Thyroid Follicular Cell-derived Carcinomas in a Background of Multiple Adenomatous Nodules Leading to a Diagnosis of PTEN Hamartoma Tumor Syndrome in an Adult Patient With a Novel RECQL4 Mutation.

BACKGROUND: Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) is a complex disorder. Carriers develop hamartomatous tumors, with an increased risk for developing malignant tumors in multiple organs. Surveillance to facilitate the early detection and treatment of malignancies is extremely important. CASE REPORT: A 31-year-old male presented with a 10 cm left lobe thyroid gland mass. After fine needle aspiration a left hemithyroidectomy was performed, which demonstrated a minimally invasive follicular thyroid carcinoma (FTC, stage pT3a) and microscopic classical papillary thyroid carcinoma (PTC) in the background of about 50 separate adenomatous nodules (0.2-5 mm). Immunostaining showed loss of PTEN protein in the minimally invasive FTC and in all of the nodules tested, with uninvolved parenchyma serving as an internal control. Kaiser Permanente Northern California (KPNC) Hereditary Cancer Panel, testing for 62 genes, was performed and showed germline mutations in PTEN and RecQ like helicase 4 (RECQL4) genes. Completion thyroidectomy subsequently performed demonstrated about 60 follicular cell-derived adenomatous nodules (0.3-10 mm). Genetic counseling and evaluation documented Cowden syndrome (CS) in the family. Thus, PHTS was confirmed. CONCLUSION: This report documents synchronous FTC and PTC in a background of multiple follicular adenomatous nodules with a novel RECQL4 mutation in an adult patient with PHTS. As such, documented the loss of PTEN protein in a thyroid gland affected by multiple adenomatous nodules aided in diagnosing PHTS.

Current and Future Role of Tyrosine Kinases Inhibition in Thyroid Cancer: From Biology to Therapy.

Thyroid cancer represents a heterogenous disease whose incidence has increased in the last decades. Although three main different subtypes have been described, molecular characterization is progressively being included in the diagnostic and therapeutic algorithm of these patients. In fact, thyroid cancer is a landmark in the oncological approach to solid tumors as it harbors key genetic alterations driving tumor progression that have been demonstrated to be potential actionable targets. Within this promising and rapid changing scenario, current efforts are directed to improve tumor characterization for an accurate guidance in the therapeutic management. In this sense, it is strongly recommended to perform tissue genotyping to patients that are going to be considered for systemic therapy in order to select the adequate treatment, according to recent clinical trials data. Overall, the aim of this article is to provide a comprehensive review on the molecular biology of thyroid cancer focusing on the key role of tyrosine kinases. Additionally, from a clinical point of view, we provide a thorough perspective, current and future, in the treatment landscape of this tumor.

Cystathione ß-Synthase Is Increased in Thyroid Malignancies.

BACKGROUND: Cystathione ß-synthase (CBS) catalyzes the conversion of homocysteine and cysteine to hydrogen sulfide (H2S) and cystathione, via the trans-sulfuration pathway. CBS protein expression levels are increased in several different human malignancies, with increased protein expression correlating with parameters such as tumor stage, anaplasia, metastases, and chemotherapy resistance. MATERIALS AND METHODS: This study employed tissue microarrays to examine CBS expression in benign thyroid tissue, thyroid oncocytomas, thyroid follicular adenomas, and in follicular, papillary, anaplastic, and medullary thyroid carcinomas. RESULTS: CBS expression was increased in all thyroid carcinomas types compared to benign thyroid tissue, but not in thyroid follicular adenomas or oncocytomas. A similar pattern was observed for nicotinamide phosphoribosyltransferase (NAMPT) tissue microarray analysis comparing thyroid adenomas and follicular carcinomas. CONCLUSION: For the first time, we showed that an H2S-syntheszing enzyme plays a role in thyroid malignancies. Additionally, our data suggest that CBS and NAMPT immunohistochemistry may be useful in differentiating follicular adenomas from follicular carcinomas.

