Long-term follow-up of cystic thyroid nodules treated with percutaneous ethanol injection (PEI) using two different approaches.

BACKGROUND AND AIM: Cystic thyroid nodules (CNs), although generally benign, can cause compressive or aesthetic problems. Percutaneous ethanol injection (PEI) can represent an alternative to surgery. The present retrospective study evaluates: (i) the long-term outcome of CNs after PEI; (ii) the differences between two different PEI protocols; (iii) the CNs response according to the liquid component. MATERIALS AND METHODS: The study comprises 358 nodules post-PEI followed for at least 2 years. PEI was performed according to two different treatment protocols with a single (Foggia) or double (Turin) alcohol injection. CNs were divided according to their composition: cystic (CYS) >90%, mainly cystic (M-CYS) 75-90%, mixed (MIX) 50-75%, solid-mixed (S-MIX) 35-50%. The volume reduction rate (VRR) was defined as nodule volume (mL) after PEI/nodule volume (mL) before PEI x 100. RESULTS: The 1-year VRR was significantly higher than that at 6 months (89.5% vs 72.9%, P = 0.0005), no differences were observed after 1 year. A significant difference between Turin and Foggia was observed only in VRR at early visit (79% vs 86%, respectively, P = 0.002) and recurrence rate (14% vs 24%, respectively, P = 0.001). Minor side-effects were infrequent. In 192 nodules with a 10-year follow-up CYS showed higher VRR than MIX and S-MIX nodules (P < 0.001). CONCLUSION: Our study reported that the long-term outcome of CNs treated with PEI is excellent regardless of the PEI technique utilized; the larger the cystic amount, the higher the VRR. Based on present results, PEI can be considered as the first-line choice for treating thyroid CNs.

A large family with hereditary MTC: role of RET genetic analysis in differential diagnosis between MEN 2A and FMTC.

Germline mutations of the RET proto-oncogene cause three different cancer syndromes: multiple endocrine neoplasia type 2A (MEN 2A), multiple endocrine neoplasia type 2B (MEN 2B) and familial medullary thyroid carcinoma (FMTC). In the absence of biochemical and/or clinical evidence of pheochromocytoma and hyperparathyroidism, patients with MEN 2A disease display the same phenotype of FMTC disease, although prognosis and clinical management in both affected and unaffected familial members are quite different. We studied a family with hereditary MTC, whose proband was referred to us because of enlarged cervical nodes and increased calcitonin serum levels 28 years after the total thyroidectomy for MTC. Cervical node dissection was carried out and subsequently the presence of MTC metastasis was histologically confirmed. A RET genomic mutation at codon 634 (TGC-->TTC) was identified in the proband and in seven out of 19 familial members studied. Accordingly, a hereditary disease was suggested. However, the strong association of RET mutation at codon 634 with the presence of pheochromocytoma in MEN 2 disease suggested a more rigorous management in all gene carriers. Indeed, during the follow-up pheochromocytoma was subsequently identified in the proband. This finding suggests that all families with a pedigree suggestive of FMTC should be regarded at risk from MEN 2A disease, at least when a critical mutation in the RET cysteine domain is detected.

Radioiodine and percutaneous ethanol injection in the treatment of large toxic thyroid nodule: a long-term study.

