Gender oncology: recommendations and consensus of the Italian Association of Medical Oncology (AIOM).

BACKGROUND: Following the development of gender medicine in the past 20 years, more recently in the field of oncology an increasing amount of evidence suggests gender differences in the epidemiology of cancers, as well as in the response and toxicity associated with therapies. In a gender approach, critical issues related to sexual and gender minority (SGM) populations must also be considered. MATERIALS AND METHODS: A working group of opinion leaders approved by the Italian Association of Medical Oncology (AIOM) has been set up with the aim of drafting a shared document on gender oncology. Through the 'consensus conference' method of the RAND/University of California Los Angeles (UCLA) variant, the members of the group evaluated statements partly from the scientific literature and partly produced by the experts themselves [good practice points (GPPs)], on the following topics: (i) Healthcare organisation, (ii) Therapy, (iii) Host factors, (iv) Cancer biology, and (v) Communication and social interventions. Finally, in support of each specific topic, they considered it appropriate to present some successful case studies. RESULTS: A total of 42 articles met the inclusion criteria, from which 50 recommendations were extracted. Panel participants were given the opportunity to propose additional evidence from studies not included in the research results, from which 32 statements were extracted, and to make recommendations not derived from literature such as GPPs, four of which have been developed. After an evaluation of relevance by the panel, it was found that 81 recommendations scored >7, while 3 scored between 4 and 6.9, and 2 scored below 4. CONCLUSIONS: This consensus and the document compiled thereafter represent an attempt to evaluate the available scientific evidence on the theme of gender oncology and to suggest standard criteria both for scientific research and for the care of patients in clinical practice that should take gender into account.

Gender-related differences in patients with carcinoid syndrome: new insights from an Italian multicenter cohort study.

BACKGROUND: The incidence of neuroendocrine neoplasm (NEN) and related carcinoid syndrome (CaS) has increased markedly in recent decades, and women appear to be more at risk than men. As per other tumors, gender may be relevant in influencing the clinical and prognostic characteristics of NEN-associated CS. However, specific data on carcinoid syndrome (CaS) are still lacking. PURPOSE: To evaluate gender differences in clinical presentation and outcome of CaS. METHODS: Retrospective analysis of 144 CaS patients from 20 Italian high-volume centers was conducted. Clinical presentation, tumor characteristics, therapies, and outcomes (progression-free survival, PFS, overall survival, OS) were correlated to gender. RESULTS: Ninety (62.5%) CaS patients were male. There was no gender difference in the site of primary tumor, tumor grade and clinical stage, as well as in treatments. Men were more frequently smokers (37.2%) and alcohol drinkers (17.8%) than women (9.5%, p = 0.002, and 3.7%, p = 0.004, respectively). Concerning clinical presentation, women showed higher median number of symptoms (p = 0.0007), more frequent abdominal pain, tachycardia, and psychiatric disorders than men (53.3% vs 70.4%, p = 0.044; 6.7% vs 31.5%, p = 0.001; 50.9% vs. 26.7%, p = 0.003, respectively). Lymph node metastases at diagnosis were more frequent in men than in women (80% vs 64.8%; p = 0.04), but no differences in terms of PFS (p = 0.51) and OS (p = 0.64) were found between gender. CONCLUSIONS: In this Italian cohort, CaS was slightly more frequent in males than females. Gender-related differences emerged in the clinical presentation of CaS, as well as gender-specific risk factors for CaS development. A gender-driven clinical management of these patients should be advisable.

Sellar and parasellar lesions in the transition age: a retrospective Italian multi-centre study.

