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1.  Non-Alpine thyroid angiosarcoma 
Angiosarcoma is a very rare entity of soft tissue neoplasm with an aggressive and destructive biological behavior. Thyroid angiosarcoma is usually reported in Alpine regions, with only exceptionally rare cases arising in non-mountainous areas. In the Alpine regions it constitutes 2–10% of all malignant thyroid tumors.
We report a case of a thyroid non-Alpine angiosarcoma in a 71-year-old female with a 10 years old multinodular goiter. The cervical mass underwent rapid growth in the last year, and she was referred for surgical treatment. A 15 cm mass was found on the right side of the neck invading adjacent tissues and displacing the trachea without obvious invasion of this organ. Fine needle aspiration cytology showed “carcinoma”. Lung metastasis were present. Although difficult, total thyroidectomy was possible with resection of an esophageal implant. Post-operatively, she had respiratory failure that eventually recovered, but, on 39th post-operative day, she died of violent hemoptysis, probably due to invasion by mediastinal metastasis.
A clear distinction between angiosarcoma and anaplastic carcinoma of the thyroid is considerably difficult, despite treatments and prognosis are practically the same. However, in recent years, a thyroid malignancy exhibiting phenotypical features of endothelial differentiation was described. Keratin positivity cannot be reported as necessarily indicative of epithelial differentiation.
Optimal treatment for thyroid angiosarcoma remains unclear, not only because the prognosis is poor, despite multimodal therapeutic efforts, but also because it is a very rare entity.
PMCID: PMC3731721  PMID: 23570682
Thyroid angiosarcoma; Non-Alpine
2.  Expression of epithelial-mesenchymal transition regulators SNAI2 and TWIST1 in thyroid carcinomas 
Epithelial–mesenchymal transition is an important mechanism of epithelial tumor progression, local invasion and metastasis. The E-cadherin (CDH1) repressor SLUG (SNAI2) and the basic helix–loop–helix transcription factor TWIST1 inhibit CDH1 expression in poorly differentiated malignancies as inducers of epithelial– mesenchymal transition. Epithelial–mesenchymal transition has been implicated in progression from well to poorly differentiated/anaplastic thyroid carcinoma but the expression of SNAI2 and TWIST1 proteins and their phenotypic association in human thyroid cancers has not been extensively studied. We examined the expression of SNAI2, TWIST1 and CDH1 by immunohistochemistry in a panel of well-differentiated and anaplastic thyroid cancers and by qRT-PCR in thyroid cell lines. Ten normal thyroids, 33 follicular adenomas, 56 papillary thyroid carcinomas including 28 follicular variants, 27 follicular carcinomas and 10 anaplastic thyroid carcinomas were assembled on a tissue microarray and immunostained for SNAI2, TWIST1 and CDH1. Most (8/10) anaplastic thyroid carcinomas demonstrated strong nuclear immunoreactivity for SNAI2 with associated absence of CDH1 in 6/8 cases (75%). TWIST1 was expressed in 5/10 anaplastic thyroid carcinomas with absence of CDH1 in 3/5 (60%) cases. These findings were confirmed in whole sections of all anaplastic thyroid carcinomas and in a separate validation set of 10 additional anaplastic thyroid carcinomas. All normal thyroids, follicular adenomas, papillary and follicular thyroid carcinomas were negative for SNAI2 and TWIST1 (P<0.0001) and all showed strong diffuse immunoreactivity for CDH1 (P=0.026). Expression of SNAI2, TWIST1 and CDH1 mRNA varied in a normal thyroid, papillary carcinoma and two anaplastic thyroid carcinoma cell lines tested, but the highest levels of CDH1 mRNA were detected in the normal thyroid cell line while the anaplastic thyroid carcinoma cell line demonstrated the highest levels of SNAI2 and TWIST1 mRNA. Our findings support the role of epithelial–mesenchymal transition in the development of anaplastic thyroid carcinoma.
PMCID: PMC3559085  PMID: 22899291
anaplastic thyroid carcinoma; CDH1; SNAI2; thyroid carcinoma; thyroid cell lines; TWIST1
3.  Follicular Adenoma and Carcinoma of the Thyroid Gland 
The Oncologist  2011;16(5):585-593.
Follicular neoplasms of the thyroid gland include benign follicular adenoma and follicular carcinoma. Currently, a follicular carcinoma cannot be distinguished from a follicular adenoma based on cytologic, sonographic, or clinical features alone. As a result, all patients with a follicular neoplasm should, at minimum, undergo a diagnostic thyroid lobectomy and isthmusectomy. A completion thyroidectomy is necessary for invasive follicular carcinoma. The overall ten-year survival for patients with minimally invasive follicular carcinoma is 98% compared with 80% in patients with invasive follicular carcinoma.
Learning Objectives
After completing this course, the reader will be able to: Discuss the differentiation of follicular adenoma from follicular carcinoma.Explain novel developments in the diagnosis and treatment of follicular carcinoma.
This article is available for continuing medical education credit at
Follicular neoplasms of the thyroid gland include benign follicular adenoma and follicular carcinoma. Currently, a follicular carcinoma cannot be distinguished from a follicular adenoma based on cytologic, sonographic, or clinical features alone. The pathogenesis of follicular carcinoma may be related to iodine deficiency and various oncogene and/or microRNA activation. Advances in molecular testing for genetic mutations may soon allow for preoperative differentiation of follicular carcinoma from follicular adenoma. Until then, a patient with a follicular neoplasm should undergo a diagnostic thyroid lobectomy and isthmusectomy, which is definitive treatment for a benign follicular adenoma or a minimally invasive follicular cancer. Additional therapy is necessary for invasive follicular carcinoma including completion thyroidectomy, postoperative radioactive iodine ablation, whole body scanning, and thyrotropin suppressive doses of thyroid hormone. Less than 10% of patients with follicular carcinoma will have lymph node metastases, and a compartment-oriented neck dissection is reserved for patients with macroscopic disease. Regular follow-up includes history and physical examination, cervical ultrasound and serum TSH, and thyroglobulin and antithyroglobulin antibody levels. Other imaging studies are reserved for patients with an elevated serum thyroglobulin level and a negative cervical ultrasound. Systemic metastases most commonly involve the lung and bone and less commonly the brain, liver, and skin. Microscopic metastases are treated with high doses of radioactive iodine. Isolated macroscopic metastases can be resected with an improvement in survival. The overall ten-year survival for patients with minimally invasive follicular carcinoma is 98% compared with 80% in patients with invasive follicular carcinoma.