Surgery is generally recommended for large thyroid toxic nodules (TTNs). When surgery is not applicable, both radioactive iodine (RAI) and percutaneous ethanol injection (PEI) are alternative treatments. In this retrospective study, the long-term efficacy of nonsurgical treatments was evaluated in 43 patients with TTN, selected on the basis of presence of hyperthyroidism and a fairly large nodule (3- and 4-cm in diameter) completely inhibiting controlateral lobe captation during scintigraphy. Twenty-one patients were treated by RAI (administered dose 670+/-160 MBq; range 555-925) and twenty-two were treated by PEI (6+/-1 sessions; range 5-9). FT4, FT3, thyrotropin (TSH), and nodule volume were assessed before and at fixed intervals after treatment. Median follow-up was 36 months (range, 12-84). Compared to baseline values, with both therapies, serum FT4, FT3, and nodule volume were decreased (p < 0.01) and serum TSH was increased (p < 0.01), after 3 months and during the entire follow-up. Nodule volume reduction percentage was 66.8+/-22.0 and 78.4+/-18.0, in the RAI- and PEI-treated groups, respectively. At the end of follow-up, 34 patients were euthyroid (16 RAI- and 18 PEI-treated). Four RAI-treated patients (19%) showed slightly high TSH levels (4.2-5.3 mU/L), whereas three PEI-treated patients (13.6%) still had suppressed TSH levels, although being clinically asymptomatic. One RAI-treated patient (4.8%) showed overt hypothyroidism during the follow-up period and was then treated with L-thyroxin. One patient (4.6%), who was initially cured by PEI, became newly hyperthyroid during the follow-up period. Both treatments were well-tolerated. In conclusion, both of these nonsurgical treatments are effective and may be chosen also for relatively large TTNs. Specifically, RAI seems to be more effective for treating hyperthyroidism but has minimal sequelae of subclinical or clinical hypothyroidism, while, after PEI treatment the possibility of stable subclinical hyperthyroidism or hyperthyroidism relapse should be taken into account.

Percutaneous ethanol injection may be a definitive treatment for symptomatic thyroid cystic nodules not treatable by surgery: five-year follow-up study.

We present a prospective study on the long-term efficacy of percutaneous ethanol injection (PEI) treatment for thyroid cystic nodules. Among patients referred for symptomatic thyroid cystic nodules who had relapsed after two aspirations or whose nodules could not be aspirated due to the thickness of the cystic fluid, PEI was given when surgery was either refused or contraindicated. Forty-three patients were treated; the mean basal volume of the cysts was 38.4 mL. The purpose of the study was to evaluate long-term efficacy of PEI treatment on: (1) amelioration of symptoms and signs of local compression and (2) nodule volume reduction. In three subjects (7%), PEI failed to induce a significant (>50%) nodule reduction, so that surgical treatment was performed. In 40 patients (93%), an impressive nodule shrinkage was observed, reaching a plateau after 24 months (volume reduction = 91.9%+/-11.4%). A new PEI session was needed in two patients in whom a recurrence was noted within the first 6 months. After 6 months, no significant (> or =1 mL volume) nodule regrowth was observed up to 60 months. Both symptoms and tracheal displacement rapidly (within 1 month) and significantly (p<0.01) improved. After PEI, mild pain was the only side effect observed. No suspicious cytology was observed in any residual nodule greater than 1 mL 6 and 24 months after the last PEI session. Our data suggest that PEI is a first-line safe, effective, probably definitive, treatment for cystic thyroid nodules for which surgery is either refused or contraindicated.

Treatment of large cold benign thyroid nodules not eligible for surgery with percutaneous ethanol injection.

We studied the effect of percutaneous ethanol injection (PEI) in the treatment of cold, cytologically benign, large (>10 mL) thyroid nodules (CBNs) in 41 patients. The end-point of our study was to evaluate the efficacy of PEI on: 1) local symptomatology, assessed by an arbitrary symptom score; and 2) nodule volume and tracheal displacement (at ultrasonography). Follow-up ranged from 12-36 (21 +/- 9) months. Symptom score was significantly reduced (P < 0.01) after 6 months and at the end of the follow-up (2.1 +/- 0.3 vs. 0.2 +/- 0.5 and vs. 0.2 +/- 0.4). A significant (P < 0.01) nodule volume reduction was observed, without differences between solid or mixed CBNs; the reduction was 50% or more in 92.7% of patients. Neither clinical parameters nor pretreatment nodule ultrasonographic features were related to nodule reduction. Disappearance or significant reduction (>0.5 cm) of tracheal displacement was obtained in 61% and in 39% of patients, respectively. One patient experienced prethyroid region edema, pain, and mild fewer, which reversed within 1 week; and one patient had dysphonia, caused by vocal cord palsy, which reversed spontaneously within 1 month. At the end of the follow-up, nodules with just necrotic material at cytology showed a greater (P < 0.05) volume reduction than nodules with residual benign thyroid cells. Our data suggest that PEI is a safe and effective treatment of large CBNs, although sometimes serious side effects do occur.