BACKGROUND: Sellar/parasellar lesions have been studied in the adult and paediatric age range, but during the transition age their epidemiology, clinical manifestations, management and treatment outcomes have been poorly investigated. MATERIALS AND METHODS: An Italian multicentre cohort study, in which hospital records of patients with diagnosis of sellar/parasellar lesions during the transition age and young adulthood (15-25 years), were reviewed in terms of prevalence, clinical and hormonal features at diagnosis, and outcomes where available. Both pituitary neuroendocrine tumours (pituitary tumours, Group A) and non-endocrine lesions (Group B) were included. RESULTS: Among Group A (n = 170, 46.5% macroadenomas), the most frequent were prolactin and GH-secreting tumours, with a female predominance. Among Group B (n = 28), germinomas and Rathke cells cysts were the most common. In Group A, the most frequent hormonal deficiency was gonadal dysfunction. Galactorrhoea and amenorrhoea were relatively common in female patients with prolactinomas. Pre-surgical diabetes insipidus was only seen in Group B, in which also hormone deficiencies were more frequent and numerous. Larger lesions were more likely to be seen in Group B. Patients in Group B were more frequently male, younger, and leaner than those of Group A, whereas at last follow-up they showed more obesity and dyslipidaemia. In our cohort, the percentage of patients with at least one pituitary deficiency increased slightly after surgery. CONCLUSIONS: The management of sellar/parasellar lesions is challenging in the transition age, requiring an integrated and multidisciplinary approach. Hormone and metabolic disorders can occur many years after treatment, therefore long-term follow-up is mandatory.

Risk factors for gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs): a three-centric case-control study.

PURPOSE: Risk factors for sporadic GEP-NENs are still not well defined. To identify the main clinical risk factors represents the aim of this study performed by three Italian referral centers for NENs. METHODS: We performed a retrospective case-control study including 148 consecutive sporadic GEP-NENs and 210 age- and sex-matched controls. We collected data on clinical features, cancer family history and other potential risk factors. RESULTS: Mean age was 58.3 ± 15.8 years; 50% males, primary site was pancreas (50.7%), followed by ileum (22.3%). The 62.8% and 29.1% of cases were G1 and G2, respectively; the 40% had locally advanced or metastatic disease at diagnosis. Independent risk factors for GEP-NENs were: family history of non-neuroendocrine GEP cancer (OR 2.16, 95% CI 1.31-3.55, p = 0.003), type 2 diabetes mellitus (T2DM) (OR 2.5, 95% CI 1.39-4.51, p = 0.002) and obesity (OR 1.88, 95% CI 1.18-2.99, p = 0.007). In the T2DM subjects, metformin use was a protective factor (OR 0.28, 95% CI 0.08-0.93, p = 0.049). T2DM was also associated with a more advanced (OR 2.39, 95% CI 1.05-5.46, p = 0.035) and progressive disease (OR 2.47, 95% CI 1.08-5.34, p = 0.03). Stratifying cases by primary site, independent risk factors for pancreatic NENs were T2DM (OR 2.57, 95% CI 1.28-5.15, p = 0.008) and obesity (OR 1.98, 95% CI 1.11-3.52, p = 0.020), while for intestinal NENs family history of non-neuroendocrine GEP cancer (OR 2.46, 95% CI 1.38-4.38, p = 0.003) and obesity (OR 1.90, 95% CI 1.08-3.33, p = 0.026). CONCLUSION: This study reinforces a role for family history of non-neuroendocrine GEP cancer, T2DM and obesity as independent risk factors for GEP-NENs and suggests a role of metformin as a protective factor in T2DM subjects. If confirmed, these findings could have a significant impact on prevention strategies for GEP-NENs.

Gender in Endocrine Diseases: Role of Sex Gonadal Hormones.

Gender- and sex- related differences represent a new frontier towards patient-tailored medicine, taking into account that theoretically every medical specialty can be influenced by both of them. Sex hormones define the differences between males and females, and the different endocrine environment promoted by estrogens, progesterone, testosterone, and their precursors might influence both human physiology and pathophysiology. With the term Gender we refer, instead, to behaviors, roles, expectations, and activities carried out by the individual in society. In other words, "gender" refers to a sociocultural sphere of the individual, whereas "sex" only defines the biological sex. In the last decade, increasing attention has been paid to understand the influence that gender can have on both the human physiology and pathogenesis of diseases. Even the clinical response to therapy may be influenced by sex hormones and gender, but further research is needed to investigate and clarify how they can affect the human pathophysiology. The path to a tailored medicine in which every patient is able to receive early diagnosis, risk assessments, and optimal treatments cannot exclude the importance of gender. In this review, we have focused our attention on the involvement of sex hormones and gender on different endocrine diseases.