PMCID: PMC3228182  PMID: 21482585
Follicular thyroid carcinoma; Follicular adenoma; Follicular neoplasm
4.  Oral acantholytic squamous cell carcinoma shares clinical and histological features with angiosarcoma 
Head & Face Medicine  2008;4:17.
acantholytic squamous cell carcinomas (ASCC) and intraoral angiosarcoma share similar histopathological features. Aim of this study was to find marker for a clear distinction.
Four oral acantholytic squamous cell carcinomas and one intraoral angiosarcoma are used to compare the eruptive intraoral growth-pattern, age-peak, unfavourable prognosis and slit-like intratumorous spaces in common histological staining as identical clinical and histopathological features. Immunohistochemical staining for pancytokeratin, cytokeratin, collagen type IV, γ2-chain of laminin-5, endothelial differentiation marker CD31 and CD34, F VIII-associated antigen, Ki 67-antigen, β-catenin, E-cadherin, α-smooth-muscle-actin and Fli-1 were done.
Cytokeratin-immunoreactive cells can be identified in both lesions. The large vascularization of ASCC complicates the interpretation of vascular differential markers being characteristic for angiosarcoma. Loss of cell-cell-adhesion, monitored by loss of E-cadherin and β-catenin membrane-staining, are indetified as reasons for massive expression of invasion-factor ln-5 in ASCC and considered responsible for unfavourable prognosis of ASCC. Expression of Fli-1 in angiosarcoma and cellular immunoreaction for ln-5 in ASCC are worked out as distinguishing features of both entities.
Fli-1 in angiosarcoma and ln-5 in ASCC are distinguishing features.
PMCID: PMC2515303  PMID: 18671846
5.  Follicular thyroid adenoma dominated by spindle cells: report of two unusual cases and literature review 
Primary spindle cell neoplasms of the thyroid gland are quite rare. They encompass a heterogeneous group of benign and malignant lesions of mesenchymal and epithelial origin. We herein describe two unusual follicular thyroid adenomas dominated by spindle cells with occasional areas of colloid-forming follicular differentiation. The tumors affected a 77-year woman and a 70-year old man; both had a long-history of monoclonal gammopathy of unknown significance (MGUS). One tumor presented as a large cold thyroid nodule and the other was an autopsy finding. The tumors were predominantly composed of fibroblast-like spindled cells. One case showed prominent meningioma-like concentric perivascular arrangement and contained cytoplasmic melanin-like pigment. Stromal hyalinization was a prominent feature of both. By immunohistochemistry, the spindled cells expressed vimentin, pankeratin (KL1), thyroglobulin and TTF1 consistent with a follicular differentiation. They did not stain with calcitonin, CEA and other lineage-specific mesenchymal, neuroendocrine and melanocytic markers. There was no evidence of metastasis at autopsy (case 2) or at last follow-up 2 years after surgery (case 1). These cases demonstrate the diversity of follicular thyroid neoplasms and the unusual occurrence of extensive spindle cell metaplasia. These uncommon lesions need to be distinguished from spindle cell medullary carcinoma, paucicellular spindle cell anaplastic carcinoma, spindle cell foci in papillary and follicular carcinoma, solitary fibrous tumor and other rare benign and malignant mesenchymal lesions.
PMCID: PMC3294228  PMID: 22400075
Spindle cell neoplasm; thyroid; follicular adenoma; TTF1; pigmented
6.  Nonalpine Thyroid Angiosarcoma in a Patient with Hashimoto Thyroiditis 
Thyroid angiosarcoma is an uncommon thyroid carcinoma and its incidence is the highest in the European Alpine regions. Thyroid angiosarcoma is also a very aggressive tumor that can rapidly spread to the cervical lymph nodes, lungs, and brain or can metastasize to the duodenum, small boewl, and large bowel. Although it is histologically well defined, clear-cut separation between the angiosarcoma and anaplastic thyroid carcinoma is difficult. A 49-year-old Caucasian female patient, born and resident in Southern Italy (Calabria), in an iodine-sufficient area, was admitted to the Surgery Department because she presented with a painless mass in the anterior region of neck enlarged rapidly in the last three months. After total thyroidectomy and right cervical lymphadenectomy, postoperative histological examination revealed the presence of a thyroid angiosarcoma with positive staining for CD31 and for both Factor VIII-related antigen and Vimentin and only partially positive for staining pancytokeratin and presence of metastasis in cervical, supraclavicular, mediastinal and paratracheal lymph nodes. The patient started adjuvant chemotherapy and she was treated for 6 cycles with Doxorubicin, Dacarbazine, Ifosfamide, and Mesna (MAID). After 22 months from surgery, the patient is still alive without both local and systemic recurrence of the disease.
PMCID: PMC3855954  PMID: 24349811
7.  QPRT: a potential marker for follicular thyroid carcinoma including minimal invasive variant; a gene expression, RNA and immunohistochemical study 
BMC Cancer  2009;9:93.
The differential diagnosis between follicular thyroid adenoma and minimal invasive follicular thyroid carcinoma is often difficult for several reasons. One major aspect is the lack of typical cytological criteria in well differentiated specimens. New marker molecules, shown by poly- or monoclonal antibodies proved helpful.
