Intermediate-risk thyroid carcinoma: indicators of a poor prognosis

ABSTRACT Objective: The intermediate-risk (IR) category includes tumors with different degrees of aggression. We aimed to identify the risk factors associated with unfavorable response to initial treatment and compare the effect of low/high radioactive iodine (RAI) therapy. Subjects and methods: A total of 614 IR patients were selected from a database, during 1972-2015. All patients underwent total thyroidectomy and RAI therapy and were reclassified after 12-18 months into the favorable (complete/indeterminate) response group and the unfavorable (biochemical/incomplete structural) response group. A total of 92 patients were assessed for late response (mean: 9.19 ± 5.73 years). Age, gender, tumor size, histology, multifocality, vascular invasion, extrathyroidal extension, presence and number of lymph node metastasis, and stimulated thyroglobulin at ablation (sTg) were evaluated. Results: Mean age at diagnosis was 41.47 ± 15.81 years, and 83.6% of the patients were female. Within 12-18 months after initial therapy, unfavorable response was detected in 41.2% of the patients and was associated, in multivariate analysis, with lymph node metastasis (p = 0.041; odds ratio [OR] = 1.9), presence of more than five metastatic lymph nodes (p = 0,017; OR = 2.6), and sTg > 10 ng/mL (p = 0.005; OR = 10.0). For patients with a longer follow-up, sTg >10 ng/mL was associated with unfavorable response (p = 0.002; OR = 6.8). A higher RAI dose was not related to better prognosis at the end of the follow-up. Conclusion: A sTg level of >10 ng/mL and lymph node metastasis were associated with an unfavorable response 12-18 months after initial treatment. A RAI dose below 150 mCi was proven sufficient to treat IR patients.

La densidad óptica nuclear como indicador diagnóstico en el carcinoma papilar de tiroides / Nuclear optical density as a diagnostic indicator in papillary thyroid carcinoma

Introducción: El carcinoma papilar de tiroides es la causa más frecuente de cáncer de naturaleza endocrina. Constituye la variante histológica de mejor pronóstico, sin embargo, en ocasiones es motivo de importantes dudas diagnósticas con otras variantes de evolución tórpida, lo que dificulta que un mayor número de pacientes se beneficie con un tratamiento individualizado y conservador. Por esta razón, se desarrollan estudios en los que cada vez más se añaden procedimientos morfométricos y densitométricos, los que permiten disminuir la subjetividad en el diagnóstico histopatológico. Objetivo: Determinar la densidad óptica nuclear en el carcinoma papilar de tiroides. Método: Se realizó un estudio morfométrico de serie de casos con 12 pacientes con carcinoma papilar de tiroides, atendidos en el Hospital Provincial Universitario Vladimir Ilich Lenin. Se seleccionaron 36 campos y se midieron 965 núcleos celulares, lo que constituyó la muestra del estudio. Se determinó la densidad óptica nuclear como indicador morfométrico del carcinoma papilar de tiroides. Resultados: El valor de la densidad óptica nuclear fue 1,14, considerado bajo. Conclusiones: Se determinó la densidad óptica nuclear del carcinoma papilar de tiroides en los casos estudiados, lo que puede contribuir a su diagnóstico histopatológico(AU)

Background: Papillary thyroid carcinoma is the most frequent cause of endocrine cancer. It is an histological variant with the best prognosis, however, sometimes it is a reason for significant diagnostic doubts with other variants of torpid evolution, which makes it difficult for a greater number of patients to benefit from an individualized and conservative treatment. For this reason, studies are developed in which more and more morphometric and densitometric procedures are added, which allow reducing the subjectivity in the histopathological diagnosis and could represent a tool of great value. Objective: To determine the nuclear optical density in papillary thyroid carcinoma. Method: A morphometric study of a series of cases was carried out with 12 patients with this histopathological diagnosis, attended at the Vladimir Ilich Lenin University Provincial Hospital. We chose 36 fields and 965 cell nuclei were measured, which constituted the study sample. Nuclear optical density was determined as a morphometric indicator of papillary thyroid carcinoma. Results: The value of nuclear optical density was 1, 14. It is considered low. Conclusion: Nuclear optical density of papillary thyroid carcinoma was determined in the studied cases that may contribute to histopathological diagnosis(AU)

A case of tumor-to-tumor metastasis of cutaneous malignant melanoma.

