High periostin expression correlates with aggressiveness in papillary thyroid carcinomas

Periostin is a mesenchyme-specific gene product, which acts as an adhesion molecule during bone formation and supports osteoblastic cell line attachment and spreading. However, periostin expression is activated in a large variety of epithelial human tumors and correlates with their aggressiveness. Knowledge of expression of periostin in thyroid tumors is still scanty. The aim of the present work was to investigate periostin expression in differentiated neoplasms of the thyroid and to correlate it with several clinical and molecular features of these tumors. Periostin expression was evaluated by quantitative PCR and immunohistochemistry in normal thyroid tissues, papillary thyroid carcinomas (PTCs), follicular thyroid carcinomas (FTCs), and follicular adenomas (FAs). Periostin mRNA levels were also evaluated in several thyroid tumor cell lines. PTCs show mean periostin mRNA levels significantly higher than corresponding normal tissues. In five PTCs, periostin mRNA values were at least 30-fold higher than corresponding normal tissues. Conversely, mean periostin mRNA levels of FTCs and FAs were similar to those of normal tissues. Consistent with mRNA studies, periostin was detectable by immunohistochemistry in cancerous epithelial cells only in several cases of PTCs but not in normal tissue, FTCs, and FAs. In PTCs, periostin mRNA levels positively correlate with extrathyroidal invasion, distant metastasis, and higher grade staging. A negative correlation between periostin and expression of some markers of the thyroid-differentiated phenotype (thyroglobulin, thyrotropin receptor) was also present in the PTCs. These results indicate that an increase in periostin gene expression is present in several PTCs, in which it appears as a marker of aggressiveness. Experiments in thyroid tumor cell lines indicate that high levels of periostin mRNA are due, at least in part, to the increase in periostin promoter activity.     

Familial medullary thyroid carcinoma: clinical variability and low aggressiveness associated with RET mutation at codon 804

Sixty-one heterozygotes harboring the germline V804L mutation of the RET protooncogene were identified in five independent families. A total of 31 subjects underwent surgery. Histology identified C cell hyperplasia in 30 cases, isolated in 12 and associated with medullary thyroid carcinoma (MTC) in 18. Six patients with MTC had lymph node metastases. Among the 14 patients with basal detectable calcitonin (CT) level, 12 had MTC and 2 had isolated C cell hyperplasia. In most individuals carrying 804 RET mutation, C cell disease displayed late onset and an indolent course; a pentagastrin test was negative in the majority of heterozygotes during the first 2 decades and was positive in only half of them during the third and fourth decades of life. Interestingly, concomitant somatic M918T was detected in a 12-yr-old girl with MTC and was likely to be responsible for both the early clinical appearance and the aggressiveness of the disease. Our data show that in these gene carriers, surgery may be postponed to the fourth decade of life or until the pentagastrin stimulation test becomes positive. Indeed, our data should be confirmed on a larger series of V804L carriers, but may offer a balanced strategy to keep under control and prevent development of the full disease phenotype.     

Hyperthyroidism associated with metastatic thyroid carcinoma

We report a patient with unilateral thyroid carcinoma, who developed hyperfunction of the thyroid gland during the metastatic progression of the thyroid carcinoma. Concurrently with this event, TSI increased and it is suggested that the differentiated aggressive metastatic thyroid neoplasm had initiated the autoimmune disorder leading to TSI production and thus to hyperplasia and hyperfunction of the thyroid resulting in hyperthyroidism.     

Anaplastic thyroid carcinoma associated with Graves' disease

This report concerns a 79-year-old woman with coexisting anaplastic thyroid carcinoma (ATC) and Graves' disease (GD). The patient was referred to our clinic because of palpitation and a palpable mass on the left side of her neck. Thyroid function tests showed hyperthyroidism with elevated thyroid-stimulating antibodies. Ultrasonography of the thyroid demonstrated an adenomatous nodule-like marcated nodule (27.6 x 26.5 x 36.4 mm) with cystic degeneration inside the left lobe. (123)I thyroid scintigraphic imaging showed a cold area corresponding to the nodule with continuous uptake in the remaining thyroid tissue despite suppressed TSH levels. These findings led to a diagnosis of GD. On the other hand, the thyroid nodule could not be definitely diagnosed even after fine needle aspiration biopsy (FNAB) which produced findings suggestive of both papillary thyroid carcinoma and ATC. Open biopsy of the nodule showed an ATC. Regional lymph node metastases as well as multiple lung metastases, which could not be found at the initial visit, had been already developed by that time. Our case is pathophysiologically interesting because it suggests that GD or thyroid-stimulating antibodies (TSAb) may stimulate malignant transformation of differentiated carcinoma. It is also clinically important because it indicates that all thyroid nodules, particularly palpable cold nodules, associated with GD require careful management to detect malignancy because they are at higher risk of harboring malignancy.     