We performed global gene expression analysis of 12 follicular thyroid tumours (4 follicular adenomas, 4 minimal invasive follicular carcinomas and 4 widely invasive follicular carcinomas), followed by immunohistochemical staining of 149 cases. The specificity of the antibody was validated by western blot analysis
In gene expression analysis QPRT was detected as differently expressed between follicular thyroid adenoma and follicular thyroid carcinoma. QPRT protein could be detected by immunohistochemistry in 65% of follicular thyroid carcinomas including minimal invasive variant and only 22% of follicular adenomas.
Consequently, QPRT is a potential new marker for the immunohistochemical screening of follicular thyroid nodules.
PMCID: PMC2667537  PMID: 19321014
8.  Simultaneous occurrence of medullary and papillary thyroid microcarcinomas: a case series and review of the literature 
Papillary thyroid microcarcinoma has been demonstrated to present in association with medullary thyroid carcinoma, however, medullary thyroid carcinoma and papillary thyroid carcinoma represent rare entities. In recent years this rarity has been increasingly observed. The pathogenesis is still controversial. Genetic analysis of RET proto-oncogenes in cases of simultaneous papillary thyroid carcinoma and medullary thyroid carcinoma has so far provided conflicting results; although it seems that germline mutations play a potential role in the development of both histological types.
Case presentations
This paper describes four rare cases of simultaneous medullary thyroid carcinoma and papillary thyroid microcarcinoma with unique features:
Case one was a 43-year-old Jewish woman, born in Israel, daughter of a Latvian immigrant mother and a father born in Israel. Case two was a 44-year-old Arab woman born in Israel. Case three was a 45-year-old Jewish woman, born in Israel, daughter of Moroccan immigrant parents and is unique for the presence of lymph node metastatic medullary thyroid carcinoma, and one lymph node with metastatic papillary carcinoma found in the same side. Case four was a 77-year-old Jewish woman, born in Iraq. These cases are unique in their composition of thyroid carcinoma, consisting of histologic features of medullary thyroid carcinoma, papillary thyroid microcarcinoma, and follicular thyroid adenoma. The four cases represent different ethnicity groups that live in north Israel, and case four is notable for the advanced age of the patient (77 years).
These four cases add more data supporting the coincidental coexistence of papillary thyroid microcarcinoma and medullary thyroid carcinoma; our results may suggest that the simultaneous occurrence of medullary thyroid carcinoma and papillary thyroid microcarcinoma is generally a simple reflection of this coincidence. Endocrinologists and pathologists should be aware of this entity. The pathologist can play a pivotal role in identifying papillary thyroid microcarcinoma in concurrent existence with medullary thyroid carcinoma.
PMCID: PMC3552861  PMID: 23336429
Calcitonin RET proto-oncogene; Medullary thyroid carcinoma; Papillary thyroid carcinoma; Papillary thyroid microcarcinoma
9.  Fatal poorly differentiated angiosarcoma of the scalp 
Cutaneous angiosarcoma is a very rare but aggressive tumor. Angiosarcoma of the scalp is very rare, and a review of the world literature revealed less than 60 cases. Here, the author reports a case of poorly differentiated angiosarcoma of the scalp. The pathological diagnosis was very difficult. A 70-year-old Japanase man was admitted to our hospital complaining of red mass of the scalp. An excisional biopsy was done. The biopsy showed proliferation of malignant spindle cells in the dermis. Apparent differentiation was not recognized. Invasion into the lateral dermis and subcutis was recognized. There were many mitotic figures and a few foci of necrosis. The size was 2 × 2 × 3 cm. Intracytoplasmic vacuoles were recognized in the malignant tumor cells in some places. A few vague vasoformative features were recognized in one very small area. Immunohistochemically, the malignant spindle cells were positive for factor VIII-related antigen (F-VIII-RA), Ulex lectin, CD31, CD34, vimentin, p53 protein. The Ki-67 labeling was 76%. In contrast, the tumor cells were negative for cytokeratins, epithelial membrane antigen, desmin, S100 protein, α-smooth muscle antigen, bcl-2, melanosome, and myoglobin. The intracytoplasmic vacuoles were strongly positive for F-VIII-RA, Ulex lectin, CD31, and CD34, The abortive vasoformative channels were moderately positive for these endothelial markers. A pathologic diagnosis of angiosarcoma of the scalp was made. Chemoradiation and immunotherapy were performed. However, the tumor recurred several times, and ultimately metastasized to the systemic bones and lungs. The patient died of systemic carcinomatosis 33 months after the first manifestation.
PMCID: PMC2897108  PMID: 20606736
Cutaneous angiosarcoma; scalp; for factor VIII-related antigen (F-VIII-RA); Ulex lectin; CD31; CD34; vimentin; p53 protein
10.  Papillary Thyroid Carcinoma Variants 
Head and Neck Pathology  2011;5(1):51-56.
Papillary thyroid carcinomas are the most common thyroid cancers and constitute more than 70% of thyroid malignancies. The most common etiologic factor is radiation, but genetic susceptibility and other factors also contribute to the development of papillary thyroid carcinoma. The most common variants include conventional, follicular variant and tall cell variant. However, many other uncommon variants have been described including oncocytic, columnar cell, diffuse sclerosing and solid forms. Immunohistochemical staining with TTF-1 and thyroglobulin is very useful in confirming the diagnosis of papillary thyroid carcinoma especially in metastatic sites. Markers such as HBME-1 and CITED1 can assist in separating some difficult cases of follicular variants of papillary thyroid carcinomas from follicular adenomas. Molecular studies have shown that the BRAF V600E mutation is found mainly in papillary and anaplastic thyroid carcinomas. Other molecular markers such as HMGA2 and insulin-like growth factor II mRNA binding protein 3 have been used recently as molecular tests to separate papillary thyroid carcinoma and its variants from follicular adenomas and other benign thyroid nodules.
