Papillary Thyroid Carcinoma Lesions Research Articles

Prognostic Significance of the Proportion of Tall Cell Components in Papillary Thyroid Carcinoma.

Tall cell variant (TCV) of papillary thyroid carcinoma (PTC) shows a poorer prognosis than conventional PTC. The World Health Organization (WHO) classification defines TCV as the tall cell component (TCC) in ≥50% of PTC lesions. We investigated whether and how the proportion of TCC affects the prognosis of patients with PTC with TCC. Seventy patients with TCC in ≥30% of their PTC lesions and 210 age- and gender-matched controls with no TCC who underwent locally curative surgery at Kuma Hospital (2006-2014) were enrolled. The 70 PTC patients were divided into two categories: TCC ≥50% (TCC-major, n=19) and TCC 30-49% (TCC-minor, n=51). We performed univariate and multivariate analyses of the relationships between disease-free survival (DFS) and variables including the TCC proportion in 276 patients who had no distant metastases at surgery (median follow-up 64months). In the univariate analysis, TCC-major, TCC-minor, old age (≥65years), clinical node metastasis, significant extrathyroid extension (Ex), and high Ki-67 labeling index (≥5%) significantly affected the DFS. In the multivariate analysis, TCC-major and Ex independently affected the DFS, but TCC-minor did not. In an analysis excluding TCC-major patients, TCC-minor was not an independent prognostic factor for DFS. Studies or larger patient series with longer follow-ups are necessary, but we speculate that in PTC with TCC, TCC-major significantly and independently affects the DFS, whereas TCC-minor does not. Our findings indicate that the WHO definition of TCV is appropriate and that the prognostic impact of TCC-minor is limited.

Clinical significance of HBME-1, Galectin-3, and CK19 expression and the status of BRAF mutation in papillary thyroid carcinoma

Abstract Objective The aim of this study was to explore the clinical significance of the expression of proteins human bone marrow endothelial cell markers (HBME-1), Galectin-3, and cytokeratin19 (CK19), as well as the status of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutation in papillary thyroid carcinoma (PTC). Methods Immunohistochemical staining was performed in 82 specimens each of PTC and papillary benign lesions to detect the expression of HBME-1, Galectin-3, and CK19. Polymerase chain reaction (PCR) and gene sequencing were performed on 60 specimens each of PTC and papillary benign lesions to detect the status of BRAF mutation. Results The positive expression ratios of HBME-1, Galectin-3, and CK19 in PTC were 98.8%, 97.6% and 100% respectively, which were significantly higher than the expressions in papillary benign lesions (P < 0.05). No significant relationship was observed between the expression of these makers and the clinicopathological features of PTC. The sensitivity of co-expression of HBME-1 and CK19 or HBME-1 and Galectin-3 as diagnostic criteria of PTC was 99.9%, with a specificity of 95.4%. BRAF mutation was detected in 40 of 60 PTC (66.7%) specimens. There was a statistical difference in BRAF mutations between PTC and papillary benign lesions (P < 0.05); there were no associations between BRAF mutation and the clinicopathological features of PTC. Conclusion Combined immunohistochemical staining of HBME-1, Galectin-3, and CK19 can further improve the sensitivity and specificity of differential diagnosis of PTC. BRAF mutation is a significant genetic event, which may have diagnostic value for PTC.

Expression of prostaglandin E2 and EP receptors in human papillary thyroid carcinoma.