We report a case of tumor-to-tumor metastasis of a cutaneous malignant melanoma to a synchronous thyroid Hurthle cell carcinoma. A 42-year-old male underwent a biopsy of right inguinal lymphadenopathy which showed metastatic melanoma. The primary lesion was identified on his right posterior leg, and staging workup discovered a synchronous left thyroid lobe nodule concerning for a follicular neoplasm. He underwent excision of the primary melanoma, right inguinal lymphadenectomy, and total thyroidectomy. The resected thyroid contained a 6.6-cm, well-encapsulated left-sided nodule, red-brown in color and homogenous in consistency, with areas of focal hemorrhage and no grossly identifiable calcification. Microscopically, large tumor cells with distinct cell borders were present, with deeply eosinophilic and granular cytoplasm, large nuclei with prominent nucleoli, and loss of polarity consistent with oncocytes. A microscopic single focus of vascular invasion was identified, and a diagnosis of angioinvasive Hurthle cell carcinoma was made. Within the Hurthle cell carcinoma, multiple deposits of metastatic melanoma were seen. These findings were indicative of tumor-to-tumor metastasis of the cutaneous melanoma to the angioinvasive Hurthle cell carcinoma. Our findings show the ability of melanoma to metastasize to a pre-existing neoplasm.

Impact of image analysis and artificial intelligence in thyroid pathology, with particular reference to cytological aspects.

OBJECTIVE: Thyroid pathology has great potential for automated/artificial intelligence algorithm application as the incidence of thyroid nodules is increasing and the indeterminate interpretation rate of fine-needle aspiration remains relatively high. The aim of the study is to review the published literature on automated image analysis and artificial intelligence applications to thyroid pathology with whole-slide imaging. METHODS: Systematic search was carried out in electronic databases. Studies dealing with thyroid pathology and use of automated algorithms applied to whole-slide imaging were included. Quality of studies was assessed with a modified QUADAS-2 tool. RESULTS: Of 919 retrieved articles, 19 were included. The main themes addressed were the comparison of automated assessment of immunohistochemical staining with manual pathologist's assessment, quantification of differences in cellular and nuclear parameters among tumour entities, and discrimination between benign and malignant nodules. Correlation coefficients with manual assessment were higher than 0.76 and diagnostic performance of automated models was comparable with an expert pathologist diagnosis. Computational difficulties were related to the large size of whole-slide images. CONCLUSIONS: Overall, the results are promising and it is likely that, with the resolution of technical issues, the application of automated algorithms in thyroid pathology will increase and be adopted following suitable validation studies.

Characterizing the three-dimensional organization of telomeres in papillary thyroid carcinoma cells.

The relationship between the three-dimensional (3D) nuclear telomere architecture and specific genetic alterations in papillary thyroid carcinoma (PTC), in particular in cancer stem-like cells (CSLCs), has not yet been investigated. We isolated thyrospheres containing CSLCs from B-CPAP, K1, and TPC-1 PTC-derived cell lines, representative of tumors with different genetic backgrounds within the newly identified BRAFV600E -like PTC subgroup, and used immortalized normal human thyrocytes (Nthy-ori 3.1) as control. We performed quantitative fluorescence in situ hybridization, 3D imaging, and 3D telomere analysis using TeloView software to examine telomere dysfunction in both parental and thyrosphere cells. Among the 3D telomere profile, a wide heterogeneity was observed, except for telomere intensity. Our findings indicate that CSLCs of each cell line had longer telomeres than parental cells, according to telomere intensity values, which correlate with telomere length. Indeed, the thyrosphere cells had lower numbers of lower-intensity telomeres (≤5,000 arbitrary fluorescent units, a.u.), compared with parental cancer cells, as well as parental control cells, (p < 0.0001). The B-CPAP thyrospheres showed a decreased number of higher intensity telomeres (>17,000 a.u.) than K1 and TPC-1 cells, as well as control cells (p < 0.0001). By selecting PTC-derived cell lines with different genetic backgrounds characteristic of BRAFV600E -like PTC subgroups, we demonstrate that thyrosphere cells with BRAFV600E and TP53 mutations show shorter telomeres than those harboring RET/PTC or BRAFV600E and wild-type TP53. Hence, our data reveal a trend towards a decrease in telomere shortening in CSLCs, representing the early cancer-promoting subpopulation, as opposed to parental cells representing the tumor bulk cells.

