Type Of Thyroid Carcinoma Research Articles

Aggressiveness of Therapy and Prognosis of Patients with Hürthle Cell Papillary Thyroid Carcinoma

Hürthle cell papillary thyroid carcinoma (HCPTC) has been studied separately from other types of thyroid carcinoma in relatively few studies. The aim of our study was to determine the factors associated with the survival of patients with HCPTC in Slovenia, an iodine-deficient region. A total of 1552 patients with thyroid carcinoma were seen at our institute during the period of 1976-2003; of them, 42 patients (33 females, 9 males; age 10-85 years, median 56.5 years) had histopathologically verified HCPTC. The data on the patients' gender, age, disease history, extent of disease, morphologic characteristics, therapy, locoregional control, disease-free interval, and survival were collected. The statistical correlation between possible prognostic factors and the disease-free interval and survival was analyzed by chi2 test and log rank analysis. The tumor diameter ranged from 1 to 9 cm (median, 3 cm). Extrathyroid tumor growth was found in 19 patients, lymph node metastases in 13 patients, and distant metastases in 2 patients. Primary treatment consisted of total or near-total thyroidectomy (39 patients), lobectomy (2 patients), radioiodine ablation of the thyroid remnant (37 patients), external irradiation (14 patients), and chemotherapy (3 patients). Locoregional recurrence was diagnosed in four patients, and dissemination in 1 patient during the follow-up period of 0.75-20 years (median, 5.5 years). Three patients died of thyroid carcinoma during the follow-up period. The 5-year and 10-year survivals were 94% and 87%, respectively. The 5-year and 10-year disease-free intervals were 93% and 81%, respectively. The factors correlated with the survival were: age, extrathyroid tumor growth, primary tumor stage, and regional and distant metastases. Although extrathyroidal tumor growth was found in 45% of the patients with HCPTC, our patients had a favorable prognosis. Long-term survival and locoregional control of disease are likely after the radical tumor resection, radioiodine ablation of the thyroid remnant, and external irradiation.

Understanding the Genotype of Follicular Thyroid Tumors

Tumors of the thyroid with a follicular growth pattern are controversial and can be diagnostically challenging for the pathologist. This group of tumors includes both follicular derived lesions (adenomas and carcinomas) and papillary carcinoma (follicular variant of papillary carcinoma). H&E morphology has classically been the gold standard for diagnosis. In the past several decades, however, several important molecular markers have been identified that may be unique to different types of thyroid carcinomas. These include the translocations RET/PTC and PAX8-PPARgamma and point mutations in the BRAF and RAS genes. Other molecular events in tumor suppressor genes may be useful for diagnosis of these tumors as well. None of the mutational markers are very sensitive, and there is some question regarding specificity for malignancy, because mutations have also been described in histologically benign tumors. However, with increasing availability of molecular testing for the general pathologist, a molecular testing panel used in conjunction with the H&E morphology and immunohistochemical stains may become useful in the clinical setting for the diagnosis of thyroid tumors.

Synchronous Occurrence of a Follicular, Papillary and Medullary Thyroid Carcinoma in a Recurrent Goiter

The simultaneous occurrence of different types of thyroid carcinoma in a single patient is an unusual event. We report the case of a 52-year-old man with the history of two previous thyroid operations for benign goiters, who developed a recurrent goiter. The patient was referred to our department for thyroidectomy. In the pathohistological examination the specimen showed a 5 cm follicular carcinoma and a 0.3 cm papillary microcarcinoma in the right lobe as well as a 1.5 cm medullary carcinoma in the left lobe. All tumors were clearly separated from each other, representing the pure entity of each type. Postoperatively, RET germline mutation was ruled out by sequence analysis of peripheral blood leucocytes. Postoperative I-131-radioiodine scan showed multiple lung and liver metastases, while calcitonin was negative. There is no known common cause of these three different tumor types and they developed most independently from each other. The personal history of our patient was interesting in two aspects: (1) he suffered a period of severe staphylococcal sepsis with temporal immunosuppression and (2) he worked for long years as a coremaker in a foundry. This work represented possible long term exposure to inhalative carcinogenous toxins like hydrazine, which caused thyroid parafollicular cell adenomas in an animal model.

