Follicular neoplasms of the thyroid. Total circumferential evaluation of the fibrous capsule.

Fourteen encapsulated follicular neoplasms were extensively dissected without tangential sectioning to represent the circumference of the entire capsule on sequential histologic sections. A thorough evaluation of these sections divided the 14 cases into five benign adenomas, seven encapsulated carcinomas with only intracapsular angioinvasion, and two minimally invasive carcinomas with focal capsular invasion. Among these nine early-stage follicular carcinomas it was found that angioinvasion occurred multicentrically in at least seven and showed a geographically even distribution. Angioinvasion was found far more often than capsular invasion on the circumference of all nine early-stage carcinomas. Multiple sections produced by this extensive dissection aided the disclosure of minute but convincing findings of angioinvasion. Also, a fibrous capsule as thick as 3.8 mm at its maximum thickness as well as an irregular interface between the capsule and parenchyma were often found to be characteristic of these early-stage carcinomas. Thus, upon comparison with 38 previous cases of similarly localized follicular neoplasms, in which randomly sampled histologic sections yielded diagnoses of benign adenoma (21 cases) and encapsulated or minimally invasive carcinoma (17 cases), extensive circumferential evaluation of the capsule is considered to allow not only effective distinction of follicular neoplasm with slight invasive capability from benign adenoma but also adequate assessment of invasive foci with application of strict criteria. Despite the similarity of clinical prognosis among all the above adenomas and early-stage carcinomas, given the limited follow-up period, an extensive examination method introduced herein is practically useful and necessary for identification of malignancy in encapsulated follicular neoplasms.     

PAX8-PPARgamma rearrangement in thyroid tumors: RT-PCR and immunohistochemical analyses

A PAX8-PPARgamma rearrangement has been recently identified in follicular thyroid carcinomas, but not in follicular adenomas or other thyroid tumors. We report here the analyses of PAX8-PPARgamma in a series of 118 thyroid tumors using a newly developed RT-PCR assay to detect this rearrangement in frozen and paraffin-embedded tissues and using immunostaining with a PPARgamma antibody. PAX8-PPARgamma was detected by RT-PCR in eight of 15 (53%) follicular carcinomas and two of 25 (8%) follicular adenomas but not in 35 papillary carcinomas (including 12 follicular variants), 12 Hurthle cell carcinomas, 12 Hurthle cell adenomas, two anaplastic carcinomas, one poorly differentiated carcinoma, or 16 hyperplastic nodules. The prevalence was higher in follicular carcinomas from patients with a history of radiation exposure (three of three). Strong, diffuse nuclear immunostaining with the PPARgamma antibody correlated with the presence of PAX8-PPARgamma detected by RT-PCR. Most sporadic follicular carcinomas positive for PAX8-PPARgamma were overtly invasive, whereas tumors lacking the rearrangement were predominantly minimally invasive. The two follicular adenomas positive for PAX8-PPARgamma had trabecular growth pattern and thick capsule, but no invasion, and thus may represent "pre-invasive" follicular carcinomas. The absence of PAX8-PPARgamma rearrangements in Hurthle cell tumors and papillary thyroid carcinomas highlights the differences in the molecular pathogenesis of these thyroid tumors.     

Galectin-3 expression in hyalinizing trabecular tumors of the thyroid gland

Galectin-3, a beta-galactoside-binding lectin, is overexpressed in many neoplasms and may be useful when differentiating between benign and malignant thyroid neoplasms. Recently, interest has focused on the classification and biologic behavior of hyalinizing trabecular tumors (HTTs). In this study we compared galectin-3 expression in a number of different thyroid neoplasms to gain insight into the biologic behavior of HTT. Formalin-fixed, paraffin-embedded tissues from 153 thyroid neoplasms were stained with a monoclonal antibody to galectin-3. These tumors included 58 HTTs, 60 papillary carcinomas, 21 follicular carcinomas, and 14 follicular adenomas. Reactivity was graded as negative, weak, or strong by three observers. The average patient age was similar in the patients with HTTs, papillary carcinomas, and follicular adenomas. The patients with follicular carcinomas were approximately a decade older than all other groups of patients. All groups of thyroid neoplasms occurred more frequently in female patients. Follow-up revealed metastatic disease in patients with papillary (36.6%) and follicular carcinomas (19%) but not in patients with follicular adenomas or HTTs. Galectin-3 immunostaining showed that 60% of the HTTs were negative or had weak (H) (1+) staining and 40% had strong (2-3+) staining. In the majority of the reactive cases, staining was diffuse and predominantly cytoplasmic. Fifty of the 60 (83%) papillary carcinomas and 11 of the 21 (52%) follicular carcinomas showed strong immunostaining. The immunostaining was also diffuse in the majority of papillary and follicular carcinomas. The strong immunoreactivity seen in most of the carcinomas was in contrast to the relatively weak or negative immunostaining in the majority of follicular adenomas (93%). The immunophenotype of HTT, as characterized by galectin-3 expression, is intermediate between that of benign and malignant thyroid tumors, suggesting that some tumors with strong staining may behave like carcinomas, although this was not noted in our cases. Our study suggests that the variable pattern of galectin-3 expression may reflect a difference in biologic behavior between HTT and papillary thyroid carcinoma.     