Volumetric and texture analysis of pretherapeutic 18F-FDG PET can predict overall survival in medullary thyroid cancer patients treated with Vandetanib.

PURPOSE: The metabolically most active lesion in 2-deoxy-2-(18F)fluoro-D-glucose (18F-FDG) PET/CT can predict progression-free survival (PFS) in patients with medullary thyroid carcinoma (MTC) starting treatment with the tyrosine kinase inhibitor (TKI) vandetanib. However, this metric failed in overall survival (OS) prediction. In the present proof of concept study, we aimed to explore the prognostic value of intratumoral textural features (TF) as well as volumetric parameters (total lesion glycolysis, TLG) derived by pre-therapeutic 18F-FDG PET. METHODS: Eighteen patients with progressive MTC underwent baseline 18F-FDG PET/CT prior to and 3 months after vandetanib initiation. By manual segmentation of the tumor burden at baseline and follow-up PET, intratumoral TF and TLG were computed. The ability of TLG, imaging-based TF, and clinical parameters (including age, tumor marker doubling times, prior therapies and RET (rearranged during transfection) mutational status) for prediction of both PFS and OS were evaluated. RESULTS: The TF Complexity and the volumetric parameter TLG obtained at baseline prior to TKI initiation successfully differentiated between low- and high-risk patients. Complexity allocated 10/18 patients to the high-risk group with an OS of 3.3 y (vs. low-risk group, OS = 5.3 y, 8/18, AUC = 0.78, P = 0.03). Baseline TLG designated 11/18 patients to the high-risk group (OS = 3.5 y vs. low-risk group, OS = 5 y, 7/18, AUC = 0.83, P = 0.005). The Hazard Ratio for cancer-related death was 6.1 for Complexity (TLG, 9.5). Among investigated clinical parameters, the age at initiation of TKI treatment reached significance for PFS prediction (P = 0.02, OS, n.s.). CONCLUSIONS: The TF Complexity and the volumetric parameter TLG are both independent parameters for OS prediction.

Noninvasive follicular thyroid neoplasm with papillary-like nuclear features: A distinct clinicopathologic entity.

OBJECTIVE: The objective of this study is to retrospectively evaluate follicular variant of papillary thyroid carcinoma (FVPTC) and reclassify encapsulated FVPTC as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) according to the criteria proposed by The Endocrine Pathology Society working group in 2015 to correlate with outcome. MATERIALS AND METHODS: Retrospective review of case records of all patients diagnosed as carcinoma of thyroid between 2015 and 2016 was done for the histologic subtype. Gross and microscopic features on resected specimens of FVPTC were reviewed and subtyped as invasive and encapsulated based on capsular/vascular invasion; the encapsulated forms were further studied for size, number, follicular architecture, nuclear features, presence of psammoma bodies, stromal fibrosis, necrosis, mitoses, and lymph node status. RESULTS: Out of the 383 patients with thyroid carcinomas in the study period, 349 were PTC which included 106 FVPTC. Thirty-three patients fulfilled the criteria to be labeled as NIFTP. Total thyroidectomy was performed in 8 patients and hemithyroidectomy in 25 patients. Lymph node dissection along with total thyroidectomy was done in 3 and completion thyroidectomy following hemithyroidectomy was done in 9. There were 29 single and 4 multiple lesions with size varying from 0.2 to 7 cm including 5 lesions measuring <1 cm. The involvement was confined to one lobe in 31 and both lobes in 2 specimens. Patients are on follow-up with no recurrence till date. CONCLUSION: Thyroid carcinomas currently diagnosed as FVPTC should be evaluated for criteria of NIFTP to avoid overtreatment as they have an indolent behavior.

