Biffoni M

Hepatocyte growth factor (HGF) stimulates tumour invasiveness in papillary carcinoma of the thyroid

The present study has investigated the functional role of the Met receptor in primary cultures of 20 papillary carcinomas and of normal thyroid cells obtained from the same patients. Normal and tumour cells grew as adherent cells, formed a confluent monolayer after 10–20 days, had epithelial morphology, and were immunoreactive for cytokeratin, vimentin, and thyroglobulin. The potential effect of hepatocyte growth factor (HGF) on cell invasiveness was investigated in Boyden chambers, using a nucleopore filter coated with Matrigel as the barrier and HGF as the chemoattractant. Tumour cells of five out of seven cases of papillary carcinoma were more responsive to HGF than the corresponding normal cells in terms of the number of migrated cells per mm2. Involvement of the Met receptor in the HGF‐induced migratory response was suggested by the observation that the agonistic anti‐Met monoclonal antibody (MAb) DO‐24 was equally effective. HGF did not affect the proliferative activity of thyroid cells. Under the same experimental conditions, 10 per cent fetal bovine serum (FBS) induced a two‐fold increase in [3H]thymidine incorporation into normal cells and tumour cells. These findings are consistent with the possibility that HGF plays a crucial role in determining the invasiveness of tumour cells in papillary carcinoma of the thyroid. Copyright

High Rate of Recurrence After Lobectomy for Solitary Thyroid Nodule

OBJECTIVE To evaluate the long-term outcome of patients treated by lobectomy for solitary thyroid nodule. DESIGN Retrospective study. SETTING University hospital. PATIENTS 83 patients admitted with a clinical diagnosis of solitary thyroid nodule. INTERVENTIONS Preoperative ultrasonography showed a solitary nodule in 32 patients and this finding was confirmed intraoperatively in 24 cases (77%). 59 patients with multinodular goitres were treated by total thyroidectomy and 24 with solitary nodule by lobectomy. MAIN OUTCOME MEASURES Postoperative complications and freedom from nodule recurrence and/or parenchymal irregularity. RESULTS One patient after lobectomy and 3 after total thyroidectomy developed temporary recurrent laryngeal nerve injury. Postoperative temporary hypoparathyroidism occurred in 13 patients (22%) after total thyroidectomy and in no patient after lobectomy (p = 0.02). Neither permanent recurrent laryngeal nerve injury nor permanent hypoparathyroidism occurred after either procedure. Among patients who underwent lobectomy, 6 had an adenoma and 18 had a nodular hyperplasia. At 4-year follow-up, the freedom rate from any thyroid nodule recurrence or parenchymal irregularity was 44.7%, and the freedom rate from nodular recurrence was 74%. Men tended to have a 4-year freedom rate from nodular relapse poorer than women (48% vs. 87%. p = 0.07). Nodular recurrence occurred in one patient operated on for an adenoma, and all the other recurrences occurred in patients with nodular hyperplasia. CONCLUSIONS The mid-term freedom rate from thyroid nodule recurrence or parenchymal irregularity after lobectomy for solitary nodule of the thyroid is unsatisfactory. This observation calls for a better evaluation of long-term results after lobectomy for this condition and identification of risk factors predictive of recurrence. This would enable a more appropriate preoperative selection of patients undergoing lobectomy, indicating total thyroidectomy for those patients with solitary nodule at high risk of recurrence.

Erythropoietin activates cell survival pathways in breast cancer stem-like cells to protect them from chemotherapy.

Recombinant erythropoietin (EPO) analogs [erythropoiesis-stimulating agents (ESA)] are clinically used to treat anemia in patients with cancer receiving chemotherapy. After clinical trials reporting increased adverse events and/or reduced survival in ESA-treated patients, concerns have been raised about the potential role of ESAs in promoting tumor progression, possibly through tumor cell stimulation. However, evidence is lacking on the ability of EPO to directly affect cancer stem-like cells, which are thought to be responsible for tumor progression and relapse. We found that breast cancer stem-like cells (BCSC) isolated from patient tumors express the EPO receptor and respond to EPO treatment with increased proliferation and self-renewal. Importantly, EPO stimulation increased BCSC resistance to chemotherapeutic agents and activated cellular pathways responsible for survival and drug resistance. Specifically, the Akt and ERK pathways were activated in BCSC at early time points following EPO treatment, whereas Bcl-xL levels increased at later times. In vivo, EPO administration counteracted the effects of chemotherapeutic agents on BCSC-derived orthotopic tumor xenografts and promoted metastatic progression both in the presence and in the absence of chemotherapy treatment. Altogether, these results indicate that EPO acts directly on BCSC by activating specific survival pathways, resulting in BCSC protection from chemotherapy and enhanced tumor progression.

