Pathological findings of the retrospective diagnosis of NIFTP (non-invasive follicular thyroid neoplasm with papillary-like nuclear features) in 84 cases from Turkey and systematic review.

AIM: The terminology of "noninvasive follicular thyroid neoplasm with papillary-like nuclear features" (NIFTP) was introduced in 2016; and estimated to cause significant effects in the clinical management of thyroid nodules. The aim of our study is to review our cases that were previously diagnosed as non-invasive encapsulated follicular variant PTC (NI/E-FVPTC) which are compatible with NIFTP and to correlate their follow-up. METHOD: All thyroidectomy cases evaluated in the last 15 years were screened, and possible NIFTP cases were determined among patients with NI/E-FVPTC and they were re-examined microscopically. Revised histopathological criteria were used for the retrospective diagnosis of NIFTP. Histopathological findings were correlated to follow up information. RESULTS: Totally 2138 cases had been previously diagnosed with PTC; 481 (22.5%) of them were FVPTC. After microscopic reevaluation of potential NIFTP cases, 84 cases (3.9%) received final diagnosis of NIFTP. 78.6% of NIFTP patients were female (F/M: 66/18); mean age was 49.0, tumor diameter was 22.7 mm and follow-up time was 66.4 months. 17.9% of NIFTP cases were multifocal and 13.1% were bilateral. No recurrence, lymph node involvement or distant metastasis was detected in any of the patients who were followed up. The mean age of the patients who had total thyroidectomy and received RAI was significantly higher than those who did not. CONCLUSION: Although conservative treatment of NIFTP with lobectomy is recommended, age of the patients has been continuing to be the most important determinant for the clinicians to decide on total thyroidectomy and RAI ablation therapy at our institution.

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.

Involvement of centrosomes in nuclear irregularity of thyroid carcinoma cells.

Nuclear irregularities including nuclear pseudoinclusions and nuclear grooves are characteristic of papillary thyroid carcinoma cells and are regarded as important diagnostic clues in histopathology. We observed nuclear features of thyroid carcinoma cell lines (KTC-1 and TPC-1) in various culture conditions and performed immunocytochemical examinations for cytoskeleton molecules to clarify the morphogenesis of thyroid carcinoma nuclei. We found that nuclear irregularities presenting as bean-like nuclei (BLNs) and donut-like nuclei (DLNs) appeared in cells from confluent cultures, but not in cells from sparse cultures. On immunocytofluorescence analyses, clusters of gamma-tubulin, representing a centrosome, frequently localized at the indentation of BLNs or in the hole of DLNs of thyroid carcinoma cells. In conclusion, we suggest that cell-to-cell contact may affect nuclear changes such as BLNs and DLNs in cancer cell lines and that centrosomes may be involved in the morphogenetic process of these nuclear changes.

Fine needle aspiration cytology of mixed medullary-follicular thyroid carcinoma: a case report.

BACKGROUND: Mixed medullary-follicular thyroid carcinoma (MMFTC) is a rare tumor that has been regarded as a clinicopathologic variant of medullary thyroid carcinoma. MMFTC represents a diagnostic challenge by fine needle aspiration cytology (FNAC). CASE: A 77-year-old woman had a palpable mass on the left side of the neck. It was diagnosed as follicular neoplasm by FNAC; she underwent total thyroidectomy. Pathology revealed follicular carcinoma. Radioactive iodine was administered. An enlarging mass was present in the left mandible later. FNAC showed suspicious follicular neoplasm with predominance of oncocytic cells. Pathology revealed follicular carcinoma with parafollicular cell differentiation. Immunohistochemical analysis demonstrated positive status for thyroglobulin and calcitonin. Simultaneous expression of thyroglobulin and calcitonin within the same neoplastic cell was considered. She underwent several courses of radioactive iodine therapy without significant effect. Interestingly, her serum calcitonin level was not elevated. CONCLUSION: Coexpression of thyroglobulin and calcitonin in the same cell is very rare. The component of medullary carcinoma should be considered when encountering an atypical thyroid carcinoma with predominance of cells showing oncocytic changes on FNAC and with clinically poor response to conventional treatment. Immunohistochemistry and pathologic analyses are helpful to confirm the diagnosis, especially in the absence of elevated serum calcitonin level.

Computerized nuclear morphometry in thyroid follicular neoplasms.

