Raf-1 Kinase Inhibitory Protein Expression in Thyroid Carcinomas

Raf-1 kinase inhibitory protein (RKIP) has been implicated in several fundamental signal transduction pathways that control cellular growth, differentiation, apoptosis and migration. RKIP is reduced in a variety of human carcinomas, but RKIP expression in thyroid carcinomas has not been analyzed at the protein level. In this study, we examined the immunohistochemical expression of RKIP in various subtypes of thyroid carcinoma. Immunostaining for RKIP was performed on 104 cases of primary thyroid carcinoma (40 papillary, 29 follicular, 11 medullary, 11 poorly differentiated, and 13 anaplastic carcinomas) and 26 cases of nodal metastatic tumor (17 papillary, 4 medullary, and 5 anaplastic carcinomas). Normal thyroid tissue and all cases of follicular, papillary, and medullary carcinomas showed uniform, strong cytoplasmic immunoreactivity for RKIP. With the exception of one case, poorly differentiated carcinomas also revealed strong RKIP expression. In contrast, RKIP expression was completely absent in all anaplastic carcinomas. The transition zone from the differentiated carcinoma component (strong RKIP expression) to the anaplastic carcinoma component (no RKIP expression) demonstrated a completely opposite pattern of RKIP immunoreactivity. This reduction of RKIP expression in anaplastic carcinoma was statistically significant (P?<?0.0001). Additionally, RKIP expression of nodal metastatic tumors corresponded with that of primary tumors: metastatic papillary and medullary carcinomas showed uniform, strong cytoplasmic RKIP immunoreactivity, in contrast, in metastatic anaplastic carcinomas, RKIP expression was completely absent. RKIP expression is significantly reduced in anaplastic thyroid carcinoma as compared to other subtypes of thyroid carcinoma. Further studies are necessary to elucidate the precise mechanism of RKIP action in anaplastic thyroid carcinoma.     

Papillary carcinoma of the thyroid gland with anaplastic transformation in the metastatic foci. An immunohistochemical study

An immunohistochemical study was made on an autopsy case of papillary carcinoma of the thyroid with anaplastic transformation in the metastatic foci occurring in a 72-year-old woman. The anaplastic carcinoma cells were sarcomatous in appearance, and they were vimentin-positive and cytokeratin-negative. Whereas, papillary tumor cells which were intermingled in the anaplastic carcinoma contained both cytokeratin and vimentin. The close correlation between tumor cell anaplasia and the expression of the different intermediate filament proteins in thyroid carcinoma was briefly discussed.     

PAPILLARY CARCINOMA OF THE THYROID GLAND WITH ANAPLASTIC TRANSFORMATION IN THE METASTATIC FOCI An Immunohistochemical Study

An immunohistochemical study was made on an autopsy case of papillary carcinoma of the thyroid with anaplastic transformation in the metastatic foci occurring in a 72-year-old woman. The anaplastic carcinoma cells were sarcomatous in appearance, and they were vimentin-positive and cytokeratin-negative. Whereas, papillary tumor cells which were intermingled in the anaplastic carcinoma contained both cytokeratin and vimentin. The close correlation between tumor cell anaplasia and the expression of the different intermediate filament proteins in thyroid carcinoma was briefly discussed.     

Papillary carcinoma of the thyroid with anaplastic transformation: diagnostic pitfalls in fine-needle aspiration biopsy

A case of coexistent papillary and anaplastic carcinoma of the thyroid is presented. The diagnosis of papillary carcinoma was made by fine-needle aspiration biopsy (FNAB); however, it did not correspond to the aggressive clinical behavior of the tumor. Subsequent biopsies revealed anaplastic carcinoma in the thyroid and pretracheal tissue. This case most likely represents anaplastic transformation in a pre-existing papillary carcinoma. The limitations of diagnosing this entity by FNAB as well as some possible solutions are discussed.     