Immunoexpression of HBME-1, High Molecular Weight Cytokeratin, Cytokeratin 19, Thyroid Transcription Factor-1, and E-cadherin in Thyroid Carcinomas

To examine the immunohistochemical alterations associated with the histological dedifferentiation of thyroid carcinomas, we performed staining for HBME-1, high molecular weight cytokeratin (HCK), CK 19, thyroid transcription factor-1 (TTF-1) and E-cadherin (E-CD) on 125 various types of thyroid carcinomas. The HBME-1 staining was strong and diffuse in follicular carcinoma (FC), papillary carcinoma (PC), and poorly differentiated carcinoma (PDC), while it was rare in undifferentiated carcinoma (UC) as well as in benign lesions. Strong, diffuse staining for CK19 and HCK was predominantly found in PC, and these markers were not much found in other carcinomas. TTF-1 uniformly stained the tumor cells of all cases of PC, FC and Hurthle cell carcinoma (HC) and 42% of the PDC, while there was only focal staining in one case of the UC. Compared to the strong, diffuse reactivity in the benign lesions, E-CD staining was noted in 67% of PC, 80% of FC, 83% of HC, 58% of PDC and none of the UC. These results suggest that HBME-1 may be a marker for well-differentiated carcinomas while CK19 and HCK are phenotypic markers for papillary carcinoma. The loss or reduced expression of TTF-1 and E-CD may be markers for dedifferentiation.

Where to Set the Threshold Between Well Differentiated and Poorly Differentiated Follicular Carcinomas of the Thyroid

A critical review of the literature reveals that different types of thyroid carcinomas have been interpreted as poorly differentiated, including the tall and columnar cell variants as well as carcinomas with insular, trabecular, and solid growth patterns. In some publications the growth patterns have been emphasized, while in others histologic patterns and cytologic features are considered important for identification. However, insular, trabecular, nodular, and solid growth patterns lack specificity because they can be observed in hyperplastic lesions and benign thyroid tumors. The cytologic features of the vast majority of poorly differentiated thyroid carcinomas are similar to or overlap with those of papillary or follicular carcinomas. Cytologic atypia, mitotic activity, and necrosis--believed by some investigators to be useful clues in the diagnosis of poorly differentiated carcinomas--do not reflect cell differentiation, especially in endocrine organs. It is therefore not surprising that the immunohistochemical profile and the molecular abnormalities described in this heterogeneous group of carcinomas lack specificity and are not useful diagnostic tools. Because poorly differentiated thyroid carcinomas have not been well defined, currently it is not possible to set the threshold between well-differentiated and poorly differentiated thyroid carcinomas with follicular phenotype. The authors believe that the vast majority of poorly differentiated thyroid carcinomas are in fact examples of papillary or follicular carcinomas with unusual growth patterns.

Proteome analysis identified maspin as a special feature of papillary thyroid carcinoma

This study aimed at investigating new mechanisms of carcinogenesis in thyroid cancer at the molecular level and at finding potential protein markers involved in the initiation of the different histological subtypes. For this, we performed differential proteome analysis on primary cultured thyrocytes (PT) and transformed thyrocytes (TT) derived from 238Pu alpha-particle irradiation using 2-dimensional electrophoresis (2-DE) and peptide mass fingerprinting (PMF) with matrix-assisted laser desorption/ionisation-time of flight mass spectrometry (MALDI-TOF MS). Image analysis showed that one protein was very strongly expressed in TT; 55 proteins were weaker, different in intensity, including 26 spots that were increased in PT, and 29 spots were decreased. The hot spot was identified as maspin, a unique member of the serpin family considered to be a class II tumor suppressor gene. To clarify the role of maspin in thyroid carcinogenesis we searched for protein expression in 20 normal (tumor-free) tissues, as well as in 20 follicular adenomas (FAD), 20 papillary carcinomas (PTC), 20 follicular carcinomas (FTC), 20 poorly differentiated carcinomas (PDTC), and 20 undifferentiated carcinomas (UTC). Maspin protein expression was detectable in none of the cases of normal tumor-free thyroid tissue, nor in FAD, FTC, PDTC and UTC. In contrast 14 of 20 PTC (70%) showed a moderate or strong cytoplasmic staining; 4 of these 14 cases had a moderate cytoplasmic and nuclear staining. In conclusion, we hypothesize that maspin protein expression is a special feature in the cascade of PTC genesis and that the way of initiating PTC is different from other thyroid carcinoma types.

