DNA ploidy in papillary carcinoma of the thyroid gland in children and adolescents

OBJECTIVE: To evaluate DNA ploidy in papillary thyroid carcinoma in children in correlation to the clinical course of the disease. METHODS: Flow cytometric DNA ploidy measurements were performed on formalin-fixed, paraffin-embedded tumor specimens from 14 children and 14 adult patients with papillary carcinoma of the thyroid gland. Analysis of DNA content was performed blind to patient's age and clinical presentation. RESULTS: Seven patients presented with cervical metastasis, one patient had distal metastasis and four patients had local invasion. All patients underwent total thyroidectomy. Seven children underwent bilateral modified neck dissection. Twenty-five tumors expressed diploid DNA content. No statistically significant difference in DNA content was observed between the tumors from child and adult patients. No correlation was found between DNA content and aggressive presentation in the pediatric group. CONCLUSION: Our primary results indicate that diploid DNA content is common in papillary thyroid carcinoma in children and aggressive clinical presentation is not associated with DNA aneuploidy. Larger prospective studies and long-term clinical follow-up is warranted to document the clinical significance of these observations.     

Intratumoral DNA content heterogeneity in laryngeal squamous cell carcinoma.

Multiple tissue samples obtained from sections cut by Michaels and Gregor's method obtained from 21 consecutive total laryngectomies for squamous cell carcinoma were studied for intratumoral DNA content heterogeneity or homogeneity. Concordant DNA ploidy was manifested in all samples of five (23.8%) carcinomas (two diploid and three aneuploid), while 16 carcinomas (76.2%) demonstrated a variable DNA ploidy (diploid and aneuploid). Analysis of cellular proliferative activity demonstrated remarkable intratumoral stability in both concordant and discordant carcinomas. These data indicate there is a considerable heterogeneity of DNA ploidy but the proliferative rate is relatively stable within the carcinomas. Clinical implications of our findings are also presented.     

DNA flow cytometry of acinic cell carcinomas of major salivary glands

Fifteen acinic cell carcinomas from an equal number of patients were analysed for their DNA content and proliferative (S-phase) index by flow cytometry from archival tissues. Seven of the carcinomas manifested a diploid DNA content. None of the patients with diploid acinic cell carcinomas died of their carcinomas and none developed metastases in follow-up periods extending for 10 or more years. Four of eight patients with aneuploid acinic cell carcinomas have died because of their malignancies within a 10 year period after the first surgical removal of the carcinoma. Five of the eight patients exhibited metastases. Although the number of cases does not permit strong correlations between histopathological features, abnormalities in DNA content and outcome of patients, it was noted that carcinomas with prominent necrosis, tubuloductal differentiation and 'dedifferentiated' areas displayed more aggressive biological courses.     

Flow cytometric DNA content of adenoid cystic carcinoma of submandibular gland. Correlation of histologic features and prognosis

Flow cytometric analysis of nuclear DNA content was performed in 26 adenoid cystic carcinomas of the submandibular gland using archived, paraffin-embedded tissues. The DNA content was compared with multiple histologic parameters and clinical course. Ten carcinomas (38%) were aneuploid and 16 (62%) diploid. Aneuploid carcinomas demonstrated a higher frequency of solid cytoarchitecture, lymph node metastases, and advanced clinical stage, as compared with diploid carcinomas. Other histologic features predicting aggressive clinical behavior also correlated with abnormal DNA content and included invasion of nerves larger than 0.25 mm and intravascular extension. Our data suggest that DNA content analysis can be an effective objective parameter in the clinicopathologic assessment of adenoid cystic carcinoma.     