Somatostatin analogs therapy in gastroenteropancreatic neuroendocrine tumors: current aspects and new perspectives.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare tumors that present many clinical features secreting peptides and neuroamines that cause distinct clinical syndromes such as carcinoid syndrome. However most of them are clinically silent until late presentation with mass effects. Surgical resection is the first line treatment for a patient with a GEP-NET while in metastatic disease multiple therapeutic approaches are possible. GEP-NETs are able to express somatostatin receptors (SSTRs) bounded by somatostatin (SST) or its synthetic analogs, although the subtypes and number of SSTRs expressed are very variable. In particular, SST analogs are used frequently to control hormone-related symptoms while their anti-neoplastic activity seems to result prevalently in tumor stabilization. Patients who fail to respond or cease to respond to standard SST analogs treatment seem to have a response to higher doses of these drugs. For this reason, the use of higher doses of SST analogs will probably improve the clinical management of these patients.

Predictors of morbidity and mortality in acromegaly: an Italian survey.

OBJECTIVE: To describe demographic and hormonal characteristics, comorbidities (diabetes mellitus and hypertension), therapeutic procedures and their effectiveness, as well as predictors of morbidity and mortality in a nationwide survey of Italian acromegalic patients. DESIGN: Retrospective multicenter epidemiological study endorsed by the Italian Society of Endocrinology and performed in 24 tertiary referral Italian centers. The mean follow-up time was 120 months. RESULTS: A total of 1512 patients, 41% male, mean age: 45±13 years, mean GH: 31±37 µg/l, IGF1: 744±318 ng/ml, were included. Diabetes mellitus was reported in 16% of cases and hypertension in 33%. Older age and higher IGF1 levels at diagnosis were significant predictors of diabetes and hypertension. At the last follow-up, 65% of patients had a controlled disease, of whom 55% were off medical therapy. Observed deaths were 61, with a standardized mortality ratio of 1.13 95% (confidence interval (CI): 0.87-1.46). Mortality was significantly higher in the patients with persistently active disease (1.93; 95% CI: 1.34-2.70). Main causes of death were vascular diseases and malignancies with similar prevalence. A multivariate analysis showed that older age, higher GH at the last follow-up, higher IGF1 levels at diagnosis, malignancy, and radiotherapy were independent predictors of mortality. CONCLUSIONS: Pretreatment IGF1 levels are important predictors of morbidity and mortality in acromegaly. The full hormonal control of the disease, nowadays reached in the majority of patients with modern management, reduces greatly the disease-related mortality.

Measuring calcitonin in washout of the needle in patients undergoing fine needle aspiration with suspicious medullary thyroid cancer.

Calcitonin measurement in washout of the needle after aspiration (WO-Ct) has been rarely evaluated. Here we analyzed the role of WO-Ct in a series of subjects who underwent fine needle aspiration (FNA) with suspicious medullary thyroid cancer (MTC). Twenty-one patients referred following elevated serum calcitonin (S-Ct) or suspicious MTC by cytology. All patients underwent re-evaluation of S-Ct, FNA, and measurement of WO-Ct. S-Ct and WO-Ct were assessed by chemiluminescence assay (IMMULITE 2000, Diagnostic Products Corporation, USA). S-Ct showed elevated value in six subjects (mean 368.8 ± 373.9 pg/ml), of which three cases were cytologically classified as Class 5. WO-Ct obtained in this group (304.0 ± 309.3 pg/ml) was no different from S-Ct. After surgery MTC was confirmed in all patients. In the other 15 patients MTC was excluded by cytology or histology. Two subjects had moderately skewed S-Ct with nonmedullary histology. In the remaining 13 patients S-Ct resulted normal (6.2 ± 5.6 pg/ml) and WO-Ct low (2.9 ± 2.2 pg/ml). Significant (two-tailed P < 0.05, r(2) = 0.27, 95% confidence interval = 0.017-0.81) correlation was found between S-Ct and WO-Ct in nonmedullary patients but not in MTC patients. This study showed that WO-Ct can play a role in diagnosing primary and metastatic MTC. The procedure is easy, cost effective, and should be used in patients undergoing FNA with elevated S-Ct. Further studies and guidelines for the method are needed to use this technique in clinical routine. Until this any institute should use itself cut-off.