Differences in tumor cell proliferation, HLA DR expression and lymphocytic infiltration in various types of thyroid carcinoma.

The proliferative activity of various thyroid carcinoma forms (papillary, follicular, medullary, anaplastic) was investigated using two second generation antibodies against Ki-67 that can be used on paraffin-embedded sections. Poorly-differentiated carcinomas had a higher proliferation than well-differentiated forms. Papillary carcinoma stained significantly more often with either antibody than follicular carcinoma. A solid growth pattern correlated with high Ki-67 expression while an increase in follicular elements and a high amount of psammoma bodies coincided with lower proliferation.HLA class II expression and infiltrating lymphocytes are prerequisites for an immune defense against cancer. In this study, HLA DR was increased in poorly-differentiated carcinomas, especially in the anaplastic type. The increase in HLA DR was correlated with Ki-67 positivity. On tumor-infiltrating lymphocytes, HLA DR was well expressed in papillary carcinoma and relatively poorly expressed in follicular carcinoma, but there was no significant correlation with carcinoma type or morphological parameters. CD 45 R0, which might recognize memory cells, was found mostly in anaplastic and papillary carcinomas, and correlated well with HLA DR expression. These findings imply that an active but variable immune response is present in thyroid carcinoma.

RET/PTC activation in hyalinizing trabecular tumors of the thyroid.

Hyalinizing trabecular tumor (HTT) of the thyroid is a neoplasm of follicular derivation with a histogenesis that is still the subject of debate. Morphologic affinities between HTT and papillary carcinoma, including nuclear pseudoinclusions and grooves, suggest that these tumors may be of similar origin. The authors investigated the relationship between these two types of tumors by assessing HTT for the presence of rearrangements of the proto-oncogene rearranged during transfection (RET) that, in thyroid tumors, are specific for papillary carcinoma. A series of 14 HTTs, including two cases associated with classic papillary carcinoma, was studied by means of immunohistochemistry and reverse transcription-polymerase chain reaction. Seven follicular adenomas with focal hyalinized trabecular areas served as control cases. Three of the 14 HTT cases under consideration displayed rearrangements of RET generating the RET/papillary thyroid carcinoma type 1 (PTC1) oncogene. In another case, RET expression was detected focally by immunohistochemistry alone. Finally, in one mixed HTT-papillary carcinoma sample, RET/PTC1 expression was detected, but only in the papillary component. None of the control follicular adenomas contained rearrangements of RET/PTC. These findings demonstrate that a comparable percentage (28.6%) of HTTs and papillary carcinomas exhibit the same RET proto-oncogene alterations. Thus, HTT may represent the "hyalinizing trabecular" variant of papillary carcinoma rather than a separate entity.

Descriptive epidemiology of thyroid cancer in Los Angeles County, 1972-1995.

To examine the descriptive epidemiologic features of incident thyroid cancers diagnosed among Los Angeles County residents between 1972 and 1995. The Los Angeles County/University of Southern California Cancer Surveillance Program (CSP) collected data on 8820 newly diagnosed thyroid cancer of cases occurring in Los Angeles County. Average annual age-adjusted incidence rates were calculated to study the epidemiology of each of the major histologic types of thyroid carcinoma. For all races combined, the age-adjusted incidence rates were 2.5 per 100,000 males and 6.0 per 100,000 females. Differences in incidence by ethnicity were particularly striking, with Filipinos demonstrating the highest incidence rates (4.44 per 100,000 males, 11.3 per 100,000 females). Over the 23-year period, thyroid cancer incidence rates increased 1.5% per year for males and 1% per year for females. By histology, papillary carcinoma rates increased over time and follicular carcinoma rates decreased. Non-Spanish surnamed white men employed in certain white-collar occupations and radiologic technicians were at greater risk of thyroid cancer. Additional research on the epidemiologic risk factors for thyroid cancer, particularly for gender and ethnicity, is needed to explain the marked elevated incidence rates among females and the Filipino population in Los Angeles County.

