, i.e., carcinoma showing thymus-like element (CASTLE). Sixteen cases of cervical lymph node aspirates with metastatic nasopharyngeal carcinoma are also reviewed. While it is important to recognize CASTLE of the thyroid because of its distinctly good prognosis, its cytologic features closely resemble those in metastatic nasopharyngeal carcinoma. Diagn Cytopathol 1996;15:224–227. © 1996 Wiley-Liss, Inc.     

Intrathyroidal epithelial thymoma/carcinoma showing thymus‐like differentiation; comparison with thymic lymphoepithelioma‐like carcinoma and a possibility of development from a multipotential stem cell

The purpose of our article is to describe the immunohistochemical findings of intrathyroidal epithelial thymoma/carcinoma showing thymus‐like differentiation (ITET/CASTLE) of the thyroid in detail, to clarify the difference between ITET/CASTLE and thymic lymphoepithelioma‐like carcinoma (LELC), and to discuss the pathogenesis of ITET/CASTLE. We immunohistochemically examined five ITET/CASTLE and eight LELC cases. All of ITET/CASTLE cases were strongly positive for CD5, P63, high‐molecular‐weight cytokeratin and B‐cell CLL/lymphoma‐2. Carcinoembryonic antigen‐positive carcinoma cells were found in four ITET/CASTLE cases. Neuroendocrine marker‐positive carcinoma cells were scattered in all cases. Immunohistochemical findings in thymic LELC were essentially similar to those in ITET/CASTLE, but the sensitivity was different. There is a possibility that ITET/CASTLE and thymic LELC are not the quite same disease entity. We think that ITET/CASTLE is derived from ectopic thymus, but not related to solid cell nests.     

Clinicopathologic significance of intrathyroidal epithelial thymoma/carcinoma showing thymus-like differentiation: a collaborative study with Member Institutes of The Japanese Society of Thyroid Surgery

Intrathyroidal epithelial thymoma (ITET)/carcinoma showing thymus-like differentiation (CASTLE) is a rare malignant tumor having histopathologic features similar to those of squamous cell carcinoma of the thyroid and other organs and a more favorable prognosis. It is thought to originate from ectopic thymic tissue or embryonic thymic rest in or adjacent to the thyroid. We investigated clinicopathologic features of 25 cases of ITET/CASTLE. The sensitivity and specificity of the pathologic diagnosis of ITET/CASTLE by immunohistochemical staining with CD5, a marker of carcinoma of thymic origin, were 82% and 100%, respectively. The 5- and 10-year cause-specific survival rates were 90% and 82%, respectively. Nodal metastasis and tumor extension predict a worse prognosis. Of 22 patients who had curative surgery, 10 (45%) underwent adjuvant radiation therapy, and no locoregional recurrence was seen in any of them. This is the first study demonstrating the survival curve for patients with ITET/CASTLE. Our findings suggest that curative resection followed by radiation therapy may effectively prevent locoregional recurrence and CD5 immunostaining is useful for diagnosing ITET/CASTLE.     

Spindle epithelial tumor with thymus-like differentiation (SETTLE) of the thyroid with neck lymph node metastasis: A case report

Spindle epithelial tumor with thymus-like differentiation (SETTLE) is an extremely rare type of thyroid tumor. It has been reported only 20 times in the English literature. This tumor occurs predominantly in young patients and has a protracted clinical course despite the occurrence of metastases. In the recent literature SETTLE has been considered to be a tumor of low malignant potential with distant metastases developing some years after diagnosis. Herein we report a case of SETTLE in a 22-yr-old man in which a lymph node metastasis developed soon after the primary tumor manifestation. Histological examination of the tumor showed the predominantly monophasic variant of SETTLE. The primary and metastatic lesions were highly cellular tumors composed of sheets of spindle cells that were positive for pan-cytokeratin and vimentin and negative for thyroglobulin, calcitonin, and S-100 protein.     