Tumor and normal thyroid spheroids: from tissues to zebrafish.

BACKGROUND: Multicellular spheroids represent an interesting experimental model with promising applications in the pre-clinical studies on anticancer drugs. We recently demonstrated that thyroid spheroids recapitulate the features of the original tissues, in either the differentiated and "stem-like" components. Here we were aimed to characterize thyroid spheroids and to investigate in vivo the proangiogenic potential of patient-derived xenografts (PDX) of spheroids obtained from papillary thyroid cancer (PTC) and the matched normal tissues. METHODS: Spheroids cultures were obtained from 11 PTCs and matched normal tissues and characterized by immunohistochemistry. The expression of p53, involved in the regulation of stem cell homeostasis, was evaluated. The proangiogenic effect of thyroid spheroids was assessed by the injection in zebrafish embryos. RESULTS: Thyroid spheroids are enriched in stem-like cells, as shown by the positivity for the stem cell marker OCT4, and by the low level of p53 expression. Interestingly, PTCs and normal thyroid tissues have a detectable p53 expression, whereas the derived spheroids are mainly constituted by cells that express p53 at a lower level. Finally, we show that PDXs derived from PTC or normal spheroids stimulate the migration and the growth of sprouting vessels toward the implant into the zebrafish embryos. CONCLUSIONS: We report the characterization of multicellular spheroids obtained from PTCs and normal thyroid tissues, showing that they are enriched in stem-like cells. Moreover, we established xenografts of spheroids in zebrafish, demonstrating that they stimulate neoangiogenesis. This in vivo model could be considered as a valuable platform to test the effects of anticancer drugs.

Noninvasive follicular thyroid neoplasm with papillary-like nuclear features.

PURPOSE OF REVIEW: The purpose of this review is to present an overview regarding the renaming of encapsulated follicular variant of papillary thyroid cancer as 'noninvasive follicular thyroid neoplasm with papillary-like nuclear features'. RECENT FINDINGS: A recent retrospective study has shown the excellent clinical outcomes of noninvasive encapsulated follicular variant of papillary thyroid cancer, for which the diagnosis is based on a thorough examination of all tumor tissue and its capsule to exclude any vascular or capsular invasion. Given the extremely low malignant potential of this entity, the term cancer was eliminated from its name, as this tumor requires less aggressive follow-up and treatment. SUMMARY: The low-risk tumor was previously treated conservatively prior to its renaming. However, elimination of the term cancer from its name may decrease the psychological and social consequences of its diagnosis.

Thyroid carcinoma showing thymus-like elements: a clinicopathologic, immunohistochemical, ultrastructural, and molecular analysis.

OBJECTIVES: To investigate the clinicopathologic, immunophenotypic, ultrastructural, and molecular features of thyroid carcinoma showing thymus-like elements (CASTLE). METHODS: We retrospectively analyzed the clinicopathologic data of 10 patients with CASTLE and described the immunophenotypic and ultrastructural features of these tumors. The expression of Epstein-Barr virus-encoded RNA and the gene status of EGFR, C-KIT, and HER-2 were also assessed by molecular techniques. RESULTS: The tumor cells were positive for CD5, CD117, p63, HMWK, EGFR, GLUT-1, Pax8, E-cadherin, bcl-2, and p53 in all cases and for CA-IX, CEA, p16, HER-2, and neuroendocrine markers in some cases. Ultrastructural examination indicated that the tumor cells contained large quantities of tonofilament with abundant intercellular desmosomes, including intracytoplasmic neuroendocrine granules in one case. EGFR gene amplification in two patients and polyploidy of chromosome 7 in one patient were identified by fluorescence in situ hybridization. Sequencing analysis revealed that a synonymous mutation, Q787Q 2363 (G→A), occurred on exon 20 of the EGFR gene in three patients. CONCLUSIONS: GLUT-1 can be used as a novel biomarker for CASTLE, and combined detection of GLUT-1 with CD5 and CD117 aids in the diagnosis of this tumor. Aberrant expression of Bcl-2, p53, p16, E-cadherin, EGFR, C-KIT, and HER-2 may play important roles in the development of CASTLE.

