Expression of CD44 and cyclin D1 in fine needle aspiration cytology of papillary thyroid carcinoma

OBJECTIVE: To compare the expression pattern of CD44 and cyclin D1 immunostaining in fine needle aspiration specimens of papillary carcinoma of the thyroid and nonpapillary lesions. STUDY DESIGN: The study was performed on 80 fine needle aspiration cytologic smears of thyroid lesion retrospectively using monoclonal antibodies and on histologic material from a proportion of cases. RESULTS: Most papillary carcinomas expressed intense cell membrane or diffuse cytoplasmic staining for CD44 (97.8%). Focal immunoreactivity was observed in follicular neoplasms (28.5%) and nodular goiter (4.7%). There was no difference in CD44 immunostaining between follicular carcinoma and adenoma. Cyclin D1 was expressed in the nuclei of most papillary carcinomas (79.2%). Focal nuclear immunoreactivity was noted in nodular goiters (23.5%) and follicular neoplasms (10%). In resected specimens, all papillary carcinomas (19 cases) showed intense membranous or granular CD44 immunoreactivity. Focal cyclin D1 expression was noted in 52.6%. There was no difference in CD44 and cyclin D1 expression between the group of papillary carcinomas with regional lymph node metastasis as compared to those without metastasis. Positive staining for both CD44 and cyclin D1 would strongly favor papillary carcinoma, although further studies on cytologic material are necessary to verify this diagnostic approach. CONCLUSION: Most papillary carcinomas express CD44 and cyclin D1, whereas it is less common in follicular neoplasms and nodular goiter. This may be helpful in diagnostically difficult cases.     

Potential diagnostic markers in nodular lesions of the thyroid gland: an immunohistochemical study

Aims: The differential diagnosis of thyroid nodules in routine practice can be problemmatic for both pathologists and clinicians. Effective treatment requires a determination of the biological nature of the lesions. For this reason, ancilliary diagnostic markers along with histological examination of the nodules may be useful. The objective of this study was to evaluate the diagnostic usefulness of novel markers in the diagnosis of hyperplastic and neoplastic nodules. Methods: Forty eight thyroid lesions forming four diagnostic groups including adenomatous goiters (AS), follicular adenomas (FA), follicular (FC) and papillary carcinomas (PC) were examined using standard immunohistochemical methods. Monoclonal antibodies against galectin-3, matrix metalloproteinases (MMPs) -2 and -7 and endothelial markers CD31 and CD105 were used. Results: The cytoplasmatic expression of galectin-3 was positive in all cases of papillary carcinoma. Moreover, statistically significant differences between fused groups of benign (AS and FA) and malignant lesions (FC and PC) were found Fischer's exact test (p = 0.0001). No significant differences in cytoplasmic expression of MMPs -2 and -7 and in vascular density assessed by using of both endothelial markers between benign lesions and malignant tumors were revealed. Conclusions: Galectin-3 appears to be a useful marker in the diagnosis of papillary carcinoma only. The matrix metalloproteinases-2 and -7 are not helpful in distinguishing hyperplastic and neoplastic thyroid nodules. Endothelial markers do not appear to be suitable for thyroid differential diagnosis. A panel of antibodies in the differential diagnosis of thyroid nodular lesions would seem most suitable and further studies with larger sets of patients are awaited.     

Expression of FAS/APO 1/CD 95 in thyroid tumors

Using immunohistochemistry, Fas/Apo-1 protein expression was investigated in thyroid cancers of 67 patients. Thyroid biopsies from twenty eight patients with benign thyroid diseases were also examined. The patients with thyroid cancer manifested a variable histology of the cancer, including 14 patients with follicular carcinoma, 48 with papillary carcinoma, 5 patients with medullary carcinoma. The benign thyroid disease involved nodular goitre in 11 patients and follicular adenoma in other 17 patients. The study aimed at examining immunohistochemical expression of Fas protein in order to determine whether the level of its expression correlated with histological diagnosis. In individual patients Fas expression was more prevalent in thyroid carcinomas as compared to benign tumors (p=0.001). A marked increase in Fas expression was found in papillary carcinoma, as compared to follicular and medullary carcinomas (p=0.02). In conclusion, Fas was significantly more frequently overexpressed in thyroid cancer, indicating its role in thyroid tumorigenesis.     