Thyroid carcinoma showing thymus‐like differentiation (CASTLE): Case report with cytomorphology and review of the literature

Thyroid carcinoma showing thymus‐like differentiation (CASTLE) is a rare tumor of the thyroid gland or adjacent soft tissues of the neck. Given the comparatively good prognosis of CASTLE, it is crucial to distinguish this neoplasm from other more aggressive thyroid neoplasms that can have similar or overlapping cytomorphological features. However, there is little information about the cytomorphology of CASTLE available in the literature. Here we report the cytomorphology and histology of thyroid CASTLE in a 52‐year‐old woman and present a review of the literature. Diagn. Cytopathol.2011;39:204–209. © 2010 Wiley‐Liss, Inc.     

Warthin-like papillary carcinoma of the thyroid

BACKGROUND: Warthin-like papillary carcinoma of thyroid is characterized by distinct papillary formations lined by tumor cells with oncocytic cytoplasm, nuclear features of papillary carcinoma, and brisk lymphoplasmacytic infiltrates in the papillary stalks. This tumor derives its name from its close resemblance to Warthin tumor of major salivary glands. DESIGN: The clinicopathologic features of 17 patients with Warthin-like papillary carcinoma were studied. RESULTS: Fifteen tumors occurred in women and 2 arose in men (age range, 23-63 years). The lesions ranged in size from 3 mm to 2.5 cm. Fine-needle aspiration biopsies were performed in 7 cases; 4 were diagnosed as papillary carcinoma, 2 as consistent with lymphocytic thyroiditis, and 1 as atypical cells. All 17 tumors were confined to the thyroid; 6 showed prominent cyst formation and the remaining tumors were solid. In each case, the tumor arose in a background of lymphocytic thyroiditis. Nodal metastases were identified in 3 cases; however, none showed distant metastases. In 7 cases, foci of papillary microcarcinoma and follicular variant of papillary carcinoma were found in other areas of the thyroid. CONCLUSIONS: Warthin-like tumors can be mistaken for benign lymphoepithelial lesions of the thyroid, Hürthle cell carcinoma, and tall cell variant of papillary carcinoma in both fine-needle aspiration and histology specimens. Follow-up information on the previously reported cases has suggested that these tumors behave similarly to usual papillary carcinoma. The extensive lymphocytic infiltration in these tumors and their association with chronic lymphocytic thyroiditis may suggest a role for immunological mechanisms in the pathogenesis of thyroid tumors.     

Carcinoma of the neck showing thymic-like elements (CASTLE): report of a case and review of the literature

Carcinoma showing thymic-like elements (CASTLE) is a rare tumor affecting thyroid and neck soft tissues, which has to be distinguished from squamous cell and anaplastic thyroid carcinoma, because it has a better prognosis. We report a new case of CASTLE which occurred in a patient submitted to total thyroidectomy with central neck dissection. The tumor stained positively for CD5, which seems to be the most useful marker in the differential diagnosis. By the analysis of the 18 cases reported in literature, total thyroidectomy with selective modified neck dissection should be the treatment of choice and radiotherapy should be considered for patients with positive nodal status.     

Carcinoma showing thymus like elements: Report of a case with EGFR T790M mutation

Carcinoma showing thymus‐like differentiation of the thyroid (CASTLE) is a rare tumor involving the thyroid and perithyroidal soft tissues. It shares morphological, immunohistochemical and molecular similarities with thymic carcinomas. Due to its relatively better prognosis, it needs differentiation from other primary and metastatic tumors of this region. A 40‐year‐old lady presented with a gradually progressive anterior neck swelling for one year. Imaging showed bulky right and left lobes of thyroid along with a solid soft tissue mass in the pretracheal region. Fine needle aspiration smears showed features of poorly differentiated carcinoma. Total thyroidectomy with excision of the mass revealed histopathological features characteristic of CASTLE, with evidence of thyroiditis in adjoining thyroid. Epidermal growth factor receptor (EGFR) assay revealed presence of EGFR T790M somatic mutation in exon 20. The same was not detectable on direct sequencing. We present a rare case of CASTLE, occurring in association with Hashimoto thyroiditis, with emphasis on cytological features and report for the first time the presence of a low level somatic mutation in EGFR (EGFR T790M mutation).     