Global skeletal uptake of technetium-99m methylene diphosphonate in female patients receiving suppressive doses of L-thyroxine for differentiated thyroid cancer.

This study was carried out in order to investigate the possible detrimental effects on bone of levothyroxine (l-T4) suppressive therapy in female patients who had undergone surgery for differentiated thyroid cancer (DTC). Twenty female (14 premenopausal and 6 postmenopausal) patients receiving l-T4 suppressive therapy for DTC were studied. The sample was selected in such a way as to avoid factors influencing bone metabolism other than l-T4. All patients were monitored by sensitive thyroid-stimulating hormone, free triiodothyronine and free thyroxine assays throughout the follow-up. Nineteen healthy (12 premenopausal and 7 postmenopausal) matched women served as controls. In all subjects bone turnover was evaluated by the measurement of global skeletal uptake of technetium-99m methylene diphosphonate (GSU); bone mineral density (BMD) was measured by quantitative computed tomography at the lumbar spine (LS) and by dual-energy X-ray absorptiometry both at the LS and at three femoral sites: the femoral neck, Ward's triangle and the greater trochanter. No significant difference was found in either GSU or BMD between patients (treated for an average period of 68 months) and controls in the whole sample or in any subgroup. Furthermore, no correlations were found between either GSU or BMD and the duration of therapy, daily doses of l-T4 or results of thyroid function tests. Our data show that carefully monitored l-T4 therapy does not influence skeletal turnover (directly reflected by GSU) or the bone density of the spine and femur.

Pre-Cushing's syndrome not recognized by conventional dexamethasone suppression-tests in an adrenal "incidentaloma" patient.

Pre-Cushing's syndrome has been recently diagnosed in 6-12% of patients affected with incidentally discovered adrenal masses. Some of these patients have been described to show transient hypoadrenalism after surgery, similarly to those affected with overt Cushing's syndrome. We studied a 70-year-old male patient with a large left adrenal mass, incidentally discovered, who displayed 24-h urinary free cortisol levels at the upper limit of the normal range, normal dexamethasone overnight and low-dose suppression tests and not suppressed ACTH levels, increased 17-hydroxyprogesterone response to ACTH stimulation and low upright plasma renin activity with normal serum aldosterone levels; furthermore, DHEAS level was low and 75 Selenium-cholesterol scintigraphy showed unilateral uptake concordant with the side of the mass. Soon after left adrenalectomy, he complained of acute hypoadrenalism requiring cortisol replacement therapy: ten months after surgery he is still hypoadrenal. Moreover, stimulated 17-hydroxyprogesterone and plasma renin activity in clino- and orthostatic posture have become normal. We propose that conventional dexamethasone suppression-tests may be not enough sensitive in this kind of patients and that in selected cases the absence of controlateral uptake at scintigraphy may be more reliable in predicting post-surgical hypoadrenalism.

Percutaneous ethanol injection of large thyroid cystic nodules.