Serum metabolic profiling and features of papillary thyroid carcinoma and nodular goiter

Thyroid carcinoma is a common endocrine malignancy worldwide, accounting for approximately 1% of all diagnosed cancers and about 91.5% of the malignancies of head and neck. However, differentiating malignant thyroid nodules from benign ones remains a diagnostic challenge. Thus, novel molecular markers that enable non-invasive diagnostics for malignant thyroid nodules are urgently needed. In the present study, a metabonomic investigation based on liquid chromatography-LTQ Orbitrap mass spectrometry was employed for serum metabolic profiling of 30 cases of papillary thyroid carcinomas (PTC), 80 cases of nodular goiters (benign thyroid nodules) and 30 cases of healthy controls. According to the results of multivariate statistical data analysis, the significantly changed metabolites among these three groups were defined. It was found that most of these metabolites decreased in the sera of both malignant and benign thyroid cases due to the increased metabolic rate, which is in accordance with clinical features. The major metabolic differences between benign and malignant nodules occurred in lipid metabolism. Especially, the content of 3-hydroxybutyric acid, an intermediate product of fatty acid metabolism, was much higher in the PTC group than that in the nodule goiter and control groups, indicating its potential as a diagnostic marker for PTC and nodular goiters. These results show that the serum metabolic profiling method is a powerful tool for distinguishing thyroid carcinoma from nodular goiter and healthy controls.     

Proteomic identification of new biomarkers and application in thyroid cytology

OBJECTIVE: To validate proteins identified by proteomics as potentially usable markers in thyroid pathology. STUDY DESIGN: Frozen sections of thyroid tumors were manually micro-dissected and proteins extracted. Two-dimensional (2D) gel electrophoresis and subsequent liquid chromatography/mass spectroscopy were performed, and differentially expressed proteins were identified. Validation of candidates for tumor markers (galectin-1, galectin-3, S100C and voltage-dependent anion channel 1 [VDAC1]) was done by immunohistochemistry in 21 cell blocks from fine needle aspiration biopsies (FNAB) and corresponding histology specimens (13 cases). RESULTS: Galectin-3 was negative in benign lesions and positive in FNAB from papillary carcinoma (5 of 5), follicular variant of papillary carcinoma (1 of 4) and follicular carcinoma (1 of 2). S100C was positive in some benign lesions: hyperplasia (2 of 4), goiter (1 of 3) and follicular adenoma (1 of 3), with predominantly nuclear pattern of staining. S100C was positive in malignant lesions, showing cytoplasmic location. Galectin-1 was negative in benign lesions and positive in follicular carcinoma (1 of 2), papillary carcinoma (2 of 5) and follicular variant of papillary carcinoma (1 of 4). VDAC1 was detected in benign and malignant lesions, showing a strong positivity in follicular carcinomas. CONCLUSION: Immunohistochemical validation of potential markers is a crucial step before clinical application in diagnosis. Galectin-3, galectin-1 and S100C can be used to help in discriminating benign and malignant thyroid lesions.     

Neutrophil gelatinase-associated lipocalin (NGAL) immunohistochemical expression in follicular cell-derived thyroid tumors: a novel diagnostic tool?