PMCID: PMC3037461  PMID: 21221869
Papillary thyroid carcinoma; Follicular variant; Tall cell; Columnar cell; BRAF mutation; RET/PTC; HMGA2
11.  Electron microscopic analysis of an angiosarcoma of the thyroid from a non-Alpine endemic goiter region: A case report and brief review of the literature 
Oncology Letters  2014;8(5):2117-2121.
Angiomatoid tumors of the thyroid gland are rare endocrine neoplasms, which exhibit an aggressive behavior. Angiosarcomas of the thyroid are generally reported from the European Alpine region and have a histogenesis that has been under debate for a number of years. The current study presents a rare case of angiosarcoma of the thyroid in a 62-year-old Turkish female. The patient had a 10-year history of goiter and was from the Black Sea region, an endemic goiter region of Turkey. The patient was not taking any medication at the time of admission and swelling had been observed on the right side of the neck throughout the previous few months. Thyroid function tests, which analyzed the levels of thyroid-stimulating hormone, thyroxine and triiodothyronine, were within the normal limits, however, the histopathological findings were consistent with an angiosarcoma of the thyroid. The patient rejected the complementary surgery and chemotherapy options, and is currently disease-free (as per the 15-month follow-up). The current study describes a case of angiosarcoma that was characterized by Weibel-Palade bodies, and light microscopy and immunohistochemical findings, as well as an endothelial origin, which was demonstrated via electron microscopy. To the best of our knowledge, this is the first reported case of angiosarcoma of the thyroid in a patient from Turkey to be validated by electron microscopy. Furthermore, this case is one of the few reported thyroid angiosarcoma cases in a non-Alpine region.
PMCID: PMC4186527  PMID: 25289092
thyroid angiosarcoma; non-Alpine; endemic goiter; CD31 antibody
12.  Poorly differentiated ("insular") carcinoma of the thyroid gland--two cases report. 
Poorly differentiated ("insular") carcinoma of the thyroid shares insular, trabecular, and solid histological patterns that are different from those of papillary, follicular, medullary, and anaplastic varieties. This tumor is situated morphologically and biologically in the intermediate position between the well differentiated (papillary and follicular) and the totally undifferentiated (anaplastic) thyroid tumors. We report two cases of insular carcinoma of the thyroid, occurring in 39-year-old and 52-year-old women. Grossly, these cases showed a lobulated mass with fibrous septa. The histologic finding showed characteristic "insular" growth pattern with focal follicular or papillary areas. Thyroglobulin was demonstrated within cytoplasmic paranuclear vacuoles of the neoplastic cells. Calcitonin and amyloid were not demonstrated. The aspiration cytology showed high cellularity, low grade of atypia, presence of clusters, nests, and trabeculae of cells with poorly outlined cytoplasm. The ultrastructural finding showed primordial cells having cytoplasmic organelles such as rough endoplasmic reticulum, mitochondria, and free ribosomes. We believe that its separation from other types of thyroid carcinoma will lead to a more accurate estimate of its biologic behavior and a more appropriate therapeutic approach.
PMCID: PMC3054275  PMID: 9142665
13.  Thyroid-like follicular carcinoma of the kidney: A report of two cases and literature review 
Oncology Letters  2014;7(6):1796-1802.
There have only been a few reports of thyroid-like follicular carcinoma of the kidney (TLFCK) to date. In the present study, two patients with TLFCK are reported. Patient 1 was a 65-year-old male exhibiting repeated hematuria and right back pain. No tumors were located in the patient’s thyroid or lungs. The physical examination revealed percussion tenderness over the right kidney region was noticed. Enhanced computed tomography (CT) indicated a right renal pelvic carcinoma, for which the patient underwent a radical right nephrectomy. Patient 2 was a 59-year-old male with a mass in the right kidney, located during a health examination and who exhibited no obvious clinical symptoms. The patient was clinically diagnosed with right renal carcinoma, confirmed by an enhanced CT. The patient underwent a radical right nephrectomy. The clinical features, imaging results, pathology, immune phenotypes, treatment and prognosis were analyzed. The associated literature was also reviewed. The cut surface of each tumor showed gray-white material with a central solid area, including scattered gray-brown necrotic and gray hemorrhagic areas and small cystic cavities. Microscopically, the arrangement of the tumor cells mimicked thyroid follicles with red-stained colloid-like material in the lumen. No renal hilar lymph node involvement was noted. The tumor tissue of patient 1 was immunohistochemically positive for vimentin, epithelial membrane antigen (EMA), cytokeratin (CK), CK7, and neuron specific enolase; and negative for CK34BE12, synapsin (Syn), CK20, cluster of differentiation 56 (CD56), CD10, Wilm’s tumor-1 (WT-1), CD34, CD57, P53, CD99, thyroid transcription factor-1 (TTF-1), CD15 and thyroglobulin (TG); with a Ki-67 labeling index (LI) of 30%. The tumor tissue of patient 2 was immunohistochemically positive for vimentin, EMA, CK7 and CK20; and negative for CD56, CD10, WT-1, CD34, CD57, P53, CD117, TTF-1, CD15, CD99, TG, chromogranin A and Syn; with a Ki-67 LI of 20%. TLFCK is a rare renal tumor with low malignancy but medium invasiveness. It morphologically resembles thyroid follicular carcinoma but does not express TTF-1 or TG. Radical nephrectomy can achieve good patient outcomes.
PMCID: PMC4049768  PMID: 24932236
thyroid-like follicular carcinoma of the kidney; features; treatment; prognosis
14.  Actual Incidence and Clinical Behaviour of Follicular Thyroid Carcinoma: An Institutional Experience 
The Scientific World Journal  2014;2014:952095.
