Luca Foppiani

Absence of histological malignancy in a patient cohort with follicular lesions on fine-needle aspiration

Follicular lesions account for 4–6% of all thyroid fine-needle aspiration (FNA) cytologies. To date, no cytological criteria exist to distinguish follicular adenoma from carcinoma. For this purpose, histological evaluation after surgical exeresis is required. From 1993 to 2000 we performed 1238 US-assisted FNA biopsies in patients admitted to our unit for uni-or multi-nodular goiters. In the latter goiters, FNA was performed in the dominant nodule. Cytological examination revealed a follicular lesion in 71 patients (5.7%). All patients came from regions of Northern Italy with moderate iodine deficiency. In 48%, the lesion presented as a solitary nodule, while in the other 52% it occurred in the context of a multinodular goiter. Surgical exeresis of the neoplasm was recommended in all cases. Sixty-three patients (89%) underwent surgery (Group 1) while the other 8 patients (11%) opted for follow-up (Group 2). In Group 2, the mean nodule volume (3.2±0.5 ml) at baseline was slightly smaller (p=0.08) than that found in Group 1 (5.4±0.7 ml). In Group 1, histological examination after surgery showed a follicular adenoma in 52 patients (83%) and a colloid goiter in the others (17%). No malignancy was detected. Group 2 underwent a median follow-up of 46 months (range 24–96 months) on L-thyroxine suppressive regimen (dose range 75–125 μg/day), with TSH levels ranging from 0.1 to 0.3 mIU/l. Throughout the follow-up, no patient developed clinical or ultrasonographic features that could be considered worrisome for malignancy; thus, no further biopsy was performed. However, an overall slight increase (median +5.2%) in nodular volume in respect to baseline was observed. Although institutional and cytological bias cannot be ruled out, our data do not confirm the reported incidence of malignancy in histological specimens of follicular lesions diagnosed on FNA cytology, and prompt us to suggest a less aggressive first-step approach (i.e. careful clinical and instrumental evaluation, and suppressive LT4 therapy) for these lesions, unless anamnestic reports or clinical and ultrasonographic features of the nodules suggest malignancy.

The Hypothalamic‐Pituitary‐Adrenal and Gonadal Axes in Rheumatoid Arthritis

Abstract: The hypothalamic‐pituitary‐adrenal (HPA) and the hypothalamic‐pituitary‐gonadal (HPG) axes involvement or response to immune activation seems crucial for the control of excessive inflammatory and immune conditions such as autoimmune rheumatic diseases, including rheumatoid arthritis (RA). However, female patients seem to depend more on the HPA axis, whereas male patients seem to depend more on the HPG axis. In particular, hypoandrogenism may play a pathogenetic role in male RA patients because adrenal and gonadal androgens, both products of the HPA and HPG axes, are considered natural immunosuppressors. A significantly altered steroidogenesis of adrenal androgens (i.e., dehydroepiandrosterone sulfate, DHEAS and DHEA) in nonglucocorticoid‐treated premenopausal RA patients has been described. The menopausal peak of RA suggests that estrogens and/or progesterone deficiency also play a role in the disease, and many data indicate that estrogens suppress cellular immunity, but stimulate humoral immunity (i.e., deficiency promotes cellular Th1‐type immunity). A range of physical and psychosocial stressors are also implicated in the activation of the HPA axis and related HPG changes. Chronic and acute stressors appear to have different actions on immune mechanisms with experimental and human studies indicating that acute severe stressors may be even immunosuppressive, while chronic stress may enhance immune responses. The interactions between the immunological and neuroendocrine circuits is the subject of active and extensive ongoing research and might in the near future offer highly promising strategies for hormone‐replacement therapies in RA.

Focus on high-risk DTC patients: high postoperative serum thyroglobulin level is a strong predictor of disease persistence and is associated to progression-free survival and overall survival.