The objective of the present study is to determine the role of prostaglandin E2 (PGE2) and downstream EP receptors in the development of human papillary thyroid carcinoma (PTC). A total of 90 thyroid specimens excised from patients undergoing total or subtotal thyroidectomy in the Department of General Surgery, the Fifth Affiliated Hospital of Sun Yat-sen University, China, from August 2013 to September 2014, were analyzed. The quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemical analyses were employed to examine the messenger RNA (mRNA) and protein expression, respectively. The expressions and significances of cyclooxygenase-2 (COX-2), microsomal prostaglandin E synthase-1 (mPGES-1), PGE2, and EP receptors in PTC and nodular goiter were investigated. The COX-2 mRNA and protein expression level significantly increased in the PTC tissues than in the paired noncarcinoma tissues adjacent to the PTC or nodular goiter tissues. The mPGES-1 protein expression was also significantly upregulated in the PTC tissues. All the four subtypes of EP receptors (EP1-4) could express in the thyroid tissues, while only the EP4 mRNA and protein levels significantly increased in the PTC tissues. The local production of PGE2 had a higher-level expression in the PTC tissues than in the noncarcinoma thyroid tissues adjacent to the PTC lesion and the benign nodular goiter tissues. The induction of PGE2 biosynthesis as well as the overexpression of EP4 in PTC suggested that this pathway might play an important role in the carcinogenesis and progression of PTC. These observations raise the possibility that pharmacological inhibition of mPGES-1 and/or EP4 may hold therapeutic promise in this common cancer.

Hashimoto's Thyroiditis Does Not Affect Ultrasonographical, Cytological, and Histopathological Features in Patients with Papillary Thyroid Carcinoma.

The association between papillary thyroid carcinoma (PTC) and Hashimoto's thyroiditis (HT) is controversial. In this study, we aimed to compare preoperative thyroid functions, ultrasonography (US) features, fine-needle aspiration biopsy (FNAB) results, and histopathological characteristics of PTC in patients with and without HT. Data of 919 PTC patients were reviewed retrospectively. The diagnosis of HT was based on histopathological examination and patients were grouped as HT and non-HT. There were 1321 PTC lesions in 919 patients among which 317 (34.5 %) had coexistent HT. There were no significant differences in nodule volume, longitudinal diameter, texture, echogenicity, marginal regularity, presence of microcalcification and hypoechoic halo, and peripheral vascularization in patients with and without HT (p > 0.05, for all parameters). Macrocalcification was observed more frequently in the non-HT group (p = 0.021). FNAB results were similar in the two groups (p = 0.105). Distribution of variants, capsule invasion, vascular invasion, and extrathyroidal extension were observed with similar rates in the HT and non-HT groups. Lymph node metastasis was significantly higher in patients without HT (p = 0.012). Of the carcinomas, 66.1 % (n = 874) were papillary thyroid microcarcinoma (PTMC). Tumor size was lower in PTMC lesions coexistent with HT (p = 0.026). We observed lower rates of capsule invasion, extrathyroidal extension, and lymph node metastases in PTMC with HT compared to without HT (p = 0.007, p = 0.003, and p = 0.015, respectively). This study showed that US features, FNAB results, and histopathological findings of PTC lesions are not influenced by the presence of HT. However, PTMC seems to be related with less aggressive histopathological behavior in HT.

Identification of occult tumors by whole-specimen mapping in solitary papillary thyroid carcinoma

We undertook this study to estimate an accurate incidence and spread patterns of occult papillary thyroid carcinoma (PTC) in patients with a preoperative diagnosis of solitary PTC by using whole-specimen mapping of all specimens after a total thyroidectomy. Enrolled prospectively in this whole-thyroid mapping study are 82 consecutive patients who underwent a total thyroidectomy under a preoperative diagnosis of solitary PTC. All thyroidectomy specimens were serially sectioned in 2 mm thickness and whole-thyroid mapping was carried out for additional foci of occult PTC. The frequencies of occult lesions detected in the whole and contralateral lobe were determined, and clinicopathologic factors associated with multifocality were assessed. Whole-thyroid mapping revealed 66 occult PTC lesions missed by preoperative ultrasound in 37 (45.1%) of the 82 patients. The great majority (92.5%) of the occult PTC was smaller than 3 mm in size and 25 patients (30.5%) had contralateral lesions. We found that the male sex was an independent predictor of multifocality (odds ratio (OR), 3.00; 95% CI, 1.11-8.14), adjusting for preoperative findings. Analysis with pathologic parameters showed that the male sex (OR, 5.03; 95% CI, 1.68-15.08) and extrathyroidal extensions (OR, 3.03; 95% CI, 1.03-8.95) were associated with multifocal PTC. However, none of the clinicopathologic factors evaluated predicted contralateral PTC. Our study demonstrates the diagnostic limitations of ultrasound for the detection of multifocal PTC and the need to consider the possibility of occult lesions in the management of solitary PTC, especially in male patients.