Primary squamous cell carcinoma of the thyroid gland: an entity with aggressive clinical behaviour and distinctive cytokeratin expression profiles

AIMS: Primary squamous cell carcinoma of the thyroid gland is uncommon. This study aims to identify the clinicopathological features and the pattern of expression of cytokeratins and oncoproteins in this tumour. METHODS AND RESULTS: Histological slides from Chinese patients with thyroid cancer treated in our institution from 1980 to 1999 were reviewed. Patients with primary squamous cell carcinoma of the thyroid were identified and their clinical records were analysed. The expression of cytokeratins (CKs), p53 and p21 in these cases were also studied by an immunohistochemical method. Four women (mean age 71 years) with squamous cell carcinoma of thyroid were found. The main presenting features were signs and symptoms of airway obstruction in three patients and neck swelling in one. The tumours were located at the right lobe (n=2), left lobe (n=1) or in both lobes of the thyroid (n=1). One patient died shortly after admission and the other three died within 4 months after thyroidectomy. The p53 protein was positive in 50% (2/4) of the tumours and p53+ tumours were poorly differentiated. The tumours were negative for p21. CK19 was expressed in all the tumours while CK7 expression was noted in 3/4 of the tumours. One carcinoma showed focal positivity to CK18. The tumours were negative for CKs 1, 4, 6, 10/13 and 20. The pattern of cytokeratin expression in squamous cell carcinoma of the thyroid gland was different from carcinoma showing thymus-like differentiation (CASTLE) of the thyroid gland and oesophageal squamous cell carcinoma. CONCLUSIONS: Squamous cell carcinoma of the thyroid has aggressive clinical behaviour and characteristic CK expression pattern. p53 over-expression in these tumours was associated with tumour differentiation.     

The association of well-differentiated thyroid carcinoma with insular or anaplastic thyroid carcinoma; evidence for dedifferentiation in tumor progression

The sequence of tumorigenesis in the thyroid is unclear. It has been proposed that anaplastic carcinomas of the thyroid develop by dedifferentiation in pre-existing differentiated carcinomas. We reviewed all anaplastic and insular (poorly differentiated) thyroid carcinomas in a consultation practice of thyroid pathology that included more than 400 thyroid cancers. Sixteen tumors (4%) were classified as anaplastic or insular (poorly differentiated) thyroid carcinomas. We examined these cases to determine whether these carcinomas were associated with well-differentiated neoplasms of follicular cell derivation. Ten patients were women and 6 were men, and ages ranged from 29 to 85 years; 10 patients with anaplastic carcinomas and 2 with insular carcinomas were 56 years or older, whereas 3 of the 6 patients with insular carcinomas were 31 years or younger. Four tumors were composed exclusively of anaplastic carcinoma; all were represented only by incisional biopsies. One insular carcinoma infiltrated and destroyed all underlying thyroid tissue. In the remaining total, subtotal, or hemithyroidectomy specimens, areas of well-differentiated papillary or follicular carcinoma were found. Some differentiated papillary lesions had a wide spectrum of morphologies, including Hurthle cell, tall cell, and columnar cell features. In the literature, simultaneous or previous occurrence of well-differentiated thyroid carcinomas with anaplastic carcinomas is extremely variable, ranging from 7–89% of cases. in experimental animals, serial transplantation of differentiated thyroid tumors has been shown to lead to anaplastic transformation. Our findings suggest that the majority of anaplastic thyroid carcinomas in humans arise from well-differentiated tumors. However, only a very small number of differentiated carcinomas progress to anaplastic lesions; the factors underlying this phenomenon remain to be identified.     