Introduction No parameters predicting recurrence are available for high-risk differentiated thyroid cancer (DTC) patients, and 2-year-follow-up is required to modify the initial prognostic classification. High thyroglobulin (Tg) levels before 131I-remnant-ablation, during L-thyroxine-withdrawal (ablation-Tg) have undetermined predictive/prognostic significance in low-risk DTC patients. Our study aimed to assess the positive predictive value (PPV) of ablation-Tg in high-risk DTC patients and to evaluate whether high ablation-Tg levels were associated with progression-free-survival (PFS) and overall survival (OS). Patients and Methods We selected 243 high-risk DTC patients. All patients underwent total thyroidectomy and 131I-remnant-ablation (initial therapy). Clinical data obtained during a median 5-year follow-up were used to assess the response and outcome. The association between disease persistence/recurrence after initial therapy, ablation-Tg, and other risk-factors (T, N, G, histology, and MACIS score) was evaluated through univariate and multivariate analyses, as was the association between PFS, OS ablation-Tg, and other risk factors. Results Ablation-Tg of 50 &mgr;g/L or greater displayed the highest PPV(97%) for disease persistence. In the univariate analysis, high levels of ablation-Tg were confirmed in patients with persistent disease after initial therapy: the higher the odds ratios, the higher the ablation-Tg levels. On multivariate analysis, ablation-Tg was the best predictive factor, especially on comparing patients with ablation-Tg levels of 50 &mgr;g/L or greater and those with ablation-Tg less than 2 &mgr;g/L (adjusted OR, 818). In a multivariate Cox model, ablation-Tg was the factor most closely associated with PFS (HR, 65.9). The prognostic value of ablation-Tg was confirmed by the overall-survival curves and adjusted risk estimates (adjusted HR = 26.7). Conclusions Ablation-Tg levels of 50 &mgr;g/L or greater are a valuable initial predictor of disease persistence/recurrence in high-risk DTC patients. A significant association emerged between high ablation-Tg levels of 50 &mgr;g/L or greater and both progression-free survival (PFS) and overall survival (OS).

Low thyroglobulin concentrations after thyroidectomy increase the prognostic value of undetectable thyroglobulin levels on levo-thyroxine suppressive treatment in low-risk differentiated thyroid cancer

Design: Recombinant human TSH-stimulated thyroglobulin (Tg) levels (rhTSH-Tg) are sufficient for early follow-up of low-risk differentiated thyroid cancer (DTC) patients after thyroidectomy and radioiodine (131I) remnant ablation (RAI). Serum Tg levels at the time of remnant ablation (ablation-Tg) is thought to be related with rhTSH-Tg and may be predictive of recurrent disease. During long-term follow-up, Tg levels on levo-T4 (L-T4) suppressive treatment (suppressive-Tg) is sufficiently sensitive to avoid further evaluations in patients with undetectable rhTSH-Tg. The aim of our study was to verify whether, in a subgroup of low-risk DTC patients, the association of low ablation-Tg levels (<10 μg/l) with undetectable suppressive-Tg concentrations has a sufficient negative predictive value (NPV) for recurrence of disease, leading to avoid rhTSH testing. Methods: We enrolled 169 low-risk DTC patients treated by thyroidectomy + RAI and undetectable suppressive-Tg at 12-month follow-up. In all patients, we retrospectively evaluated ablation-Tg and rhTSH-Tg. For all patients, 2-yr follow-up was available. Results: Based on rhTSH-Tg>2 μg/l, relapsing disease was histologically proven in 2 patients. rhTSH-Tg levels between 0.6–2.0 μg/l, with no evidence of disease, was observed in 10 patients (6%). One hundred and fifty-seven patients showed undetectable rhTSH-Tg. The NPV of undetectable suppressive-Tg was 92.8%. The ablation-Tg level was <10 μg/l in 140 patients. In this group, the NPV of undetectable suppressive-Tg was 100%. Conclusion: Our data indicate that undetectable suppressive-Tg value, combined with ablation-Tg levels <10 μg/l, may avoid a significant number of high-cost rhTSH-Tg test.

TSH-secreting adenomas: rare pituitary tumors with multifaceted clinical and biological features.