Thyroid incidentaloma identified by ¹8F-fluorodeoxyglucose positron emission tomography with CT (FDG-PET/CT): clinical and pathological relevance.

OBJECTIVE: The percentage of patients with thyroid cancer incidentally diagnosed during a (18) F-fluorodeoxyglucose Positron Emission Tomography with computed tomography (CT) (FDG-PET/CT) for nonthyroid diseases ranges between 26% and 50%. DESIGN: Retrospective assessment of the clinical and pathological features of thyroid incidentalomas at FDG-PET/CT, aiming to identify potential predictors of malignancy. PATIENTS: Fifty-two patients with incidental thyroid uptake at FDG-PET/CT were retrospectively included [38 W, age 64·1 ± 12·5 years (mean ± SD)]. An arbitrary cut-off level of 5·0 for the 'maximum standardized uptake value' (SUV max) was chosen to differentiate benign from malignant tumours. Complete thyroid function, neck ultrasonography (US) features, and cyto-histological results were reported for all cases. RESULTS: In our institution, the prevalence of incidental thyroid (18) F-fluorodeoxyglucose ((18) F-FDG) uptake was nearly 1·76%. The prevalence of focal uptake correlated with greater risk of malignancy (P < 0·01). In particular, the euthyroidism (P < 0·003) and a SUV max >5·0 (P < 0·0001) were associated with the diagnosis of thyroid cancer. Diffusely increased FDG-PET/CT uptake in the thyroid was related to benign conditions. CONCLUSIONS: The presence of focal uptake with high SUV max and euthyroidism correlate with high likelihood of malignancy. Performing a neck US would have to be recommended in all patients with euthyroidism and an incidental FDG-PET/CT focal thyroid uptake. We do not suggest to use FDG-PET/CT as a screening tool for thyroid cancer in the general population, because of both its high cost and low incidence of thyroid incidentaloma at FDG-PET/CT.

Gene variants associated to malignant thyroid disease in familial adenomatous polyposis: a novel APC germline mutation.

BACKGROUND AND AIM: Familial adenomatous polyposis (FAP) is an autosomal inherited syndrome characterized by hundreds to thousands colorectal adenomatous polyps with oncological transformation lifetime risk of 100%. FAP is mainly associated with mutations in APC (autosomal dominant inheritance) or MUTYH (autosomal recessive inheritance) genes. Affected individuals are at increased risk of developing extra-intestinal tumors. Lifetime risk of developing thyroid carcinoma has been described in previous reports of about 2-12%, mainly in females, and the mean age is below 30 yr. About 95% of cancers are papillary thyroid carcinomas (PTC), mostly multifocal. The aim of this study was to evaluate the frequency of PTC among our series of FAP patients and to assess the type of gene mutation associated with the disease. METHODS: Fifty-four subjects from 36 FAP families were selected (29 females/25 males) and the mean age (±SD) at diagnosis was 28.8±10.8 yr. All patients underwent blood examination for thyroid hormones and antibodies, germline mutational analysis of APC and/or MUTYH genes, thyroid ultrasound, and endocrinological evaluation. RESULTS: In 13/54 (24.1%) subjects, an eumetabolic thyroid disease was found: plurinodular disease in 7/54 (13.0%); single nodule in 4/54 (7.4%); in 2/54 patients (3.7%), we found a malignant nodule characterized after total thyroidectomy as a classical PTC. Both patients were female and showed a classic FAP phenotype. Mutational analysis revealed in the first patient the APC germline mutation 3183_87del ACAAA and in the second patient the del9-10 (del9080dup11) novel APC variant; the first mutation has been already reported in association with PTC; to our knowledge the second mutation has never been previously reported in association with FAP. CONCLUSIONS: In the population examined, the estimated prevalence of thyroid malignant diseases was 3.7%. In both patients, the identified APC gene pathogenetic variants mapped within the 5' region of the gene, previously reported as a PTC-associated mutational hot spot. Both patients had classic FAP phenotype and genetic analysis revealed two pathogenetic APC mutations: c.3183_87delACAAA, a recurrent pathogenetic variant and del9-10 (del9080dup11), a novel, not previously described genomic rearrangement. In agreement with previous studies, the morpho-functional surveillance of thyroid in FAP series should be recommended. A better insight into the overall genotype-phenotype correlation of APC gene mutations would be helpful for the identification of at-risk individuals.