Follicular thyroid carcinoma classically accounts for 10–32% of thyroid malignancies. We determined the incidence and the behaviour of follicular thyroid carcinoma in an endemic goitre area. A comparative analysis between minimally invasive and widely invasive follicular thyroid carcinoma was performed. The medical records of all patients who underwent thyroidectomy from October 1998 to April 2012 for thyroid malignancies were reviewed. Those who had a histological diagnosis of follicular carcinoma were included. Among 5203 patients, 130 (2.5%) were included. Distant metastases at presentation were observed in four patients. Sixty-six patients had a minimally invasive follicular carcinoma and 64 a widely invasive follicular carcinoma. In 63 patients an oxyphilic variant was registered. Minimally/widely invasive ratio was 41/26 for usual follicular carcinoma and 25/38 for oxyphilic variant (P < 0.05). Patients with widely invasive tumors had larger tumors (P < 0.001) and more frequently oxyphilic variant (P < 0.05) than those with minimally invasive tumours. No significant difference was found between widely invasive and minimally invasive tumors and between usual follicular carcinoma and oxyphilic variant regarding the recurrence rate (P = NS). The incidence of follicular thyroid carcinoma is much lower than classically retained. Aggressive treatment, including total thyroidectomy and radioiodine ablation, should be proposed to all patients.
PMCID: PMC3967639  PMID: 24741369
15.  Ectopic Thyroid Tissue in the Adrenal Gland: A Report of Two Cases with Pathogenetic Implications 
Thyroid  2013;23(12):1644-1650.
Background: Ectopic thyroid tissue is usually found anywhere along the embryonic descent pathway of the medial thyroid anlage from the tongue to the trachea (Wölfler area). However, ectopic thyroid tissue in the adrenal gland (ETTAG) is not easy to understand on the basis of thyroid embryology; because it is so rare, the possibility of metastasis should first be considered. Here, we describe two cases of ETTAG with pathogenetic implications and review the associated literature.
Patient findings: Two cases of ETTAG presented as incidental cystic adrenal masses in adult females, one having a congenital hernia of Morgagni. The ETTAG was histologically indistinguishable from normal orthotopic thyroid tissue, and its follicular nature was confirmed by immunohistochemical positivity for thyroglobulin, thyroperoxidase, thyroid transcription factor-1 (TTF-1/Titf-1/Nkx2.1), cytokeratin AE1/AE3, cytokeratin 7, pendrin, human sodium iodide symporter, paired box gene 8, and forkhead box E1 (TTF-2), as well as positivity for the messenger RNA of the thyroglobulin gene by in situ hybridization analysis. No C cells (negativity for calcitonin, chromogranin, and synaptophysin) were present. Neither BRAF nor KRAS mutations were detected with real-time polymerase chain reaction analysis. Further work-up did not show evidence of thyroid malignancy.
Summary: ETTAG is a rare finding, with only seven cases reported; women are much more frequently affected than men (8:1), and it usually presents in the fifth decade (mean age 54, range 38–67) as a cystic adrenal mass incidentally discovered on abdominal ultrasonography and/or in computed tomography images. ETTAG is composed of normal follicular cells without C cells. The expression of some transcription factors (TTF-1, paired box gene 8, and FOXE1) involved in development and/or migration of the medial thyroid anlage is preserved. Coexistence of a congenital hernia of Morgagni in one patient suggests an overdescent of medial thyroid anlage–derived cells in its pathogenesis.
Conclusion: Although ETTAG pathogenesis remains unknown, the lack of C cells together with the coexistence of a congenital defect of the anterior diaphragm (hernia of Morgagni) in one of our patients could suggest an overdescent of medial thyroid anlage–derived cells in the origin of this heterotopia.
PMCID: PMC3868403  PMID: 23510370
16.  The new molecular markers DDIT3, STT3A, ARG2 and FAM129A are not useful in diagnosing thyroid follicular tumors 
Modern Pathology  2011;25(4):537-547.
Preoperative characterization of thyroid follicular lesions is challenging. Fine-needle aspiration specimens cannot differentiate follicular carcinomas from benign follicular neoplasias. Recently, promising markers have been detected using modern molecular techniques. We conducted a retrospective study to confirm the usefulness of immunohistochemical staining for the protein markers, DDIT3, STT3A (ITM1), ARG2 and FAM129A (C1orf24) in separating benign and malignant thyroid follicular lesions. Formalin-fixed, paraffin-embedded thyroid tissue from 30 in-house cases (15 follicular carcinomas and 15 follicular adenomas), as well as 8 follicular carcinomas and 21 follicular adenomas on tissue microarray slides were stained immunohistochemically for DDIT3, STT3A, ARG2 and FAM129A expression. Control tissue consisted of thyroid parenchyma adjacent to the tumors and 11 separate cases of normal thyroid parenchyma. All in-house cases of follicular adenomas, follicular carcinomas and adjacent normal thyroid tissue showed positive immunostaining with anti-DDIT3 and anti-STT3A. Anti-ARG2 and anti-FAM129A polyclonal antibodies showed positive staining in 20 and 60% of in-house follicular adenomas, and 40 and 87% of in-house follicular carcinomas, respectively. Monoclonal anti-FAM129A demonstrated positive staining in 13 and 33% of in-house follicular adenomas and follicular carcinomas, respectively. Polyclonal anti-DDIT3, -STT3A and -FAM129A antibodies showed positive staining in all tissue microarray slides of follicular carcinoma and in 76, 85 and 81% of the follicular adenomas, respectively. Monoclonal anti-STT3A stained 81% of the follicular adenoma cores. Anti-ARG2 stained positive in 13% of follicular carcinomas and 10% of follicular adenomas on the tissue microarray slides. In conclusion, DDIT3, STT3A, ARG2 and FAM129A immunohistochemistry does not appear to be useful in the diagnosis of thyroid follicular neoplasias, as they do not reliably distinguish follicular thyroid carcinoma from follicular thyroid adenoma.
PMCID: PMC3318159  PMID: 22157935
ARG2; C1orf24; DDIT3; FAM129A; ITM1; STT3A; thyroid carcinoma
17.  Childhood thyroid cancer in England and Wales. 
British Journal of Cancer  1995;72(3):777-783.