Thymic carcinoma involving the thyroid gland: Report of two cases

Two new cases of thymic carcinoma involving the thyroid gland and manifesting as thyroid tumors are presented. One tumor occurred within the thyroid gland and the other totally involved the thyroid gland. Microscopically they showed lobular architecture separated by fibrous bands and consisted of solid islands of squamoid to spindled epithelial cells with whorl formation resembling Hassall's corpuscle and variable amounts of lymphocytes. The squamoid to spindled epithelial cells were positive for cytokeratin but negative for thyroglobulin and calcitonin and the majority of lymphocytes showed a T-cell phenotype. One of the two cases had been diagnosed initially as squamous cell carcinoma of the thyroid. This type of thyroid carcinoma is relatively rare, but it should be differentiated from other types of thyroid carcinomas, especially squamous cell carcinoma, medullary carcinoma, or anaplastic carcinoma of the thyroid.

Diagnostic Problems in Differentiated Carcinomas of the Thyroid

In this review article we consecutively address the following issues: differential diagnosis of follicular adenomas and minimally invasive follicular carcinomas, with a special emphasis on the hyalinizing trabecular tumours; differential diagnosis of benign and malignant papillary lesions; individualization of the variants of papillary carcinoma that carry a guarded prognosis; differential diagnosis of differentiated thyroid carcinomas exhibiting foci of other types of thyroid carcinoma, namely mucoepidermoid and poorly differentiated carcinoma; and, finally, the diagnostic problems raised by the so-called mixed medullary-follicular carcinomas.

Polysialic Acid of the Neural Cell Adhesion Molecule in the Human Thyroid

We recently reported that the gold-labeled monoclonal antibody MAb 735, reactive with a long-chain form of alpha-2,8-linked polysialic acid (polySia) found on the neural cell adhesion molecule (NCAM), is useful to immunohistochemically distinguish small-cell lung carcinomas from neuroendocrine carcinomas with higher grade of differentiation (carcinoids) and other types of lung carcinomas (Am J Pathol 1991;139:297). In this study, we tested the occurrence of polySia in various types of malignant thyroid tumors and C-cell hyperplasia to determine whether polySia is a useful adjunct for the differential diagnosis of medullary thyroid carcinoma (MTC) and other thyroid neoplasms and to distinguish primary from secondary (reactive) C-cell hyperplasia (CCH). We examined formaldehyde-fixed and paraffin-embedded sections of 79 thyroid lesions, consisting of 33 MTC (14 familial and 19 sporadic tumors), 13 follicular, 11 papillary, 16 anaplastic carcinomas, and four glands with primary and two with secondary CCH. We applied a direct and an indirect immunogold-silver technique for polySia, CT, and CEA detection, respectively. All 33 MTC showed a strong cell-surface-associated immunoreactivity for polySia, which was sensitive to endoneuraminidase digestion. The polySia immunoreactivity of nerves served as an internal control in all specimens. Immunoreactivity for CT and CEA was present in all MTC with the exception of one recurrent tumor with features of an anaplastic MTC type. All other thyroid neoplasms were nonreactive for polySia, CT, and CEA. Primary CCH associated with MTC showed a strong polySia immunostaining, which was less intense in primary CCH not combined with MTC. In normal-appearing C cells and in secondary CCH, staining for polySia was absent in the majority of cases. We conclude that polySia of NCAM is a valuable marker to distinguish medullary carcinomas from other types of thyroid carcinomas. Furthermore, it allows for the discrimination of primary from secondary C-cell hyperplasia and may be helpful to better define the normal range of C cells in unaffected members of a family with a history of multiple endocrine neoplasia (MEN)-II.

Pathology of sporadic and hereditary medullary thyroid carcinoma.