Exploration of BRAFV600E as a diagnostic adjuvant in the non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP).

The non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) and encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) are distinguished from classical papillary thyroid carcinoma with predominantly follicular architecture (CPTCPFA) by distinct histomorphologic and molecular features. CPTCPFA frequently harbor the oncogenic variant BRAFV600E while NIFTP and EFVPTC are largely RAS driven. CPTCPFA have rare papillae and intranuclear pseudoinclusions that may distinguish them from NIFTP or EFVPTC. We evaluated for BRAFV600E mutation using mutation-specific BRAF (VE1) antibody immunohistochemistry (BRAFVE) as part of an immunomorphologic tumor panel, often including HBME1, for follicular-patterned lesions with nuclear atypia. An archival search identified cases of NIFTP, CPTCPFA, or EFVPTC between 2015-2017, and demographic data, tumor characteristics, molecular data, and metastases were documented. Our search yielded 275 tumors across categories, and 208 were tested with BRAFVE. Sixty-one NIFTP and 31 sub-centimeter NIFTP were tested, and none (0/92) were positive for BRAFVE. Nineteen CPTCPFA and 14 sub-centimeter CPTCPFA were tested with 18 of 33 (54.5%) BRAFVE positive. Sixty-one EFVPTC and 21 sub-centimeter EFVPTC were tested, with 12 of 81 (14.8%) positive. Mean follow-up time was 1.5 years. Six (4.6%) patients with concurrent classical papillary thyroid carcinoma had local lymph node metastases at time of NIFTP diagnosis, as did 15 of 111 (13.5%) EFVPTC. Six of 34 (14.7%) CPTCPFA had local nodal metastases with five being considered the primary lesion. One EFVPTC (0.9%), BRAFVE negative, metastasized to femur. The findings indicate that BRAFVE used in conjunction with routine sampling of follicular-patterned tumors is a useful diagnostic adjuvant.

Expression of human telomerase reverse transcriptase (hTERT) in thyroid neoplasms.

PURPOSE: Distinction of thyroid neoplasms that include papillary carcinoma (PC) and follicular carcinoma (FC) from benign thyroid neoplasms can be performed successfully by histopathologic examination in most of the cases. However, in some cases it may be difficult to distinct PC and FC as well as FC and follicular adenoma (FA) and also FA and the dominant nodule of multinodular goiter (MNG) histopathologically. In this study, we aimed to determine the role of expression of the human telomerase reverse transcriptase (hTERT) in the distinction of thyroid neoplasms and its relation with prognostic factors by immunohistochemical methods. METHODS: This retrospective study included 138 cases histopathologically diagnosed with benign and malignant thyroid neoplasia. Sections obtained from formalin-fixed paraffin- embedded blocks were stained with hTERT antibody. Cases were divided into hTERT-positive and -negative categories according to hTERT expression score that included percentage and intensity of staining in neoplastic cells. RESULTS: hTERT expression was negative in 93 (67.4%) and positive in 45 (32.6%) patients. Twenty-three (46.0%) of 50 PC, 12 (36.0%) of 33 FA, 1 (10.0%) of 10 FC, 4 (13.0%) of 31 MNG, 2 (66.0%) of 3 medullary carcinoma (MC) patients were found hTERT (+), showing that the difference between PC and FC was significant (p=0.034). There was also a significant difference between FA and MNG (p=0.030). There was no difference between FA and FC (p=0.117). CONCLUSION: The high expression of hTERT can be useful for making a differential diagnosis between PC and FC, and between FA and MNG when histopathological findings are equivocal.

Extracellular Superoxide Dismutase Expression in Papillary Thyroid Cancer Mesenchymal Stem/Stromal Cells Modulates Cancer Cell Growth and Migration.