Expression of thyrotrophin receptor gene in thyroid carcinoma is associated with a good prognosis

OBJECTIVE The clinical course of thyroid carcinoma is very variable. It is well known that thyroid carcinomas of similar histology can behave differently in terms of local invasion and distant metastases: there is no reliable way to predict the disease course with confidence. In the present study we compared the TSH receptor and c-myc mRNA levels in different stages of thyroid carcinomas to identify whether they are useful markers for thyroid tumour biological behaviour and prognosis. DESIGN Thyroid tumour specimens were used as the source of RNA. The TSH receptor and c-myc mRNA levels were detected by Northern blot analysis and quantitated by laser densitometry. PATIENTS Thyroid tissues were obtained from five patients with multinodular goitres, 22 with differentiated and three with anaplastic carcinomas. MEASUREMENTS Total cellular RNA was extracted from thyroid tissue specimens and blotted onto nylon membranes. Northern blot analysis was used to detect TSH receptor and c-myc mRNA. The mRNA levels were then quantitated by laser densitometry and compared with each disease stage. RESULTS TSH receptor mRNA levels were significantly lower in carcinomas as compared to benign tumours. With advancing disease stage, the neoplastic tissues generally showed a progressive decline in TSH receptor mRNA levels. Interestingly, in two specimens from patients with distant metastases, TSH receptor mRNA levels were not significantly reduced and were comparable to those in benign tumours. Both patients are still alive, one of them 18 years after operation, indicating that tumour histology is dissociated from its biological behaviour, c-myc mRNA levels were increased but not significantly so in stage 1–3 carcinomas. However, in stage 4 carcinomas c-myc expression was significantly increased. Thus c-myc overex-pression is associated with poor prognosis. Although there is a negative correlation between TSH receptor and c-myc mRNA levels, the correlation was not significant. CONCLUSIONS These results indicate that decreased TSH receptor and increased c-myc gene expression levels are associated with thyroid cell de-differentiation. They are useful markers for thyroid tumour de-differentiation and disease prognosis.     

Diarrhoea associated with medullary carcinoma of the thyroid

Diarrhoea, which is present in roughly one third of cases of medullary carcinoma of the thyroid, was investigated in five cases.Excessive loss of water and electrolytes in the stools was the major factor. Steatorrhoea was mild or absent, and intestinal absorption of glucose and vitamin B(12) was normal; the histological appearance of the small intestinal mucosa was normal or subnormal. Water and sodium diarrhoea seems to be linked to a sometimes considerable increase in the rate of transit through the small intestine and colon, and may be relieved by codeine or codethyline. The frequent increase in the maximum blood sugar level during an oral tolerance test should not be interpreted as evidence of a paradiabetic condition. In fact, the intravenous glucose tolerance test is usually normal and the excessive rise in blood sugar after oral administration seems to be the consequence of the increased rate of transit through the small intestine.The link between the tumour and the disordered motility seems definite in view of certain cases in which removal of the tumour caused the diarrhoea to disappear immediately. Production by the tumour of serotonin or other derivatives of tryptophan or of kallikrein, which activates bradykinin, is rare. With regard to prostaglandins, high concentrations have been observed in the tumours and in the venous blood draining the tumours, but their presence in systemic blood is inconstant. The only hormonal substance, concentration of which seems to be definitely increased in the systemic blood of patients with a medullary carcinoma of the thyroid, is thyrocalcitonin but this hormone does not seem to have any effect on the motor activity of the digestive tract.     

Octreotide for medullary thyroid carcinoma associated diarrhoea.

Medullary thyroid carcinoma associated diarrhoea can be disabling. A 75-yr-old man with metastatic medullary thyroid carcinoma and refractory diarrhoea is described. Subcutaneous administration of the somatostatin analogue, octreotide, 100 micrograms thrice daily, resulted in a sustained improvement in diarrhoea and disappearance of faecal incontinence without reducing calcitonin levels. Octreotide therapy should be considered as symptomatic treatment for otherwise refractory diarrhoea associated with medullary thyroid carcinoma.     

