Ilenia Marturano

Update on thyroid cancer treatment

Surgery and radioiodine therapy are usually effective for most patients with differentiated thyroid cancer. However, poorly differentiated and anaplastic thyroid carcinomas represent a challenge to physicians on the basis of the current cancer treatment modalities. These cancer subtypes are often lethal and refractory to radioiodine therapy as well as most of the common chemotherapy drugs. Several kinase inhibitors are promising targeted therapies for these malignancies; however, clinical trials involving these drugs have provided controversial results and their clinical use is still under debate. Advanced medullary thyroid carcinomas may also be refractory to conventional therapies and novel kinase inhibitors may also be useful to control tumor progression in certain patients. Novel evidence is emerging that thyroid cancer is a stem cell disease, thereby implying that the driving force of thyroid cancers is a subset of undifferentiated cells (thyroid cancer stem cells) with unlimited growth potential and resistance to conventional therapeutic regimens. Thyroid cancer stem cells have been proposed as responsible for tumor invasiveness, metastasis, relapse and differentiation. Therefore, drugs that selectively target these cells could serve as a cornerstone in the treatment of poorly differentiated thyroid cancer.

Descriptive Epidemiology of Human Thyroid Cancer: Experience From a Regional Registry and The “Volcanic Factor”

Thyroid cancer (TC), the most common endocrine tumor, has steadily increased worldwide due to the increase of the papillary histotype. The reasons for this spread have not been established. In addition to more sensitive thyroid nodule screening, the effect of environmental factors cannot be excluded. Because high incidences of TC were found in volcanic areas (Hawaii and Iceland), a volcanic environment may play a role in the pathogenesis of TC. In January 2002, the Regional Register for TC was instituted in Sicily. With a population of approximately five million inhabitants with similar genetic and lifestyle features, the coexistence in Sicily of rural, urban, industrial, moderate-to-low iodine intake, and volcanic areas provides a conducive setting for assessing the environmental influences on the etiology of TC. In Sicily, between 2002 and 2004, 1,950 new cases of TC were identified, with an age-standardized rate (world) ASR(w) = 17.8/105 in females and 3.7/105 in males and a high female/male ratio (4.3:1.0). The incidence of TC was heterogeneous within Sicily. There were 2.3 times more cases in the Catania province (where most of the inhabitants live in the volcanic area of Mt. Etna): ASR(w) = 31.7/105 in females and 6.4/105 in males vs. 14.1 in females and 3.0 in males in the rest of Sicily. Multivariate analysis documented that residents in the volcanic area of Mt. Etna had a higher risk of TC, compared to the residents in urban, industrial, and iodine deficient areas of Sicily. An abnormally high concentration of several chemicals was found in the drinking water of the Mt. Etna aquifer, which provides water to most of the residents in the Catania province. Our data suggest that environmental carcinogen(s) of volcanic origin may promote papillary TC. Additional analyses, including cancer biological and molecular features, will allow a better understanding of risk factors and etiopathogenetic mechanisms.

The BRAFV600E Mutation Influences the Short- and Medium-Term Outcomes of Classic Papillary Thyroid Cancer, But Is Not an Independent Predictor of Unfavorable Outcome

INTRODUCTION The prognostic usefulness of BRAF(V600E) evaluation in papillary thyroid cancer (PTC) has been analyzed in many studies, with controversial conclusions. AIM To analyze the clinical relevance of BRAF(V600E) measurement in a homogenous series of PTC patients followed in a single institution. METHODS One hundred three classical variant PTC patients who underwent total thyroidectomy in the 3-year period between 2005 and 2008 were retrospectively selected, and BRAF(V600E) assessment was performed using paraffin-embedded archival specimens in 2013. All patients were actively followed at our medical center, with an average follow-up of 55±13 months. RESULTS BRAF(V600E) mutation-positive cancers (55.3%) were more frequently associated with lymph node metastasis (p=0.01) and advanced TNM stage (III-IV) (p=0.03). These findings were also confirmed in the subset of 42 microcarcinomas. BRAF(V600E)-positive patients were also at a higher risk of persistent disease (OR 3.5 [95% confidence interval {CI} 1.2-10.3], p=0.03) in univariate but not multivariate analysis (OR 2.8 [CI 0.7-11.8], p=0.2). Lymph node involvement was an independent predictor of persistent disease (OR 30.9 [CI 6.0-159.0], p<0.0001). Kaplan-Meier curves confirmed a higher percentage of persistent/recurrent disease in BRAF(V600E)-positive patients (p=0.02). However, the BRAF(V600E) mutation did not change the recurrence rate of PTC in subgroup analyses on the basis of other established risk factors (p=0.2). CONCLUSIONS BRAF(V600E)-positive tumors were at higher risk of developing more aggressive behavior and were associated with less favorable outcomes in the short and medium term, but the BRAF(V600E) mutation was not an independent predictor of unfavorable outcome. Therefore, its use as a prognostic marker in clinical practice is not advisable.