Malignant glomus tumor of the thyroid gland where is heretofore an unreported organ: a case report and literature review.

Glomus tumors are relatively uncommon clinically benign tumors. Malignant glomus tumors are rare, and only a small number develop metastatic foci. The usual location is deep dermis or subcutis, but it has been reported in various locations. A 55-year-old man presented with an incidentally found thyroid mass. Neck ultrasound showed a mass with a heterogeneous hypoechoic calcific mass in the right lobe. Right lobectomy specimen showed the 3.6-cm-sized calcified mass composed of sheets of uniform round to polygonal cells and intervening staghorn-shaped vessels. Occasional cellular atypism and necrosis with increased mitotic activity (up to 7 per 10 high-power fields) were found. Infiltration to the residual thyroid parenchyma, vessel, thyroidal capsule, and strap muscle was found. These tumor cells were strongly positive for smooth muscle actin, collagen type IV, and vimentin with pericellular reticulin-cuffing. Ultrastructurally, closely packed oval-shaped tumor cells having cytoplasmic mitochondria, rough endoplasmic reticulums with pinocytotic vesicles along the plasmalemmal surface and thin filaments of 6 nm in diameter were surrounded by thick basal lamina. That mass was diagnosed as a malignant glomus tumor. Incidentally, a 0.5-cm-sized papillary carcinoma was found through entire embedding. Complete thyroidectomy with chemotherapy was done. Thirty months later, multiple metastases developed in the brain and lung, and he expired. To our knowledge, neither benign nor malignant thyroid glomus tumor has been previously described. Here, we describe the first case of a malignant glomus tumor in the thyroid gland.

Intrathyroidal tumors presenting with extranodal extension: what are we missing?

Extranodal extension (ENE) is an indicator of poor prognosis in well-differentiated thyroid cancer (WDTC). We have demonstrated that extrathyroidal extension (ETE) predicts ENE in patients with positive lymph nodes, indicating concordance between primary tumor and lymph node biology. In an effort to determine if there were other histologic features of the primary tumors that indicated an aggressive biology, we examined a subset of patients with intrathyroidal (T1/T2) disease whose lymph nodes had ENE. A review was conducted from January 2004 to March 2013. The histologic features of ETE-negative/ENE-positive tumors (group A, 12 cases) were compared with a random sample of ETE-negative/ENE-negative node-positive patients (group B, 27 cases). Cases were reviewed for size, capsule presence, infiltration, sclerosis, lymphocytic thyroiditis (LT), psammoma bodies, lymphovascular invasion (LVI), perineural invasion (PNI), architecture/cytomorphology, and focality. Size was compared using the Mann-Whitney test, while the remaining features were compared using a Fischer exact test. The breakdown of pathologic features of groups A/B were as follows: 2.28 cm/1.46 cm mean tumor size, 90 %/67 % unencapsulated, 100 %/89 % infiltrative, 100 %/89 % sclerotic, 60 %/52 % LT, 30 %/59 % positive psammoma bodies, 0 %/11 % LVI, 0 %/4 % PNI, 90 %/96 % classic architecture, 50 %/44 % multifocal. Neither size (p = 0.072) nor the other nine histologic features examined reached statistical significance. None of the histologic features appeared to significantly predict ENE. Further examination of intrathyroidal tumors at a molecular level is necessary to determine if there are any identifiable features of intrathyroidal tumors that predict ENE and thus a more aggressive phenotype.