Papillary thyroid carcinoma: Comparison between CT features and pathologic findings

Objective To evaluate the relationship between the CT imaging features and pathologic findings of papillary thyroid carcinoma (PTC) and papillary thyroid mierocareinoma (PTMC), as well as the CT appearances of Non-papillary thyroid carcinoma(N-Pq'C). Methods CT features of 229 PTC ,42 PTMC and 36 N-PTC patients with 264, 57 and 41 lesions respectively were analyzed retrospectively, and comparison was made with the pathologic findings. All data were analyzed by X2test. Results (1) Of PTC lesions, 25.4% (67/264) of the lesions and 2. 9% (24/828) of metastatic lymph nodes showed cystic changes. Cyst formation with intracystic high density papillary-like nodules were found in 31.3% (21/67)of the PTC lesions and 37.5% (9/24) of metastatic lymph nodes. The histologic appearances of these tumors demonstrated fibrous tissue forming the wall of cyst, and papillary-like tumor tissue. (2) 75.2% (112/149) of PTC and 33.3% (5/15) of PTMC showed multiple small granular and fine calcifications, and there was statiscally significant difference between the two (P 0.05). However, the degree of enhancement in PTC lesions were less than that of N-PTC, 36. 6% (94/257) of PTC and 54. 1% (20/37) of N-PTC lesions showed significant enhancement, and there was statistically significant difference (P < 0. 05). 75. 1% of PTC (172/229) and 52. 8% of (19/36)N-PTC had cervical lymph node metastases, with a propensity for PTC to have more Ⅵ region metastatic lymph nodes, 80.8% (139/172) vs 57.9% (11/19), which was statistically significant (both P <0. 05). (4) Distant metastases to bone or lung were rare, but N-PTC(5/36) were more likely to produce distant metastases than PTC (5/229), and there was statistically significant difference (P < 0.01). Conclusion Multiple, small granular and fine calcifications were found more frequently in PTC than PTMC. Compared with N-PTC, the papillary-like mural nodules of PTC showed less enhancement on post-contrast CT and cervical lymph node metastases were more frequently seen in PTC. Key words: Thyroid neoplasms; Carcinoma; papillary; Tomography; X-ray computed; Pathology

Clinical significance of BRAF V600E mutation in 154 patients with thyroid nodules.

The aim of the present study was to investigate the prevalence of the BRAF V600E mutation in papillary thyroid carcinoma (PTC) patients from eastern coastal China and to determine whether it is correlated with the clinicopathological features of PTCs with or without current Hashimoto thyroiditis (HT). The BRAF V600E mutation status was analyzed in 206 thyroid nodules of 154 patients undergoing thyroidectomy using polymerase chain reaction and bi-directional sequencing. Multivariate analysis was performed to investigate the association of the BRAF V600E mutation with clinicopathological features. Thyroid nodules were classified as PTC, nodular goiter (NG), adenomatoid nodule, adenoma and HT. The BRAF V600E mutation was observed in 61.5% of PTCs analyzed; it was also detected in one normal tissue adjacent to PTC and one NG. One patient exhibited double mutations in the BRAF gene; the BRAF V600E mutation in the PTC lesion and the BRAF K601E mutation in the contralateral NG lesion. Patients harboring the BRAF V600E mutation had higher thyroid stimulating hormone levels (2.453±1.464 vs. 1.966±1.296 mIU/l), a reduced occurrence of papillary thyroid microcarcinoma (55.0 vs. 88%), and a higher occurrence of lymph node metastasis (LNM; 42.5 vs. 16.0%) compared with those with wild-type BRAF (all P<0.05). Binary logistic regression analysis revealed that the BRAF V600E mutation was associated with LNM of PTC (hazard ratio, 5.051; 95% confidence interval, 1.068-23.893; P=0.041). Conversely, no association was identified between the BRAF V600E mutation and HT (38.5 vs. 67.3%, χ2=3.656, P=0.056). Thus, in regional PTCs, the BRAF V600E mutation was prevalent, suggesting that it may be an early and phenotypically defining molecular event in PTC, and may represent an independent factor that predicts LNM.