Differential diagnosis of follicular adenoma (FA) and follicular carcinoma (FC) of the thyroid can be challenging in the routine practice of surgical pathology because the diagnosis of FC is strictly defined and identification depends on the presence of invasion of the capsule or blood vessels. These features may be equivocally presented in the histological sections and interpreted subjectively by different pathologists, so an objective approach to solve this problem is essential. Computerized morphometry is a scientific tool to evaluate cellular changes and it can enhance the interpretation of morphological features by the transformation of pathological changes in cells to a qualitative form. The present study investigated the diagnostic role of objective computerized nuclear morphometry in follicular neoplasms. Thirty-six cases of thyroid FC and 36 cases of FA from patients who were matched by age and sex were studied. Four nuclear parameters were selected and analyzed: mean nuclear area, mean nuclear perimeter, largest to smallest diameter ratio of the nuclei, and coefficient of variation of the nuclear area. The results indicate that all the chosen nuclear variables were significantly correlated with the FA and FC studied. In conclusion, computerized nuclear morphometry can be considered a helpful ancillary tool for differential diagnosis of FA and FC.

Fine needle aspiration biopsy of mixed medullary-follicular thyroid carcinoma. A report of two cases.

BACKGROUND: Mixed differentiated thyroid carcinomas are rare tumors, difficult to recognize on fine needle aspiration biopsy (FNAB). Most cases are diagnosed only after histologic investigation. CASES: The cases entailed two cytologic samples and a thyroidectomy specimen. Two FNAB thyroidectomy specimens from a 60-year-old man presenting with a solitary thyroid nodule (case 1) were investigated. Both cytologic samples were referred as atypical, with a mixture of features indicating a proliferating follicular lesion but also containing some characteristics of medullary carcinoma. The serum calcitonin level was borderline. Surgery was recommended because of a suspicion of malignancy. The diagnosis of mixed medullary follicular carcinoma was established after a complex histologic investigation. The tumor was encapsulated, with partly microfollicular architecture. Immunohistochemistry was positive for both calcitonin and thyreoglobulin. Electron microscopy from the formol-paraffin block found neurosecretory granules in many cells. The patient was well one year after the operation. One FNAB and thyroidectomy specimen from a 47-year-old woman with long-treated lymphoplasmocellular thyroiditis (case 2) was investigated. The tumor in case 2 was diagnosed on FNAB as medullary carcinoma. Only after histologic and immunohistochemical investigation was mixed differentiation proven. CONCLUSION: Mixed differentiated thyroid tumors are a diagnostic challenge on fine needle aspiration. Irrespective of their rarity, they can be suspected if combined features are present. FNAB recognition of the medullary component in both cases was of crucial importance. Nevertheless, definitive diagnosis remains a histologic problem due to the necessity for topographic information.

Simulated microgravity alters differentiation and increases apoptosis in human follicular thyroid carcinoma cells.

This study focuses on the effects of simulated microgravity (0g) on the human follicular thyroid carcinoma cell line ML-1. Cultured on a three-dimensional clinostat, ML-1 cells formed three-dimensional MCTSs (MCTS diameter: 0.3 +/- 0.01 mm). After 24 and 48 h of clinorotation, the cells significantly decreased fT3 and fT4 secretion but up-regulated the thyroid-stimulating hormone-receptor expression as well as the production of vimentin, vinculin, and extracellular matrix proteins (collagen I and III, laminin, fibronectin, chondroitin sulfate) compared with controls. Furthermore, ML-1 cells grown on the clinostat showed elevated amounts of the apoptosis-associated Fas protein, of p53, and of bax but showed reduced quantities of bcl-2. In addition, signs of apoptosis became detectable, as assessed by terminal deoxynucleotidyl transferase-mediated dUTP digoxigenin nick end labeling, 4', 6-diamidino-2-phenylindole staining, DNA laddering, and 85-kDa apoptosis-related cleavage fragments. These fragments resulted from enhanced 116-kDa poly(ADP-ribose)polymerase (PARP) activity and apoptosis. These observations suggest that clinorotation elevates intermediate filaments, cell adhesion molecules, and extracellular matrix proteins and simultaneously induces apoptosis in follicular thyroid cancer cells. In conclusion, our experiments could provide a regulatory basis for the finding that astronauts show low thyroid hormone levels after space flight, which may be explained by the increase of apoptosis in thyrocytes as a result of simulated 0g.