Tumor stroma-secreted growth factors, cytokines, and reactive oxygen species (ROS) influence tumor development from early stages to the metastasis phase. Previous studies have demonstrated downregulation of ROS-producing extracellular superoxide dismutase (SOD3) in thyroid cancer cell lines although according to recent data, the expression of SOD3 at physiological levels stimulates normal and cancer cell proliferation. Therefore, to analyze the expression of SOD3 in tumor stroma, we characterized stromal cells from the thyroid. We report mutually exclusive desmoplasia and inflammation in papillary and follicular thyroid cancers and the presence of multipotent mesenchymal stem/stromal cells (MSCs) in non-carcinogenic thyroids and papillary thyroid cancer (PTC). The phenotypic and differentiation characteristics of Thyroid MSCs and PTC MSCs were comparable with bone marrow MSCs. A molecular level analysis showed increased FIBROBLAST ACTIVATING PROTEIN, COLLAGEN 1 TYPE A1, TENASCIN, and SOD3 expression in PTC MSCs compared to Thyroid MSCs, suggesting the presence of MSCs with a fibrotic fingerprint in papillary thyroid cancer tumors and the autocrine-paracrine conversion of SOD3 expression, which was enhanced by cancer cells. Stromal SOD3 had a stimulatory effect on cancer cell growth and an inhibitory effect on cancer cell migration, thus indicating that SOD3 might be a novel player in thyroid tumor stroma.

Multicellular spheroids from normal and neoplastic thyroid tissues as a suitable model to test the effects of multikinase inhibitors.

Multicellular three-dimensional (3D) spheroids represent an experimental model that is intermediate in its complexity between monolayer cultures and patients' tumor. In the present study, we characterize multicellular spheroids from papillary (PTC) and follicular (FTC) thyroid cancers and from the corresponding normal tissues. We show that these 3D structures well recapitulate the features of the original tissues, in either the differentiated and "stem-like" components. As a second step, we were aimed to test the effects of a small multikinase inhibitor, SP600125 (SP), previously shown to efficiently induce cell death in undifferentiated thyroid cancer monolayer cultures. We demonstrate the potent effect of SP on cell growth and survival in our 3D multicellular cultures. SP exerts its main effects through direct and highly significant inhibition of the ROCK pathway, known to be involved in the regulation of cell migration and ß-catenin turnover. Consistently, SP treatment resulted in a significant decrease in ß-catenin levels with respect to basal conditions in tumor but not in normal spheroids, indicating that the effect is promisingly selective on tumor cells.In conclusion, we provide the morphological and molecular characterization of thyroid normal and tumor spheroids. In this 3D model we tested in vitro the effects of the multikinase inhibitor SP and further characterized its mechanism of action in both normal and tumor spheroids, thus making it an ideal candidate for developing new drugs against thyroid cancer.

Metachronous anaplastic sarcoma of the kidney and thyroid follicular carcinoma as manifestations of DICER1 abnormalities.

Anaplastic sarcoma of the kidney (ASK) is a tumor found in the pediatric age group and shows many histopathological similarities to pleuropulmonary blastoma (PPB). We present a 12-year-old girl diagnosed with ASK and, 3 years later, with thyroid follicular carcinoma (TFC) with DICER1 abnormalities. Germline insertion/deletion (p. G1809_S1814delinsA) and independent somatic mutations (p. E1705K in ASK, p. E1813D in TFC) were identified. All of these abnormalities are in the catalytic domain of RNase IIIb. Single-nucleotide polymorphism genotyping microarray revealed independent copy number alterations (trisomy 8, monosomy 10, loss of 17p, and partial gain of 17q in ASK; trisomy 5 and partial loss of Xq in TFC). The copy number alteration pattern of ASK was similar to the pattern previously reported in PPB. The present case implies that ASK is a renal counterpart of PPB and that ASK with DICER1 abnormalities should be suspected in a broader age group than PPB.

Clinical utility of TERT promoter mutations and ALK rearrangement in thyroid cancer patients with a high prevalence of the BRAF V600E mutation.