P63蛋白在甲状腺肿瘤中表达的意义

目的:探讨p63蛋白在甲状腺腺瘤、甲状腺乳头状癌、甲状腺滤泡癌、鳞状细胞癌和甲状腺髓样癌中的表达意义,探索这些甲状腺疾病的可能起源,以及这些疾病病因之间有无联系。方法:运用免疫荧光法检测10例甲状腺腺瘤、25例甲状腺乳头状癌、4例甲状腺滤泡状癌、2例髓样癌和2例甲状腺鳞状细胞癌中p63的表达。结果:p63在甲状腺腺瘤、甲状腺乳头状癌、甲状腺滤泡癌、甲状腺鳞状细胞癌和甲状腺髓样癌中均有表达。p63在鳞状细胞癌和髓样癌中表达最高,在甲状腺乳头状癌中其表达与患者年龄、性别、肿块位置、肿块大小和有无转移无明显相关性。结论:①甲状腺组织内存在p63阳性标记的干细胞;②甲状腺乳头状癌、滤泡癌、鳞状细胞癌等可能起源相似。干细胞是多功能细胞,向不同方向分化,形成不同疾病;③p63在甲状腺鳞状细胞癌和髓样癌中表达最高,说明在鳞状细胞癌中残留干细胞较多,与肿瘤的生物学特性一致。     

DNA content and proliferative activity of myoepitheliomas

This report adds 16 myoepitheliomas of salivary glands to the 47 already recorded in the literature. It includes, for the first time, a flow cytometric analysis of their ploidy (DNA content) and proliferative capacity (S-phase fraction). Thirteen myoepitheliomas were diploid; three were aneuploid in their DNA content. A high proliferative capacity was always associated with an abnormal DNA content. Only one diploid myoepithelioma had a high S-phase fraction. Both flow-cytometric parameters are good predictors of an aggressive biological behaviour. Recurrences, however, were all the outcome of incomplete primary removal of the myoepitheliomas. Four of the twelve (33 per cent) diploid myoepitheliomas recurred and one, with high S-phase fraction, led to the death of the patient. Two of the three (67 per cent) aneuploid myoepitheliomas recurred. Extensive loco-regional invasion by one killed the patient. The other has clinical evidence of distant metastasis.     

Hürthle cell tumors of the thyroid. A flow cytometric DNA analysis

Twenty-five Hürthle cell tumors of the thyroid gland, histopathologically classified into three groups--adenomas, carcinomas, and indeterminant--have been studied by DNA flow cytometry using archived, paraffin-embedded tissues. Tumor ploidy characteristics were correlated with patient follow-up and survival with the conclusions that (1) nuclear DNA ploidy alone does not distinguish benign from malignant Hürthle cell tumors; (2) diploid DNA Hürthle cell carcinomas behave far less aggressively than aneuploid Hürthle cell carcinomas; and (3) all patients with aneuploid carcinomas died of their disease or are alive with persistent carcinoma.     

Comparative genomic instabilities of thyroid and colon cancers

OBJECTIVES: To assess the forms and extent of genomic instability in thyroid cancers and colorectal neoplasms and to determine if such measurements could explain the generally excellent prognosis of thyroid malignant neoplasms compared with colon carcinoma. DESIGN: Tumor genome analyses. Genomic instability was measured by the following 4 methods, listed in ascending order based on the size of events detected: inter-simple sequence repeat polymerase chain reaction (ISSR-PCR), fractional allelic loss (FAL) analysis, array-based comparative genomic hybridization (aCGH), and spectral karyotyping (SKY). RESULTS: The genomic instability index of 32 thyroid carcinomas, 59 colon carcinomas, and 11 colon polyps was determined by ISSR-PCR; no difference was seen among the 3 groups by this method. Fractional allelic loss rates were comparable in thyroid cancers and colon polyps and lower than FAL rates in colorectal cancers. Indolent papillary thyroid carcinomas were essentially diploid with no large-scale alterations in chromosome number or structure when evaluated by aCGH or SKY. In anaplastic thyroid cancers, aCGH revealed abundant chromosome alterations. Colorectal carcinomas showed extensive copy number changes and chromosomal rearrangements when analyzed by aCGH and SKY. CONCLUSIONS: Genomic alterations in papillary thyroid carcinoma, such as in benign colon polyps, are principally smaller events detected by ISSR-PCR. With the more aggressive tumor types (ie, anaplastic thyroid and colorectal carcinomas), larger events detected by FAL analysis, aCGH, and SKY were revealed. We hypothesize that mutations caused by smaller genomic alterations enable thyroid cells to achieve a minimal malignant phenotype. Mutations for aggressive biological behavior appear with larger genomic events.     