Chronic urticaria associated with thyroid carcinoma: report of 4 cases.

Chronic urticaria is a common condition that can be very disabling when severe. A variety of causes has been reported to induce urticaria, including food, infections, drugs and other factors. In more than 50% of cases of chronic urticaria, however, the cause remains unknown and cannot be ascribed to allergic, physical, environmental or other factors. Although an association between chronic idiopathic urticaria and malignancy has been occasionally reported, such an association remains controversial because it is difficult to demonstrate it is not just coincidental. Here we report the cases of four female patients with occult papillary carcinoma of the thyroid who developed chronic urticaria. In all of these cases, removal of the tumor led to prompt resolution of the urticarial lesions, thus suggesting a pathogenetic relationship between the two. This is the first report of papillary thyroid carcinomas associated with chronic urticaria and highlights how chronic urticaria may be an important cutaneous marker for patients with thyroid carcinoma.     

VEGF-D expression correlates with colorectal cancer aggressiveness and is downregulated by cetuximab

AIM： To gain mechanistic insights into the role played by epidermal growth factor receptor （EGFR） in the regulation of vascular endothelial growth factors （VEGFs） in colorectal cancer （CRC）. METHODS： The impact of high-level expression of the growth factor receptors EGFR and VEGF receptor （VEGFR）3 and the VEGFR3 ligands VEGF-C and VEGF-D on disease progression and prognosis in human CRC was investigated in 108 patients using immu- nohistochemistry. Furthermore, the expression of the lymphangiogenic factors in response to the modulation of EGFR signalling by the EGFR-targeted monoclonal antibody cetuximab was investigated at the mRNA and protein level in human SW480 and SW620 CRC cell lines and a mouse xenograft model. RESULTS： Human CRC specimens and cell lines displayed EGFR, VEGF-C and VEGF-D expression with varying intensities. VEGF-C expression was associated with histological grade. Strong expression of VEGF-D was significantly associated with lymph node metas- tases and linked to a trend for decreased survival in lymph node-positive patients. EGFR blockade with cetuximab resulted in a significant decrease of VEGF-D expression in vitro and in vivo. CONCLUSION： In conclusion, the expression of VEGF-D in colorectal tumours is significantly associated with lymphatic involvement in CRC patients and such expression might be blocked effectively by cetuximab.     

Hashimoto's thyroiditis is associated with papillary thyroid carcinoma: role of TSH and of treatment with L-thyroxine

The possible association between Hashimoto's thyroiditis (HT) and papillary thyroid carcinoma (PTC) is a still debated issue. We analyzed the frequency of PTC, TSH levels and thyroid autoantibodies (TAb) in 13?738 patients (9824 untreated and 3914 under l-thyroxine, l-T(4)). Patients with nodular-HT (n=1593) had high titer of TAb and/or hypothyroidism. Patients with nodular goiter (NG) were subdivided in TAb-NG (n=8812) with undetectable TAb and TAb+NG (n=3395) with positive TAb. Among untreated patients, those with nodular-HT showed higher frequency of PTC (9.4%) compared with both TAb-NG (6.4%; P=0.002) and TAb+NG (6.5%; P=0.009) and presented also higher serum TSH (median 1.30 vs 0.71?μU/ml, P<0.001 and 0.70?μU/ml, P<0.001 respectively). Independently of clinical diagnosis, patients with high titer of TAb showed a higher frequency of PTC (9.3%) compared to patients with low titer (6.8%, P<0.001) or negative TAb (6.3%, P<0.001) and presented also higher serum TSH (median 1.16 vs 0.75?μU/ml, P<0.001 and 0.72?μU/ml, P<0.001 respectively). PTC frequency was strongly related with serum TSH (odds ratio (OR)=1.111), slightly related with anti-thyroglobulin antibodies (OR=1.001), and unrelated with anti-thyroperoxidase antibodies. In the l-T(4)-treated group, when only patients with serum TSH levels below the median value (0.90?μU/ml) were considered, no significant difference in PTC frequency was found between nodular-HT, TAb-NG and TAb+NG. In conclusion, the frequency of PTC is significantly higher in nodular-HT than in NG and is associated with increased levels of serum TSH. Treatment with l-T(4) reduces TSH levels and decreases the occurrence of clinically detectable PTC.