TSH-secreting pituitary adenomas (TSH-omas) are a rare cause of hyperthyroidism in clinical practice. As their diagnosis is often delayed, these tumors are mostly diagnosed as macroadenomas, preventing an effective and radical cure and leading to serious local and systemic comorbidities. In addition to neurosurgery, medical therapy with the effective and tolerable SS analogs is a fundamental tool for the treatment of TSH-omas. We report 3 cases of TSH-macroadenomas which displayed different clinical presentations. All patients showed increased free-thyroid hormone levels with inappropriately normal (2 patients) or high (1 patient) TSH levels. Magnetic resonance imaging (MRI)/computed tomography (CT) evidenced a pituitary macroadenoma and octreoscan was positive in all patients. In the 2 patients who underwent neurosurgery, hormonal hypersecretion by the tumor normalized. Histology showed nuclear pleomorphism and fibrosis, whereas immunohistochemistry showed positivity for TSH and, in a lesser amount, for FSH. In one of these patient (case 1), however, the presence of a tumor remnant inside the left cavernous sinus prompted us, in accordance with the patient, to start therapy with octreotide-long-acting release. As the third patient had a cardiac comorbidity which contraindicated neurosurgery, he underwent satisfactory treatment with long-acting SS analogs alone which normalized thyroid hormone levels. In this case, previous treatment with amiodarone confused and delayed the correct diagnosis of TSH-oma. As a result of improved laboratory and morphological techniques, TSH-omas should currently be diagnosed in early stages, thus enabling most patients to be managed satisfactorily through a combined approach.

Cabergoline modulation of α-subunits and FSH secretion in a gonadotroph adenoma

Most non-functioning pituitary adenomas respond poorly to medical therapy. We describe the case of a 62-year-old man who presented with clinical features of an invasive macroadenoma. Baseline hormonal evaluation revealed increased FSH and α-subunit (α-SU) levels. Trans-sphenoidal exeresis followed by radiotherapy (RT) was performed. Almost all neoplastic cells were intensely immunoreactive for α-SU. On PCR analysis, specific amplification products were observed for somatostatin 2, 3 and 5 receptors as well as for both short and long isoforms of the dopamine D2 receptor. In vitro, α-SU and FSH were released into the medium by adenoma cells and increased after TRH stimulation. After surgery, α-SU and FSH levels were still elevated. Short-term slow-release lanreotide treatment did not modify either α-SU or FSH levels. Cabergoline was started and a fast and long-lasting decrease in α-SU and, to a lesser extent, in FSH was observed. The tumor remnant was unmodified on magnetic resonance imaging 3 years after surgery and RT. This case report shows that the in vitro expression of somatostatin receptors may not be directly associated to the in vivo response of α-SU and FSH to lanreotide, probably because of a functional uncoupling of the receptors. Cabergoline should be considered as an effective therapy for hormonal, and perhaps proliferative, control of gonadotroph adenoma remnants before the effects of RT are fully effective.

Thyroid storm as precipitating factor in onset of coma in an elderly woman: case report and literature review

Thyroid storm is an uncommon but life-threatening manifestation of hyperthyroidism which, unless appropriately treated by combined therapy, causes 30–60% of deaths in hospitalized patients. Mental deterioration leading to apathy and eventually coma is a rare clinical presentation of this pathology, frequently observed in the elderly. We present the case of a 77-year-old hypertensive woman who was hospitalized for fast onset of coma, probably due to the unusual combination of a hypernatremic hyperosmolar state and an unexpected thyroid storm (TS). Although not definitely ascertained, the possible etiology was the hyperthyroid phase of chronic autoimmune thyreopathy (Hashitoxicosis). Notably, the significant adjunctive role of thyroid hyperfunction in the pathogenesis of coma was confirmed by the fact that, although metabolic abnormalities were overcome, complete and satisfactory recovery of the patient’s mental and physical condition occurred only with normalization of thyroid hormones by antithyroid treatment. Our case highlights the importance of properly evaluating thyroid function in elderly patients who show a sudden progressive impairment in their mental condition, for early detection of potentially fatal conditions such as thyroid storm or myxedematous coma.

Thyroid lobe ablation with iodine- ¹³¹I in patients with differentiated thyroid carcinoma: a randomized comparison between 1.1 and 3.7 GBq activities.