Although cases of “malignant goitre with amyloid stroma” had already been described by the turn of this century in the German literature (Burk 1901; Jaquet 1906; Stoffel 1910), it is only 30 years since medullary carcinoma of the thyroid (MTC) was first clearly separated from the other types of thyroid carcinoma (Hazard et al. 1959). During the following decade, the classical histological features of MTC were described (Williams et al. 1966), the thyroid C-cell as the cell of origin delineated (Williams 1966), and the link with calcitonin (CT) production demonstrated (Cunliffe et al. 1968; Milhaud et al. 1968). It was, in addition, realized that a proportion of cases of MTC were genetically determined, occurring in association with phaeochromocytoma, or with phaeochromocytoma and multiple mucosal neuromas (Williams 1965; Schimke et al. 1968; Williams and Pollock 1966). Afterwards, the terms multiple endocrine neoplasia (MEN) 2 and MEN 3 were introduced by Steiner et al. (1968) and Khairi et al. (1975), respectively, to distinguish these combinations of tumours from Wermer’s syndrome (parathyroid, pituitary, and endocrine pancreatic tumours), which was given the name MEN 1 as it was described first. MEN 2 has been subsequently subdivided into MEN 2A (which includes MTC, phaeochromocytoma, and hyperparathyroidism) and MEN 2B (which refers to the neuromata syndrome including MTC, phaeochromocytoma, mucosal neuromata, gastrointestinal ganglioneuromatosis and marfanoid habitus) (Chong et al. 1975), and the term MEN 2B is now more commonly used than MEN 3 to designate the neuromata syndrome. The genetic defects leading to the development of familial MTC inherited in the setting of the MEN 2 syndromes are described in detail in R.F. Gagel et al., this volume. The aetiology and concrete pathogenesis of sporadic (non-hereditary) MTC has, in contrast, not yet been elucidated. It is, however, generally accepted that exogenous factors such as hypercalcaemia, hypervitaminoses D and A and irradiation known to be associated with higher incidence of MTC in various mammals are not carcinogenic to human C-cells (Saad et al. 1984a).KeywordsThyroid CarcinomaMedullary Thyroid CarcinomaMultiple Endocrine Neoplasia TypeMultiple Endocrine NeoplasiaMedullary CarcinomaThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Mucin production in metastatic papillary carcinoma of the thyroid.

Although textbooks often state that demonstration of mucin in a metastatic carcinoma excludes the possibility of a thyroidal primary tumor, mucin recently has been reported in various types of thyroid carcinoma, particularly medullary carcinoma. The presence of mucin in papillary carcinoma has not been extensively studied, even though this tumor not uncommonly presents with lymph node metastasis. We stained 40 lymph nodes containing metastatic papillary carcinoma of the thyroid for mucin. Mucin was demonstrable by mucicarmine stain in the colloid, luminal borders, and cytoplasm in 18 (45%), 9 (22.5%), and 7 (17.5%) cases respectively; 17 cases (42.5%) were completely negative. With alcian blue staining, mucin was seen in 9 (22.5%), 9 (22.5%), and 7 (17.5%) cases; 25 cases (62.5%) were negative. Most of the cytoplasmic vacuoles were target-like, with a peripheral rim of sulfated acid mucin and a central core of neutral mucin. The psammoma bodies stained consistently with mucicarmine, alcian blue, and periodic acid-Schiff. We conclude that papillary carcinoma of the thyroid should be included in the differential diagnoses for a mucin-producing metastatic carcinoma.

Carcinoembryonic Antigen and Nonspecific Cross-Reacting Antigen in Thyroid Cancer An Immunocytochemical Study Using Polyclonal and Monoclonal Antibodies

The expression of carcinoembryonic antigen (CEA) and related antigens in formalin-fixed paraffin-embedded tissues of 200 primary thyroid carcinomas and 22 nonmalignant thyroid lesions was studied immunocytochemically by using three monoclonal antibodies recognizing different epitopes on CEA and related antigens. The monoclonal antibody 431/31 defined epitope (present only on CEA) was found exclusively on 77% of the medullary thyroid carcinomas and on 100% of hyperplastic C-cell nodules adjacent to infiltrating C-cell carcinomas. The monoclonal antibodies 374/14 and 250/183, defining epitopes present on CEA and the nonspecific cross-reacting antigens 95 or 55, reacted with 88% and 82%, respectively, of the medullary carcinomas, but labelled also many nonmedullary thyroid carcinomas (follicular 34% and 18%, papillary 42% and 30%, anaplastic 18% and 13%), follicular adenomas, and nonneoplastic follicle-cell lesions. Similar results were obtained by using a polyclonal CEA antiserum preabsorbed with lyophilized spleen tissue. The findings suggest that nonspecific cross-reacting antigens can be expressed by all types of thyroid carcinoma, while CEA is present only in C-cell tumors of this organ.