Prognostic factors in squamous cell carcinoma of the larynx

Sixty-three patients with squamous cell carcinoma of the larynx were included in a retrospective study examining the influence of the following prognostic indicators: localization, size of primary tumor, presence or absence of neck metastases, disease stage and histologic grade of differentiation. Flow cytometric analysis of the cell cycle, DNA ploidy and proliferative activity as direct prognostic indicators of tumor aggression was performed on paraffin-embedded blocks of specimens taken from 36 patients. Supraglottic tumor localization (p = 0.008), greater tumor size (p = 0.0064), local neck metastases (p = 0.00009), higher clinical disease stage (p = 0.0030), DNA aneuploidy (p = 0.0091), higher overall activity (p = 0.0001), and higher overall proliferative activity of diploid tumors (p = 0.0017) were found to be significant single unfavorable prognostic indicators of overall survival, whereas the histological grade of differentiation was not found to be a reliable prognostic indicator (p = 0.988). Only a higher overall proliferative activity of tumor cells was confirmed by the multivariate analysis as a reliable unfavorable prognostic indicator (p = 0.013). Cellular DNA content (ploidy, overall proliferative activity and overall proliferative activity of diploid tumors) correlated significantly with primary localization and size of the tumor, the presence of local metastases in the neck and the disease stage.     

Malignancy grading and cytophotometric evaluation of T1 lip carcinomas

Histological malignancy grading using the score system set out by Jakobsson et al. in combination with static DNA cytofluorometry was applied to 20 T1 squamous cell carcinomas of the lower lip, 11 with and 9 without lymph node metastases. The mean malignancy score was 18.0 for tumours with metastases and 13.0 for those without (P less than 0.05, chi square test). Nuclear polymorphism, mode of invasion, vascular invasion, and cellular response were the single factors with the strongest influence. All but 3 carcinomas were DNA diploid, but DNA ploidy and proliferative activity (S-phase) yielded no prognostic information. However, hypertetraploid cells were found in all DNA diploid carcinomas with metastases, but in only half of those without (P less than 0.05).     

Association of nuclear, cytoplasmic expression of galectin-3 with beta-catenin/Wnt-pathway activation in thyroid carcinoma

OBJECTIVES: To characterize the localization of galectin-3 in benign and malignant thyroid neoplasms and to correlate this with alterations in beta-catenin and cyclin D1 expression. DESIGN: Immunohistochemical study of 116 paraffin-embedded archival specimens from 113 patients who had undergone thyroidectomy and tissue placed into a commercially available tissue microarray. SETTING: Tertiary care hospital. INTERVENTIONS: Thyroid tissue microarrays were stained by standard immunohistochemical protocols with monoclonal antibodies against galectin-3, beta-catenin, and cyclin D1. MAIN OUTCOME MEASURES: Nuclear and cytoplasmic expression of galectin-3 was correlated with clinical parameters, beta-catenin, and cyclin D1 expression. RESULTS: Both cytoplasmic (56%) and nuclear (42%) galectin-3 expression was observed in most malignant neoplasms but was absent in benign thyroid specimens (P<.001). Among carcinomas, cytoplasmic galectin-3 expression was observed in papillary thyroid carcinomas (82%) and follicular (33%) and medullary (9%) carcinomas but was absent in anaplastic carcinomas (P<.001). Galectin-3 nuclear expression was observed in papillary thyroid carcinomas (62%) and follicular carcinomas (33%) but was undetectable in medullary, anaplastic carcinomas (P<.001). Cytoplasmic but not nuclear galectin-3 was inversely correlated with American Joint Committee on Cancer TNM stage (P = .02). There was a strong correlation between cytoplasmic and nuclear beta-catenin expression and both nuclear (P = .04) and cytoplasmic (P = .003) galectin-3 expression. Similarly, there was a strong association between galectin-3 nuclear (P<.001) and cytoplasmic (P<.001) expression and cyclin D1 expression. CONCLUSION: Cytoplasmic and nuclear galectin-3 expression seem to be associated with activation of the Wnt-signaling pathway in well-differentiated thyroid neoplasms, suggesting that galectin-3 plays a role in thyroid carcinogenesis.     