BACKGROUND: Mutations in the TERT promoter, ALK rearrangement, and the BRAF V600E mutation are associated with aggressive clinicopathologic features in thyroid cancers. However, little is known about the impact of TERT promoter mutations and ALK rearrangement in thyroid cancer patients with a high prevalence of BRAF mutations. METHODS: We performed Sanger sequencing to detect BRAF V600E and TERT promoter mutations and both immunohistochemistry and fluorescence in situ hybridization to identify ALK rearrangement on 243 thyroid cancers. RESULTS: TERT promoter mutations were not present in 192 well-differentiated thyroid carcinomas (WDTC) without distant metastasis or in 9 medullary carcinomas. However, the mutations did occur in 40 % (12/30) of WDTC with distant metastasis, 29 % (2/7) of poorly differentiated carcinomas and 60 % (3/5) of anaplastic carcinomas. ALK rearrangement was not present in all thyroid cancers. The BRAF V600E mutation was more frequently found in WDTC without distant metastasis than in WDTC with distant metastasis (p = 0.007). In the cohort of WDTC with distant metastasis, patients with wild-type BRAF and TERT promoter had a significantly higher response rate after radioiodine therapy (p = 0.024), whereas the BRAF V600E mutation was significantly correlated with progressive disease (p = 0.025). CONCLUSIONS: The TERT promoter mutation is an independent predictor for distant metastasis of WDTC, but ALK testing is not useful for clinical decision-making in Korean patients with a high prevalence of the BRAF V600E mutation. Radioiodine therapy for distant metastasis of WDTC is most effective in patients without BRAF V600E and TERT promoter mutations.

Protein kinase Akt activity in human thyroid tumors.

We studied the expression and activation of the main effector protein kinase of phosphatidylinositol-3-kinase cascade (PI3K) ­ Akt in conventionally normal tissues, benign and highly differentiated (with and without metastases) human thyroid tumors. There was a difference in the Akt1 amount in tumor tissue compared with normal tissue in papillary carcinomas and tissue of multinodular goiter. Akt expression both in tumor and conventionally normal tissues of follicular adenoma was significantly lower than in follicular carcinoma. The lowest level of Akt expression was observed in tissues of multinodular goiter. Total activity of all three isoforms of Akt1/2/3 was lower in tumors compared to conventionally normal tissue. Thus, Akt activity (according to Thr308 phosphorylation) is not associated with proliferative processes in the tumor tissue of the thyroid. Apoptosis level detected in these tissues was not associated with the protein kinase activity either. Possible mechanisms of signaling cascade PI3K/Akt inhibition in thyroid tumors are discussed.

NITRIC OXIDE SYNTHASE ACTIVITY AND ITS CONCENTRATION IN THE TISSUES OF HUMAN THYROID CARCINOMAS.

The study of the activity of the constitutive form of nitric oxide synthase (cNOS) revealed that in the papillary thyroid carcinomas it corresponded to that detected in unchanged extratumoral tissue, while the enzyme activity in follicular carcinoma was half lesser. At the same time, the activity of inducible nitric oxide synthase (іNOS) was higher in the papillary and follicular carcinomas. Such changes in the enzyme activity were associated with an increase in its level in papillary carcinomas, and with minor changes in follicular carcinomas. In medullary carcinomas the parameters under study corresponded to those in unchanged tissue, and in the papillary carcinoma metastases without changes in enzyme activity of nitric oxide formation, the level of the latter was much higher. Elevated levels of nitric oxide and іNOS activity in papillary thyroid carcinomas did not depend significantly on the aggression characteristics of the latter, being however absent in tumors of T4 category on a background of reduced cNOS activity and less expressed in tumors surrounded by the tissue in the presence of a chronic thyroiditis. Furthermore, in the papillary carcinomas of papillary or follicular structure nitric oxide level did not differ from the normal range, being slightly higher in tumors of solid or heterogeneous structure with presence of solid areas, whereas in carcinomas of papillary-follicular structure it was twice, and in tissue of solidinsular structure three times higher. іNOS hyperactivity was observed in the carcinomas of different structure, except for tumors of solid structure, in the tumor of which enzyme activity was within the normal range, and in tumor of solid-insular structure where it was significantly higher (as well as cNOS activity) compared with tumors of other structure. Nitric oxide generating system is involved in the transformation of thyroid cells and progression of tumor growth, including through apoptosis regulation, as shown by the results of an analysis of data obtained both in the present study and previously. The nature of such involvement in papillary thyroid carcinomas with different histological structure is different. Key words: nitric oxide; constitutive and inducible nitric oxide synthase; thyroid carcinoma; apoptosis.