Radiometabolic treatment of hyperthyroidism with a calculated dose of 131-iodine: results of one-year follow-up.

Oral administration of radioactive iodine (131I) is a well-known and effective procedure for the treatment of hyperthyroidism. However, the optimal dose is still a matter of debate, as is the frequency of recurrence and hypothyroidism. The aim of our study was to evaluate the 1-yr outcome of a calculated dose of 131I activity in the treatment of hyperthyroidism, following the guidelines published jointly by the Italian Society of Endocrinology and the Italian Society of Nuclear Medicine. We studied 84 patients affected with hyperthyroidism (55 with Graves’ disease and 29 with toxic adenoma), who were treated with a dose of 131I activity obtained by using the formula from the guidelines. In all patients serum free T4, free T3, and TSH were measured before, and 2, 6, and 12 months after radiometabolic therapy. A thyroid scan and thyroid uptake with 131I were also performed before treatment, and a thyroid ultrasound scan was obtained before and 1 yr after treatment. One year after treatment, 22 out of 55 patients with Graves’ diseases (40.0%) had persistence/recurrence of hyperthyroidism, whereas only 1 patient of the 29 with toxic adenoma (3.4%) was still in a hyperthyroid state. The frequency of hypothyroidism in patients responsive to therapy was higher in subjects with Graves’ disease (45.5%), than in those with toxic adenoma (17.3%, p=0.02). Overall size reduction of the target lesion was 56.2±23.1%. In conclusion, the dose calculation suggested by the guidelines represents an effective method for treating thyroid toxic adenoma. In subjects with Graves’ disease, we propose using a pre-determined 131I activity, which is higher than that derived from the guidelines. Such an approach would reduce the incidence of recurrent/persistent hyperthyroidism. On the other hand, an increase in post-131I hypothyroidism should not be regarded as a negative effect in these patients, since hypothyroidism is easily corrected, and the risk of worsening ophthalmopathy is reduced.

Improving the prediction of malignancy in cytologically suspicious thyroid nodules

Background: Fine needle cytology aspirates (FNA) classified as THY4 are a heterogeneous group suspicious for malignancy [papillary thyroid cancer (PTC)], which is confirmed in 50–80% of cases after surgery. Aim: To better stratify THY4 FNA specimens for the relative risk of malignancy. Methods: We retrospectively analyzed 78 thyroid nodules classified as THY4 because of the presence of atypical cells, hypercellular trabeculae and/or intranuclear inclusions (ICI), in the absence of papillae. Two subgroups were identified: group 1 (38 nodules), showing ICI with (no.=17) or without (no.=21) trabeculae and cellular atypia, and group 2 (40 nodules), showing trabeculae and atypia but without ICI. Results: PTC was detected at histology in 56/78 of the patients (71.8%). Malignancy occurred in 36/38 (94.7%) of the patients in group 1 and in 20/40 (50.0%) of the patients in group 2. Therefore, the positive predictive value (PPV) for PTC was 97.3% in the ICI+ specimens (group 1), with a sensitivity of 64.3% and specificity of 95.2%. When only ICI was present, without atypia and trabeculae, the PPV and specificity were similar (95.0 and 95.2%, respectively), but the sensitivity was decreased (48.7%). In specimens without ICI (group 2), the PPV was only 50.0%; however, combined with young age (<40 yr) and male gender, it reached a value similar to that of group1. Conclusions: In ICI+ specimens compared to ICI-, the risk of PTC is nearly doubled, since PPV increases from 50.0% to 97.3%. This observation suggests that surgery should be considered mandatory in all lesions classified THY4 at FNA, although the relevant difference in terms of cancer risk between ICI- vs ICI+ nodules might be an useful information for both the clinician and the patient.

The antiepileptic drug carbamazepine can cause adrenal insufficiency in patients under hormone replacement therapy for congenital adrenal hyperplasia.