Oncocytic lesions of the neuroendocrine system.

This paper reviews the pathologic features of lesions which are oncocytic and involve classic endocrine organs. The history of the oncocytic cell, its morphologic and ultrastructural features, and important immunohistochemical findings are reviewed. Oncocytic proliferations including non-neoplastic and neoplastic of the thyroid, parathyroid, adrenal (both cortex and medulla), and pituitary are described. Their clinical relevance, functional capacity and capability, and where appropriate, prognostic implications are discussed. Important and relevant molecular biological information is included where appropriate.

Highlighting nuclear membrane staining in thyroid neoplasms with emerin: review and diagnostic utility.

Immunohistochemical staining (IHC) with emerin, an integral inner nuclear membrane protein, highlights nuclear membrane details in papillary thyroid carcinoma (PTC). We evaluated emerin for highlighting nuclear shape, grooves, inclusions, circumferential nuclear membrane irregularities ("garlands"), deep "stellate" membrane invaginations, and crescents in 34 fine-needle aspiration (FNA) cell blocks, PTC (n = 24) and follicular neoplasms (FN) (n = 10). Tissue microarrays were also examined for 182 cases, PTC (n = 95) and non-PTC (n = 87). Emerin IHC of PTC revealed a predominantly oval nuclear shape in the majority of cases, with FN demonstrating round nuclei and FV of PTC showing a roughly equal distribution of round and oval shapes. In addition to oval nuclear shape, the presence of emerin-positive nuclear grooves, circumferential emerin nuclear "garlands," nuclear crescent shapes, and chromatin clearing on cell block H&E staining were significant predictors of PTC by regression analysis. Emerin IHC of thyroid FNA and surgical specimens serves as a useful adjunct to conventional H&E staining in the diagnosis of PTC and its distinction from FN by delineating diagnostic nuclear membrane irregularities ("garlands" and crescents), nuclear grooves, and a characteristic oval nuclear shape. In diagnostically challenging cases with limited cellularity, emerin staining can help to provide a more definitive diagnosis of PTC.

The prognostic significance of nodal metastases from papillary thyroid carcinoma can be stratified based on the size and number of metastatic lymph nodes, as well as the presence of extranodal extension.

BACKGROUND: Ultrasound and prophylactic dissections have facilitated identification of small-volume cervical lymph node (LN) metastases in patients with papillary thyroid carcinoma (PTC). Since most staging systems do not stratify risk based on size or number of LN metastases, even a single-microscopic LN metastasis can upstage a patient with low-risk papillary thyroid microcarcinoma (PMC) to an intermediate risk of recurrence in the American Thyroid Association (ATA) system and to an increased risk of death in the American Joint Committee on Cancer (AJCC) staging system (stage III if the metastatic node is in the central neck or stage IVA if the microscopic LN metastasis is identified in the lateral neck). Such microscopic upstaging may lead to potentially unnecessary or additional treatments and follow-up studies. The goal of this review is to determine if the literature supports the concept that specific characteristics (clinically apparent size, number, and extranodal extension) of LN metastases can be used to stratify the risk of recurrence in PTC. SUMMARY: In patients with pathological proven cervical LN metastases (pathological N1 disease; pN1), the median risk of loco-regional LN recurrence varies markedly by clinical staging, with recurrence rates for patients who are initially clinically N0 (clinical N0 disease; cN0) of 2% (range 0%-9%) versus rates of recurrence for patients who are initially clinically N-positive (clinical N1 disease; cN1) of 22% (range 10%-42%). Furthermore, the median risk of recurrence in pN1 patients varies markedly by the number of positive nodes, <5 nodes (4%, range 3%-8%) vs. >5 nodes (19%, range 7%-21%). Additionally, the presence of extranodal extension was associated with a median risk of recurrence of 24% (range 15%-32%) and possibly a worse disease-specific survival. CONCLUSION: Our previous paradigm assigned the same magnitude of risk for all patients with N1 disease. However, small-volume subclinical microscopic N1 disease clearly conveys a much smaller risk of recurrence than large-volume, macroscopic clinically apparent loco-regional metastases. Armed with this information, clinicians will be better able to tailor initial treatment and follow-up recommendations. Implications of N1 stratification for PTC into small-volume microscopic disease versus clinically apparent macroscopic disease importantly relate to issues of prophylactic neck dissection utility, need for pathologic nodal size description, and suggest potential modifications to the AJCC TNM (tumor, nodal disease, and distant metastasis) and ATA risk recurrence staging systems.