To evaluate the effect of percutaneous ethanol injection (PEI) in the treatment of large compressive thyroid cystic nodules (TCN), we studied 20 patients, potential candidates for surgery (tracheal displacement, nodule volume over 10 mL at ultrasonography) and not cured by aspiration alone: 14 experienced a recurrence after two complete evacuations of cystic fluid (watery nodules, WN); in six an aspiration was impossible because the cystic fluid was very thick (viscous nodules, VN). To exclude malignancy, both cytocentrifugate from WN and the smears from VN were examined. WN were treated with 1-4 sessions of conventional PEI; in VN a first PEI session was performed with the purpose of reducing the density of cystic fluid; then if cystic fluid was successfully aspirated, one or more PEI sessions were performed. Thyroid palpation, ultrasonography with nodule volume assessment, and assays for FT3, FT4, and TSH were performed 1 and 6 months after the last PEI. At month 6, 17 patients (85%) had volume reduction of more than 90% of the initial nodule volume; in 2 patients (10%) there was a reduction between 50 and 90%, and in one patient (5%) an appreciable swelling persisted after 3 injections. Nodule volume was significantly decreased below baseline at month 1 (10.9 +/- 13.3 vs 39 +/- 24 mL, p < 0.001), with a further reduction at month 6 (5 +/- 11.7 mL, p < 0.01 vs 1st month value). In most of the nodules the cystic portion completely disappeared; the residual tissue showed fibrous features, often with calcifications. In 11 patients follow-up was prolonged over the sixth month (15 +/- 4 months); the nodule volume did not significantly differ from the sixth month (3 +/- 2.2 mL) and the end of the follow-up (2.8 +/- 2.3 mL). In conclusion, we demonstrate that PEI may be a safe and effective procedure in the treatment of large TCN.

Nonfunctioning adenomas of the pituitary.

The term "nonfunctioning" pituitary adenomas (NFPA) implies heterogeneity, since it relies on a clinical definition that is mainly related to tumor mass. The first complaint is often of impaired visual function, and despite the secretion of gonadotropins, hypogonadism is frequent. NFPA must be differentiated from prolactinomas, because of the therapeutic implications, but although prolactin (PRL) levels greater than 200 ng/mL indicate prolactinoma, PRL levels of 100 to 150 ng/mL are equivocal. An assessment of gonadotropin response to gonadotropin-releasing hormone (GnRH) is of no use, but the thyrotropin-releasing hormone (TRH) test is invaluable. NFPA are monoclonal in origin, but genetic mutations data have not clarified their etiology, which remains largely unknown. Proliferating cell nuclear antigen expression is increased in recurrent adenomas, as is abnormality and overexpression of the protein kinase C family in aggressive tumors. Mutations of tumor-suppressor genes, such as the p53 and Rb genes, and of the metastasizing suppressor gene nm23, have been found in invasive tumors. Immunohistochemistry data confirm that most NFPA originate from gonadotroph cells; many NFPA are negative for all anterior pituitary hormones tested, although isolated or clustered cells are often positive for glycoprotein hormones or their subunits. Silent gonadotroph and also silent growth hormone (GH) or corticotroph tumors can constitute the anatomical basis for clinical NFPA. The heterogeneity of the immunohistochemistry data is reflected in the receptor complex of these tumors. Dopaminergic receptors have recently been visualized in vivo and there are also receptors for TRH or GnRH, since levels of alpha or beta subunits and intact gonadotropins increase after TRH or GnRH stimulation. As a result, three second-line pharmacological approaches have been tried: dopamine agonists, octreotide, and GnRH superagonists or antagonists, with tumor shrinkage of up to 11% to 20%. However, surgery should be tried first.

Thyroid hypoechogenicity after methimazole withdrawal in Graves' disease: a useful index for predicting recurrence?