Hurthle cell tumours of the thyroid. Personal experience and review of the literature.

Hurthle cell carcinoma represents about 5% of differentiated thyroid carcinomas. The prognosis of the malignant type of the tumour is still under debate as some Authors have reported that Hurthle cell adenoma occasionally behaves like Hurthle cell carcinoma. Aim of the present study was to evaluate previously reported data and personal experience on the clinical and pathological features of patients affected by Hurthle cell tumour that may predict disease progression and death. In the literature, factors potentially associated with decreased survival were identified and include: age, disease stage, tumour size, extra-glandular invasion, lymph node disease, distant metastases, extensive surgery, radioiodine treatment. From 1992 to 2003, the Authors identified 28 patients affected by Hurthle cell tumour, 9 with Hurthle cell adenoma and 19 with Hurthle cell carcinoma. Of these, 22 were females and 6 males. Mean age of patients affected by adenoma was 49.7 years (range 30-72) vs. 49.3 years (range 15-72) in Hurthle cell carcinoma patients. In all patients, total thyroidectomy was performed. At histology, 9 adenomas, 5 "minimally invasive" and 14 invasive carcinomas were found. Post-operatively, in Hurthle cell carcinoma patients, TNM staging showed 9 patients with stage I, 5 stage II, 4 stage III and one stage IVa (UICC, 2002). All invasive carcinomas underwent (131)I therapy (91-585 mCi). One Hurthle cell carcinoma patient received external beam radiotherapy. The mean follow-up period was 62 months (range 6-324). Relapse was not observed in any of the cases with adenoma. Only one Hurthle cell carcinoma patient showed distant lung metastases at 60 months' follow-up. In conclusion, Hurthle cell carcinoma was not found to present a more aggressive behaviour than follicular carcinoma, when risk factors, including extent of tumour invasion, were taken into account. None of the patients with Hurthle cell adenoma showed a relapse or death caused by the tumour.

Pattern of regional metastases and prognostic factors in differentiated thyroid carcinoma.

The meaning of nodal metastases in well-differentiated thyroid carcinoma is controversial. The Authors analyse the impact of lymphatic spread reviewing 1503 cases of well-differentiated thyroid carcinoma treated at the National Cancer Institute of Rome between 1988 and 2005, in order to detect significant prognostic factors through multivariate analysis. Overall, 462 cases of locally advanced well-differentiated thyroid carcinoma, were considered. A multivariate analysis of a subgroup, comprising 97 N+ consecutive cases of well-differentiated thyroid carcinoma, previously untreated, was performed to study prognostic factors for local (N+) and distant (M+) metastasis in well-differentiated thyroid carcinoma. Of the 97 cases, 88 were submitted to surgery for a large well-differentiated thyroid carcinoma, 9 for occult differentiated thyroid carcinoma. After surgery, 12 patients were lost to follow-up, 8 resulted pathologically negative, therefore only 77 cases of pN1 well-differentiated thyroid carcinoma were studied. Considering all cases of well-differentiated thyroid carcinoma, 10-year-overall survival was 58.7% for locally advanced well-differentiated thyroid carcinoma, compared to 94.8% in low stage cases. Neck dissection, margin infiltration and extra-capsular spread were significant prognostic factors. The Authors present a retrospective study of 77 patients with primary differentiated thyroid carcinoma, submitted to thyroidectomy and neck dissection aimed at analysing distribution of nodal metastases according to Robbins' levels classification and defining their prognostic value. All N1b cases, retrospectively reviewed (n. 77), presented clinical and histological evidence of neck nodes metastases from differentiated thyroid carcinoma; histological reports indicated tumour localisation and topographical distribution of metastases; papillary carcinoma was the most common type (72 cases), followed by follicular carcinoma (5 cases). Surgical treatment always comprised total thyroidectomy and 6(th) level dissection. Overall 52 cases were submitted to monolateral neck dissection, 25 to bilateral neck dissection. Treatment of the lateral neck was postero-lateral neck dissection (n. 53), selective lateral neck dissection (n. 20), modified radical and radical (n. 29). Cervical level IV was the most frequently involved (52%), extra-capsular spread of metastases was identified in 22% of the cases. Statistically significant prognostic factors for distant metastases and recurrence on the neck were follicular carcinoma (p < 0.01) and extra-capsular spread (p < 0.001). Age, pT, sex, number of positive nodal metastases, T-extension and the number of nodal positive levels were not significant. In the Authors' experience, histological grade of differentiation, wide tumour excision and neck dissection, in cases of N1b well-differentiated thyroid carcinoma, without residual disease (R1, R2), in the central and lateral neck, are determinant prognostic factors. Extracapsular spread in particular, was found to be a highly predictive factor either of distant metastasis or regional recurrence.