A total of 154 cases of thyroid cancer in children under 15 were registered in England and Wales over a period of 30 years, an incidence of about 0.5 per million per year. A total of 4.5 cases per year were registered in 1963-72, 4.9 in 1973-82 and 5.8 in 1983-92. A rapid rise in incidence with age occurred after the age of 5. Malignancy was confirmed in 92% of the cases in which tissue was available. Of these, 68% were papillary carcinomas, 11% follicular carcinomas and 17% medullary carcinomas. There were two spindle cell tumours with mucous cysts and one teratoma. The increased frequency but small size of medullary carcinomas in the second half of the period suggested that this increase was due to the introduction of screening; it accounted for most of the rise in crude incidence rats with time. The sex ratio (F:M) in all registered cases in the differentiated follicular cell carcinoma groups in children aged under 10 was 1.2:1, and 3.6:1 in the older children. Five children with differentiated thyroid cancer of follicular cell origin died up to 17 years after diagnosis. Two of the eight children aged 9 or less with a 20 year follow-up died, compared with three of 28 older children. An unusual group of differentiated carcinomas showed solid or follicular architecture. These tumours were unencapsulated, often widely invasive, contained psammoma bodies but little or no papillary architecture and the nuclei often lacked prominent grooving. This childhood type of papillary carcinoma contrasted with the classical type commonly found in the adult, which was present in one of 13 confirmed papillary carcinomas in children aged less than 10, compared with 20 of 35 older children. These observations show that thyroid carcinoma in very young children has a different spectrum of histological types from both older children and adults. From the age of about 10 well-differentiated papillary carcinomas rapidly increase in frequency in females, so that the other types come to form only a small proportion of the total. These differences, and the lower incidence but poorer prognosis of thyroid carcinoma in men and the poorer prognosis in post- as compared with premenopausal women, are compatible with a major role for sex hormones in thyroid carcinogenesis in females during the reproductive period. This study documents the incidence of childhood thyroid cancer in England and Wales, explains the rise in crude incidence rates, shows differences between carcinomas in children under and over the age of ten which may correlate with puberty, and draws attention to an unusual aggressive type of childhood papillary carcinoma. It illustrates the value to crude registry data of a pathology review.
PMCID: PMC2033913  PMID: 7669594
18.  The Role of Epithelial Mesenchymal Transition Markers in Thyroid Carcinoma Progression 
Endocrine pathology  2013;24(4):10.1007/s12022-013-9272-9.
Understanding the molecular mechanisms involved in thyroid cancer progression may provide targets for more effective treatment of aggressive thyroid cancers. Epithelial-mesenchymal transition (EMT) is a major pathologic mechanism in tumor progression and is linked to the acquisition of stem-like properties of cancer cells. We examined expression of ZEB1 which activates EMT by binding to the E-box elements in the E-cadherin promoter, and expression of E-cadherin in normal and neoplastic thyroid tissues in a tissue microarray (TMA) which included 127 neoplasms and 10 normal thyroid specimens. Thyroid follicular adenomas (FA, n=32), follicular thyroid carcinomas (FTC, n=28), and papillary thyroid carcinomas (PTC, n=57) all expressed E-cadherin and were mostly negative for ZEB1 while most anaplastic thyroid carcinomas (ATC, n=10) were negative for E-cadherin, but positive for ZEB1. A validation set of 10 whole sections of ATCs showed 90% of cases positive for ZEB1 and all cases were negative for E-cadherin. Analysis of three cell lines (normal thyroid, NTHY-OR13-1; PTC, TPC-1 and ATC, THJ-21T) showed that the ATC cell line expressed the highest levels of ZEB1 while the normal thyroid cell line expressed the highest levels of E-Cadherin. Quantitative RT-PCR analyses showed that Smad7 mRNA was significantly higher in ATC than in any other group (p<0.05). These results indicate that ATCs show evidence of EMT including decreased expression of E-cadherin and increased expression of ZEB1 compared to well differentiated thyroid carcinomas and that increased expression of Smad7 may be associated with thyroid tumor progression.
PMCID: PMC3875396  PMID: 24126800
Thyroid carcinoma; Anaplastic thyroid carcinoma; ZEB1; Smad7; E-cadherin
19.  Synergistic Signaling of KRAS and Thyroid Hormone Receptor β Mutants Promotes Undifferentiated Thyroid Cancer through MYC Up-Regulation12 
Neoplasia (New York, N.Y.)  2014;16(9):757-769.
Undifferentiated thyroid carcinoma is one of the most aggressive human cancers with frequent RAS mutations. How mutations of the RAS gene contribute to undifferentiated thyroid cancer remains largely unknown. Mice harboring a potent dominant negative mutant thyroid hormone receptor β, TRβPV (ThrbPV/PV), spontaneously develop well-differentiated follicular thyroid cancer similar to human cancer. We genetically targeted the KrasG12D mutation to thyroid epithelial cells of ThrbPV/PV mice to understand how KrasG12D mutation could induce undifferentiated thyroid cancer in ThrbPV/PVKrasG12D mice. ThrbPV/PVKrasG12D mice exhibited poorer survival due to more aggressive thyroid tumors with capsular invasion, vascular invasion, and distant metastases to the lung occurring at an earlier age and at a higher frequency than ThrbPV/PV mice did. Importantly, ThrbPV/PVKrasG12D mice developed frequent anaplastic foci with complete loss of normal thyroid follicular morphology. Within the anaplastic foci, the thyroid-specific transcription factor paired box gene 8 (PAX8) expression was virtually lost and the loss of PAX8 expression was inversely correlated with elevated MYC expression. Consistently, co-expression of KRASG12D with TRβPV upregulated MYC levels in rat thyroid pccl3 cells, and MYC acted to enhance the TRβPV-mediated repression of the Pax8 promoter activity of a distant upstream enhancer, critical for thyroid-specific Pax8 expression. Our findings indicated that synergistic signaling of KRASG12D and TRβPV led to increased MYC expression. Upregulated MYC contributes to the initiation of undifferentiated thyroid cancer, in part, through enhancing TRβPV-mediated repression of the Pax8 expression. Thus, MYC might serve as a potential target for therapeutic intervention.