Facial nerve function after parotidectomy for neoplasms with deep localization.

PurposeTo determine whether the deep location of a parotid gland neoplasm is specific risk factor for facial nerve paralysis after parotidectomy.MethodsWe retrospectively reviewed 88 patients, including 59 with a benign superficial neoplasm of the parotid treated by superficial parotidectomy (group 1); 5 with a benign deep neoplasm treated by total parotidectomy (group 2); 20 with a malignant superficial neoplasm treated by total parotidectomy (group 3); and 4 with a malignant deep neoplasm treated by total parotidectomy (group 4).ResultsTemporary facial nerve paralysis developed in 10.3%, 20%, 10%, and 50% of groups, 1, 2, 3, and 4, respectively. Permanent facial nerve paralysis developed in 0%, 0%, 10% and 50% of groups 1, 2, 3, and 4, respectively.ConclusionThe risk factor associated with nerve damage resulting from surgery for parotid neoplasms were malignancy and deep localization. However, the deep location of a benign tumor was not a major risk factor for permanent paralysis.

Ectopic Intrathyroidal Thymus in Children: A Long-Term Follow-Up Study

Background: Ectopic intrathyroidal thymus has recently been reported in children as a cause of surgery and/or invasive diagnostic procedures when mistaken for a thyroid nodule. Thymus has a unique appearance at ultrasound (US). Methods: We report a follow-up study (mean 34 months, range 6–84) performed by US on 9 children (5 females) with a mean age of 6.3 ± 3.2 years with intrathyroidal thymic inclusions diagnosed by US as ‘incidentalomas’. None has palpable nodules. Results: Intrathyroidal thymic inclusions appeared on US as a hypoechoic area, with regular linear or punctuate internal hyperechoic echoes. The 2 oldest patients (13 and 17 years) showed a regression in both size and hypoechogenicity of thymic inclusions over time – reflecting the normal thymic involution with advancing age. Conclusions: Indeed, the lack of progression seen in our 9 patients over a mean time of 34 months confirmed the substantially benign and self-limited nature of this process. The increasing use of thyroid ultrasonography in children may result in an increased detection of intrathyroidal thymic inclusions – an embryologic anomaly that should be considered in the differential diagnosis of thyroid nodules in children and adolescents.

Different expression of TSH receptor and NIS genes in thyroid cancer: role of epigenetics

The TSH receptor (TSHR) and sodium/iodide symporter (NIS) are key players in radioiodine-based treatment of differentiated thyroid cancers. While NIS (SLC5AS) expression is diminished/lost in most thyroid tumors, TSHR is usually preserved. To examine the mechanisms that regulate the expression of NIS and TSHR genes in thyroid tumor cells, we analyzed their expression after inhibition of ras-BRAF-MAPK and PI3K-Akt-mTOR pathways and the epigenetic control occurring at the gene promoter level in four human thyroid cancer cell lines. Quantitative real-time PCR was used to measure NIS and TSHR mRNA in thyroid cancer cell lines (TPC-1, BCPAP, WRO, and FTC-133). Western blotting was used to assess the levels of total and phosphorylated ERK and Akt. Chromatin immunoprecipitation was performed for investigating histone post-translational modifications of the TSHR and NIS genes. ERK and Akt inhibitors elicited different responses of the cells in terms of TSHR and NIS mRNA levels. Akt inhibition increased NIS transcript levels and reduced those of TSHR in FTC-133 cells but had no significant effects in BCPAP. ERK inhibition increased the expression of both genes in BCPAP cells but had no effects in FTC-133. Histone post-translational modifications observed in the basal state of the four cell lines as well as in BCPAP treated with ERK inhibitor and FTC-133 treated with Akt inhibitor show cell- and gene-specific differences. In conclusion, our data indicate that in thyroid cancer cells the expression of TSHR and NIS genes is differently controlled by multiple mechanisms, including epigenetic events elicited by major signaling pathways involved in thyroid tumorigenesis.