Refractory thyrotoxicosis induced by iodinated contrast agents treated with therapeutic plasma exchange. A case report.

Excess free iodide in the blood (ingested or injected) may cause thyrotoxicosis in patients at risk. Iodinated contrast solutions contain small amounts of free iodide and may be of significance for patients affected by Graves' disease, multinodular goiter or living in areas of iodine deficiency. Herein, we report a 57 elderly woman with a clinical history of multinodular goiter presented with a thyrotoxicosis induced by an iodinate contrast agent used during computed tomography scan. Because of the patient's resistance to conventional antithyroid drugs, she was treated with therapeutic plasma exchange (TPE). TPE is used in the treatment of several immunologic and nonimmunologic disorders. Temporary improvement after TPE in cases with thyrotoxicosis has been reported. In our patient's case, we observed an improvement in the thyroid hormone laboratory values as well as clinical findings. TPE can be an addition treatment when standard therapies for thyrotoxicosis fail providing the clinician with an adjuvant tool for rapid preparation of such a patient for thyroidectomy surgery.

Malignant insulinoma presenting as metastatic liver tumor. Case report and review of the literature.

Insulin-secreting tumors are the commonest hormone-producing neoplasm of the gastrointestinal tract. They occur with an incidence of 4 cases per million per year. About 10% of them are metastatic and malignant insulinomas very rarely observed in children and in elderly. We report a rare case of very large malignant insulinoma in a 71-year-old woman admitted in our Oncological Institute on October 2005. She presented with fasting hypoglicemia (blood glucose 35 mg/dl) and high serum insulin levels (insulin 115.9 microU/ml). A computerized tomographic scan showed a pancreatic tail lesion of about 6 cm in max diameter and multiple liver metastases. A whole body scintiscan using 111In-DTPA-D-Phe1-octreotide was made and an increased uptake in the tail of the pancreas has been found. The patient was submitted to liver biopsy and the diagnosis of a metastatic insulin-secreting tumor was immunoistochemically confirmed. Due to the presence of some hypoglicemic episodes uncontrolled by medical treatment, on December 2005 the patient was admitted to surgical intervention with a body and tail pancreatic resection. Post-operatively the patient experienced again syncope with hypoglycemia and hyperinsulinemia. It was then decided to start a schedule of treatment with somatostatin analog (octreotide subcutaneously 500 microg three times a day) with a good control of blood glucose levels (101 mg/dl). A trans-arterial chemioembolization was planned but the patient died for pancreatic and cardiovascular complications before this treatment started.

Second generation ultrasonographic contrast agents in the diagnosis of neoplastic thyroid nodules.

To verify whether the use of second generation ultrasonographic contrast agents leads to an improvement in the differential diagnosis of thyroid nodules, twenty patients, eligible for uninodular goiter surgery were studied. All patients previously underwent complete hormonal profile, bidimensional thyroid ultrasonographic, Colour Doppler evaluation and 99 mTc scintiscan. All nodules were as well evaluated before and after sulphur-hexafluoride administration. Wash-in time, contrast agent intra-nodular flow and wash-out time were evaluated. These data were compared with the cytology and histology findings. On the basis of the histological examination we divided our study population in 2 groups: in the group of neoplastic lesions (4 follicular adenomas and 6 carcinomas) an early wash-in was observed, with an homogeneous peripheral pattern enhancement, a rapid centripetal progression and an extended persistence of the contrast agent inside the nodule. In 6 out of 10 cases of thyroid neoplasia a fast wash-out was observed. In the group of benign lesions, in the patients affected by nodular goiter, an intra-nodular perfusion as opposite to the healthy surrounding parenchyma was observed. Even though ultrasound contrast agent technique has a limited invasivity and is more expensive than Fine Niddle Aspiration (FNA), the preliminary data of this pilot study suggest that this method might prove useful, to differentiate benign from malignant thyroid nodules.

