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.

PRRT: identikit of the perfect patient.

Peptide receptor radionuclide therapy (PRRT) has been strengthened since the publication of NETTER-1. Nevertheless, the correct positioning in the therapeutic algorithm is debated, and no optimal sequence has yet been standardized. Possible criteria to predict the response to PRRT in neuroendocrine tumors (NET) have been proposed. The aim of this review is to define the perfect identity of the eligible patient who can mostly benefit from this therapy. Possible predictive criteria which have been analysed were: primary tumor site, grading, tumor burden, FDG PET and 68Ga-PET uptake. Primary tumor site and 68Ga-PET uptake do not play a pivotal role in predicting the response, while tumor burden, FDG PET uptake and grading seem to represent predictive/prognostic factors for response to PRRT. The heterogeneity in trial designs, patient populations, type of radionuclides, previous therapies and measurement of outcomes, inevitably limits the strength of our conclusions, therefore care must be taken in applying these results to clinical practice. In conclusion, the perfect patient, selected by 68Ga-PET uptake, will likely have a relatively limited liver tumor burden, a ki67 index <20% and will respond to PRRT irrespective to primary tumor. Nevertheless, we have mostly prognostic than predictive factors to predict the efficacy of PRRT in individual patients, while a promising tool could be the NETest. However, to date, the identikit of the perfect patient for PRRT is a puzzle without some pieces and still we cannot disregard a multidisciplinary discussion of the individual case to select the patients who will mostly benefit from PRRT.

Surveillance of patients with differentiated thyroid cancer and indeterminate response: a longitudinal study on basal thyroglobulin trend.

PURPOSE: This is a longitudinal study of retrospective data aimed at verifying whether repeated measurements of serum non-stimulated thyroglobulin (Tg) allow the prediction of persistent disease in patients with differentiated thyroid cancer (DTC) and indeterminate response. METHODS: We examined 145 DTC patients with indeterminate response to therapy followed up for a median time of 68 months. Tg measurements and neck ultrasound (US) were performed every 6-12 months. The changes over time of repeated measurements of basal Tg were analyzed through the multilevel linear regression. RESULTS: Seventy (48.3%) out of 145 patients spontaneously achieved an excellent response, while persistent indeterminate response was observed in 62 (42.7%) patients. The remaining 13 (9.0%) patients had progression: 3/13 with biochemical disease and 10/13 with structural disease. Tg steadily increased in patients with progressive disease (mean percentage change + 27.1% at each follow-up visit), while Tg decreased in patients without any evidence of progression (mean percentage change - 8.8%). This different trend between the two groups was not related to either different values of median TSH at baseline (0.32 vs 0.28 mIU/l, respectively) or to different trend of TSH during follow-up (p = 0.76). Basal Tg values did not increase in three out of ten patients with structural disease that was identified by neck US. CONCLUSIONS: The importance of the study is that, in DTC patients with indeterminate response, rising values of unstimulated Tg, independently from the basal levels, may be useful to identify patients with progressive disease. These results are also useful to avoid unnecessary TSH stimulation.

Lymph node location is a risk factor for papillary thyroid cancer-related death.

PURPOSE: Papillary thyroid cancer (PTC) has good prognosis with a very low chance of mortality. The prognostic role of metastatic lymph node location was judged controversial and more recently (TNM VIII ed.) was considered to have no impact on the prognosis of older patients. The aim of the study was to evaluate the role of metastasized node location on PTC-related mortality. METHODS: PTC-related mortality was analysed in a consecutive retrospective series of 1653 PTC patients followed at our Thyroid Clinic (mean follow-up 5.9 years). RESULTS: Sixteen out of 1653 patients (0.96%) died because of PTC. Average age was 68 years at presentation and 74.7 at death. F/M ratio was 1:1. The death rate increased in relation to the lymph node status: 0.2% in N0, 0.3% in N1a and 3.0% in N1b. CONCLUSIONS: The presence of lymph node metastases in the N1b compartment should be considered as a risk factor for distant metastatic spread and for cancer-related death and included in post-surgery evaluation.

Tall cell and diffuse sclerosing variants of papillary thyroid cancer: outcome and predicting value of risk stratification methods.