Purpose The present study was undertaken to evaluate the ablation rate after administration of 1.1 or 3.7 GBq of iodine-131 (131I) to patients with low-risk differentiated thyroid carcinoma (DTC) primarily treated by lobectomy. Patients and methods Enrolled were 136 consecutive patients affected by histologically proven low-risk DTC previously treated by lobectomy. Patients were randomized to receive a single dose of 1.1 or 3.7 GBq of 131I in an equivalence trial. Successful thyroid ablation was defined as a negative diagnostic whole-body scan and stimulated thyroglobulin levels lower than 2 ng/ml in the absence of thyroglobulin antibodies. Results The patient demographic and clinical data were well balanced at baseline. The ablation rate was significantly (P<0.01) higher in patients treated with 3.7 GBq (75%) than in those treated with 1.1 GBq (54%) of radioiodine. No relevant side effects occurred in either group. Conclusion Radioiodine lobe ablation with a single administration of 3.7 GBq is a simple and safe mode of treatment, achieving an ablation rate higher than that of 1.1 GBq. This procedure may be offered as an alternative to completion thyroidectomy in highly selected DTC patients who had experienced complications during initial surgery or for whom completion thyroidectomy is contraindicated.

Uncommon association of germline mutations of RET proto-oncogene and CDKN2A gene

INTRODUCTION Calcitonin measurement is advised in the diagnosis of thyroid nodules, as it is an accurate marker of medullary thyroid carcinoma (MTC). C-cell hyperplasia (CCH)-induced hypercalcitoninemia cannot be distinguished from that induced by MTC, unless surgery is performed. CASE We report the clinical and biological features of a patient with a family history of cancer, including melanoma and pancreatic cancer, who had previously undergone surgery for melanoma. He presented the unusual association of papillary thyroid carcinoma (PTC), normocalcemic hyperparathyroidism, and hypercalcitoninemia with a pathological response to pentagastrin, which was histologically deemed secondary to CCH. Multiple endocrine neoplasia (MEN) 2A was diagnosed. RET gene analysis showed a p.V804M missense mutation in exon 14, a low- but variably penetrant defect found in both sporadic and MEN2A-associated MTC/CCH, and a p.G691S polymorphism in exon 11. Furthermore, the germline P48T mutation was found in the CDKN2A gene exon 1, which is known to be associated with melanoma and pancreatic cancer. The patient showed the uncommon coexistence of a germline mutation in two suppressor genes, RET and CDKN2A; this finding, deemed to be a mere coincidence, did not modify the phenotype expected by each single mutation. CCH associated with V804M RET mutation is a precancerous condition and surgery is recommended. In order to exclude MTC, surgery is advised in patients with a pathological calcitonin response to pentagastrin, in the absence of thyroid autoimmunity. CCH-induced hypercalcitoninemia can be associated with thyroid cancers other than MTC (e.g., PTC). Family history is important in scheduling specific genetic screening in high-risk patients and their relatives.

Hypopituitarism in the Elderly: Multifaceted Clinical and Biochemical Presentation

UNLABELLED Hypopituitarism (HYPO) is a rare and under-investigated pathology in the elderly. AIM to review our case records of patients > or =65 yrs with first diagnosis of anterior global hypopituitarism, in order to evaluate presentation symptoms, etiology, biochemical and hormonal pictures, pituitary morphology, and efficacy of therapy. PATIENTS 15 patients (65-82 yrs) were studied: in 11 (73%) HYPO was secondary to pituitary macroadenoma (non-secreting in 10 and GH-secreting in 1); in 3 it was associated to empty sella, and in 1 to pituitary hypoplasia. RESULTS major presenting symptoms were visual-field defects and asthenia (40%) but also memory and/or gait impairment and nausea (30%) and depression (20%) were significantly observed. Dyslipidemia (73%), anemia (20%) and severe hyponatremia (13%) were found. After starting substitutive therapy and clinical improvement, 10 patients with macroadenoma underwent uneventful neurosurgery, which improved visual alterations but not pituitary function. Immunohistochemistry showed positivity for FSH in one patient and for GH in one patient. Six out of the eight patients with a post-surgical tumor remnant required treatment (surgery/radiotherapy/somatostatin analogue treatment in the acromegalic patient). CONCLUSIONS The diagnosis of HYPO is often delayed in the elderly, since symptoms may be ascribed to aging and associated comorbidities. In our series, most of the aspecific symptoms were retrospectively addressed to HYPO since their resolution/improvement with replacement therapy. The prevalent cause of HYPO remains non-functioning pituitary macroadenomas. Hyponatremia can be a life-threatening presenting symptom. Symptoms considered apparently aspecific in the elderly should be investigated in order to possibly diagnose an important treatable disorder as HYPO.