HPIP promotes thyroid cancer cell growth, migration and EMT through activating PI3K/AKT signaling pathway.

Hematopoietic pre-B cell leukemia transcription factor (PBX)-interacting protein (HPIP), a co-repressor for the transcription factor PBX, is a nucleo-cytoplasmic shuttling protein. Increasing evidence suggests that HPIP is an oncogene which is frequently overexpressed in many human carcinomas. However, the role of HPIP in thyroid carcinoma is still unclear. Therefore, in this study, we investigated the role of HPIP in thyroid carcinoma, and explored the underling mechanism. We found that the expression of HPIP is upregulated in thyroid carcinoma cell lines. Knockdown of HPIP inhibits thyroid carcinoma cell proliferation, migration/invasion and epithelial-mesenchymal transition (EMT). HPIP knockdown also reduces thyroid tumor growth in nude mice. Furthermore, knockdown of HPIP significantly inhibits the expression of phosphorylated PI3K and AKT in thyroid carcinoma cells. Taken together, these results suggest that knockdown of HPIP inhibits the proliferation, migration and EMT by suppressing the PI3K/AKT pathway, and HPIP may be a potential therapeutic target for the treatment of thyroid carcinoma.

Safety and tolerability of sorafenib in patients with radioiodine-refractory thyroid cancer.

Effective adverse event (AE) management is critical to maintaining patients on anticancer therapies. The DECISION trial was a multicenter, randomized, double-blind, placebo-controlled, Phase 3 trial which investigated sorafenib for treatment of progressive, advanced, or metastatic radioactive iodine-refractory, differentiated thyroid carcinoma. Four hundred and seventeen adult patients were randomized (1:1) to receive oral sorafenib (400 mg, twice daily) or placebo, until progression, unacceptable toxicity, noncompliance, or withdrawal. Progression-free survival, the primary endpoint of DECISION, was reported previously. To elucidate the patterns and management of AEs in sorafenib-treated patients in the DECISION trial, this report describes detailed, by-treatment-cycle analyses of the incidence, prevalence, and severity of hand-foot skin reaction (HFSR), rash/desquamation, hypertension, diarrhea, fatigue, weight loss, increased serum thyroid stimulating hormone, and hypocalcemia, as well as the interventions used to manage these AEs. By-cycle incidence of the above-selected AEs with sorafenib was generally highest in cycle 1 or 2 then decreased. AE prevalence generally increased over cycles 2-6 then stabilized or declined. Among these AEs, only weight loss tended to increase in severity (from grade 1 to 2) over time; severity of HFSR and rash/desquamation declined over time. AEs were mostly grade 1 or 2, and were generally managed with dose interruptions/reductions, and concomitant medications (e.g. antidiarrheals, antihypertensives, dermatologic preparations). Most dose interruptions/reductions occurred in early cycles. In conclusion, AEs with sorafenib in DECISION were typically grade 1 or 2, occurred early during the treatment course, and were manageable over time.

Identification of Unique, Heterozygous Germline Mutation, STK11 (p.F354L), in a Child with an Encapsulated Follicular Variant of Papillary Thyroid Carcinoma within Six Months of Completing Treatment for Neuroblastoma.