Unusual thyroid carcinoma with excessive extracellular hyaline globules: a case of "hyalinizing papillary carcinoma".

We present an unusual case of papillary thyroid carcinoma in a 47-year-old Japanese woman. The tumor, 0.8 cm in diameter, was located in the upper left lobe of the thyroid. Histologically, we observed a microfollicular-like and trabecular arrangement of the tumor cells with marked hyalinized stroma and hyaline globules. Immunohistochemically, tumor cells were positive for thyroglobulin and thyroid transcription factor 1. Hyaline stroma and globular bodies were immunopositive for laminin and type IV collagen. MIB-1 index was approximately 1% without membranous immunoreactivity. Under the electron microscope, hyaline stroma and globules showed electron-dense, complex meshwork structures composed of granular and fibrous elements similar to the structure of the lamina densa. Genetic analysis demonstrated a BRAF(V600E) mutation. Based on these findings, we diagnosed the present tumor as a rare morphological variation of papillary thyroid carcinoma with excessive hyaline globules consisting of basal membrane materials.

Clinical, sonographic and cytological evaluation of small versus large thyroid nodules.

OBJECTIVE: To study the clinical presentation, thyroid function tests, ultrasound (US) features, cytology and surgical pathology results of patients undergoing fine needle aspiration (FNA) biopsy of thyroid nodules and to determine if a significant difference exists in the above variables between small (less than 1 cm) and large (1 cm or more) thyroid nodules. METHODS: The study is a retrospective chart review study involving patients undergoing FNA of thyroid nodules at Marshall University Endocrine Clinic. Study data on patient demographics, clinical presentation, physical examination findings, thyroid function tests, US features, cytology and surgical pathology were collected and analyzed. RESULTS: A total of 122 patients were included in the study including 18 patients with small and 104 patients with large thyroid nodules. Females were 88%. The overall mean age of patients was 56 +/- 15 years. Most of the patients (63%) were asymptomatic on presentation. Only 20% patients had their nodules reported to be palpable on physical examination. Solitary nodules as well as the dominant nodule in multi-nodular goiters in both groups were more frequently localized to the right lobe of thyroid gland. The mean US size was 0.7 +/- 0.15 cm for small and 2.4 +/- 1.2 cm for large nodules. Patients with small nodules presented at an earlier age (45 +/- 14 years Vs 58 +/- 15, years p = 0.008) and were more likely to have family history of thyroid cancer (p = 0.023), as compared to patients with large nodules. However, there was no other significant difference identified in clinical presentation, cytology results and prevalence rate of thyroid cancer between patients with small and large thyroid nodules. CONCLUSION: In this study patients with small thyroid nodules presented at an earlier age and were more likely to have family history of thyroid cancer as compared to those with large nodules. There were no other significant differences in other study variables between small and large thyroid nodules. Further studies with large sample size in each group are needed to verify our results.

Tumor-associated macrophages (TAMs) form an interconnected cellular supportive network in anaplastic thyroid carcinoma.