Discrimination of follicular cell-derived benign and malignant tumors of the thyroid is one of the major problems encountered in surgical pathology. In the present study, we evaluated the immunohistochemical expression of NGAL, an iron-binding protein involved in the infiltrative potential of cancer cells, in a cohort of tumors including 8 follicular adenomas (FA), 2 Hurthle cell adenomas (HA), 2 atypical adenomas (AA), 8 minimally invasive follicular carcinomas (MIFC), 9 widely invasive follicular carcinomas (WIFC), 3 Hurthle cell carcinomas (HC) and 8 papillary carcinomas (PC) with 5 follicular-variant PC (FVPC) and 3 not otherwise specified (PC-NOS). Our goal was to test whether evaluation of NGAL immunoexpression may be of use in the differential diagnosis of benign and malignant thyroid neoplasias. 92% of benign tumors (specificity) were negative for NGAL, whereby NGAL immuno-expression was found in 82% (sensitivity) of malignant tumors, and, specifically, in 100% of MIFC, in 87% of WIFC, in 100% of HC, in 80% of FVPC. None of the PC-NOS displayed NGAL staining. When only tumors with a follicular architecture were considered, NGAL specificity for malignant lesions was 92%; sensitivity, positive predictive value and negative predictive value were 92%, 96% and 85%. Diagnostic accuracy of NGAL expression in the differential diagnosis between benign and malignant follicular tumors was 92%. In conclusion, NGAL protein seems to represent a marker of malignant follicular cell-derived thyroid tumors, and especially of those with follicular architecture. Hence assessment of its expression might be of use with respect to differential diagnosis from follicular benign neoplasias.     

超声诊断结节性甲状腺肿合并甲状腺微小乳头状癌的价值

目的:探讨超声诊断结节性甲状腺肿合并甲状腺微小乳头状癌的价值。方法:2010年1月至2014年12月选择来我院进行诊治的结节性甲状腺肿患者80例,病理诊断为结节性甲状腺肿合并甲状腺微小乳头状癌30例(恶性组)和单纯结节性甲状腺肿50例(良性组),都进行常规二维超声、超声弹性成像和超声造影检查。结果:恶性组结节多呈现单发、内部低回声、钙化形态不规则特征,与良性组对比差异有统计学意义(P0.05)。恶性组病灶内的血流最小流速明显小于良性组(P0.05),阻力指数与搏动指数明显高于良性组(P0.05)。良性组弹性成像多为2~3分,恶性组多为4~5分,组间对比差异都有统计学意义(P0.05)。恶性组的造影剂平均通过时间明显少于对照组(P0.05),两组的显影时间、达峰时间、峰值强度对比差异无统计学意义(P0.05)。结论:常规超声诊断结节性甲状腺肿合并甲状腺微小乳头状癌的良恶性有一些特异性的征象,超声弹性成像与超声造影可为临床诊断提供补充,有助于提高甲状腺微小乳头状癌的诊断准确率。     

An Immunohistochemical Study of Leu 7 and PCNA Expression in Thyroid Neoplasms

Monoclonal Antibody (MoAb) HNK, or anti-leu-7, is reactive with several neuroendocrine and nonneuroendocrine tumors. The aim of this study is to examine anti-leu-7 reactivity in thyroid neoplasms and its relationship to cellular proliferation as determined by anti-PCNA reactivity. The expression of anti-leu-7 in 56 thyroid neoplasms (24 papillary carcinomas, 14 follicular carcinomas, two medullary carcinomas and 16 follicular adenomas) was examined immunohistochemically. Papillary and follicular thyroid carcinomas reacted with anti-leu-7 in a membranous and cytoplasmic pattern in 88% and 93% of cases, respectively. The adjacent benign tissues were nonreactive. Only eight cases diagnosed as follicular adenomas were reactive with anti-leu-7. Furthermore, the mean proliferative index (PI), as measured by the percentage of nuclei immunoreactive with anti-PCNA, was greater than 30% in all thyroid neoplasms reactive with anti-leu-7. The PI was 58% for papillary carcinomas and 68% and 48% for follicular carcinomas, and follicular adenomas, respectively. Lesions originally classified as follicular adenomas that were nonreactive with anti-leu-7 had a PI of 24% and were reclassified as hyperplastic nodules. These data suggest that anti-leu-7 may be useful for characterizing thyroid neoplasia.     