Galectin-3 Immunohistochemical Expression in Thyroid Neoplasms.

Galectin-3 has been implicated in the regulation of cellular growth, differentiation and malignant transformation in various organs including thyroid gland. It has been extensively studied as an immunohistochemical (IHC) marker in thyroid malignancy. To evaluate the diagnostic role of Galectin-3 (Gal-3) in differentiating malignant from benign thyroid neoplasm. In this observational study we evaluated Gal-3 expression in a spectrum of malignant (30) and benign (20) thyroid neoplasms. The final common diagnosis arrived at after histopathologic evaluation of H&E stained sections by two pathologist's was considered the gold standard. The malignant neoplasms included Papillary Thyroid Carcinoma (PTC), Follicular Thyroid Carcinoma (FTC), Medullary Thyroid Carcinoma (MTC), insular carcinoma, Anaplastic Thyroid Carcinoma (ATC), and metastatic carcinoma. The benign neoplasms included Follicular Adenoma (FA), Hurthle cell adenoma and hyalinizing trabecular adenoma. IHC staining for Gal-3 was performed for all neoplasms with the polymeric method using lyophilized mouse monoclonal antibody. Statistical analysis was done using 2x2 contingency table. Chi-square test with Yates correction was used to calculate p-value to ascertain statistical significance. Gal-3 expression was significantly higher in malignant thyroid neoplasms as compared to benign neoplasms (p<0.0001). Gal-3 expression in differentiating malignant from benign neoplasms was found to have sensitivity of 86%, specificity of 85%, positive predictive value of 89.66% and negative predictive value of 80.95%. However, no statistical significance was observed (p=0.4718) when comparing PTC and other malignant lesions in terms of Gal-3 expression. Gal- 3 expression in PTC was found to have sensitivity of 91.3%, specificity of 85%, positive predictive value of 87.5% and negative predictive value of 89.47%. Diffuse and strong IHC staining for Gal-3 differentiates malignant from benign tumours. This marker can assist in the diagnosis of thyroid neoplasms with equivocal morphologic features. This study highlights the high sensitivity of Gal-3 for PTC.

Detection of BRAF Mutations on Direct Smears of Thyroid Fine Needle Aspirates Using the Cell Transfer Technique

Introduction: A mutation of the BRAF gene is the most common genetic alteration in papillary thyroid carcinoma (PTC). Molecular techniques that can identify BRAF mutations could be an important ancillary tool in the diagnosis of thyroid carcinoma, especially in cases of indeterminate thyroid fine needle aspirates (FNA). The cell transfer technique (CTT) has proven to be useful for obtaining cells for molecular testing from FNA direct smears. Materials and Methods: PCR-based BRAF molecular testing was performed on one air-dried and one ethanol-fixed CTT smear prepared from a thyroid FNA and on sections obtained from the corresponding thyroidectomy formalin-fixation paraffin embedded (FFPE) blocks from 31 cases diagnosed by histopathologic assessment as classical PTC (18), follicular variant PTC (4), follicular carcinoma (1), follicular adenoma (1) and benign non-neoplastic lesions (7). Results: BRAF testing was successfully performed on 30/31 air-dried CTT (97%), 28/31 ethanol-fixed CTT (90%) and 28/31 FFPE (90%). The results included 12 BRAF mutations and 18 wild types (WT) for the air-dried CTT, 14 BRAF mutations and 14 WT for the ethanol-fixed CTT and 13 BRAF mutations and 15 WT for the FFPE. The concordance rate between air-dried and ethanol-fixed CTT was 96% and was 86% between CTT and FFPE. There were 2 mutations detected on CTT which were WT on the corresponding FFPE. Conversely, 2 mutations identified on the FFPE were WT on the corresponding CTT. Conclusions: Using the FFPE as the gold standard, the sensitivity and specificity for detection of BRAF mutation on the CTT direct smears were 85% and 87%, respectively. BRAF mutation is a highly specific marker for thyroid carcinoma. For those patients with indeterminate thyroid FNA results, the use of CTT to select atypical cells for the BRAF mutation analysis should enhance the diagnostic sensitivity for thyroid FNA and reduce the need for repeat aspirates.