Papillary thyroid carcinoma (PTC) is rare in children, although it is a known secondary malignancy after treatment for neuroblastoma (NB). The interval between NB treatment completion and PTC is usually more than 5 years. A 4-year-old, female patient with a high risk adrenal NB was found to have a 2.9-cm, right thyroid nodule on surveillance chest computed tomography (CT) 6 months after completion of her NB treatment (induction chemotherapy, tumor resection, autologous stem cell transplantation, external beam radiation to the abdominal tumor site, immunotherapy, and retinoic acid). Posttreatment surveillance included iodine-123-metaiodobenzylguanidine scans and CT scans. Fine-needle aspiration of the thyroid nodule diagnosed a follicular neoplasm, which was negative for BRAF, NRAS, KRAS, HRAS, PAX8/PPARg, and RET/PTC mutations, without evidence of metastatic NB. Nodule histology demonstrated an encapsulated follicular variant of PTC (FVPTC). Next-generation sequence analysis for a 46 cancer-gene profile was performed on both tumors with subsequent peripheral blood DNA testing. A heterozygous missense mutation in STK11 (F354L) was identified in both the NB and FVPTC. This mutation was also detected in peripheral blood mononuclear cells. Two additional heterozygous somatic missense mutations of uncertain significance were identified: KDR/VEGF receptor 2 (Q472H) on chromosome 4 and MET (N375S) on chromosome 7. To our knowledge, this is the shortest reported duration from completion of NB treatment to detection of thyroid cancer. The association of the STK11 gene with Peutz-Jeghers syndrome, lung adenocarcinomas, and medullary thyroid cancer leads to a possible association between this genetic variant and our patient's tumors.

MMP2 and MMP9 participate in S1P-induced invasion of follicular ML-1 thyroid cancer cells.

The bioactive lipid sphingosine-1-phosphate (S1P) has emerged as a potent inducer of cancer cell migration and invasion. Previously, we have shown that S1P induces invasion of ML-1 follicular thyroid cancer cells via S1P receptors 1 and 3 (S1P1,3). Matrix metalloproteinases (MMPs) are zinc-dependent proteolytic enzymes used by cells for degradation of the extracellular matrix during invasion and migration. In the present study, we examined the role of MMP2 and MMP9 for S1P-induced invasion of ML-1 cells, and found that S1P regulates the secretion and activity of MMP2 and MMP9 via S1P1,3. Both pharmacological inhibitors and siRNA knockdown of MMP2 and MMP9 could attenuate S1P-induced invasion. Additionally, we show that calpains and Rac1 mediate S1P-induced secretion of MMP2 and MMP9. In conclusion, MMP2 and MMP9 participate in S1P-evoked follicular ML-1 thyroid cancer cell invasion.

Helicase-like transcription factor: a new marker of well-differentiated thyroid cancers.

BACKGROUND: The preoperative characterization of thyroid nodules is a challenge for the clinicians. Fine-needle aspiration (FNA) is the commonly used pre-operative technique for diagnosis of malignant thyroid tumor. However, many benign lesions, with indeterminate diagnosis following FNA, are referred to surgery. There is an urgent need to identify biomarkers that could be used with the FNA to distinguish benign thyroid nodules from malignant tumors. The purpose of the study is to examine the level of expression of the helicase-like transcription factor (HLTF) in relation to neoplastic progression of thyroid carcinomas. METHODS: The presence of HLTF was investigated using quantitative and semi-quantitative immunohistochemistry in a series of 149 thyroid lesion specimens. Our first clinical series was composed of 80 patients, including 20 patients presenting thyroid adenoma, 40 patients presenting thyroid papillary carcinoma, 12 patients presenting thyroid follicular carcinoma and 8 patients presenting anaplastic carcinoma. These specimens were assessed quantitatively using computer assisted microscopy. Our initial results were validated on a second clinical series composed of 40 benign thyroid lesions and 29 malignant thyroid lesions using a semi-quantitative approach. Finally, the HLTF protein expression was investigated by Western blotting in four thyroid cancer cell lines. RESULTS: The decrease of HLTF staining was statistically significant during thyroid tumor progression in terms of both the percentage of mean optical density (MOD), which corresponds to the mean staining intensity (Kruskall-Wallis: p < 0.0005), and the labelling index (LI), which corresponds to the percentage of immunopositive cells (Kruskall-Wallis: p < 10-6). Adenomas presented very pronounced nuclear HLTF immunostaining, whereas papillary carcinomas exhibited HLTF only in the cytoplasm. The number of HLTF positive nuclei was clearly higher in the adenomas group (30%) than in the papillary carcinomas group (5%).The 115-kDa full size HLTF protein was immunodetected in four studied thyroid cancer cell lines. Moreover, three truncated HLTF forms (95-kDa, 80-kDa and 70-kDa) were also found in these tumor cells. CONCLUSIONS: This study reveals an association between HLTF expression level and thyroid neoplastic progression. Nuclear HLTF immunostaining could be used with FNA in an attempt to better distinguish benign thyroid nodules from malignant tumors.