甲状腺显示胸腺样分化癌的临床病理学分析

目的 探讨显示胸腺样分化的甲状腺癌(CASTLE)的临床病理学特征、免疫表型和鉴别诊断.方法 回顾性分析8例CASTLE的临床、影像和病理学资料,采用EnVision法进行免疫组织化学标记,原位杂交法检测EBER.结果 男4例,女4例,平均年龄为48.8岁(25～57岁),均表现为前颈部肿块,其中2例伴有声音嘶哑.影像学上多表现为低密度肿块,增强后可强化.术中显示7例肿瘤位于甲状腺下极或中下极,1例位于上极.肿瘤呈结节状,平均直径为4.3 ca.4例周界清楚,4例累及甲状腺外组织.镜下,肿瘤由大小不一的岛状、巢状或叶状分布的瘤细胞和纤维性间质组成,后者伴有多少不等的慢性炎性细胞浸润,其中3例呈淋巴上皮瘤样.2例瘤巢中可见鳞状分化,类似胸腺哈氏小体.免疫组织化学标记显示,瘤细胞表达细胞角蛋白、CD5、bcl-2、p63和CD117,部分表达癌胚抗原,不表达甲状腺球蛋白和甲状腺转录因子1.8例原位杂交检测EBER均为阴性.2例分别于第一次术后12年和22个月发生局部复发,予以再次手术.随访4～55个月,8例患者均健在.结论 CASTLE是一种低度恶性的甲状腺癌,其病理形态和免疫表型与胸腺癌相似.

Abstract：

Objective To study the clinicopathologic features, immunophenotypes and differential diagnosis of thyroid carcinoma showing thymus-like differentiation (CASTLE). Methods The clinical and pathologic features of 8 cases of CASTLE were reviewed. Immunohistochemical study was performed using a panel of antibodies. ln-situ hybridization for Epstein-Barr virus-encoded RNA (EBER) was also carried out.Results There were altogether 4 males and 4 females. The age of the patients ranged from 25 to 57 years (mean =48.8 years). All of them presented with painless mass at the anterior neck. Two patients also complained of hoarseness of voice. On CT scan, the tumor had a low density with contrast enhancement.Seven cases were located in the mid to lower pole and the remaining one in the upper pole of thyroid gland.Four cases were relatively circumscribed. The other 4 cases showed evidence of extrathyroidal invasion.Grossly, the tumor had a nodular or lobulated appearance and was gray-white in color, with a mean diameter of 4. 3 cm. Microscopically, the tumor was infiltrative and consisted of islands, nests or lobules of epithelial cells separated by thick fibrous septa. The fibrous stroma showed various degree of lymphoplasmacytic infiltration, resulting in a prominent lymphoepithelioma-like pattern in 3 cases. Two cases showed squamoid differentiation, mimicking thymic Hassall corpuscles. Immunohistochemically, the tumor was consistently positive for cytokeratins, CD5, bcl-2, p63 and CD117. CEA was variably expressed. The staining for thyroglobin and TFl was negative. There was no labeling for EBER in all the cases. Two patients experienced local recurrence at 22 months and 12 years after surgery, respectively. They were treated with re-resection. All patients remained well on follow up. The duration of follow up ranged from 4 to 55 months.Conclusions CASTLE is a low-grade thyroid carcinoma with the morphologic features and immunophenotypes overlapping with those of thymic carcinoma. Awareness of this rare entity is important to both the pathologists and clinicians.     