Carcinoembryonic antigen in thyroid cancer.

Serum levels of carcinoembryonic antigen (CEA) were measured by radioimmunoassay in 35 patients affected by various histological types of thyroid carcinoma: 9 papillary, 7 follicular, 4 undifferentiated, 15 medullary. All patients with nonmedullary thyroid carcinoma were studied preoperatively. No patient with follicular thyroid carcinoma showed CEA levels above normal limits ( 320 ng/ml) were found in 2 of the 4 patients with medullary thyroid carcinoma studied before treatment and in the 4 patients (>320->320- 23-15 ng/ml) studied after total thyroidectomy alone; 3 of them had distant metastases. High levels (65-50-13 ng/ml) were also found in 3 other patients without metastases studied after total thyroidectomy plus radiotherapy. Thyroidectomy plus radiotherapy rapidly decreased CEA levels (from >320 to 20 ng/ml) in a patient without metastases, while the same treatment failed to reduce CEA levels consistently (from > 320 to 112 ng/ml) in a patient with distant metastases. The data suggest than high levels of CEA are frequent but not constant in patients with medullary thyroid carcinoma; in other histological types CEA is present only in sporadic cases. Since in the positive cases of medullary thyroid carcinoma CEA levels seem to be related to the effectiveness of the therapy, CEA assay may be useful in the management and follow up of this tumour.

Immunohistologig study of thyroidal medullary carcinoma and pancreatic insulinoma

An indirect immunofluorescent antibody technique, preceded by trypsin digestion of the tissue sections, was applied to six cases of medullary carcinoma of thyroid (MCT) and three cases of insulinoma in order to examine the state of antigenic preservation of peptide hormones in tumor tissues, which had been fixed in formalin and embedded in paraffin for periods up to 18 years for MCT and 10 years for insulinomas. By this method both C-cells of normal thyroid and tumors of MCT were shown to contain calcitonin. Other types of thyroid carcinoma did not contain calcitonin, and no increase in C-cells was found in various thyroidal diseases. The tumor cells of MCT demonstrated a large amount of immunoreactive calcitonin, particularly in the medullary (solid) form, and a decreased amount in the amyloid form. Following trypsin digestion, specific immunofluorescence for calcitonin was also noted in the amyloid stroma. This might be related to the presence of entrapped secretory granules from cell debris in the amyloid substance. The immunohistochemistry can distinguish the poorly differentiated follicular carcinoma of thyroid from MCT, as illustrated in one case. Beta cells of normal pancreatic islets and tumor cells of insulinoma, but not the accompanied amyloid, were shown to contain insulin by indirect immunofluorescent stain. In the diagnosis of insulinoma, this method equals the electron microscopy for its sensitivity, and surpasses it for simplicity in technique. In general, the trypsin treated sections showed a significant improvement over the untreated preparations in the quality of immunofluorescence, thus facilitating microscopic interpretation on tumor tissues. The results did not appear to be affected by the duration of tissue preservation in the paraffin blocks. The improved immunohistologic method may be recommended for routine use in prospective and retrospective studies of certain endocrine tumors.

SPONTANEOUS AND EXPERIMENTALLY INDUCED UPTAKE OF RADIOACTIVE IODINE IN METASTASES FROM THYROID CARCINOMA: A PRELIMINARY REPORT*†

METASTATIC carcinoma of the thyroid can be successfully treated with radioiodine when the lesions concentrate this isotope (1). The usefulness of this method depends upon the percentage of cases in which such concentration can be demonstrated. A technique of inducing uptake of radioiodine in metastases that previously showed none would increase the usefulness of the method. Clinically we have been successful in inducing such uptake in several cases with subsequent amelioration of the disease. In a recent publication by Marinelli et at. (2), it is reported that “approximately 15 per cent of thyroid cancers may be expected to accumulate radioactive iodine in some degree.” This conclusion is based on findings in a selected group of 19 cases modified by an estimation of relative frequency of various types of thyroid carcinoma. The present paper is a report on 14 unselected cases of metastatic thyroid carcinoma studied at Montefiore Hospital up to June 1947.