Ultrasonography scoring systems can rule out malignancy in cytologically indeterminate thyroid nodules

PurposeTo assess the accuracy and reproducibility of ultrasonography classification systems in characterizing cytologically indeterminate thyroid nodules.MethodsWe retrospectively identified 49 nodules that had been surgically resected owing to features classified as indeterminate according to 2010 Italian Consensus on Thyroid Cytology criteria. Three experienced sonographers independently reviewed original sonographic images of each nodule and classified it using the 2015 American Thyroid Association (ATA) guidelines and the Thyroid Imaging Reporting and Data System (TI-RADS) classification proposed by Korean radiologists; later, images were reviewed jointly to obtain consensus classifications of each nodule. Original cytology slides were similarly reviewed by three experienced cytopathologists, who reclassified the nodule (independently, then jointly) according to revised Italian Consensus on Thyroid Cytology (ICTC-2014) criteria. Consensus ICTC-2014, ATA, and TI-RADS classifications were analyzed against surgical histology reports to estimate each system’s sensitivity, specificity, positive and negative predictive values.ResultsOf the 49 indeterminate nodules examined, 30 (61.2 %) were histologically benign. Consensus ICTC-2014 classification correctly classified malignant nodules with positive predictive value of 50 % and negative predictive value of 90 %. Sonographic classification of nodules as intermediate to high suspicion by ATA or TI-RADS category 4c displayed positive predictive value of 63 and 71 %, respectively; positive predictive values dropped to 44 and 42 % when lower positivity thresholds were used (ATA low suspicion, TI-RADS category 4a). Negative predictive values for ATA and TI-RADS were 91 and 74 %, respectively, with higher positivity thresholds and 100 % for both with lower thresholds. All systems displayed appreciable inter-observer variability (Krippendorff alphas: ATA 0.36, TIRADS 0.42, ICTC-2014 0.74).ConclusionsWith stringent negativity cut-offs, American Thyroid Association and Thyroid Imaging Reporting and Data System assessment of cytologically indeterminate thyroid nodules allows high-confidence exclusion of malignancy.

CYSTIC HYGROMA OF THE BREAST: A RARE LESION

Lymphangiomas are congenital malformations of lymphatic vessels. More than 50% of these lesions are present at birth; 90% are diagnosed by the age of 2. These lesions do not expand very rapidly but they tend to infiltrate surrounding tissues; their degeneration into malignant tumors is an extremely rare occurrence. They are mostly located in the neck region and the axilla; breast lymphangioma is very rare. Surgery is usually performed for aesthetic reasons and in order to make a differential diagnosis with other, more common lesions. The surgical procedure involves the excision of the mass; other methods, such as radiotherapy and sclerotherapy, have proved to be completely ineffective.

Risk Stratification of Neck Lesions Detected Sonographically During the Follow-Up of Differentiated Thyroid Cancer

CONTEXT The European Thyroid Association (ETA) has classified posttreatment cervical ultrasound findings in thyroid cancer patients based on their association with disease persistence/recurrence. OBJECTIVE The objective of the study was to assess this classifications ability to predict the growth and persistence of such lesions during active posttreatment surveillance of patients with differentiated thyroid cancer (DTC). DESIGN This was a retrospective, observational study. SETTING The study was conducted at a thyroid cancer center in a large Italian teaching hospital. PATIENTS Center referrals (2005-2014) were reviewed and patients selected with pathologically-confirmed DTC; total thyroidectomy, with or without neck dissection and/or radioiodine remnant ablation; abnormal findings on two or more consecutive posttreatment neck sonograms; and subsequent follow-up consisting of active surveillance. Baseline ultrasound abnormalities (thyroid bed masses, lymph nodes) were classified according to the ETA system. Patients were divided into group S (those with one or more lesions classified as suspicious) and group I (indeterminate lesions only). We recorded baseline and follow-up clinical data through June 30, 2015. MAIN OUTCOMES The main outcomes were patients with growth (>3 mm, largest diameter) of one or more lesions during follow-up and patients with one or more persistent lesions at the final visit. RESULTS The cohort included 58 of the 637 DTC cases screened (9%). A total of 113 lesions were followed up (18 thyroid bed masses, 95 lymph nodes). During surveillance (median 3.7 y), group I had significantly lower rates than group S of lesion growth (8% vs 36%, P = .01) and persistence (64% vs 97%, P = .014). The median time to scan normalization was 2.9 years. CONCLUSIONS The ETAs evidence-based classification of sonographically detected neck abnormalities can help identify papillary thyroid cancer patients eligible for more relaxed follow-up.

Incidental Parathyroid Adenomas with Normocalcemia Discovered During Thyroid Operations: Report of Three Cases

Abstract We report three cases of parathyroid adenoma incidentally discovered during a total thyroidectomy. No patients showed any clinical or chemical features that led us to suspect a hyperparathyroidism condition before operation, but a macroscopically enlarged parathyroid was discovered during the dissection and it was removed in all three cases. All patients had a single adenoma confirmed by a histological analysis. Calcemia decreased after operation in every case but only one patient needed temporary adjunctive therapy. No permanent hypoparathyroidism or recurrent hyperparathyroidism was observed. We recommend that any enlarged parathyroid discovered during neck surgery should thus be removed in order to avoid the risks of future surgical procedures due to successive bouts of clinical hyperparathyroidism.