The association of colour flow Doppler sonography and conventional ultrasonography improves the diagnosis of thyroid carcinoma.

OBJECTIVE: In the present study, we compared the results of conventional ultrasonography (US) and colour flow Doppler sonography (CFDS) with those of US guided fine needle aspiration biopsy (FNAB) and of pathologic staging of resected thyroid nodules, to assess the relative importance of US and CFDS in discriminating malignant thyroid nodules. SUBJECTS AND STUDY DESIGN: We retrospectively reviewed records of 230 patients submitted to US-guided FNAB before surgery for solitary, not hot thyroid nodules. Before US guided FNAB, they were examined with conventional US and CFDS. Conventional US evaluated nodule size, echogenicity, presence of halo sign and microcalcifications. CFDS evaluated the vascular pattern classified as types I, II and III. Twenty-seven patients with inadequate cytology were excluded from this study (11.7%). RESULTS: Two hundred and three patients underwent surgery. At histology a thyroid carcinoma was found in 36 patients (17.7%) and a benign nodule was observed in 167 patients (82.3%). We did not find any difference in cancer prevalence between nodules with a primary tumour size < or =1 cm and those >1 cm (17.6 vs. 17.7%; p = 0.99). A solid echo texture was not statistically significant to suggest malignancy (p = 0.32). Microcalcifications were seen in 83.3% (30/36) of malignant nodules and in 33.5% (56/167) of benign nodules. These results were statistically significant (p < 0.0001). The type III flow as determined by CFDS was a statistically significant criterion to suggest malignant disease (p < 0.005). The most predictive findings of malignancy on conventional US was the combination of microcalcifications plus the absence of halo sign (sensitivity 75%, specificity 71.9%, p < 0.0001). The combination of an absence of halo sign on conventional US and a type III pattern on CFDS presented the higher sensitivity (83.3%) for malignancy with a specificity of 43.7%. Microcalcifications on US in combination with a type III CFDS pattern showed a lesser sensitivity (80.6%) with an improved specificity (75.4%). In our opinion, the better balanced combination of US and CFDS features was the absence of halo sign plus microcalcifications and a type III CDFS pattern (sensitivity 72.2%, specificity 77.2%). CONCLUSIONS: The combination of conventional US and CFDS provides benefits in increasing the screening sensitivity and accuracy in distinguishing malignant thyroid nodules.

Malignant glucagonoma. New options of treatment.

Few cases of malignant glucagonomas have been described in the literature. In this paper we present a case of a 77-year-old woman with necrolytic migratory erythema and high plasma glucagon and chromogranin A levels caused by a neuroendocrine tumour. An abdominal CT scan suggested a pancreatic lesion and two liver metastases. The patient underwent pancreatic debulking and liver metastasectomy. Histological and immunohistochemical investigations revealed a well differentiated neuroendocrine tumour with vascular invasion and scattered immunopositivity for somatostatin receptors. The patient was treated with octreotide (20 mg i.m. every 28 days) for three years without side effects. Three months after surgery symptoms of disease recurred accompanied by hyperglucagonaemia and newly diagnosed liver lesions. The patient was treated with octreotide (30 mg i.m. every 28 days) and interferon-alpha (6 MU s.cc 3 times per week) plus three cycles of hepatic chemoembolisation. Symptoms resolved after the first month of therapy, hormone levels decreased compared to untreated levels and metastatic growth slowed as observed by radiographic evidence. The patient is now asymptomatic with persistent hepatic disease and normal serum glucagon levels forty months after primary treatment. So far, only few immunohistochemical studies are reported on malignant glucagonoma and combined treatment schedules. We demonstrated, for the first time, a scattered immunopositivity for somatostatin receptors in a malignant glucagonoma. For this reason, the somatostatin analogs therapy was instituted. A combined antiproliferative medical treatment and the hepatic chemoembolization have been able to control tumor growth and disease symptoms for a long time after surgery.