OBJECTIVE: A characteristic thyroid ultrasonographic picture with diffuse or scattered low echogenicity has been described in Graves' disease (GD). Thyroid hypoechogenicity in GD at onset has been considered a prognostic index of relapse after medical treatment; moreover, thyroid hypoechogenicity is regularly observed in GD at the onset, but not in patients with 'burned-out' disease. The aim of this study was to evaluate the usefulness of thyroid hypoechogenicity changes in predicting GD relapse. DESIGN: Longitudinal prospective study of previously untreated patients with GD. PATIENTS: Thirty-nine consecutive patients aged 10-72 years were treated with methimazole (MMI) for 12-24 months on a titration regimen. Evaluation of patients in remission or with relapse was done 12 and 24 months after MMI withdrawal. MEASUREMENTS: Thyroid ultrasonography and TSH receptor antibodies (TRAb) were evaluated in basal conditions and then one month after MMI withdrawal. Thyroid hypoechogenicity score (assessed by the same observer with the same equipment) was graded as: 0 absent; 1 mild; 2 moderate; 3 marked. At the withdrawal evaluation a score < 2 and a TRAb value < 10 U/l were considered as normal. RESULTS: Twelve and 24 months after withdrawal, there were 10 (25.6%) and 17 (44.7%) relapses, respectively. Neither thyroid hypoechogenicity score nor TRAb values evaluated in basal conditions, showed significant differences between patients remaining euthyroid and those who became again hyperthyroid. In the whole group, the thyroid hypoechogenicity score was significantly lower at the withdrawal than in basal conditions (1.1 +/- 1.1 vs 2 +/- 0.8; P < 0.0001); it was significantly lower in patients in remission (P < 0.001), but not in those who relapsed. The thyroid hypoechogenicity score at withdrawal was normal in 23/29 (79.3%) of patients still euthyroid and in 4/10 (40%) of those who relapsed up to the 12th month (P < 0.05); it was normal in 19/21 (90.4%) of patients still euthyroid and in 7/17 (41.2%) of those who relapsed up to the 24th month (P < 0.05). A normal thyroid hypoechogenicity score at withdrawal of MMI had a higher specificity (0.95) and sensitivity (0.59) with respect to TRAb values (0.86 and 0.53, respectively) for the prediction of the relapse of hyperthyroidism at the 24th month. CONCLUSIONS: Basal thyroid hypoechogenicity cannot be used as an index of relapse of GD. MMI treatment induces evident changes in thyroid hypoechogenicity, mainly in patients who subsequently go into remission. The absence or a low grade of thyroid hypoechogenicity after MMI treatment seems to be a favourable prognostic index of remission of hyperthyroidism in GD.

A thyroid hormone receptor beta gene polymorphism associated with Graves' disease.

Autoimmune thyroid diseases (AITDs) are clustered in families, but the nature of this clustering is still poorly understood. One possible approach to the identification of genetic factors interacting with the AITDs is the study of the association between polymorphic markers and AITDs themselves. In the present study we have shown an association between an allele of a HindIII restriction fragment length polymorphism (EA beta H) intragenic to c-erbA beta, which codes for the thyroid hormone beta receptor, and Graves' disease. This polymorphism can be detected by PCR followed by digestion with the restriction enzyme HindIII. The allelic frequencies were analysed in a panel of DNAs extracted from a population of individuals affected by thyroid disease and originating from southern Italy. A control group (n = 120) from the same area was also analysed. The distribution of EA beta H alleles was significantly different (P < 0.001) in Graves' disease (n = 94) but not in autoimmune thyroiditis (n = 60), as compared with controls. Also the distribution of the EA beta H genotypes was significantly different in Graves' patients (P = 0.003), as compared with controls, the homozygous state EA beta H+/EA beta H+ being more frequent in Graves' patients than in all the other groups. We did not find any association between EA beta H genotypes and clinical parameters in Graves' patients, including eye signs, thyroid volume and level of TSH-binding inhibiting immunoglobulins. Our data support the idea that Graves' disease is a genetically distinct group within the AITDs.

Subgroups of Graves' patients identified on the basis of the biochemical activities of their immunoglobulins.