Encapsulated papillary oncocytic neoplasms of the thyroid: morphologic, immunohistochemical, and molecular analysis of 18 cases

Encapsulated papillary oncocytic neoplasms (EPONs) of the thyroid are rare tumors, whose relationship to other thyroid tumors has not been thoroughly elucidated. Earlier, they have been regarded as variants of papillary thyroid carcinoma (PTC), hyperplastic lesions, and follicular neoplasms. Eighteen EPONs were retrieved from our surgical pathology files and reviewed for defining morphologic features. Cases having the typical nuclear features of PTC were excluded. Immunohistochemistry (IHC) for CK19, HBME1, and CD56 was carried out. Microdissection, polymerase chain reaction, and sequencing of exon 15 of the BRAF gene were completed. Cases were evaluated for rearranged in transformation/papillary thyroid carcinoma RET/PTC rearrangement by fluorescent in situ hybridization (FISH). The majority of the tumors exhibited a distinctive histologic appearance. They were composed of true papillae lined by a single layer of predominantly cuboidal cells with oncocytic cytoplasm; hobnailing was typically prominent. Three tumors showed taller cells with uniformly apical nuclei and no hobnailing. Ten of 18 cases showed vascular and/or capsular invasion; hence, if the diagnostic criteria used to evaluate follicular neoplasms are applied, more than half of the tumors would be considered minimally invasive carcinomas. No cases were immunoreactive with antibodies to HBME1, whereas only 1 of 13 was immunoreactive for CK19. Six of 7 interpretable cases were immunoreactive for CD56. No BRAF point mutations or RET/PTC rearrangements were identified in the examined cases. All patients were alive at the time of last follow-up and no locally recurrent disease had been reported; however, 1 case was remarkable for a lymph node metastasis. Our results confirm that EPONs are histologically, immunohistochemically, and molecularly distinct from papillary thyroid carcinoma and seem to be most related to follicular neoplasms.     

Implications of follicular neoplasms, atypia, and lesions suspicious for malignancy diagnosed by fine-needle aspiration of thyroid nodules

OBJECTIVE: To break out subcategories of atypical and suspicious cytologic interpretations of thyroid aspirations and correlate those with final histologic diagnosis. SUMMARY BACKGROUND DATA: Fine-needle aspiration (FNA) of thyroid nodules has become the primary diagnostic tool in the initial evaluation of thyroid nodules. Management of thyroid nodules is based on statistical data correlating a specific cytologic reading with the probability of malignancy. Two particular cytologic readings that frustrate both cytopathologists and surgeons are follicular neoplasms and cells that show atypia. In most reported series, follicular neoplasms and cells showing atypia are included in a broad "suspicious" category, with reported overall malignancy rates generally between 20% and 30%. However, there is interest in determining whether these suspicious lesions can be subcategorized, allowing a more accurate assessment of the risk of malignancy. In addition, there is recent evidence that the incidence of follicular cancer may be declining in this country, possibly decreasing the probability that a "follicular neoplasm" will prove to be a follicular cancer. METHODS: From January 1994 through December 2000, 709 thyroid FNAs were performed at a single institution. Those interpreted as suspicious and the subsequent histologic reports were reviewed. From this set, four specific categories were defined, and the clinical records for patients whose cytology matched these categories form the subject of this study. These four categories are follicular neoplasms without atypia, follicular neoplasms with atypia, atypia, and suspicious for malignancy. In addition, lesions with nondiagnostic cytology were reviewed. Only lesions for which there was histologic follow-up were considered. RESULTS: Ninety-eight aspirates were categorized as follicular neoplasms without atypia, follicular neoplasms with atypia, or atypia alone. Of 74 follicular neoplasms without atypia, only 5 (6.8%) were malignant, and none of these were follicular thyroid cancers. Nine of the lesions were follicular neoplasms with atypia, and four (44.4%) of these were malignant, including two that were invasive follicular cancers. Of 15 lesions showing atypia alone, 3 (20%) were malignant, all of which were papillary thyroid cancers. Twenty-five additional patients had lesions highly suspicious for malignancy. Twenty-one (84%) of these lesions were malignant, the majority being papillary thyroid cancers. Only one was a follicular cancer. Fifty patients with nondiagnostic cytology had subsequent action taken. Thirty-one of these lesions were resected, with five (16.1%) proving to be malignant. CONCLUSIONS: Thyroid nodules whose FNA is diagnosed as highly suspicious for malignancy should be resected unless there are significant contraindications to a surgical procedure. The extremely low rate (2%) of invasive follicular cancers among all follicular neoplasms may reflect changing histologic criteria for follicular carcinoma, a true change in the disease frequency, or both. For thyroid nodules whose cytology shows a follicular neoplasm without atypia, malignancy rates of 8% or less may allow nonsurgical options, including reevaluation in selected populations. Continued efforts to correlate malignancy rates to specific cytologic criteria will allow patients to make more informed decisions regarding their medical care.     