Effects on bone mineral density by treatment of benign nodular goiter with mildly suppressive doses of L-thyroxine in a cohort women study.

OBJECTIVES: Thyroid diseases and their treatment may influence the osseous system. The influence that prolonged suppressive L-thyroxine (LT4) therapy may have on inducing subclinical hyperthyroidism on bone metabolism is still a matter of debate. The aim of the present study was to assess the effects of chronic LT4 treatment at mildly inhibiting serum thyroid-stimulating hormone (TSH) doses on bone mineral density (BMD) and biochemical bone remodeling markers in a cohort of women with benign nodular goiter, and to verify the efficacy of the treatment on nodule size. SUBJECTS AND STUDY DESIGN: A total of 200 euthyroid Caucasian women with nodular goiter (age 52.1 +/- 9; 80 pre- and 120 postmenopausal) were enrolled: 96 had been treated with LT4 for at least 3 years and a matched group of 104 had untreated goiter. LT4 therapy was given at a dose sufficient to reduce TSH under the lower limit of the normal range (0.27-4.20 microIU/ml) without suppressing it below the limit of assay sensitivity (0.005 microIU/ml) and maintaining normal serum values of free triiodothyronine (FT3) and free thyroxine (FT4). The adequacy of the dose was evaluated on the basis of serum TSH levels. The osteopenic effect of LT4 treatment was evaluated directly by total body and lumbar spine dual-energy X-ray absorptiometry (DEXA) and indirectly by biochemical parameters (alkaline phosphatase, osteocalcin, calcium, parathyroid hormone) at the baseline and throughout the follow-up. The efficacy of LT4 schedule on thyroid nodule size was assessed on the basis of the ultrasonographic evaluation. RESULTS: Mineralometric data showed no significant difference between BMD values for treated and untreated patients in both pre- and postmenopausal status. In all patients, serum markers of bone turnover were in the normal range, with no differences in the treated and control groups. The TSH concentrations were significantly lower in treated than in untreated patients (p < 0.0001); FT3 and FT4 were in the normal range for all patients. Evaluation of nodule size during follow-up showed a reduction of > or = 30% in 32 of 96 treated patients (33.3%) versus none in those untreated, whilst nodule size remained unmodified in 60 treated patients (62.5%) versus 35 (33.6%) in those untreated, and an increase in nodule size and/or development of new nodules was found in 4 treated patients (4.2%) versus 69 of the 104 untreated patients (66.3%). CONCLUSIONS: This study suggests that at slightly suppressing TSH doses, LT4 therapy has no adverse effects on BMD in both pre- and postmenopausal women, while having an efficacy on nodule size comparable with that reported using an LT4 schedule able to maintain TSH near or below the assay sensitivity limit.

Adrenal glands metastases from malignant melanoma. Laparoscopic bilateral adrenalectomy.

Adrenal metastases from Malignant Melanoma (MM) represent a debated therapeutical problem particularly in the case of disseminated disease. Surgical treatment, however, seems to be able to provide improvement on survival. Laparoscopic adrenalectomy is considered a gold standard procedure in benign adrenal disease but its value in malignancy, in terms of oncological effectiveness, is not known. A case of bilateral adrenal malignant melanoma metastases is reported. The patient, affected by superficial spreading melanoma of the right foot, eleven years after the primary developed a right adrenal metastasis. The relapse was treated by laparoscopic right adrenalectomy. One year later the patient had a new metastasis in the left adrenal gland and was submitted to laparoscopic left adrenalectomy. The two step laparoscopic bilateral adrenalectomy showed to be quite easy to perform, providing a complete removal of the whole glands, without adrenal tissue crushing and without neoplastic tissue dissemination in abdominal cavity. The postoperative course was excellent and the patient was discharged within about 72 hours after the two procedures. In literature only few reports indicate the feasibility of laparoscopic adrenalectomy for malignancy. In the reported case of malignant melanoma metastasis, minimally invasive adrenalectomy was very satisfactory and the good results obtained suggest its routine use.