Spindle cell transformation of papillary carcinoma: an aggressive entity distinct from anaplastic thyroid carcinoma

Spindle cells are not routinely encountered in the context of thyroid pathology and are most often present in anaplastic thyroid carcinoma, medullary thyroid carcinoma, and benign conditions such as Riedel struma or de Quervain granulomatous thyroiditis. Only a few publications have reported papillary thyroid carcinoma admixed with a prominent spindle cell component. While these tumors are clearly distinct from anaplastic thyroid carcinoma, prognostication as to their oncologic potential is not yet established. We describe a unique case of spindle cell transformation of papillary thyroid carcinoma. The blandness of the spindle cells was so impressive as to dissuade us from a malignant diagnosis on preoperative biopsies. However, this patient unfortunately died shortly after transformation of this papillary thyroid carcinoma. We conclude that this peculiar and rare spindle cell transformation should be regarded as a potentially lethal variant of papillary thyroid carcinoma.     

Histogenesis of thyroid carcinoma

Follicular and papillary thyroid carcinoma have for many years been regarded as biologically distinct from medullary thyroid carcinoma. The recent recognition of a tumor type which is morphologically and functionally intermediate between these two categories suggests however that differentiated thyroid carcinoma may be regarded as a continuous spectrum of tumor types all of which are derived from a common thyroid stem cell, capable of developing both follicular and parafollicular tumor cells, as well as intermediate cell forms. It is also proposed that anaplastic giant cell thyroid carcinoma represents a heterogeneous group consisting of the anaplastic counterparts not only to follicular and papillary carcinoma but also to the intermediate type and to classical medullary carcinoma.     

Antineoplastic activity of 1,25(OH)2D3 and its analogue 22-oxacalcitriol against human anaplastic thyroid carcinoma cell lines in vitro

Anaplastic carcinoma of thyroid is uncommon and is associated with a poor prognosis. an effective treatment of this carcinoma has not been found. We have examined the inhibition of promotion by 1, 25(OH)2D3 and its analogue without hypercalcemia, 22-oxacalcitriol (OCT) in the thyroid anaplastic carcinoma cell line. TTA-1, thyroid anaplastic carcinoma cell line, and TAC-1, thyroid anaplastic carcinoma cells. TPC-1,2,3,4, which are all papillary carcinoma of thyroid were used as control. Tumor growth was measured by MTT assay. 1,25(OH)2D3 additive cell growth was observed in diphasic pattern in 3/4 papillary carcinoma cell lines. OCT was more effective, showing dose-dependent inhibition of cell growth in anaplastic carcinoma cell lines, than that in papillary carcinoma cells. Conclusively, OCT might be useful for the inhibition of growth in anaplastic thyroid cancer.     

Papillary thyroid carcinoma with anaplastic transformation showing a rhabdoid phenotype solely in the cervical lymph node metastasis

We describe a rare case of anaplastically transformed papillary thyroid carcinoma with a rhabdoid phenotype appearing solely in a metastatic focus. A 77-year-old man presented with a rapidly enlarging, painful right lateral cervical mass. CT scan revealed a tumor in the right upper pole of the thyroid gland and a right lateral cervical mass. Examination of surgically resected specimens disclosed that the thyroid tumor was a well-differentiated papillary carcinoma (2.0 cm in diameter), and the right lateral cervical mass was an anaplastic carcinoma (2.4 cm in diameter) showing a rhabdoid phenotype with scant amounts of a papillary carcinoma component in the periphery, considered to be transformed through the metastasis of the papillary thyroid carcinoma in a cervical lymph node. The rhabdoid cells had eccentric nuclei with conspicuous nucleoli and spherical hyaline cytoplasmic inclusions, which are immunoreactive for vimentin and sarcomeric actin. Ultrastructurally, these had globular aggregation of thin and intermediate filaments. Nuclear immunoreactivity for INI1 indicated that the tumor had no INI1 abnormalities, suggesting a secondary rhabdoid tumor. Recurrence developed in the right cervical and mediastinal lymph nodes, and the patient died of disease 6 months after surgery. A rhabdoid phenotype is a pathological hallmark indicating the aggressive nature not only in the neck region, but also in other organs.     