Analysis of ultrasound B-mode histogram in thyroid tumors

B-mode histograms of preoperative ultrasound texture were correlated to final pathological diagnoses and findings in 50 thyroid tumors (18 follicular adenomas, 6 follicular carcinomas and 26 papillary carcinomas) and 10 cases without any thyroid disease. Histograms were taken in the region of interest (ROI) and in the control area of the normal thyroid tissue. The following parameters, after subtracting the statistics of the control region from that of ROI, were evaluated; the difference of mean (D1), of standard deviation (D2), of skewness (D3), and of krutosis (D4). Likewise, Maharanobis distance (MD) was also studied. D1 was lower in papillary carcinomas than in follicular adenomas, and diminished by the relative proportion of some pathological findings, D2 and D3 of papillary carcinomas was higher than those of follicular adenomas. MD, having a significant correlation to D1 (r = -.8), revealed similar relationship with pathology as that of D1. No significant difference was observed between normal thyroid tissue and follicular adenoma, nor between follicular adenoma and follicular carcinoma in any parameter. MD showed the best correlation to malignancy. The criterion which judges the the tumor with D1 less than -2.5, or D2 more than 1 to be malignant, was expected to have sensitivity of 83% and specificity of 88%.     

组织蛋白酶D在甲状腺乳头状腺癌中的表达及临床意义

目的:研究组织蛋白酶D在甲状腺乳头状腺癌中的表达并探讨其能否成为甲状腺乳头状腺癌独立的预后因素。方法:应用免疫组化方法,对40例甲状腺乳头状腺癌、10例甲状腺滤泡型腺瘤及10例甲状腺正常组织进行了组织蛋白酶D表达的研究,并对可能影响甲状腺癌病人预后的有关因素进行了时序检验单因素生存分析。结果:19例(47.5％)甲状腺乳头状腺癌的组织蛋白酶D表达阳性,而甲状腺滤泡型腺瘤及正常组织的表达均为阴性,差异有显著性(P<0.05)。肿瘤大于4cm及有腺外侵犯者的甲状腺癌组织蛋白酶D阳性表达率(69.23％)明显高于肿瘤小于4cm及无腺外侵犯者(37.04％)(P<0.05)。经时序检验,组织蛋白酶D与甲状腺癌病人的预后并未表现出明显的相关关系。但组织蛋白酶D表达阳性病人的术后复发率为26.3％,表达阴性者复发率为14.3％,有一定的差异。结论:组织蛋白酶D在甲状腺乳头状腺癌中有一定的阳性表达率;当肿瘤大于4cm时,发生转移和侵袭的可能性明显增加,组织蛋白酶D表达阳性者其复发率有升高趋势。     