Measurement of nuclear DNA content of laryngeal carcinoma and determination of estrogen receptor (ER) level in laryngeal cancer cells

In 39 patients with laryngeal carcinoma, nuclear DNA content was measured, and the ER in cancer cells of 23 cases determined. The following results were obtained: 1. For all laryngeal carcinomas, there were two patterns-diploid and non-diploid carcinomas. The majority (27/39) belonged to the non-diploid pattern. 2. The laryngeal carcinomas of non-diploid pattern or with higher level of DNA content were easily metastasized to cervical nodes. This kind of cancers were more often seen in clinically advanced cases. Patients with these carcinomas, judged by the results of one-year's follow-up, had poor prognosis. 3. Carcinomas with diploid pattern or with lower level of DNA content had the tendency to become ER positive. The cervical node metastases was more easily taking place in ER negative carcinomas. Some indirect relationship between DNA content and ER in laryngeal cancers may exist.     

Prognostic Features in Tall Cell Papillary Carcinoma and Insular Thyroid Carcinoma

Tall cell papillary carcinoma (TCPC) and insular carcinoma (IC) are variants of thyroid carcinoma that are considered to be more aggressive than well differentiated papillary or follicular carcinoma. To determine the clinical significance of these diagnoses, we evaluated 65 patients with these tumors. There were 30 TCPCs, 27 ICs, and 8 ICs or TCPCs with focal anaplastic carcinoma (FAC). Forty-two patients (27 TCPCs, 14 ICs, and 1 FAC) are alive and free of disease. Nine patients with IC are alive with distant metastases. Ten patients (2 TCPCs, 2 ICs, and 7 FACs) died of disease. Univariate analysis of disease-free interval determined that, as for all thyroid carcinomas, patient age, tumor size, extrathyroidal extension, and lymph node metastases were significant for prognosis. ICs did significantly worse than TCPCs. Focal anaplastic dedifferentiation predicted a worse prognosis. Multivariate analysis for disease-free interval showed age, number of lymph node metastases, and tumor type to be significant. Analysis of the same factors for prediction of mortality showed that TCPC and IC were not significantly different. These data suggest that TCPC is less aggressive than IC, which often results in disseminated disease. Focal AC predicts poor survival.     

RET/PTC fusion gene rearrangements in Japanese thyroid carcinomas

The activation of RET proto-oncogene through chromosomal translocation is reported as being unique to papillary thyroid carcinomas. However, the reported prevalence of RET/PTC activation in papillary carcinoma was variable, and the clinical relevance of RET/PTC rearrangements in papillary carcinomas is still controversial. To investigate the roles of RET rearrangement in the carcinogenesis of papillary thyroid carcinoma, we have studied RET activation and p53 overexpression in various thyroid lesions of the Japanese population by immunohistochemical technique. RET activation and p53 overexpression were studied in 40 papillary carcinomas, 6 poorly differentiated carcinomas, 4 undifferentiated carcinomas, 2 medullary carcinomas, 2 follicular carcinomas and 19 follicular adenomas. RET activation was observed in 12 out of 40 papillary carcinomas, while no immunoreactivity of RET was detected in other lesions. P53 overexpression was observed in only 1 of 40 papillary carcinomas, but in 2 poorly differentiated carcinomas and 4 undifferentiated carcinomas. The prevalence of RET/PTC activation in papillary carcinoma among the Japanese population was higher than in previous reports. Immunohistochemical technique is proved to be a useful tool to detect RFT/PTC activation in thyroid tumors. RET rearrangements are restricted to a well-differentiated papillary carcinoma, suggesting that RET/PTC positive papillary carcinomas do not progress to undifferentiated carcinoma.This work was presented at the 6th Research Workshop on Head and Neck Cancer, 11 October 2002, McLean, VA.     