Proteomics for the diagnosis of thyroid lesions: preliminary report.

Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) is a unique proteomic technology that explores the spatial distribution of biomolecules directly in situ, thus integrating molecular and morphological information. The possibility of correlating distribution maps of multiple analyses with cytological features makes it an ideal research tool for discovering new diagnostic markers. A previous study showed that MALDI-IMS could help discrimination between different types of thyroid lesions, especially papillary thyroid carcinoma (PTC); the present feasibility study on ex vivo fine needle aspiration (FNA) smears describes its potential in detecting new proteomic targets of other thyroid lesions (follicular lesions, medullary carcinoma). MALDI-IMS was conducted on ex vivo FNAs obtained from surgical specimens and corresponding in vivo samples. Differences between proteomic profiles of different thyroid lesions were compared. Comparing the protein profiles of hyperplastic nodules obtained from three different patients with each other, and with a new PTC, showed a high degree of concordance, indicating good reproducibility of the IMS technology on cytological samples, suggesting its potential as a tool for biomarker discovery. Furthermore, comparison of the average proteomic profiles of hyperplastic nodules with a Hürthle cell adenoma revealed significant differences, underlying the capability of MALDI-IMS to distinguish between different thyroid lesions. Finally, the proteomic profile of medullary thyroid carcinoma was also characterized. Our results confirmed the possible role of MALDI-IMS in the search for diagnostic targets of PTC and follicular lesions, which could be applied in larger trials aimed at the identification of proteins, convertible to cost-effective diagnostic tools such as immunohistochemistry. These tests could be used to analyse in vivo cytological smears, improving the preoperative diagnosis of indeterminate thyroid nodules.

Clinicopathologic and Diagnostic Significance of p53 Protein Expression in Papillary Thyroid Carcinoma

P53 protein expression has been detected immunohistochemically in papillary thyroid carcinoma(PTC). We investigated the relations between its expression and clinicopathologic features and its significance as a diagnostic marker. We compared and evaluated 93 patients in whom thyroidectomy with lymph node dissection had been performed to treat PTC for clinicopathologic significance and 102 patients with 23 papillary thyroid overt carcinomas (POC), 57 papillary thyroid microcarcinomas(PMC), 5 follicular adenomas (FA), 5 Hashimoto's thyroiditis (HT) and 12 nodular hyperplasias (NH) for significance as a diagnostic marker. Expression of p53 protein was evaluated immunohistochemically in sections of paraffin- embedded tissue. Statistical analysis showed significantly different expression of p53 in PTC versus other benign thyroid lesions (BTL).The diagnostic sensitivity and specificity were 85.0% and 72.7%, respectively. Overexpression of p53 protein was observed in 44 of the 93 PTC cases (47.3%), but no significant correlation between p53 protein overexpression and clinicopathologic features (age, size, multiplicity, lymph node metastasis, extrathyroidal extension and vascular invasion) was noted. p53 is valuable to distinguish PTC from other BTL, but there is no correlation between p53 protein overexpression and clinicopathologic features.

Diagnostic value of CD-10 marker in differentiating of papillary thyroid carcinoma from benign thyroid lesions.

Background:Using of CD10 in accordance with clinical and histological features of thyroid lesions could be used as both diagnostic and prognostic tool, which consequently influence the management and their prognosis for survival of patients with thyroid neoplasms especially papillary thyroid carcinoma (PTC). The aim of this study was to determine its expression in PTC and different benign thyroid lesions.Materials and Methods:In this descriptive-analytic, cross-sectional study, paraffin-embedded tissues of patients with definitive pathologic diagnosis of different benign thyroid lesions and PTC were retrieved. Immunostained sections of each slides was performed using immunohistochemistry methods and expression of CD10 was compared in two groups of benign thyroid lesions and PTC.Results:From selected cases 134 sections studied in two groups of PTC (n = 67) and benign thyroid lesions (n = 67). CD10 were immunohistochemically positive in 29.9% of PTC cases, but in none of the thyroid benign lesions (0%) (P < 0.001). There was not significant relationship between expression of CD10 with age and sex of the studied population (P > 0.05).Conclusion:The results of the current study indicate that due to the higher expression of CD10 in PTC than benign thyroid lesions it might be used for differentiating mentioned lesions. But for using it as a diagnostic tool further studies with larger sample size and determination of its sensitivity, specificity and cut-off point is necessary.