PURPOSE: Tall cell (TCV) and diffuse sclerosing (DSV) variants are aggressive variants of papillary thyroid cancer (PTC). We compared the risk of recurrent/persistent disease in patients with TCV, DSV and classical PTC (cPTC) and evaluated the prognostic accuracy of initial vs. ongoing risk stratification. METHODS: A consecutive series of DSV (n = 54), TCV (n = 72) and cPTC (n = 184) patients was retrospectively analyzed. TCV and DSV patients were first risk stratified for recurrent/persistent disease without considering the histotype as a risk factor and subsequently, 6-24 months after initial treatment, re-classified on the basis of the response to therapy (ongoing risk stratification). RESULTS: Extrathyroidal extension was more frequent in DSV than in TCV and cPTC patients (p < 0.05); moreover, only DSV tumors had a higher rate of recurrent/persistent disease when compared to cPTC treated with the same protocol (total thyroidectomy followed by 131I treatment) (p < 0.01). After initial treatment, 54.2% of TCV and 20.4% of DSV patients were classified at low risk, while at ongoing risk stratification, the excellent response (low risk) was higher for both TCV (77.8%) and DSV (50.0%) patients relative to initial stratification (both p < 0.01). Using ongoing risk classification, positive predictive value (PPV) for persistent/recurrent disease was higher relative to initial risk stratification for both TCV (PPV = 93.8 vs. 39.4%) and DSV (PPV = 63.0 vs. 34.9%), p < 0.05 for both. CONCLUSIONS: In our series DSV, but not TCV patients, had poorer outcome than cPTC treated with the same protocol. Moreover, the ongoing risk stratification predicted outcome better than the initial classification in both TCV and DSV patients.

Heavy metals in the volcanic environment and thyroid cancer.

In the last two decades thyroid cancer incidence has increased worldwide more than any other cancer. Overdiagnosis of subclinical microcarcinomas has certainly contributed to this increase but many evidences indicate that a true increase, possibly due to environmental factors, has also occurred. Thyroid cancer incidence is markedly increased in volcanic areas. Thus, the volcanic environment is a good model to investigate the possible factors favoring thyroid cancer. In the volcanic area of Mt. Etna in Sicily, as well as in other volcanic areas, a non-anthropogenic pollution with heavy metals has been documented, a consequence of gas, ash and lava emission. Soil, water and atmosphere contamination, via the food chain, biocontaminate the residents as documented by high levels in the urines and the scalp hair compared to individuals living in adjacent non-volcanic areas. Trace amounts of metals are essential nutrients but, at higher concentrations, can be toxic for living cells. Metals can behave both as endocrine disruptors, perturbing the hormonal system, and as carcinogens, promoting malignant transformation. Similarly to other carcinogens, the transforming effect of heavy metals is higher in developing organisms as the fetus (contaminated via the mother) and individuals in early childhood. In the last decades environment metal pollution has greatly increased in industrialized countries. Although still within the "normal" limits for each single metal the hormesis effect (heavy metal activity at very low concentration because of biphasic, non linear cell response) and the possible potentiation effect resulting from the mixture of different metals acting synergistically can explain cell damage at very low concentrations. The effect of metals on the human thyroid is poorly studied: for some heavy metals no data are available. The scarce studies that have been performed mainly focus on metal effect as thyroid endocrine disruptors. The metal concentration in tissues has been rarely measured in the thyroid. Heavy metal accumulation and metabolism in the thyroid or the carcinogenic activity of different doses and different speciation of metals has not been investigated. These studies are now warranted to better understand thyroid biology and heavy metal role in human thyroid carcinogenesis.

Comparison of conventional L-thyroxine withdrawal and moderate hypothyroidism in preparation for whole-body 131-I scan and thyroglobulin testing.

PURPOSE: After thyroidectomy for thyroid cancer, patients often withdraw L-T4 for diagnostic or therapeutic purposes, showing signs and symptoms of hypothyroidism. A slighter hypothyroidism (reducing L-T4 to one-half) has been proposed to limit these inconveniences. We evaluated half-dose L-T4 protocol, in comparison to conventional L-T4 withdrawal, in terms of effectiveness and improvement of clinical and biochemical disorders. METHODS: We randomized 55 thyroid cancer patients into two groups: 29 patients underwent 5 weeks of half-dose of previous L-T4 treatment (HD group); 26 patients replaced L-T4 with L-T3 for 3 weeks followed by 2 weeks of withdrawal (TW group). Clinical features (Zulewsky clinical score) and biochemical parameters (lipids, liver, and muscle enzymes) were evaluated in all patients at baseline and after 5 weeks. RESULTS: Total cholesterol, creatine kinase, lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase increased at 5 weeks in both groups, but significantly more in TW, but no difference was found by clinical score. Patients who achieved the thyroid-stimulating hormone (TSH) target value (25 µU/ml) were 92.3% in TW group and 48.3% in HD group (p < 0.001). In the HD group, only basal TSH statistically correlated with the achievement of the TSH target. Receiver operating characteristic curves indicated that a basal TSH ≥0.52 µU/ml is required to reach an adequate TSH level. CONCLUSIONS: Half-dose L-T4 protocol, compared to conventional L-T4 withdrawal, is associated with less biochemical disorders but no significant clinical advantage. Therefore, the half-dose protocol reaches an adequate TSH target in 48.3% of patients and is not effective unless basal serum TSH is ≥0.52 µU/ml.