The measurement of DNA content and ploidy analysis in thyroid neoplasms

It is clear that the DNA content of endocrine cells is influenced by factors other than neoplastic change and transformation. Although it can be concluded that, in general, the DNA content of neoplasms is increased, it is less clear whether this increase in DNA content is the cause or the effect of neoplastic transformation. The actual consequences of an increased DNA content are still largely unknown. However, based on a substantial body of data on the measure of nuclear DNA content in thyroid neoplasms, several conclusions appear to be reasonable. First, the measurement of nuclear DNA content and ploidy analysis are not sufficiently reliable parameters upon which to distinguish a benign from a malignant thyroid neoplasm. Therefore, this parameter has failed to live up to the expectation that it would be a powerful diagnostic tool. Second, the measurement of nuclear DNA content is useful after a histomorphologic diagnosis has been made since it correlates very well with the prognosis and clinical outcome of the patient. It is clear that aneuploid thyroid carcinomas are responsible for earlier recurrence, an increased likelihood of distant and diffuse metastases, and an increased incidence of death compared with diploid thyroid carcinomas. Except for the rare occasion, diploidy implies a uniformly long-term survival whereas aneuploidy is associated with a variable clinical course. Irrespective of histomorphology, lethal lesions of the thyroid are invariably aneuploid, whereas lesions associated with prolonged survival or a favorable outcome can be either diploid or aneuploid. Aneuploidy in well-differentiated thyroid carcinoma is more likely in older patients, in less well-differentiated neoplasms, and in neoplasms infiltrating beyond the thyroid capsule. Age, type of neoplasm, extrathyroidal extension, and recurrent disease all appear to be more important prognostic variables than is nuclear DNA content. However, nuclear DNA content can increase the prognostic power of these variables and consequently may come to be increasingly useful in the management of some patients with thyroid neoplasms. After a histomorphologic diagnosis has been made, the measurement of nuclear DNA content and a determination of the DNA ploidy may have significant prognostic value.     

Papillary thyroid cancer with an initial presentation of abdominal and flank pain

PURPOSE: Well-differentiated thyroid cancer typically presents as a thyroid mass. Common sites of metastases upon presentation include cervical lymph nodes, lung, and bone. Well-differentiated thyroid cancer with clinically apparent kidney metastases is rare, with fewer than 20 cases reported in the literature. In the vast majority of these cases, the patients had known thyroid neoplasms at the time the renal metastases were identified. We report a case of papillary thyroid carcinoma that presented with abdominal pain in a 25-year-old woman with no previous history of thyroid disease. STUDY DESIGN: This study is a case report. RESULTS: The patient underwent radical nephrectomy for a right renal mass, which was diagnosed as papillary thyroid carcinoma follicular variant. During subsequent evaluation, metastatic disease was also identified in the patient's lungs. The patient was treated with total thyroidectomy and iodine 131. CONCLUSIONS: Papillary cancer, which ordinarily behaves in an indolent manner, can have unusual presentation, including disseminated metastasis on presentation. Renal metastases are extremely rare.     

DNA content of human squamous cell carcinoma cell lines. Analysis by flow cytometry and chromosome enumeration

Fifteen squamous cell carcinoma cell lines derived from nine patients were examined for DNA content by flow cytometry and chromosome counts. Using human peripheral blood leukocytes and nucleated trout and chicken red blood cells as standards, the DNA indexes of the squamous cell carcinoma cell lines were found to range from 1.1 to 3.3. The DNA content was a stable characteristic of individual cell lines in multiple passages over a seven-month period. Although flow cytometry could detect abnormal DNA content even in diploid tumor lines, the chromosome number correlated well with the DNA content by flow cytometry. In cases in which more than one cell line was established from the same patient, the individual cell lines were found to differ in their DNA content. The cell lines established from metastatic or recurrent tumors usually had a lower DNA content and chromosome number and exhibited a more aggressive in vitro growth pattern than the primary tumor or earlier recurrence. We hypothesize that "streamlined" and aggressive cell populations may evolve in vivo from more slowly growing hyperploid precursor tumor cell populations when in the course of random loss of DNA or chromosomes those that confer no growth advantage are lost, while those that do confer growth advantage are retained.     