An Immunohistochemical Study of Leu 7 and PCNA Expression in Thyroid Neoplasms

Monoclonal Antibody (MoAb) HNK, or anti-leu-7, is reactive with several neuroendocrine and nonneuroendocrine tumors. The aim of this study is to examine anti-leu-7 reactivity in thyroid neoplasms and its relationship to cellular proliferation as determined by anti-PCNA reactivity. The expression of anti-leu-7 in 56 thyroid neoplasms (24 papillary carcinomas, 14 follicular carcinomas, two medullary carcinomas and 16 follicular adenomas) was examined immunohistochemically. Papillary and follicular thyroid carcinomas reacted with anti-leu-7 in a membranous and cytoplasmic pattern in 88% and 93% of cases, respectively. The adjacent benign tissues were nonreactive. Only eight cases diagnosed as follicular adenomas were reactive with anti-leu-7. Furthermore, the mean proliferative index (PI), as measured by the percentage of nuclei immunoreactive with anti-PCNA, was greater than 30% in all thyroid neoplasms reactive with anti-leu-7. The PI was 58% for papillary carcinomas and 68% and 48% for follicular carcinomas, and follicular adenomas, respectively. Lesions originally classified as follicular adenomas that were nonreactive with anti-leu-7 had a PI of 24% and were reclassified as hyperplastic nodules. These data suggest that anti-leu-7 may be useful for characterizing thyroid neoplasia.     

Expression of cytokeratin 19 and protein p63 in fine needle aspiration biopsy of papillary thyroid carcinoma

OBJECTIVE: To analyze the immunocytochemical distribution of CK19 and p63 on archival cytologic smears of 27 papillary thyroid carcinomas (PTCs), 22 benign thyroid lesions and 5 malignant non-PTC lesions. STUDY DESIGN: Archival cytologic smears of 27 papillary carcinomas, 22 benign thyroid lesions and 5 malignant nonpapillary carcinomas were processed for immunocytochemical detection of CK19 and p63, and results were compared. RESULTS: CK19 showed strong cytoplasmic staining in 22/27 fine needle aspiration biopsies (FNABs) of PTCs, in 5 benign lesions and in 4 malignant lesions of the control group. p63 Positivity was present in FNABs of 20/27 PTC and in 1 FNAB of nodular hyperplasia. Eighteen FNABs of PTC (66.6%) showed both strong CK19 staining and p63-positive cells, whereas none of the control cases showed coexpression of CK19 and p63. CONCLUSION: Coexistence of strong CK19 positivity and p63-positive cells can enhance the cytologic diagnosis of PTC.     

Usefulness of fine needle aspiration of the thyroid in an endemic goiter region

The accuracy of fine needle aspiration (FNA) cytology of the thyroid was addressed in 142 nodular goiters from an endemic goiter region. The aspirations and their interpretation were based on the methodology of the Karolinska Hospital. For practical purposes, the follicular lesions were divided into type I (benign), type II (atypical benign) and type III (suspicious). Excluding the follicular lesions, the cytohistologic agreement for the whole series was 87%, with a correlation of 81.5% for carcinomas. The type I and type II follicular lesions were benign on histologic grounds; 39% of the carcinomas were detected in the type III follicular lesions. The 0.7% false-positive diagnoses increased to 15% when type III follicular lesions were included. No false negatives were recorded. These observations, together with the increase of surgically resected thyroid carcinomas after FNA was accepted as a diagnostic modality, indicate that FNA biopsy of the thyroid is an accurate diagnostic method and is useful in selecting patients for subsequent surgery in areas of endemic goiter.     

Mitochondrial D-Loop instability in thyroid tumours is not a marker of malignancy