Etiology and significance of the optically clear nucleus.

Papillary thyroid carcinoma (PTC) is diagnosed in both cytology and surgical pathology specimens on the basis of distinct nuclear morphology, characterized by nuclear elongation, chromatin clearing, intranuclear grooves, and inclusions. Although these nuclear features are specific to papillary carcinoma, they can be mimicked in some benign conditions. The majority of PTC cases do not pose diagnostic problems. However, a distinct subset of cases has generated controversy among experts. These cases are follicular patterned tumors that show minimal nuclear changes in PTC. Several investigators have explored the role of immunohistochemical markers in the histologic diagnosis of PTC. Somatic rearrangements of the RET protooncogene are the most frequent genetic abnormality found in PTC. The frequency of these rearrangements has varied according to the geographic region, radiation exposure, and methodologies used and histologic variant of PTC. Recent studies have suggested that RET/PTC may be the cause of this specific nuclear change in PTC; however, the role of RET/PTC in tumor progression still needs to be defined.

Beneficial effects of retinoic acid on extracellular matrix degradation and attachment behaviour in follicular thyroid carcinoma cell lines.

The prognosis of patients with metastasised follicular thyroid carcinoma (FTC) is limited, necessitating the search for new treatment options. Beneficial effects of retinoids have been suggested in thyroid cancer and the present study was performed to investigate the effects of retinoic acid (RA) on important determinants of metastatic behaviour in FTC: the disengagement of tumour cells from the primary tumour and the degradation of extracellular matrix, focusing on the role of the plasmin activation system and the integrin and E-cadherin families of attachment molecules. Three FTC cell lines were studied: FTC-133, derived from the primary tumour; and FTC-236 and FTC-238, derived from metastases. FTC cell lines were cultured with 0.1, 1 and 10 microM 13-cis-RA or with the solvent DMSO for 1 and 5 days. Extracellular matrix degradation by these cell lines was studied by assessing the 48-h release of radioactivity from (35)S-methionine labelled extracellular matrix proteins synthesised by the MC3T3 cell line coated onto plastic. The involvement of constituents of the plasmin activation system was investigated by semi-quantitative RT-PCR and zymography. Attachment to extracellular matrix was studied by determining the number of adhering FTC cells to extracellular matrix coated onto plastic, 3 h after seeding. The involvement of attachment molecules was studied by RT-PCR with primers for integrin subclasses and E-cadherin and immunofluorescence for E-cadherin. Five days culturing with 10 microM RA reduced the degradation of extracellular matrix significantly in all cell lines: FTC-133 by 35%, FTC-236 by 74% and FTC-238 by 31%. Zymography revealed diminished activity of urokinase type plasminogen activator (uPA) in FTC-236 and FTC-238, but not in FTC-133 cultured with RA. mRNA expression of the uPA receptor was diminished in FTC-236. In the attachment assay, 10 microM RA for 5 days increased the number of adherent cells to extracellular matrix significantly by 91% in FTC-133, 64% in FTC-236 and 87% in FTC-238. No effects of RA on integrin or E-cadherin mRNA expression were observed. Immunofluorescence, however, revealed enhanced organisation of E-cadherin along the cell membrane by RA treatment. In conclusion, the present study demonstrates beneficial effects of RA on important determinants of metastatic behaviour in FTC cell lines, e.g. decreased degradation of extracellular matrix which may in part be explained by effects on the plasmin activation system and enhanced attachment to extracellular matrix. These findings may add to the explanations for beneficial effects of retinoids in thyroid cancer.

Morphometry in the cytologic evaluation of thyroid follicular lesions.