Address for correspondence: Dr. Damiano Gullo, Endocrinology, Garibaldi-Nesima Hospital, Catania, 95100 Italy, e-mail: damiano.gullo@poste.it Received 14-03-2013, Accepted 13-05-2013 Dear Sir, Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21-OH CAH) is treated with both glucocorticoids (to suppress pituitary ACTH and adrenal androgen production) and mineralocorticoids (to reduce angiotensin II concentrations). A 25-year-old man affected by 21-OH CAH and followed at our endocrine clinic since the age of 2 months, after achievement of skeletal maturity, was treated with constant steroid doses of dexamethasone (DEX) 0.50 mg/day and fludrocortisone up to 0.1 mg/day, achieving good clinical and biochemical control of the disease. After a long period without follow-up visits the patient returned to us complaining of excessive fatigue and difficulty in concentrating. Serum ACTH, 17-OHPG, androstenedione and renin were all increased, suggesting hypoadrenalism. This condition persisted despite the progressive increase in replacement therapy dose. An effect of carbamazepine, started 3 years earlier because of epilepsy, on exogenous steroid metabolism was hypothesized. Carbamazepine (200 mg TID) was then discontinued and substituted with levetiracetam (500 mg TID), an antiepileptic drug with different pharmacokinetics characteristics. Hormone levels gradually normalized and at 45 days were all within the normal range (Table 1). The patient reported a clear improvement of his symptoms within 5 weeks after drug switch.

L’ipertiroidismo è un fattore di rischio di trombosi venosa e arteriosa: descrizione di un caso clinico

L’incidenza dell’associazione tra ipertiroidismo e trombosi non è nota. Le alterazioni coagulative che potrebbero essere coinvolte sono: l’aumentato turnover dei fattori della coagulazione con una loro aumentata sintesi endoteliale, emofilia A acquisita, sindrome da antifosfolipidi, ridotta attività fibrinolitica, un’eccessiva attività adrenergica. Il distretto più frequentemente interessato è quello cerebrale [1]. Il paziente, maschio di 57 anni con febbre, algie addominali, tachicardia e decremento ponderale, presentava TSH 0,0 microUI/ml (0,34–4,2), FT3 19,1 pmol/L (3,8–6), FT4 68,1 pmol/L (6,8–16), leucocitosi neutrofila (GB 14.600, Ne 80%), VES 99 mm (< 14), PCR 11,4 mg/dl (< 0,5), PT 65% (80–120), PTT 41 sec (23–35), fibrinogeno 668 mg/dl (1,5–4,5). L’esame obiettivo evidenziava una tiroide aumentata di volume, dolente alla deglutizione; l’ecografia tiroidea rilevava un volume aumentato (lobo destro 35 × 32 × 53 mm, lobo sinistro 32 × 34 × 49 mm); la scintigrafia tiroidea indicava scarsa fissazione del radioiodio. Veniva trattato con paracetamolo, corticosteroidi e beta bloccante con miglioramento clinico. Dopo circa 6 giorni il paziente lamentava dolore addominale a intensità crescente, con aumento degli indici di flogosi e D-Dimero. La TAC torace e addome evidenziava malattia trombo-embolica arteriosa e venosa (Fig. 1) e il paziente veniva sottoposto a terapia trombolitica e trasferito in UTIC.

Metastatic malignant struma ovarii with coexistence of Hashimoto’s thyroiditis

Summary Struma ovarii is a rare ovarian teratoma characterized by the presence of thyroid tissue as the major component. Malignant transformation of the thyroidal component (malignant struma ovarii) has been reported in approximately 5% of struma ovarii. The management and follow-up of this unusual disease remain controversial. We report the case of a woman with a history of autoimmune thyroiditis and a previous resection of a benign struma ovarii that underwent hystero-annexiectomy for malignant struma ovarii with multiple papillary thyroid cancer foci and peritoneal involvement. Total thyroidectomy and subsequent radioiodine treatment lead to complete disease remission after 104 months of follow-up. The diagnosis and natural progression of malignant struma ovarii are difficult to discern, and relapses can occur several years after diagnosis. A multidisciplinary approach is mandatory; after surgical excision of malignant struma, thyroidectomy in combination with 131I therapy should be considered after risk stratification in accordance with a standard approach in differentiated thyroid cancer patients. Learning points Malignant struma ovarii is a rare disease; diagnosis is difficult and management is not well defined. Predominant sites of metastasis are adjacent pelvic structures. Thyroidectomy and 131I therapy should be considered after risk stratification in accordance with standard approaches in DTC patients.