Prognostic factors in carcinoma of the larynx: relevance of DNA ploidy, S-fractions and localization of the tumour

The influence of the cell cycle profile and the site of the primary tumour on the overall survival were examined in 36 patients with squamous cell carcinoma of the larynx. DNA ploidy (p = 0.0091), the overall proliferative activity (p = 0.0001), the overall proliferative activity of diploid tumour cells (p = 0.0017) and primary tumour site (p = 0.0008) were found to be significant single prognostic factors of the overall survival. Multivariate analysis showed that only the overall proliferative activity was prognostically significant (p = 0.013). The results of the study show that the supraglottic site of the tumours correlates significantly with DNA ploidy (p = 0.0334) and the overall proliferative activity of tumour cells (p = 0.0159), whereas the correlation with proliferative activity of diploid tumour cells (p = 0.1416) has not been confirmed by this study. Glottic tumours showed a prognostically significant correlation with the overall proliferative activity (p = 0.0037) and proliferative activity of diploid tumour (p = 0.0054). Such a prognostic correlation was not found for DNA ploidy (p = 0.6542).     

Mixed medullary-papillary carcinoma of the thyroid: a case report

With fewer than 40 cases described in the otolaryngology literature, mixed medullary papillary thyroid carcinoma represents a rare but phenotypically distinct tumor. While isolated medullary carcinoma may be admixed with normal follicular structures, true mixed carcinoma displays morphological and immunological characteristics of medullary and papillary carcinoma within a single lesion. We report the case of a 73-year old woman initially evaluated for a multinodular thyroid goiter. The patient denied a family history of medullary thyroid carcinoma or other endocrine neoplasms. Fine needle aspiration of a nodule of the thyroid isthmus suggested a follicular neoplasm with abundant Hurthle cells and colloid present. Considering these findings, the patient underwent a left thyroid lobectomy with isthmusectomy. Histopathological analysis of the surgical specimen revealed a medullary thyroid carcinoma measuring 0.4 cm in size. Within this lesion, a distinct focus of papillary thyroid carcinoma, follicular variant, measuring 0.1 cm was also identified. Mixed medullary-papillary thyroid carcinoma is a rare clinical entity but merits consideration in the differential diagnosis of thyroid nodules particularly in patients with a family history of thyroid malignancy. The foundation of treatment of this lesion is total thyroidectomy with central compartment node dissection in the clinically N0 neck and dissection of levels II-VII in the node-positive neck.     

Thyroglossal duct carcinoma

PURPOSE OF REVIEW: The purpose of this paper is to review the presentation and management of thyroglossal duct carcinoma. RECENT FINDINGS: Recent articles have analyzed the value of preoperative investigation and have addressed some of the controversies in the management of such tumors; in particular, the optimal surgical management of the thyroid gland, as well as optimal management of lymph node metastases, the role of thyroid suppression therapy, and radioactive iodine therapy. SUMMARY: Thyroglossal duct carcinoma is uncommon, occurring in approximately 1% of all thyroglossal duct cysts. It is often diagnosed incidentally after surgical excision. Ninety-four percent of carcinomas are of thyroid origin, with most being papillary in nature, and 6% are of squamous cell origin. Incidentally discovered, well-differentiated thyroid carcinoma of the thyroglossal duct, in the presence of a clinically and radiologically normal thyroid gland, can be managed adequately by the Sistrunk operation. Those patients with more advanced disease require more aggressive treatment. This may include a total thyroidectomy with or without neck dissection in addition to the Sistrunk operation, followed by radioactive iodine therapy and thyroid-stimulating hormone suppression. The prognosis is generally excellent with adequately treated disease.