BACKGROUND: The current study was undertaken to evaluate the quantitative estimation of cytologic features on aspirated smears for the preoperative differential diagnosis of follicular lesions of the thyroid. METHODS: The subjects were 60 patients with follicular lesions of the thyroid (including 20 follicular carcinomas, 15 follicular adenomas, and 25 adenomatous goiters) whose histopathologic explorations were conducted fully postoperatively. Using a microscope connected to a computerized video system, the mean nuclear area, the mean nuclear perimeter, the circular rate, the largest to the smallest dimension ratio (LS ratio) of the nuclei, and the coefficient of variation of the nuclear area (NACV) were measured and analyzed. RESULTS: Among the quantitative morphometric parameters of nuclei, the circular rate was significantly higher in the group with adenomatous goiters than those with follicular carcinomas (P < 0.00001) and adenomas (P < 0.005). The group with follicular carcinomas had a higher LS ratio than the group with adenomatous goiters (P < 0.0005). The NACV value increased as the malignant potential of the lesion increased and showed significant differences between the groups. When a NACV of 21.5% was chosen as the cutoff point, the incidence of malignancy was significantly higher in patients with high NACV values than in those with low NACV values (P < 0.00001). Using this borderline value, it was possible to distinguish malignant from benign diseases with a sensitivity of 85.0%, a specificity of 82.5%, and an accuracy of 83.3%. CONCLUSIONS: Preoperative quantitative estimations of cytologic nuclear features are useful for the preoperative differential diagnosis of follicular lesions of the thyroid.

Hyalinizing trabecular carcinoma of the thyroid gland: report of two cases of follicular cell thyroid carcinoma with hyalinizing trabecular pattern.

Recently tumors have been reported that have an architectural pattern and cellularity similar to hyalinizing trabecular adenoma and show either parafollicular differentiation or histological findings suggestive of malignant neoplasm of the follicular cells. This study describes two cases of thyroid carcinoma of follicular cells that displayed a hylinizing trabecular pattern. The first case was a 25-year-old euthyroid woman with a cold thyroid nodule in the right lobe. On fine needle aspiration a diagnosis of papillary carcinoma was rendered. The thyroidectomy disclosed a 2-cm, firm, brown, encapsulated tumor in the right lobe. The tumor had a growth pattern and cytologic features similar to those described in hyalinizing trabecular adenoma. The differences between these neoplasms were the presence of mitotic figures, prominence of the nucleolus, capsular blood vessel invasion, and microtubule groups in the endoplasmic reticulum. The second case was a 19-year-old euthyroid woman with a cold thyroid nodule in the left lobe. A cytologic diagnosis of follicular proliferation was rendered. A 4-cm, firm, whitish, encapsulated nodule was found in the left lobectomy. The tumor cells were arranged in two clear-cut patterns: a trabecular hyalinizing pattern with a small focus of papillary growth, and a follicular pattern. These findings confirm the existence of malignant thyroid tumors with a hyalinizing trabecular pattern and illustrate the nonspecificity of this peculiar pattern, since it may also be seen in papillary carcinomas of the thyroid. The relationship between hyalinizing trabecular adenoma and papillary carcinoma of the thyroid is commented on.

Cáncer tiroídeo tipo intermedio folicular-medular; una forma inhabitual, particular y agresiva: comunicación de tres casos / Mixed medullary and follicular carcinoma of the thyroid: report of three cases

Mixed medullary and follicular carcinomas of the thyroid shares secretory and immunohistochemical features of both follicular and parafollicular thyroidal cells. We report three women, aged 34, 63 and 61 old with this type of tumor. Its diagnosis must be bore in mind in patients with thyroidal tumors and a histological appearance of a medullary or undifferentiated carcinomas. An early diagnosis of a mixed medullary and follicular carcinomas of the thyroid is important, considering its special treatment and negative prognosis

[Thyroid neoplasm of mid follicular-medullary type; an uncommon, particular and aggressive form: report of 3 cases]. / Cáncer tiroídeo tipo intermedio folicular-medular; una forma inhabitual, particular y agresiva. Comunicación de tres casos.

Mixed medullary and follicular carcinoma of the thyroid shares secretory and immunohistochemical features of both follicular and parafollicular thyroidal cells. We report three women, aged 34, 63 and 61 old with this type of tumor. Its diagnosis must be bore in mind in patients with thyroidal tumors and a histological appearance of a medullary or undifferentiated carcinoma. An early diagnosis of a mixed medullary and follicular carcinoma of the thyroid is important, considering its special treatment and negative prognosis.

Insular (poorly differentiated) carcinoma of the thyroid: an ultrastructural and immunocytochemical study of two cases.