Clinical Relevance of Vascular Endothelial Growth Factor for Thyroid Neoplasms

Angiogenesis is of vital importance during the development and progression of solid tumors. Vascular endothelial growth factor (VEGF) is a major regulator of angiogenesis and could be produced by some cancer cells. To investigate the clinical relevance of VEGF in the tumorigenesis of human thyroid, an immunohistochemical study was performed on archival materials of follicular adenomas (n= 13), Hürthle cell adenomas (n= 6), papillary carcinomas (n= 76), follicular carcinomas (n= 12), Hürthle cell carcinomas (n= 2), and anaplastic carcinomas (n= 8). Patterns of VEGF expression were analyzed in relation to histologic subtypes of thyroid tumors and were correlated to biologic indicators of papillary carcinoma. All papillary carcinomas and Hürthle cell neoplasms revealed a strong, diffuse staining reaction, whereas anaplastic carcinoma usually exhibited weak and infrequent immunoreactivity. VEGF levels were usually higher in follicular adenomas than in follicular carcinomas. With regard to prognostic value, VEGF expression did not correlate with tumor size, extent of invasion, or scores on the AGES system (i.e., patient age, tumor size, histologic grade, tumor extent, distant metastasis) or the MACIS system (i.e., metastasis, age, completeness of resection, invasion, tumor size) for papillary carcinomas (p > 0.05, respectively). The results of the current study indicate that VEGF may play a role in the development of human thyroid cancer. Determination of the angiogenic phenotype may have limited prognostic value for patients with papillary carcinoma.     

CD10表达在甲状腺滤泡性癌和滤泡型乳头状癌诊断中的作用

目的研究CD10表达在甲状腺滤泡性癌和滤泡型乳头状癌诊断中的作用。方法收集70例甲状腺良、恶性病变组织，其中包括15例滤泡性腺瘤、15例腺瘤性甲状腺肿、30例乳头状癌（包括9例滤泡型乳头状癌）和10例滤泡性癌，采用免疫组织化学方法检测CD10在上述组织中的表达。结果9例滤泡型乳头状癌中，7例表达CD10（77．8％），10例滤泡性癌中8例表达CD10（80．0％）；CD10在非滤泡型乳头状癌、滤泡性腺瘤、腺瘤性甲状腺肿和正常甲状腺组织中均不表达。结论对CD10表达的检测有助于对甲状腺滤泡性癌和滤泡型乳头状癌的诊断。     

CD10在甲状腺疾病中的表达及意义

目的研究CD10在甲状腺疾病中的表达及意义。方法收集70例甲状腺良、恶性病变组织,其中15例滤泡性腺瘤、15例腺瘤性甲状腺肿、30例乳头状癌和10例滤泡性癌。采用免疫组织化学的方法检测CD10在上述病变中的表达。结果9例滤泡型乳头状癌中,7例表达CD10,CD10阳性率为77％。10例滤泡性癌中,8例表达CD10,阳性率为80％。而在滤泡性腺瘤和腺瘤性甲状腺肿及21例普通型乳头状癌组织中CD10均不表达。CD10在滤泡型乳头状癌和滤泡性癌中的阳性率显著高于滤泡性腺瘤和腺瘤性甲状腺肿中的阳性率（P〈0．01）。结论对CD10表达的检测有助于对甲状腺滤泡性癌和滤泡型乳头状癌的诊断。     

The optically clear nucleus. A reliable sign of papillary carcinoma of the thyroid?

The clear ("Orphan Annie Eye") nucleus has been accepted as one of the important microscopic features of papillary carcinoma of the thyroid. This study undertook an examination of 100 consecutive thyroid lesions exclusive of papillary, mixed, and follicular carcinomas for the presence of these nuclei. Only two lesions (2%), a follicular adenoma and diffuse hyperplasia, had such nuclear morphology but as focal changes. Thirty-seven cases of papillary, mixed, and follicular carcinoma were also studied. Clear or empty nuclei were present in 83% of papillary carcinomas. One carcinoma of follicular type had clear nuclei in a diffuse distribution. "Pseudoclear" nuclei were noted in a variety of situations ranging from normal thyroids to diffuse hyperplasia, where they were present in 65% of cases. We conclude that clear nuclei when present as a diffuse changes in a thyroid tumor are a reliable sign of papillary carcinoma but are not pathognomonic. If the character of the clear nuclei is questionable, other histologic features of papillary carcinoma should be looked for, such as papillae with overlapping nuclei, psammoma bodies and multicocality. It was also fould that frozen sections and imprints do not demonstrate the nuclei; they appear only in fixed tissues.     