Warthin-like tumour papillary thyroid carcinoma

With less than 100 cases reported in the English literature to date, Warthin-like tumour papillary thyroid carcinoma is a relatively uncommon variant of papillary thyroid carcinoma (PTC). This term was first coined on the basis of its close morphological resemblance to the Warthin tumour that characteristically occurs in the salivary glands.We present a case of this uncommon variety of PTC, and through a brief literature review we describe the diagnostic challenges presented in distinguishing between several varieties of PTC and benign lesions to provide optimal treatment. A 48-year-old woman was referred to our department for surgical treatment of an enlarged goitre that had presented over the last year. Dominant nodule FNA revealed suspicion of a follicular neoplasm, and she was submitted to total thyroidectomy. Histopathology showed multifocal PTC on chronic lymphocytic thyroiditis ground. Left lobe foci of 0.3 cm follicular variant of PTC, 0.6 cm isthmus foci of Warthin-like tumour PTC and 1.5 cm of conventional PTC with extrathyroidal extension were reported. Previous studies showed prognosis to be similar to that for conventional PTC. Distinction between Hurthle cell tumours, tall cell and oncocytic variants of PTC or medullary carcinoma, or even lymphocytic thyroiditis and this entity, is intriguing and poses diagnostic difficulties. Data from new studies will reveal more on this uncommon tumour.

Chromatin changes in papillary thyroid carcinomas may predict patient outcome

New insights in prognostic predictions are urgently needed for papillary thyroid carcinoma (PTC). The present study aimed to investigate whether computerized analysis of chromatin texture allows the identification of PTC patients with a poor prognosis. We randomnly selected paraffin-embedded blocks from surgical specimens of 103 classic cases of PTC. During follow-up, 68 of the patients were classified as free of disease, whereas 35 presented with recurrences. Characteristics of chromatin were obtained from digitized images of at least 100 randomly selected tumor nuclei per patient. An independent series of 30 goiters was used to validate our observations. Stage, age and distant metastases were found to serve as independent prognostic factors for survival. In addition, multivariate Cox regression confirmed variable cluster prominence as an independent prognostic factor. By comparing malignant and benign nodules, we found that the PTC lesions presented with higher nuclear perimeters, nuclear areas, Minkowski fractal dimensions, optical densities and nuclear longest chords. From our results we conclude that, in conjunction with clinical and histopathological data, morphometric data may provide relevant prognostic information in PTC patients.

Prognostic Factors for Recurrence of Papillary Thyroid Carcinoma in the Lymph Nodes, Lung, and Bone: Analysis of 5,768 Patients with Average 10‐year Follow‐up

Papillary thyroid carcinoma (PTC) frequently recurs to the lymph nodes, which may not be fatal immediately but is a stressor for physicians and patients. Recurrence to the distant organs, although less frequent, is often life-threatening, and the lung and bone are organs to which PTC is likely to recur. In the present study we investigated factors predicting recurrence of PTC to the lymph nodes, lung, and bone in a large number of patients undergoing long-term follow-up. A total of 5,768 PTC patients (608 males and 5,159 females) without distant metastasis at diagnosis who underwent initial surgery between 1987 and 2004 in Kuma Hospital were enrolled in this study. The postoperative follow-up ranged from 12 to 280months, and was 129months (10.8years) on average. To date, node, lung, and bone recurrences have been detected in 389 (7%), 118 (2%), and 33 patients (0.6%), respectively, and 57 patients (1%) have died of PTC. We examined the prognostic significance of the tumor size (T), extrathyroid extension (Ex), age 55years or older (Age), male gender (Gender), clinical node metastasis (N), and extranodal tumor extension (LN-Ex) for each outcome on multivariate analysis. Age, Gender, T>2cm, N, and Ex were independent predictors of lymph node recurrence. Age, Ex, T>2cm, and N were independent prognostic factors for lung recurrence. Ex, T>4cm, and N independently predicted bone recurrence. Of these, N≥3cm had the strongest prognostic value for lymph node, lung, and bone recurrences. In contrast, Age was the strongest predictor for carcinoma death. LN-Ex also had a prognostic value for carcinoma death, although it was not a predictor of carcinoma recurrence. Ex, N≥3cm, and T>2cm also had a prognostic impact on carcinoma death. Large lymph node metastasis showed a strong prognostic impact on carcinoma recurrence not only to the lymph nodes but also to the lung and bone, and carcinoma death. Extrathyroid extension also independently predicted these recurrences and carcinoma death, although hazard ratios were lower than for large node metastasis. Age 55years or older, in contrast, was the strongest predictor of carcinoma death. Extranodal tumor extension did not independently affect recurrence, but it had prognostic significance for carcinoma death. These findings suggest that recurring PTC lesions of older patients and/or extranodal tumor extensions are difficult to control and very progressive.