PMCID: PMC4234871  PMID: 25246276
20.  Predictors of thyroid tumor aggressiveness. 
Western Journal of Medicine  1996;165(3):131-138.
Thyroid cancers are classified as papillary, follicular (including Hürthle cell), medullary, and anaplastic. Papillary cancers account for about 82% of all thyroid cancers, follicular about 8%, medullary about 6%, Hürthle cell 3%, and anaplastic 1%. The prognosis of patients with papillary thyroid cancer is usually favorable, whereas most patients with anaplastic cancer die within 6 months. The behavior of papillary thyroid cancer can be predicted by patient age, sex, tumor size, local invasion, angioinvasion, lymph node metastases, distant metastases, as well as tumor differentiation and ability to take up radioactive iodine. Thus, older male patients with larger or invasive tumors, with angioinvasion, lymph node or distant metastases, and with tumors that do not take up radioactive iodine or cannot be completely surgically resected have a worse prognosis. Anaploid tumors, tumors with a low adenylate cyclase response to thyroid-stimulating hormone tumors, tumors that are ras-and gsp-positive, and tumors that are p21-positive and p53-positive also appear to behave in a more aggressive manner. In contrast, lymphocytic thyroiditis associated with papillary thyroid cancer predicts fewer recurrences and an improved survival. The treatment of patients with papillary thyroid cancer is controversial primarily because most patients do well with relatively minimal therapy, and there are no prospective studies concerning the merits of various treatments. Much of the controversy relates to the safety of thyroidectomy versus other procedures and, to a lesser extent, when to do a central or modified radical neck dissection. The rate of recurrence is lower, and the death rate may also be lower when patients are treated initially by total thyroidectomy. The rationale for total thyroidectomy is that it enables one to use radioactive iodine to detect and treat local and distant metastases, and it makes serum thyroglobulin determination more sensitive for detecting persistent disease. Total thyroidectomy should be associated with a permanent complication rate of less than 2%. Thyroid-stimulating hormone suppression therapy is recommended by most experts for patients with differentiated thyroid cancer and supported by most clinical and laboratory studies. Central and lateral node selection is recommended for patients with palpable lymphadenopathy.
PMCID: PMC1303719  PMID: 8909165
21.  Coexistence of pulmonary sclerosing hemangioma and primary adenocarcinoma in the same nodule of lung 
Diagnostic Pathology  2011;6:41.
Pulmonary sclerosing hemangiomas (PSH) of the lung are uncommon tumors and may present cytological atypia with unusual manifestations. The development of PSH combined with other different tumors in lung is extremely rare. We report a case of coexistence of PSH and primary adenocarcinoma in a young female occurring in the same pulmonary nodular mass of right lower lobe. The solitary mass of lung was well-circumscribed on chest computed tomography (CT) and gross examination. Histologically, the mass contained two separated portions and displayed typically histological features of PSH and acinar adenocarcinoma, respectively. In PSH portion, the tumor was composed of sheets of round cells with scattered surface cuboidal cells forming small tubules. Both round and surface cells were diffusely positive for epithelial membrane antigen (EMA) and thyroid transcription factor-1 (TTF-1), but lack immunoreactivity for pancytokeratin in round cells. In adenocarcinoma portion, the tumor cells formed irregular-shaped glands with cytologically malignant cells infiltrating in fibroblastic stroma, and no TTF-1-positive round cells could be observed in this portion. Under the microscopy, there was no gradual transition of these two portions observed in mass. A diagnosis of PSH combined with primary adenocarcinoma of lung was made. There was no evidence of tumor recurrence during the period of postoperative 6-month follow-up. To our knowledge, this is the first case of coexistence of PSH and adenocarcinoma in the same nodule of lung. In addition, the biological behavior and histological differential diagnosis of this tumor were also discussed.
PMCID: PMC3117760  PMID: 21599956
22.  Pattern of regional metastases and prognostic factors in differentiated thyroid carcinoma 
The meaning of nodal metastases in well-differentiated thyroid carcinoma is controversial. The Authors analyse the impact of lymphatic spread reviewing 1503 cases of well-differentiated thyroid carcinoma treated at the National Cancer Institute of Rome between 1988 and 2005, in order to detect significant prognostic factors through multivariate analysis. Overall, 462 cases of locally advanced well-differentiated thyroid carcinoma, were considered. A multivariate analysis of a subgroup, comprising 97 N+ consecutive cases of well-differentiated thyroid carcinoma, previously untreated, was performed to study prognostic factors for local (N+) and distant (M+) metastasis in well-differentiated thyroid carcinoma. Of the 97 cases, 88 were submitted to surgery for a large well-differentiated thyroid carcinoma, 9 for occult differentiated thyroid carcinoma. After surgery, 12 patients were lost to follow-up, 8 resulted pathologically negative, therefore only 77 cases of pN1 well-differentiated thyroid carcinoma were studied. Considering all cases of well-differentiated thyroid carcinoma, 10-year-overall survival was 58.7% for locally advanced well-differentiated thyroid carcinoma, compared to 94.8% in low stage cases. Neck dissection, margin infiltration and extra-capsular spread were significant prognostic factors. The Authors present a retrospective study of 77 patients with primary differentiated thyroid carcinoma, submitted to thyroidectomy and neck dissection aimed at analysing distribution of nodal metastases according to Robbins’ levels classification and defining their prognostic value. All N1b cases, retrospectively reviewed (n. 77), presented clinical and histological evidence of neck nodes metastases from differentiated thyroid carcinoma; histological reports indicated tumour localisation and topographical distribution of metastases; papillary carcinoma was the most common type (72 cases), followed by follicular carcinoma (5 cases). Surgical treatment always comprised total thyroidectomy and 6th level dissection. Overall 52 cases were submitted to monolateral neck dissection, 25 to bilateral neck dissection. Treatment of the lateral neck was postero-lateral neck dissection (n. 53), selective lateral neck dissection (n. 20), modified radical and radical (n. 29). Cervical level IV was the most frequently involved (52%), extra-capsular spread of metastases was identified in 22% of the cases. Statistically significant prognostic factors for distant metastases and recurrence on the neck were follicular carcinoma (p < 0.01) and extra-capsular spread (p < 0.001). Age, pT, sex, number of positive nodal metastases, T-extension and the number of nodal positive levels were not significant. In the Authors’ experience, histological grade of differentiation, wide tumour excision and neck dissection, in cases of N1b well-differentiated thyroid carcinoma, without residual disease (R1, R2), in the central and lateral neck, are determinant prognostic factors. Extracapsular spread in particular, was found to be a highly predictive factor either of distant metastasis or regional recurrence.