DNA aneuploidy in follicular thyroid neoplasia

The potential value of DNA aneuploidy, in distinguishing benign from malignant follicular thyroid neoplasms, was studied. The nuclear DNA content of 65 follicular thyroid neoplasms (52 adenomas and 13 carcinomas) was determined by flow cytometric analysis of paraffin embedded material; in 58 cases preparations were technically satisfactory. In 22 follicular neoplasms DNA analysis was also performed on fresh material obtained by fine needle aspiration of surgical specimens. Cell cycle analysis was performed on both fresh and fixed specimens. An aneuploid DNA profile was found on analysis of fixed tissue in eight of 45 (18 per cent) follicular adenomas and four of 13 (31 per cent) follicular carcinomas. DNA aneuploidy was also found in six of the 22 (27 per cent) fresh preparations from follicular adenomas. The frequency of DNA aneuploidy in apparently benign and malignant follicular neoplasms was similar. Follicular thyroid neoplasia are best regarded as a single entity with a low incidence of local and distant spread. All follicular neoplasia are therefore best excised.     

Latency period of thyroid neoplasia after radiation exposure

OBJECTIVE: To determine the temporal sequence for developing benign and malignant thyroid neoplasms after radiation. SUMMARY BACKGROUND DATA: Therapeutic radiation is associated with thyroid neoplasms in humans and animals. Some question whether thyroid cancers develop de novo or from benign thyroid neoplasms. Little information, however, is available concerning the time to development of benign and malignant thyroid neoplasms after radiation exposure. METHODS: We retrospectively analyzed the records of 171 consecutive patients who had a history of exposure to radiation and were treated surgically at University of California, San Francisco-affiliated hospitals for thyroid neoplasms between 1960 and 1999. RESULTS: There were 66 men and 105 women aged 9 to 80 years (mean, 47.0 years). One hundred patients had benign and 71 had malignant tumors (58 papillary cancers, 10 follicular cancers, 1 Hurthle cell cancer, 1 medullary cancer, and 1 carcinosarcoma). The mean latency period for benign tumors was longer than that for malignant lesions (mean, 34.1 and 28.4 years, P = 0.018; median, 38.0 years and 30.0 years, P = 0.001). Follicular carcinomas developed sooner (mean, 20.5 years; median, 20 years) than did follicular adenomas (mean, 35.3 years; median, 36.5 years; P = 0.003, P = 0.0009). Patients with papillary thyroid cancers presenting as occult papillary cancers (<1 cm) and as a dominant nodule had similar latency periods (mean, 34.0 and 28.0 years P = 0.29; median, 37.5 and 30.5 years, P = 0.09), respectively. CONCLUSION: Although there could be selection bias regarding referral of patients, our data document that malignant thyroid tumors after radiation exposure, including follicular carcinomas, present earlier than do benign thyroid tumors. Occult and manifest papillary thyroid cancers present at about the same time interval after radiation exposure. Our findings question whether benign thyroid neoplasms progress to malignant thyroid neoplasms and that most occult thyroid cancers do not progress to malignant thyroid cancers in radiation-exposed patients.     

Papillary Thyroid Carcinoma Variants

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.     

Preoperative FDG-PET imaging to assess the malignant potential of follicular neoplasms of the thyroid

OBJECTIVE: When a fine needle aspiration biopsy of a thyroid nodule suggests follicular neoplasm, surgery is required for diagnosis. Establishing the diagnosis preoperatively would allow the patient to undergo the appropriate initial thyroidectomy. Preoperative [(18)F]-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging may be able to determine malignancy in follicular neoplasms. STUDY DESIGN: Prospective cases series. SUBJECTS AND METHODS: Twenty-three patients with a diagnosis of follicular neoplasm underwent presurgical FDG-PET at 60, 90, and 120 minutes after injection of fluorodeoxyglucose (F18). Thyroidectomy was performed with comparison of the histopathologic results with the FDG-PET results. RESULTS: There were 5 malignant conditions and 18 benign conditions identified with the standard uptake valve (SUV) ranging from 0.9 to 44.8. The follicular thyroid cancers that exhibited only capsular invasion had an average SUV of 3.1, whereas those with vascular invasion had an average SUV of 39.9. The SUV increased in 80% of the malignant cases but in only 50% of the benign cases. CONCLUSION: Despite certain patterns being suggestive of malignancy, FDG-PET can not consistently predict the malignant potential of a follicular neoplasm.