Prognosis of Patients with Papillary Thyroid Carcinoma Located in One Lobe Showing Lateral Node Metastasis in the Contralateral but Not Ipsilateral Compartment

Papillary thyroid carcinoma (PTC) frequently metastasizes to the lymph node in lateral compartment, which can often be detected on preoperative ultrasonography (N1b). However, PTC located in one lobe showing contralateral but not ipsilateral N1b is not common. We analyzed the clinicopathological features and prognosis of 13 patients with PTC limited in one lobe showing contralateral but not ipsilateral N1b. Sizes of the primary lesions ranged from 0.8 cm to 3.0 cm and only 2 tumors showed extrathyroid extension. Metastatic lateral node measured from 0.6 to 3.1 cm. Ten patients showed pathological central node metastasis and 5 had minute PTC lesions in the contralateral lobe. However, 3 patients did not show either of these. None of the patients have developed carcinoma recurrence or died of carcinoma to date. Taken together, PTC located in one lobe with contralateral but not ipsilateral N1b is rare and generally shows an indolent behavior. Although most patients had central node metastasis and/or minute PTC lesions in the contralateral lobe, it is also possible for carcinoma cells to metastasize directly from primary lesions to the contralateral lateral node. Total thyroidectomy with central node dissection and therapeutic MND of the contralateral compartment may be an acceptable surgical design and bilateral MND might not be mandatory.

Ultrasonographic Findings of Medullary Thyroid Carcinoma: a Comparison with Papillary Thyroid Carcinoma

ObjectiveThis study was designed to evaluate the ultrasonographic (US) findings of medullary thyroid carcinoma (MTC) as compared to findings for papillary thyroid carcinoma (PTC).Materials and MethodsThe study included 21 cases of MTC that were surgically diagnosed between 2002 and 2007 and 114 cases of PTC that were diagnosed in 2007. Two radiologists reached a consensus in the evaluation of the US findings. The US findings were classified as recommended by the Thyroid Study Group of the Korean Society of Neuroradiology and Head and Neck Radiology (KSNHNR) and each nodule was identified as suspicious malignant, indeterminate or probably benign. The findings of medullary and papillary carcinomas were compared with use of the chi-squared test.ResultsThe common US findings for MTCs were solid internal content (91%), an ovoid to round shape (57%), marked hypoechogenicity (52%) and calcifications (52%). Among the 21 cases of MTC nodules, 17 (81%) were classified as suspicious malignant nodules. The mean size (longest diameter) of MTC nodules was 19 ± 13.9 mm and the mean size (longest diameter) of PTC nodules was 11 ± 7.4 mm; this difference was statistically significant (p < 0.05). An ovoid to round shape was more prevalent for MTC lesions than for PTC lesions (p < 0.05).ConclusionThe US criteria for suspicious malignant nodules as recommended by the Thyroid Study Group of the KSNHNR correspond to most MTC cases. The US findings for MTC are not greatly different from PTC except for the prevalence of an ovoid to round shape.