PMCID: PMC2868202  PMID: 20463835
Thyroid carcinoma; Nodal metastases; Extra-capsular spread
23.  Activation of the two microRNA clusters C19MC and miR-371-3 does not play prominent role in thyroid cancer 
Chromosomal rearrangements of band 19q13.4 are frequent cytogenetic alterations in benign thyroid adenomas. Apparently, these alterations lead to the upregulation of genes encoding microRNAs of two clusters mapping to the breakpoint region, i.e. miR-371-3 and C19MC. Since members of both clusters have been associated with neoplastic growth in other tumor entities the question arises whether or not their upregulation predisposes to malignant transformation of follicular cells of the thyroid. To address this question we have quantified the expression of miR-372 and miR-520c-3p in samples of 114 thyroid cancers including eight anaplastic thyroid carcinomas, 25 follicular thyroid carcinomas, 78 papillary thyroid carcinomas (including 13 follicular variants thereof), two medullary thyroid carcinomas and one oncocytic thyroid carcinoma. Additionally, we quantified miR-371a-3p and miR-519a-3p in selected samples. While in neither of the cases miR-520c-3p and miR-519a-3p were found to be upregulated, one papillary and one anaplastic thyroid carcinoma, respectively, showed upregulation of miR-372 and miR-371a-3p. However, in these cases fluorescence in situ hybridization did not reveal rearrangements of the common breakpoint region as affected in adenomas. Thus, these rearrangements do apparently not play a major role as first steps in malignant transformation of the thyroid epithelium. Moreover, there is no evidence that 19q13.4 rearrangements characterize a subgroup of thyroid adenomas associated with a higher risk to undergo malignant transformation. Vice versa, the mechanisms by which 19q13.4 rearrangements contribute to benign tumorigenesis in the thyroid remain to be elucidated.
PMCID: PMC3538622  PMID: 23062364
Thyroid tumors; microRNAs; C19MC; miR-371-3
24.  Primary thyroid angiosarcoma: an unusual localization 
The finding of thyroid nodules is a very common occurrence in routine clinical practice. Approximately 5% to 7% of the entire population have thyroid nodules. Vascular lesions are one of the most controversial issues in thyroid pathology. These include benign lesions such as hemangiomas and, rarely, malignant tumors such as angiosarcomas or undifferentiated angiosarcomatoid carcinomas. In particular, angiosarcoma of the thyroid gland is a rare, highly aggressive malignant vascular tumor and in Italy the greatest geographical incidence of this lesion is witnessed near the Alps. Here, a case of thyroid angiosarcoma in a 71-year-old man with a history of goiter for about 20 years is described. The unusual localization of this lesion, the difficulties in reaching a definitive diagnosis for this particular histological type of primary tumor and a history of long-standing multinodular goiter in thyroid of an older man from outside the Alpine region prompted us to report this case of thyroid angiosarcoma mainly to discuss surgical, histopathological and immunohistochemical features.
PMCID: PMC3490834  PMID: 22553943
Angiosarcoma; Non-alpine region; Old man
25.  Immunohistochemical detection of epithelialmesenchymal transition associated with stemness phenotype in anaplastic thyroid carcinoma 
Anaplastic thyroid carcinoma (ATC) is a highly aggressive neoplasm resistant to radiation and chemotherapy. Epithelial-mesenchymal transition (EMT) generating cells with stem cell characteristics have been reported to be associated with chemoradioresistance in cultured cells. However, EMT and stem cell properties in ATC have not been fully investigated. In this study, we retrieved 2 thyroidectomy specimens of ATC with coexisting well differentiated thyroid carcinomas (DTCs) including one papillary carcinoma (PTC) and one follicular carcinoma (FTC). We used im-munohistochemistry to examine the expression of stem cell markers (nestin, CD133 and CD44) and a marker for EMT (E-cadherin). Intense expressions of nestin, CD133 and CD44, and no expression of E-cadherin were observed in both ATCs. In contrast, the PTC and FTC, and non-neoplastic thyroid tissue in both cases were negative for nestin and positive for E-cadherin. The expressions of CD133 and CD44 were variable in the PTC, FTC, and non-neoplastic thyroid tissue and were at a lower level of expression of these markers in the overall pattern. The results confirmed EMT, demonstrated the stem cell phenotype in ATC, and revealed the difference in expression of these markers between ATC and DTCs/non-neoplastic thyroid tissue. Nestin may be the most specific marker for stemness in ATC by immuno-histochemial staining. The results warrant future studies on a large series of cases in order to gain the understanding of the tumor biology and to provide molecular basis for restoring the sensitivities to clinical therapies.
PMCID: PMC2993225  PMID: 21151388
Anaplastic thyroid carcinoma; cancer stem cell; epithelial-mesenchymal transition; follicular thyroid carcinoma; immunohistochemistry; papillary thyroid carcinoma

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