Anaplastic spindle-cell squamous carcinoma arising in association with tall-cell papillary cancer of the thyroid: A potential pitfall

Transformation of a differentiated thyroid carcinoma is an infrequent occurrence and is usually associated with a dismal prognosis. Following a long-standing history of papillary carcinoma of the thyroid, the patient in the present report developed anaplastic thyroid carcinoma. The anaplastic component initially arose in the setting of papillary carcinoma with tall-cell features, represented a very small proportion of the tumor, and was overlooked at the time of the original diagnosis. Several years later, the patient developed a recurrent neck mass. Fine-needle aspiration (FNA) of this mass revealed a population of atypical spindle cells arranged singly and in papillary clusters which lacked the classical cytologic features of papillary carcinoma of the thyroid. Histology of the resected mass revealed an unusual and recently described subtype of thyroid carcinoma, termed "anaplastic spindle-cell squamous carcinoma," which has been reported as occurring in association with tall-cell papillary carcinoma. The FNA findings of this unusual subtype of anaplastic thyroid carcinoma are presented. Diagn. Cytopathol. 1999;21:413-418.     

KAI1 expression in thyroid neoplasms: its linkage with clinicopathologic features in papillary carcinoma

KAI1 is a metastasis suppressor gene located on human chromosome 11p11.2. Previous studies have shown that the down-regulation of KAI1 mRNA and decreased expression of its gene product are significantly linked to carcinoma progression, including metastatic ability. In this study, we investigated KAI1 protein expression in thyroid neoplasms. KAI1 overexpression was observed in 64.0% of papillary carcinoma cases, and the incidence was significantly higher than in cases of follicular carcinoma (20.0%) (p = 0.0001). In papillary carcinomas, decreased KAI1 expression was frequently observed in cases invading beyond the thyroid capsule (p = 0.001), as well as in lymph node metastases (p = 0.0047) and poorly differentiated lesions (p = 0.0299). Furthermore, in anaplastic carcinoma, the incidence of KAI1 overexpression was lower than in papillary carcinoma (p < 0.0001), and only 4.2% of the cases overexpressed this gene. These results suggest that KAI1 down-regulation is significantly related to the progression of papillary carcinoma, including lymph node metastasis, and its anaplastic transformation.     

Unusual metastases of papillary thyroid carcinoma: report of 2 cases

We present 2 cases of papillary thyroid carcinoma (PTC) with conventional morphology that metastasized to unusual sites. The first neoplasm was a PTC whose initial clinical manifestation was a large metastasis in the pancreas which mimicked a primary neoplasm. The mediastinal location of the thyroid gland was responsible for the delay in identification of the primary tumor. Eventually, the patient, a 72-year-old man, developed brain and vertebral metastases. The second case was that of a 58-year-old woman with a PTC with initial metastases in cervical lymph nodes; subsequently, the tumor spread to axillary lymph nodes and finally to the breast. Transformation to anaplastic spindle and giant cell carcinoma within the breast metastasis occurred 20 years after the primary thyroid tumor had been diagnosed and surgically treated. The metastatic anaplastic spindle and giant cell carcinoma contained rhabdoid inclusions further complicating identification. To the best of our knowledge, only 3 cases of PTC metastatic to the breast have been reported, none of them with anaplastic transformation. On the other hand, only 3 cases of PTC metastatic to the pancreas have been published, 2 of them of the tall cell variant, and in none of these cases were the first symptoms attributable to the metastasis. Brief comments about the differential diagnosis are included.     

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.     

Anaplastic thyroid carcinoma following low-dose irradiation

Low-dose irradiation of the neck in childhood is associated with a markedly increased incidence of thyroid cancer. Such carcinomas have almost all been well differentiated, papillary or follicular types. This paper describes the development of metastatic anaplastic thyroid carcinoma in cervical lymph nodes a year after subtotal thyroidectomy for well-differentiated papillary carcinoma in a 32-year-old man who had had low-dose cervical irradiation at the age of 7 years. It appears that irradiation-related thyroid carcinomas, in at least a very small number of people, may be associated with aggressive carcinoma.     