BACKGROUND: A relationship between the increased density of tumor-associated macrophages (TAMs) and decreased survival was recently reported in thyroid cancer patients. Among these tumors, anaplastic thyroid cancer (ATC) is one of the most aggressive solid tumors in humans. TAMs (type M2) have been recognized as promoting tumor growth. The purpose of our study was to analyze with immunohistochemistry the presence of TAMs in a series of 27 ATC. METHODOLOGY/PRINCIPAL FINDINGS: Several macrophages markers such as NADPH oxidase complex NOX2-p22phox, CD163 and CD 68 were used. Immunostainings showed that TAMs represent more than 50% of nucleated cells in all ATCs. Moreover, these markers allowed the identification of elongated thin ramified cytoplasmic extensions, bestowing a "microglia-like" appearance on these cells which we termed "Ramified TAMs" (RTAMs). In contrast, cancer cells were totally negative. Cellular stroma was highly simplified since apart from cancer cells and blood vessels, RTAMs were the only other cellular component. RTAMs were evenly distributed and intermingled with cancer cells, and were in direct contact with other RTAMs via their ramifications. Moreover, RTAMs displayed strong immunostaining for connexin Cx43. Long chains of interconnected RTAMs arose from perivascular clusters and were dispersed within the tumor parenchyma. When expressed, the glucose transporter Glut1 was found in RTAMs and blood vessels, but rarely in cancer cells. CONCLUSION: ATCs display a very dense network of interconnected RTAMs in direct contact with intermingled cancer cells. To our knowledge this is the first time that such a network is described in a malignant tumor. This network was found in all our studied cases and appeared specific to ATC, since it was not found in differentiated thyroid cancers specimens. Taken together, these results suggest that RTAMs network is directly related to the aggressiveness of the disease via metabolic and trophic functions which remain to be determined.

Abnormal nuclear structures (micronuclei, nuclear blebs, strings, and pockets) in a case of anaplastic giant cell carcinoma of the thyroid: an immunohistochemical and ultrastructural study.

The authors report a case of a 70-year-old woman with an anaplastic giant cell thyroid carcinoma, along with immunohistochemical and electron microscopic findings. Histologically, the tumor is characterized by mononucleated and multinucleated giant cells, lack of architectural cohesion, atypical mitoses, and extensive areas of coagulative necrosis. Tumor cells showed AE1/AE3 positivity as well as nuclear overexpression of p53 and ki-67. Semithin sections revealed multiple nuclei with heterogeneous size ranging from micronuclei to large-size (giant) nuclei. Micronuclei were confirmed by electron microscopy that disclosed also the presence of nuclear blebs, strings, and pockets. Morphological findings of these abnormal nuclear structures in conjunction with p53 and Ki-67 nuclear overexpression suggested a faulty mitotic checkpoint/mitotic catastrophe in the progression of anaplastic giant cell thyroid carcinoma.

[Expression of matrix metalloproteinases 2 and 9 and their tissue inhibitors 1 and 2 in papillary thyroid cancer: an association with the clinical, morphological and ultrastructural characteristics of a tumor].

Papillary thyroid cancer (PTC) was ascertained to be characterized by a significant expression of matrix metalloproteinases (MMP-2 and 9) and a TIMP-2 inhibitor and decreased TIMP-1 accumulation in the cytoplasm of tumor cells; at the same time a combination of high cytoplasmic MMP-9 expression with no TIMP-1, as well as triple positive co-expression of MMP-2, MMP-9, and TIMP-2 are poor immunohistochemical indicators. The results of the performed study suggest that the detection of the types of expression of MMP-9+/TIMP-1 and MMP-2+/MMP-9+/TIMP-2+ is associated with the possible progression of a tumor process and concurrent with poor clinical and morphological signs, such as the large size of the tumor, the presence of intravascular invasion and regional metastases, organ capsular invasion, and low ultrastructural tumor cell differentiation. Thus, changes in the tumor expression of the extracellular matrix enzymes MMR-2 and MMP-9 and their inhibitors TIMP-1 and TIMP-2 along with the major clinical, morphological, and ultrastructural signs of the disease are important additional indicators for analyzing the malignant potential of PTC.