Two cases of pure insular (poorly differentiated) carcinoma of the thyroid are reported, with emphasis on their ultrastructure. Notwithstanding their solid/primitive histologic character, a high degree of structural organization and differentiation was present at the submicroscopic level, namely a highly developed cytosecretory apparatus and numerous abortive/rudimentary follicles. A prominent inclusion/dot-like pattern (often paranuclear) of thyroglobulin immunoreactivity was observed, ultrastructurally corresponding to the following features: a) abortive/rudimentary follicular lumina with abundant periluminal dense bodies, and with varying amounts of colloid and microvilli, both at the intercellular and intracellular level; b) large inclusions of fibrillar/lamellar or finely granular material within dilated cisternae of endoplasmic reticulum and possibly of lysosomal nature as well, likely reflecting altered production and/or storage of thyroglobulin substrate. One tumor had many cytophenotypical attributes ascribed to differentiated papillary carcinoma (PC), whereas the other tumor was more analogous to differentiated follicular carcinoma (FC). The present study supports the concept that the insular pattern is a common pathway of dedifferentiation for follicular cell neoplasia of both PC and FC types, yet with maintenance of most of their respective cytophenotypical features, and with evidence of a high level of differentiation/maturation at the submicroscopic level.

[Histochemical and electron microscopical study on mast cells in the stroma of thyroid tumours].

To understand the number and morphology of the mast cells of throid tumours stroma, the mast cells (MCs) of 62 cases of thyroid tumour stroma were studied histochemically and electron microscopically. The number of MCs was increased significantly in thyroid tumour as compared with that in normal tissues. The number of MCs between thyroid cancer and thyroid adenoma was of no difference. When stained with Alcian Blue-Safranin, MCs in the stroma of normal thyroid were blue whereas in the stroma of thyroid tumour both blue and red mast cells could be found. The ultrastructure of the granule of the MCs was homogeneous electron-dense, which was the characteristic feature of TMCs. Degranulation of MCs adjacent to tumour cells could be seen. The significance of MCs in the stroma of thyroid tumour was discussed.

Morule with biotin-containing intranuclear inclusions in thyroid carcinoma.

One thousand and sixty cases of thyroid carcinoma were reviewed to compare morules with squamous metaplasia clinicopathologically and immunohistochemically. Morules and squamous metaplasia were found in five (0.47%) and 32 cases (3.0%) respectively. The five patients with morules were all female (age 20-36 years) including four with papillary carcinoma and one with follicular carcinoma. The 32 patients with squamous metaplasia consisted of 30 females and 2 males (age 14-78 years), all of whom had papillary carcinoma except for one follicular carcinoma. The morules demonstrated characteristic 'optically clear nuclei' (OCN), which ultrastructurally showed filamentous structures in the nuclei. The OCN were immunohistochemically demonstrated to contain intranuclear biotin. Furthermore, the morule often accompanied with the OCN was positive for Ulex Europaeus agglutinin l (UEA-l) but negative for bovine muzzle epidermal keratin (EK). On the contrary, squamous metaplasia unaccompanied with the OCN was negative for UEA-l, but positive for EK. Follow-up information revealed that one of the five patients with morules had died of the disease, one was alive with pulmonary metastasis, and three were disease-free. Eight of 32 patients with squamous metaplasia had died of the disease; of the others who were alive, four patients have had recurrence.

Role of AgNOR in diagnosis of thyroid follicular neoplasms on fine-needle aspiration smears.

This is a retrospective study to examine the role of AgNOR in differentiating thyroid follicular carcinoma and adenoma preoperatively on fine-needle aspiration (FNA) smears. Nineteen histopathology-proven cases of follicular adenoma and carcinoma were selected for this study. May-Grünwald-Giemsa-stained smears were destined and AgNOR staining technique was employed. Significant differences of AgNOR values were observed among follicular carcinoma versus adenoma (P < .05) and follicular carcinoma versus control cases (P < .01). Thereby the AgNOR technique may have some role in differentiating between benign and malignant follicular neoplasms of thyroid.

Oxyphilic follicular tumor arising in struma ovarii.

The present report describes a case of a proliferative lesion developed in a struma ovarii of a 26-year-old woman who presented with asymptomatic bilateral mature ovarian teratomas. The tumor immunohistochemically and ultrastructurally proved to be an oxyphilic follicular thyroid tumor. Although it showed some histologic features which could raise a suspicion of malignancy (solid, trabecular pattern and nuclear pleomorphism), no unequivocable signs of aggressive behaviour (high mitotic activity and vascular invasion) were evidence. The patients was alive and well 1 year after a bilateral subtotal ovariectomy.