Familial nonmedullary thyroid neoplasia

Thyroid carcinoma accounts for less than 1% of all human malignancies and carries one of the highest overall familial relative risks as compared with cancers from other sites. This is particularly true for medullary carcinoma, as well as for carcinomas of follicular cell origin in general, where inheritance has been implicated in 2.5 to 6.3% of the cases. Familial nonmedullary thyroid tumors show a variety of genetic mechanisms implicated in thyroid tumorigenesis and occur in several tumor-prone traits (e.g., familial adenomatous polyposis [FAP] and Cowden’s disease [CD]) or as the only or dominant inherited manifestation. The latter group includes the most common familial papillary carcinoma, in which environmental factors such as radiation exposure may also play an important etiological role. Familial follicular cell tumors show a variety of morphological features ranging from benign thyroid nodulation to carcinoma, usually develop in young individuals, and tend to be multicentric—an indication for total thyroidectomy to avoid tumor recurrence and potential risk of malignant transformation. The pathologist may play an important role in the histological interpretation of familial nonmedullary thyroid tumors, which may lead to further clinicogenetical investigations of the affected patient and family screening. Familial follicular cell thyroid neoplasms show a complex molecular biological pathway of tumorigenesis when compared between themselves and with their sporadic counterparts.     

Thyroid spindle epithelial tumor with thymus‐like differentiation (SETTLE): Is cytopathological diagnosis possible?

Spindle epithelial tumor with thymus-like differentiation (SETTLE) is a rare tumor of the thyroid gland which occurs predominantly in children, adolescents, and young adults. It usually presents as a painless neck or thyroid mass and only exceptionally as a diffusely enlarged thyroid gland, without metastatic disease at diagnosis. We report on the case of 12-yr-old girl who had diffusely enlarged thyroid gland for about 1 yr and was initially treated for thyroiditis. Fine-needle aspiration biopsy (FNAB) was performed 8 mo after the first admission. Cytological examination of smears showed unusual morphological features. FNAB smears were cellular, with dissociated cells, naked oval nuclei, aggregates, and groups. Three main cell types were observed: spindle, epithelioid, and epithelial. These cells were uniform, cytologically bland, with few mitotic figures. The distinction between these cells was not always unequivocal. In the background of the smears abundant red extracellular material in the form of fine, dust-like granules and irregular patches were present. It was also observed in some aggregates and groups of tumor cells. Spindle and epithelioid cells were immunocytochemically diffusely pan-cytokeratin-positive. In the differential diagnosis, medullary thyroid carcinoma and SETTLE were suggested. The final histological diagnosis was SETTLE. In cases of SETTLE presented as a diffuse thyromegaly the correct diagnosis may be delayed because clinically and ultrasonographically thyroiditis is suspected. To avoid such a delay, FNAB should be used preoperatively. It can provide specific cytological diagnosis based on morphological features and certain immunocytochemical characteristics of the tumor.     

Usefulness of S100A9 for diagnosis of intrathyroid epithelial thymoma (ITET)/carcinoma showing thymus-like differentiation (CASTLE)

AIMS: Intrathyroid epithelial tumour (ITET)/carcinoma showing thymus-like differentiation (CASTLE) is a rare malignant tumour, which is thought to originate from ectopic thymic tissue in the thyroid. The differential diagnosis between ITET/ CASTLE and squamous cell carcinoma (SCC) or undifferentiated carcinoma with squamoid component (UC-SCC) is very important, because ITET/CASTLE shows a far better prognosis than SCC or UC-SCC. In this study, we investigated the usefulness of S100A9, a marker of SCC and squamous cell epithelia, for diagnosis of ITET/CASTLE. METHODS: We immunohistochemically investigated S100A9 expression in 23 ITET/CASTLEs, 26 SCCs, and 19 UC-SCCs, as well as eight thymomas and 12 normal thymic tissues. RESULTS: All thymomas and thymic tissues showed a small number of S100A9-expressing cells in a scattered pattern in accordance with Hassall corpuscles. Twenty-one of 23 ITET/ CASTLEs showed the same pattern as thymomas or thymic tissues, while 14 SCCs and 15 UC-SCCs showed diffuse and laminated positivity of S100A9. The positive predictive value and specificity of S100A9 for diagnosis of ITET/CASTLE was 91.3 and 93.9%, respectively, and sensitivity was 75.0%. CONCLUSIONS: These findings suggest that S100A9 is a useful marker for discriminating ITET/CASTLE from SCC or UC-SCC.