Clonal Characterization of Sporadic Cribriform-Morular Variant of Papillary Thyroid Carcinoma by Laser Microdissection–BasedAPCMutation Analysis

Cribriform-morular variant (C-MV) of papillary thyroid carcinoma (PTC) is a rare and unusual neoplasm composed of multiple histologic components, including cribriform, papillary, solid, tall columnar, and morular patterns. Analyses of gross C-MV of PTC lesions has linked adenomatous polyposis coli (APC) mutations to its pathogenesis; however, the extent of involvement of mutations in the development of individual components is unclear. We report on bidirectional sequencing of the mutation cluster region (codons 1032-1565) of the APC gene in individually laser-microdissected components of a previously unreported C-MV of PTC. A silent Thr1493Thr gene variant was found in all tumoral components, whereas a 5-base-pair frameshift deletion at codon 1309 was identified only in the morules. Neither variant was observed in matched normal thyroid tissue. These results show the histologic components of C-MV of PTC to have some common mutational background, although additional somatic mutations may be involved in the development of morular structures.

Estrogen Receptor (ER)-β, But Not ER-α, Is Present in Thyroid Vessels: Immunohistochemical Evaluations in Multinodular Goiter and Papillary Thyroid Carcinoma

Estrogen receptors (ERs) have been demostrated in the vessel structures of several systems. Little is known on the presence of ERs in the thyroid vessels. We immunohistochemically evaluated both ER-alpha and ER-beta immunoreactivity (IR) in both vascular and follicular thyroid cells in tissue samples from 17 cases of multinodular goiter (MNG) and 17 cases of papillary thyroid carcinoma (PTC). ER-alpha IR was undetectable in either tissue examined. In 100% of MNG samples, nuclear ER-beta IR was detected in both endothelial and follicular cells. In PTC samples, endothelial nuclear ER-beta IR was found in 100% of cases, whereas the nuclear staining of follicular cells was found in 83% of cases. The intensity of staining of the endothelial ER-beta IR was comparable between MNG and PTC. However, when follicular cells were considered, a tendency toward a decrease in nuclear staining and a significant increase in cytoplasmic staining were found in PTC lesions as compared to MNG. This study demonstrated that ER-beta, but not ER-alpha, IR is present in the endothelium of thyroid vessels. Furthermore, although data need to be confirmed in larger observations, these results suggest the lack of differences in the pattern of vascular ER-beta IR between MNG and PTC.

Increased Expression of Vascular Endothelial Growth Factor C in Papillary Thyroid Carcinoma Correlates with Cervical Lymph Node Metastases

Despite recent studies showing that vascular endothelial growth factor C (VEGF-C) mRNA is up-regulated in papillary thyroid carcinoma (PTC), the role of VEGF-C in lymph node metastasis is still unclear. The aim of this study is to investigate the expression pattern of VEGF-C immunoreactive protein in PTC and its relationship with cervical lymph node metastasis. Tissue samples were obtained from 39 specimens of PTC (20 with and 19 without lymph node metastasis) as well as 20 benign thyroid nodules. Overexpression of the VEGF-C protein was evaluated by immunoblotting with specific anti-VEGF-C antibody in paired tumor and nontumor tissues from PTC. The data were compared with patients' clinicopathologic features and lymph node metastasis. Immunohistochemical staining was done on selected paraffin sections to determine cellular localization of VEGF-C and to assess flt-4 (or VEGFR-3)-positive vessel density in PTC lesions. Overexpression of VEGF-C was detected in 69% of the PTC and in 5% of the benign thyroid specimens. When comparing between the metastatic and nonmetastatic groups of PTC, a higher expression level of VEGF-C was detected in both the tumor (P = 0.004) and adjacent nontumor tissues (P = 0.011). Positive immunostaining for VEGF-C was confirmed in PTC tumor tissues and metastatic lymph nodes, which correlated with flt-4-positive vessel density in tumor and peritumor tissues. The increased expression of VEGF-C protein in PTC is associated with lymph node metastasis (P = 0.004) and lymphovascular permeation (P = 0.001) but is independent of other clinicopatholgic variables. The VEGF-C immunoreactive protein is overexpressed in PTC lesions, which correlates with lymph node metastases. VEGF-C expression may play a role in lymphangiogenesis of PTC and further study is necessary to evaluate the clinical application of VEGF-C as a molecular marker for tumor metastases to cervical lymph nodes.