Despite the numerous studies describing a high frequency of mitochondrial DNA (mtDNA) somatic mutations in many types of human primary tumors the mechanisms that generate such mutations and the role of mtDNA mutations in tumor development remain unclear. We present the results obtained in the study of mtDNA displacement-loop (D-Loop) region in a series of 66 thyroid tumors, and respective adjacent parenchyma, including benign (adenomas, n=30) and malignant tumors (follicular carcinomas, n=17 and papillary carcinomas, n=19). Three repetitive regions were analyzed [two mononucleotide repetitive (D310 and D568) and one dinucleotide repetitive (D514)]. Thirty-two (48.5%) of the 66 tumors [15/30 (50.0%) adenomas, 8/17 (47.1%) follicular carcinomas and 9/19 (47.4%) papillary carcinomas] harbored somatic insertions in D-Loop repetitive regions. Twenty (30.3%) of the 66 tumors [12/30 (40%) adenomas, 3/17 (17.6%) follicular carcinomas and 5/19 (26.3%) papillary carcinomas] harbored somatic insertions at the D310 mononucleotide repeat. Three (4.6%) of the 66 tumors [1/30 (3.3%) adenomas and 2/17 (11.8%) follicular carcinomas] harbored somatic insertions at the D568 mononucleotide repeat. Fifteen (22.7%) of the 66 tumors [3/30 (10.0%) adenomas, 5/17 (29.4%) follicular carcinomas and 7/19 (36.8%) papillary carcinomas] harbored somatic insertions at the D514 dinucleotide repeat. Five (7.6%) of the 66 tumors [1/30 (3.3%) adenomas, 1/17 (5.9%) follicular carcinomas and 2/19 (10.5%) papillary carcinomas] harbored somatic insertions in more than one region, and in one of them (a carcinoma) alterations were detected in the three regions. We conclude that mutations in the mtDNA D-Loop region are frequent in benign and malignant thyroid tumors and cannot be considered a marker of malignancy. Our study shows, furthermore, two repetitive regions (D310 and D514) that appear to be susceptible to mutation in thyroid tumors.     

Diagnostic utility of galectin-3 in aspirates of thyroid follicular lesions

OBJECTIVE: To investigate the expression of galectin-3 in various thyroid follicular lesions, including diffuse hyperplasia, nodular hyperplasia, and benign and malignant follicular neoplasms, to clarify the diagnostic utility of galectin-3 in aspirates of follicular lesions. STUDY DESIGN: A total of 146 follicular lesions diagnosed cytologically, obtained from patients who had undergone thyroidectomy for either benign or malignant nodules, were evaluated using Papanicolaou-stained slides and cell blocks with galectin-3 immunostaining. We primarily categorized the aspirated specimens as benign, indeterminate or suspicious for a follicular neoplasm based on cellularity, architectural arrangement of the follicular cells and presence or absence of colloid. Galectin-3 immunostaining was evaluated according to the proportion and intensity of positively stained cells. Cytologic diagnoses were correlated with the results of galectin-3 and categorized into 3 groups (benign, indeterminate for malignancy, suspicious for malignancy) and compared with the corresponding histologic diagnoses. RESULTS: When the histologic diagnoses were compared with the cytologic diagnoses, the accuracy in the distinction between benign and malignant cases was 79.5% except for 8 cytologically and 3 histologically indeterminate cases. Except for 11 indeterminate cases, there were 18 (12.3%) discrepant cases. False positive cases included 8 of 62 (12.9%) nodular hyperplasias and 1 of 42 (2.4%) follicular adenomas. Of 9 false negative cases, 4 minimally invasive carcinomas and 2 widely invasive carcinomas were included. Three follicular tumors of uncertain malignant potential were cytologically categorized as malignant, and all cases showed positivity for galectin-3. CONCLUSION: Galectin-3 could be used as a useful supplementary marker for cytologic diagnosis, although it was not an absolute marker in determining whether a lesion was benign or malignant.     

Point mutations of ras oncogenes are an early event in thyroid tumorigenesis

Identifying the nature of the genetic mutations in thyroid neoplasms and their prevalence in the various tumor phenotypes is critical to understanding their pathogenesis. Mutational activation of ras oncogenes in human tumors occurs predominantly through point mutations in two functional regions of the molecules, codons 12, 13 (GTP-binding domain) or codon 61 (GTPase domain). We examined the prevalence of point mutations in codons 12, 13, and 61 of the oncogenes K-ras, N-ras, and H-ras in benign and malignant human thyroid tumors by hybridization of PCR-amplified tumor DNA with synthetic oligodeoxynucleotide probes. None of the eight normal thyroid tissues harbored point mutations. Four of nineteen nodules from multinodular goiters (21%), 6/24 microfollicular adenomas (25%), 3/14 papillary carcinomas (21%), and 0/3 follicular carcinomas contained ras point mutations. The predominant mutation was a valine for glycine substitution in codon 12 of H-ras. None of the multinodular goiter tumors known to be polyclonal (and thus due to hyperplasia) had point mutations, whereas one of the two monoclonal adenomas arising in nodular glands contained in H-ras codon 12 valine substitution, which was confirmed by sequencing the tumor DNA. These data show that ras activation is about equally prevalent in benign and malignant thyroid neoplasms, and thus may be an early event in the tumorigenic process.     