Rare diseases in clinical endocrinology: a taxonomic classification system.

PURPOSE: Rare endocrine-metabolic diseases (REMD) represent an important area in the field of medicine and pharmacology. The rare diseases of interest to endocrinologists involve all fields of endocrinology, including rare diseases of the pituitary, thyroid and adrenal glands, paraganglia, ovary and testis, disorders of bone and mineral metabolism, energy and lipid metabolism, water metabolism, and syndromes with possible involvement of multiple endocrine glands, and neuroendocrine tumors. Taking advantage of the constitution of a study group on REMD within the Italian Society of Endocrinology, consisting of basic and clinical scientists, a document on the taxonomy of REMD has been produced. METHODS AND RESULTS: This document has been designed to include mainly REMD manifesting or persisting into adulthood. The taxonomy of REMD of the adult comprises a total of 166 main disorders, 338 including all variants and subtypes, described into 11 tables. CONCLUSIONS: This report provides a complete taxonomy to classify REMD of the adult. In the future, the creation of registries of rare endocrine diseases to collect data on cohorts of patients and the development of common and standardized diagnostic and therapeutic pathways for each rare endocrine disease is advisable. This will help planning and performing intervention studies in larger groups of patients to prove the efficacy, effectiveness, and safety of a specific treatment.

The influence of the environment on the development of thyroid tumors: a new appraisal.

Most epidemiological studies concerning differentiated thyroid cancers (DTC) indicate an increasing incidence over the last two decades. This increase might be partially explained by the better access to health services worldwide, but clinicopathological analyses do not fully support this hypothesis, indicating that there are carcinogenetic factors behind this noticeable increasing incidence. Although we have undoubtedly understood the biology and molecular pathways underlying thyroid carcinogenesis in a better way, we have made very little progresses in identifying a risk profile for DTC, and our knowledge of risk factors is very similar to what we knew 30-40 years ago. In addition to ionizing radiation exposure, the most documented and established risk factor for DTC, we also investigated the role of other factors, including eating habits, tobacco smoking, living in a volcanic area, xenobiotics, and viruses, which could be involved in thyroid carcinogenesis, thus, contributing to the increase in DTC incidence rates observed.

The tall cell variant of papillary thyroid carcinoma: clinical and pathological features and outcomes.

BACKGROUND: The tall cell variant (TCV) is a relatively rare variant of papillary thyroid cancer. Since a controversy exists whether or not the TCV has a worse outcome, the aim of our study was to retrospectively compare the clinicopathological features and outcomes in a group of TCV patients and a larger group of patients with classical papillary thyroid carcinoma (cPTC). SUBJECTS AND METHODS: Data from 30 TCV and 293 cPTC patients were analyzed. Among the 293 cPTC, we also selected a "high-risk" cPTC group (no.=103) that was treated with the same protocol used for the TCV patients. All data were managed by Cox analysis. RESULTS: Compared to all cPTC patients, TCV subjects displayed only a significantly higher rate of extrathyroid extension. At multivariate analysis, TCV was not an independent variable for the prediction of a high risk of persistent/recurrent disease. At the last follow-up observation, there was no difference in the disease status between the TCV and all cPTC patients. Moreover, "high-risk" cPTC patients had a significant increase in persistent/recurrent disease. CONCLUSIONS: In our study, although the TCV histotype is associated with a higher prevalence of extrathyroid extension, it is characterized by an outcome that is not significantly different from that of all cPTC patients and is more favorable than that of "high-risk" cPTC patients. Only those TCV patients classified as "high risk" based on specific pathological and clinical features, according to current guidelines, should be treated aggressively, such as with a total thyroidectomy, neck lymph node dissection or ablative radioiodine treatment.