Nicotinamide phosphoribosyltransferase and SIRT3 expression are increased in well-differentiated thyroid carcinomas.

Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the rate-limiting step of nicotinamide adenine dinucleotide (NAD(+)) synthesis. NAMPT expression promotes angiogenesis, DNA synthesis, cell growth and survival, and mitochondrial biogenesis and function. Sirtuin-3 (SIRT3) is an NAD(+)-dependent deacetylase which functions in conjunction with mitochondrial NAMPT to promote cell survival following genotoxic stress. NAMPT expression is increased in several human malignancies, while SIRT3 levels are increased in some malignancies and suppressed in others. Based on this, we hypothesized that NAMPT and SIRT3 expression might be increased in well-differentiated thyroid carcinomas (TCs), follicular carcinomas (FC) and papillary thyroid carcinomas (PTC). Immunohistochemical analysis for NAMPT and SIRT3 staining was performed on these tumors using tissue microarrays. NAMPT and SIRT3 expression was low in benign thyroid tissues, moderately increased in FC, and more highly expressed in PTC. Specifically we observed both NAMPT and SIRT3 to be highly expressed in well-differentiated TCs. The data suggest that mitochondrial alterations play a role in the development and maintenance of well-differentiated TC. Since an effective pharmacological NAMPT inhibitor is currently in clinical use, further studies of NAMPT overexpression in well-differentiated TCs may be useful in selecting patients for NAMPT inhibitor therapy, particularly for metastatic well-differentiated thyroid carcinomas refractory to other treatments.

Altered peptidase activities in thyroid neoplasia and hyperplasia.

BACKGROUND: Papillary thyroid carcinoma (PTC), follicular thyroid adenoma (FTA), and thyroid nodular hyperplasia (TNH) are the most frequent diseases of the thyroid gland. Previous studies described the involvement of dipeptidyl-peptidase IV (DPPIV/CD26) in the development of thyroid neoplasia and proposed it as an additional tool in the diagnosis/prognosis of these diseases. However, very little is known about the involvement of other peptidases in neoplastic and hyperplastic processes of this gland. METHODS: The catalytic activity of 10 peptidases in a series of 30 PTC, 10 FTA, and 14 TNH was measured fluorimetrically in tumour and nontumour adjacent tissues. RESULTS: The activity of DPPIV/CD26 was markedly higher in PTC than in FTA, TNH, and nontumour tissues. Aspartyl aminopeptidase (AspAP), alanyl aminopeptidase (AlaAP), prolyl endopeptidase, pyroglutamyl peptidase I, and aminopeptidase B activities were significantly increased in thyroid neoplasms when compared to nontumour tissues. AspAP and AlaAP activities were also significantly higher in PTC than in FTA and TNH. CONCLUSIONS: These data suggest the involvement of DPPIV/CD26 and some cytosolic peptidases in the neoplastic development of PTC and FTA. Further studies will help to define the possible clinical usefulness of AlaAP and AspAP in the diagnosis/prognosis of thyroid neoplasms.