Expression of human pendrin in diseased thyroids.

We examined pendrin expression in various diseased thyroid tissues by immunohistochemistry (IHC) using antiserum raised against human pendrin and by real-time quantitative RT-PCR. In normal thyroids the antiserum reacted with the apical membrane of follicular cells and its immunoreactivity was faint. In Graves' thyroids, the IHC expression of pendrin appeared in a pattern similar to that of normal thyroids but it was more extensive and stronger, especially in areas showing marked proliferation of follicular cells. The immunoreactivities of pendrin in nodular goiters varied from case to case. In follicular adenomas, pendrin was localized in the follicle-forming parts of the tumor but was negative in trabecular parts. Pendrin was negative in all follicular carcinomas, papillary carcinomas, and in one case of medullary carcinoma. In quantitive mRNA analysis, the relative values of pendrin mRNA were significantly low in papillary carcinoma (p<0.01), whereas the values in other diseased thyroids were not significantly different from those in normal thyroids. These results suggest that pendrin may play a role in thyroid hormone production as the apical porter of chloride/iodide and investigation of pendrin leads to a better understanding of functional aspects of the iodine transportation system in thyroid diseases.     

Planimetric studies on fine needle aspirates from follicular adenoma and follicular carcinoma of the thyroid

A planimetric study was performed on fine needle aspiration biopsy smears from 21 follicular thyroid adenomas, 13 follicular thyroid carcinomas and 7 nontoxic goiters. The nuclear and the cytoplasmic projected areas were measured in each smear on 50 cells with intact nuclei. The nuclear-cytoplasmic area was calculated. Significant differences in mean nuclear area were found between benign and malignant follicular neoplasms and between neoplastic cells and cells from nontoxic goiter. Planimetry of cells aspirated from follicular neoplasms permitted differentiation between carcinomas and adenomas with a high degree of statistical probability.     

Expression of hepatocyte growth factor in Hashimoto's thyroiditis with nodular lesions

Hashimoto's thyroiditis (HT) is an autoimmune thyroid disease frequently associated with hyperplastic nodules (HN)s. Hepatocyte growth factor (HGF) is expressed in benign thyroid nodules and over-expressed in malignant thyroid nodules, particularly in papillary thyroid carcinomas. To elucidate the role of HGF in the development of HNs in association with HT we evaluated, by immunohistochemistry, the expression of HGF in both nodular and extranodular tissues, obtained from 30 HTs and 15 goiter samples. Six normal thyroid glands were used as controls. All normal control tissue samples exhibited no evidence of HGF immunoreaction. HNs showed weak to moderate HGF immunoreaction, which was located exclusively in the cytoplasm of stromal cells (fibroblasts and endothelial cells). However, the percentage of positive cases was higher in HNs arisen in the context of HT, compared to HNs not associated with HT (30/30 or 100% vs 4/15 or 40%; p<0.001). HGF immunoreactivity was also detected in all extranodular tissues from HT specimens (30/30 or 100%), but we found some significant differences. In fact, while in HNs observed in the context of HT lesions HGF was expressed only in stromal cells, in the extranodular tissues from the same thyroid gland affected by HT it was also detected in the cytoplasm of the epithelial follicular cells. Furthermore, HTs showed a much higher HGF staining grade in the extranodular tissue compared to HNs. Finally, a clear positive correlation was observed in HT between the proportion of HGF expressing follicular cells and the grade of lymphoid aggregates of the thyroid gland. In conclusion, HGF is much more frequently and highly expressed in thyroid tissue with HT, compared to goiter. In HT glands HGF can be detected in both follicular thyroid cells and stromal cells, while in HNs, either from goiters or associated with HT, its expression is restricted only to the stromal cells. These data indicate that HGF may play a role in cell proliferation processes occurring in thyroid glands affected by HT, probably under the regulation of the lymphoid infiltrate.     