Graves' patient immunoglobulins (IgG) are known to activate adenylyl cyclase. Recently, we have shown that they also stimulate phospholipase A2 (PLA2). Here we analyze the relationship of these biochemical activities of Graves' IgG to thyroid growth in vitro ([3H]thymidine incorporation) and in vivo (patient goiter size) as well as to clinical indicators of severity of the disease, such as ophthalmopathy, T3 levels, T3/T4 molar ratio, and TSH binding-inhibiting IgG activity. A cluster analysis of the biochemical parameters referring to the whole population (158 subjects) led to the identification of 4 subgroups of Graves' patients based on the different capabilities of IgG to stimulate adenylyl cyclase, PLA2, and [3H]thymidine incorporation. Importantly, a trend of increasing severity of the disease from group 1 to group 4 could be identified. In particular, patients in group 4 (characterized by elevated stimulation of adenylyl cyclase, PLA2, and [3H]thymidine incorporation) had the largest goiter, highest serum concentration of T3, highest T3/T4 molar ratio, and highest prevalence of ophthalmopathy. These results indicate that Graves' IgG induce thyroid growth by stimulating both adenylyl cyclase and PLA2, and suggest a method for the subclassification of Graves' patients that identifies four groups with different degrees of severity of the disease. Moreover, this classification might lead to the targeted use of a novel therapeutic approach based on the inhibition of PLA2 and arachidonic acid metabolism.

Plasma cell granuloma of the thyroid associated with Hashimoto's thyroiditis.

A patient was diagnosed with plasma cell granuloma (PCG) of the thyroid associated with a fibrous variant of Hashimoto's thyroiditis (HT), after total thyroidectomy. Immunoperoxidase staining of the mass in the left lobe revealed polyclonal lambda and kappa chains. A literature search was conducted to determine other cases of such an association. Five other cases of PCG of the thyroid were found in the literature. None of them was associated with HT. This case-report confirms the possible association of HT with either plasmacytoma or PCG, previously only hypothesised.

[Primary angiosarcoma of the thyroid. Presentation of a case (epithelioid type) and nosological problems]. / L'angiosarcoma primitivo della tiroide. Presentazione di un caso (varietà "epitelioidea") e promlematiche nosologiche.

There is a great deal of confusion in the literature as to whether or not true angiosarcomas of the thyroid exist or whether these are all anaplastic carcinomas of the thyroid which have an angiosarcomatoid appearance. Due to the fact that undifferentiated carcinomas of this organ can strikingly resemble various sarcomas it is recommended that great care should be taken prior to qualify as an angiosarcoma a malignant thyroid tumor. A lot of viewpoints have been expressed so far in literature concerning this theme, and they can be summarized as follows. On one side and not admitting the existence of angiosarcoma in this location there are opinions which think of it as a "variant" of undifferentiated carcinoma (a pure carcinoma with a pseudovascular pattern or a carcinoma with an intermingled non-neoplastic reactive vascular component), or as a neoplasm in transition from epithelial to endothelial differentiation ("mesenchymal neometaplasia"), or as a carcinoma with aberrant expression of endothelial markers, or as a carcinoma with a non-specific uptake of endothelial antigens(e.g. from serum in case of F-VIII R-Ag positivity). On the other side there are opinions in favor of the existence of such an entity, based upon light microscopy features coupled with immunocytochemical results (endothelial antigens expression without or with cytokeratins expression) and with the possible support of electron microscopy. Anyway ultrastructural findings of specific markers (Weibel-Palade bodies, pericellular basal lamina, tight junctions, subplasmalemmal pinocytotic vesicles) according to some authors are not a prerequisite: so poorly differentiated neoplasma can fail to show those histogenetic markers.(ABSTRACT TRUNCATED AT 250 WORDS)

[Unusual endocrine behavior in adrenal carcinoma. A case study]. / Insolito comportamento endocrino di carcinoma surrenalico. Studio di un caso.

The Authors report a case of left adrenal mass incidentally discovered by upper abdominal echogram in a 40 year old man. Physical examination showed no signs of hypercortisolism and plasma cortisol and ACTH levels were in the normal range as well as urinary free cortisol. After adrenalectomy, 4 and 8 month follow-up was performed, without clinical, hormonal and TC evolution. Thirteen months later the patient was referred to our department for widespread oedema, hypertension, hypokalemia and alkalosis. These symptoms were associated with dramatically elevated concentrations of plasmatic and free urinary cortisol. TC showed a large mass in the same adrenal region and diffuse hepatic metastases. In spite of mitotane and ketoconazole therapy the patient died few weeks later.