BRAF mutations in anaplastic thyroid carcinoma: implications for tumor origin, diagnosis and treatment.

Anaplastic thyroid carcinoma is a highly aggressive neoplasm. Affected patients typically present with advanced disease where there is little hope for cure using conventional therapeutic modalities. Understanding the genetic alterations underlying the development of anaplastic thyroid carcinoma, such as mutational activation of BRAF, could help clarify its relationship with well-differentiated forms of thyroid carcinoma (ie follicular and papillary carcinoma) and could help select patients most likely to benefit from novel therapeutic strategies targeting BRAF. We tested 16 anaplastic thyroid carcinomas for the thymine (T) --> adenine (A) missense mutation at nucleotide 1796 in the BRAF gene using a newly developed assay that employs a novel primer extension method (Mutector assay). Seven of these anaplastic thyroid carcinomas arose in association with a well-differentiated thyroid carcinoma, and these were also evaluated. The 1796T --> A mutation was detected in eight (50%) of the anaplastic thyroid carcinomas, in four of five (80%) associated papillary thyroid carcinomas, and in zero of two (0%) associated follicular carcinomas. In all seven cases where anaplastic thyroid carcinoma arose in association with a well-differentiated thyroid carcinoma, BRAF status in the two components was concordant. Like papillary thyroid carcinoma, a significant percentage of anaplastic thyroid carcinomas also harbor BRAF mutations. Indeed, when papillary thyroid carcinoma and anaplastic thyroid carcinoma occur together, they consistently share the same BRAF profile, supporting the notion that many anaplastic thyroid carcinomas actually represent progressive malignant degeneration of a pre-existing well-differentiated thyroid carcinoma. The high frequency of BRAF mutations in a tumor that is generally regarded as uniformly fatal justifies evaluation of the potential benefits of anti-BRAF therapy for patients with anaplastic thyroid carcinoma.     

Metastatic breast carcinoma involving the thyroid gland diagnosed by fine-needle aspiration: a case report

Secondary involvement of the thyroid gland from a remote primary malignancy is uncommon. The distinction of metastatic carcinoma (MC) or sarcoma from a primary thyroid malignancy is important because the treatment is different. We discuss a case of a 64-yr-old female with a history of breast carcinoma, who presented with pain and swelling in her neck 5 yrs after being diagnosed with breast cancer. She had undergone mastectomy with subsequent chemotherapy and radiation for infiltrating mammary carcinoma. During the 5-yr interval, she had been free of clinically evident metastatic disease. Subsequent work-up revealed two distinct nodules in the left lobe of her thyroid gland as well as a subcutaneous mass in her right shoulder. A fine-needle aspiration (FNA) of the larger thyroid nodule showed malignant epithelial cells with features consistent with breast carcinoma in a background of benign thyroid epithelial cells and colloid. The case was signed out as metastatic breast carcinoma. Subsequent FNA and biopsy of her right shoulder lesion also revealed metastatic breast carcinoma with similar morphology to the material in the thyroid FNA.     

Histopathologic and immunohistochemical characterization of a primary papillary thyroid carcinoma in the lateral cervical lymph node

Lymph nodes in the neck are known to occasionally contain benign epithelial inclusions and can be rare primary site of various tumors usually occurring in other organs. Papillary thyroid carcinoma in the lateral neck lymph node with co-existing ectopic thyroid inclusions has not been reported previously. A 41-year-old male patient, who had normal thyroid function and no history of neck irradiation, was seen with a slowly enlarging mass in the right lateral neck. At surgery the cervical mass was found to be separate from the thyroid proper without any attachments in between. Papillary thyroid carcinoma and co-existing thyroid inclusions were identified within the lateral cervical lymph node. Immunohistochemistry detected strong and diffuse cytoplasmic positivity with antibodies against CK19 and CK903 in papillary thyroid carcinoma. Benign thyroid follicles within the lymph node were only weakly and focally stained. Thorough examination confirmed no malignancy in the total thyroidectomy specimen. Furthermore, small foci of metastatic papillary carcinoma were identified in two ipsilateral lymph nodes from neck dissection specimen. These findings suggest development of primary papillary thyroid carcinoma from malignant transformation of benign intranodal thyroid inclusions.     

p53 expression in anaplastic carcinomas arising from thyroid papillary carcinomas.