Molecular analysis of structural abnormalities in papillary thyroid carcinoma gene

Rearrangements of the RET proto-oncogene (RET/PTC) and BRAF gene mutations are the major genetic alterations in the etiopathogenesis of papillary thyroid carcinoma (PTC). We have analyzed a series of 118 benign and malignant follicular cell-derived thyroid tumors for RET/PTC rearrangements and BRAF gene mutations. Oncogenic rearrangements of RET proto-oncogene was revealed by semiquantitative RT-PCR of simultaneously generated fragments corresponding to tyrosine kinase (TK) and extracellular RET domains. The clear quantitative shift toward the TK fragment is indicative for the presence of RET rearrangements. The overall frequency of RET/PTC rearrangements in PTC was 14% (12 of 85), including 7 RET/PTC1, 2 RET/PTC3, 1 deltaRFP/RET and 2 apparently uncharacterized rearrangements. The most common T1796A transversion in BRAF gene was detected in 55 of 91 PTC (60%) using mutant-allele-specific PCR. We also identified two additional mutations: the substitution G1753A (E585K) and a case of 12-bp deletion in BRAF exon 15. Moreover, there was no overlap between PTC harboring BRAF and RET/PTC mutations, which altogether were present in 75.8% of cases (69 of 91). Taken together, our observations are consistent with the notion that BRAF mutations appear to be an alternative pathway to oncogenic MAPK activation in PTCs without RET/PTC activation. Neither RET/PTC rearrangements nor BRAF muta-tions were detected in any of 3 follicular thyroid carcinomas, 11 follicular adenomas and 13 nodular goiters. The high prevalence of BRAF mutations and RET/PTC rearrangements in PTCs and the specificity of these alterations to PTC make them potentially important markers for the preoperative tumor diagnosis.     

Evaluation of HMFG2 and thyroglobulin in the diagnosis of thyroid fine needle aspiration (FNA)

In order to appraise the usefulness of HMFG₂ and thyroglobulin (Tg) as specific markers for the diagnosis of thyroid disease, we studied 63 FNA smears. Cases tested included 30 benign (nine colloid goitres, six cases of Hashimoto's thyroiditis, six Hürthle cell adenomas, nine follicular adenomas) and 33 malignant lesions (nine follicular carcinomas, 12 papillary carcinomas, nine anaplastic carcinomas, three medullary carcinomas). All cases with malignant lesions except the anaplastic carcinomas were positive for HMFG₂. Immunoreactive cells to HMFG₂ were also found in 15 adenomas out of 30 benign cases. Positive Tg reaction was found in benign and malignant thyroid lesions, except six cases of Hashimoto's thyroiditis, nine anaplastic and three medullary carcinomas. The results obtained indicate that morphology paired with immunocytochemistry can usually depict a more specific profile of thyroid lesions for better evaluation of the pathology.     

Sensitivity and specificity of fine needle aspiration cytology in the diagnosis of tumors of the thyroid gland

A study of the preoperative fine needle aspiration cytologies in consecutive patients with primary malignant tumors (203 cases) or benign thyroid tumors (217 cases) showed a sensitivity of 0.57 and a specificity of 0.98. The sensitivity of FNA cytology in medullary and undifferentiated carcinomas was 0.82 and 0.84, respectively; none of these were microscopically misdiagnosed. The sensitivity was only 0.58 for papillary carcinomas (excluding occult carcinoma) and 0.42 for follicular carcinoma. Four reasons for these low sensitivities were identified: tumors missed at aspiration, microscopic misinterpretations, diagnoses of cellular atypia and indeterminate diagnoses. Reevaluation of the false diagnoses once more emphasized the problem of distinguishing follicular adenomas from follicular carcinomas. Microscopically undiagnosed papillary carcinomas were either the result of misinterpretations of the characteristic cytomorphologic features or of the smears being misdiagnosed as showing cellular atypia when papillary formations were missing and only one or two of the other cellular criteria were evident. The specificity of FNA cytology of thyroid tumors was found to be high enough to permit surgical intervention after a cytodiagnosis of malignancy.