AIM--To study the expression of p53 tumour suppressor gene in anaplastic carcinomas arising from thyroid papillary carcinomas. METHODS--Formalin fixed, paraffin wax embedded tissues from four cases of anaplastic carcinomas associated with thyroid papillary carcinomas were studied by immunohistochemistry with two different p53 monoclonal antibodies. RESULTS--The anaplastic component showed nuclear immunostaining in two cases, but not in the other two. In all cases the papillary carcinoma component was negative. CONCLUSION--The results support the hypothesis that p53 stimulates tumour progression in thyroid tumours.     

Mucoepidermoid carcinoma of the thyroid

Clinical and morphological features of three cases of primary mucoepidermoid carcinoma of the thyroid are described. The tumours were composed of two cell types. One of these resembled squamous epithelium and ultrastructurally showed tonofilaments and numerous desmosomes. The other cell type contained Alcian blue and mucicarmine positive mucin and, on electron microscopy, showed mucigen granules. Marked stromal fibrosis and psammoma bodies were seen in all tumours. Immunohistochemical studies showed that the tumour cells were negative for thyroglobulin. A few calcitonin-containing cells were seen in one metastatic tumour. One tumour showed, in addition to the histological features of mucoepidermoid carcinoma, anaplastic areas with obvious transition between the two histological patterns. The same thyroid also had a small thyroglobulin-positive papillary carcinoma in the opposite lobe. All tumours presented lymph node metastases. In two cases the primary tumour was confined within the thyroid capsule but that with anaplastic areas invaded surrounding structures. This patient died 13 months after diagnosis; the other patients are alive and symptomless one and 10 years since diagnosis. Mucoepidermoid carcinoma of the thyroid appears to be a clinicopathological entity that resembles papillary carcinoma in its natural history. The origin of the tumour is unclear. There is, however, some histological and immunohistological data suggesting that the tumour might be related to the ultimobranchial system although some histological features also appear to favour a common origin with papillary carcinoma.     

Warthin tumor-like variant of papillary thyroid carcinoma: A case with dedifferentiation (anaplastic changes) and aggressive biological behavior

Warthin tumor-like variant of papillary thyroid carcinoma is uncommon and approx 80 cases have been reported in the literature. This tumor is often associated with a favorable prognosis. In this report, a Warthin tumor-like variant of the papillary thyroid carcinoma, 5-cm in maximum dimension, underwent anaplastic changes in a 74-yr-old woman. The tumor was positive for CD15 and EMA, and a high proliferative index was noted in the anaplastic area. The patient developed distant metastases after operation and died of the disease 18 mo after the operation. The present case is the first reported case of Warthin tumor-like variant of papillary thyroid carcinoma with anaplastic changes.     

Intraatrial extension of thyroid cancer: a case report

A 61-year-old man, who was diagnosed with superior vena cava syndrome by papillary thyroid carcinoma, was referred to our hospital. A bulky thyroid tumor with tracheal invasion extended from the left neck to the right atrium without distant metastases. The risk of sudden death due to airway occlusion, tumor embolism or obstruction of the tricuspid valve led us to elect surgery. Extended resection of thyroid cancer was performed with cardiopulmonary bypass. Peritoneal dissemination was found via laparotomy. A histological diagnosis of anaplastic carcinoma arising from transformation of papillary carcinoma was made. After the operation, bilateral ureteral occlusion by peritoneal dissemination and multiple lung metastases were detected. The patient died with acute renal failure on postoperative day 12. Intraatrial extension of thyroid cancer is rare, and only 12 cases have been reported in the literature. We present a case of thyroid cancer with intraatrial extension.