Effective multimodal management of a giant adrenocortical carcinoma.

BACKGROUND: Adrenocortical carcinoma is a rare and aggressive tumour. The only curative treatment is surgery with negative margins. In most series, the average lesion size ranges from 5.5 to 15 cm. METHODS: We report the case of a 27-year-old female with hyperandrogenism and Cushing syndrome due to a right adrenocortical carcinoma of 19.7 cm. RESULTS: The tumour abutting on liver and vena cava and the presence two nodules in liver required extensive surgery including a right posterior sectionectomy and an en bloc resection of the adrenal mass together with the right kidney and the gallbladder. The vena cava was also resected with a reconstruction using a pericardial patch since it was invaded on its border. Pathological examination confirmed an adrenocortical carcinoma, with tumour invasion of vessels, tumour capsule, vena cava and two metastases in the liver (pT4N0M1). All margins were negative. Three months after surgery, two lung nodules, cardio-phrenic and internal mammary adenomegalies were noticed on a PET/CT scan, justifying the initiation of chemotherapy, alongside with mitotane. After a 10-month follow-up, CT scan was stable excepted for a lung nodule growing from 4 to 7 mm. Targeted stereotaxic radiotherapy was then administered. Twenty-two months after surgery, the patient has improved considerably and all signs of hyperandrogenism and Cushing syndrome have resolved. CONCLUSION: This case of adrenocortical carcinoma illustrates one of the largest tumours among those reported. It demonstrates the feasibility and effectiveness of a multimodal approach in its treatment even if it is giant and at high risk.

Preoperative treatment of benign insulinoma: diazoxide or somatostatin analogues?

Surgery is the ideal treatment of insulinoma. However, systemic therapy may be required to prevent severe preoperative hypoglycaemia, when surgery is contraindicated, delayed or refused and in case of unresectable metastatic disease. Diazoxide is commonly used but is not always effective and can cause serious side effects. Somatostatin analogues (octreotide and lanreotide) may be an alternative option. We report the case of a 27-year-old patient with insulinoma in whom diazoxide was compared with lanreotide before operation. A diagnosis of insulinoma was made on the basis of a fasting test and a 2 cm tumour confirmed in the body of the pancreas, with a high uptake of 111-In-pentreotide. Diazoxide was initiated and increased to a maximal tolerated dose of 450 mg/day. Because of dyspnoea and persisting hypoglycaemia, diazoxide was shifted to lanreotide 120 mg. All symptoms resolved without hypoglycaemia. According to the EORTC quality score of life, the score without treatment, under diazoxide, under lanreotide and after surgery were respectively 84.7, 73.3, 90.9 and 99.1. Thus, providing a positive Octreoscan, somatostatin analogues may be a safe, effective and well-tolerated option in patients with insulinoma refractory and/or intolerant to diazoxide or with a high risk of fluid retention.

Occurrence of sporadic medullary thyroid carcinoma in Graves' disease in association with a RET proto-oncogene mutation.

BACKGROUND: Graves' disease may be associated with thyroid cancer, particularly differentiated thyroid cancer. Medullary thyroid cancer (MTC) is less common. The occurrence of sporadic MTC in Graves' disease in the presence of a RET proto-oncogene has never been reported. CLINICAL PRESENTATION: A 63-year-old woman was referred for Graves' disease. A thyroid ultrasound disclosed five nodules, one of which was classified as Eu-Tirads 5 with a size of 6.7 × 6.5× 11 mm. Fine needle aspiration was reported as Bethesda class IV follicular neoplasm of a Hürthle cell subtype. Calcitonin level was found to be elevated. A total thyroidectomy confirmed the diagnosis of MTC and a bilateral cervical lymphadenectomy was performed, with four lymph nodes being infiltrated by MTC. Genetic testing revealed a M918T mutation in the RET proto-oncogene. CONCLUSION: MTC may occur in Graves' disease, especially if a nodule is present. In this case, genetic testing should always be performed even if MTC is sporadic. Increased incidence of thyroid cancer in autoimmune thyroid diseases, as well as the link existing between autoimmunity, inflammation and carcinogenesis, leads us to hypothesize that the association here reported is not coincidental.

Refractory thyroid carcinoma: which systemic treatment to use?

The incidence of thyroid cancer has increased markedly in recent decades, but has been stable in terms of mortality rates. For the most part, these cancers are treated with surgery, which may or may not be followed by radioactive iodine depending on the tumor subtype. Still, many of these cancers will recur and may be treated with radioactive iodine or another surgery. It is unclear what treatment is best for cases of locally advanced or metastatic thyroid cancer that are refractory to radioactive iodine. Chemotherapy has a very low response rate. However, in the past few years, several systemic therapies, primarily targeted, have emerged to improve the overall survival of these patients. Alternative treatments are also of interest, namely peptide receptor radionuclide therapy or immunotherapy.

Painful thyroid nodule, a misleading presentation of subacute thyroiditis.

Typical presentation of subacute thyroiditis (SAT) is an anterior neck pain radiating up to the jaw and ear, often associated with asthenia and fever. Biology shows hyperthyroidism and inflammation. The thyroid uptake is low at scintigraphy. However, the clinical presentation of SAT may be misleading. We report two cases of SAT whose initial manifestation was a painful thyroid nodule suspected of malignancy. In both cases, ultrasound feature was a heterogeneous, hypoechoic, ill-defined area with a low vascularization on colour Doppler. These areas were interpreted by radiologist as nodules. Surgery was then considered. Such a presentation should be known by clinicians to prevent unnecessary surgery.

Post-Chernobyl incidence of papillary thyroid cancer among Belgian children less than 15 years of age in April 1986: a 30-year surgical experience.

OBJECTIVE: We raised the question of a possible relationship in Belgium between the occurrence of papillary thyroid carcinoma (PTC) and age of children (<15 years) at the time of the Chernobyl nuclear plant accident in April 1986. SETTING: Referral university centre for endocrine surgery. MATERIAL AND METHODS: Thirty-year prospective study of the experience of a surgical team with PTC since the Chernobyl accident, taken out of 2349 patients operated on for any thyroid lesions from April 1986 to April 2015, comparing the incidence of PTC by age groups. MAIN OUTCOME MEASUREMENT: Comparison of PTC incidence in patients >15 years (group A) and children <15 years (group B) in April 1986. RESULTS: Out of a total of 2349 patients having undergone thyroid surgery for all types of lesions during 30 year after Chernobyl and born before April 1986, 2164 were >15 years of age at the time of the nuclear accident (group A) and 175 developed PTC (8.1%) compared to 36 PTC (19.5%) that occurred in 185 children <15 years of age (group B) in April 1986 (p < 0.001). CONCLUSIONS: Radiation exposure affected residents of countries (including Belgium) well beyond Ukraine and Belarus. This was demonstrated by a 1990 meteorological report. Over 30 years, there has been a persistent higher incidence of PTC among Belgian children below the age of 15 years at the time of the Chernobyl accident. This relationship with age has even been strengthened by the implementation of more sophisticated immunohistochemical biomarkers diagnostic technology since April 2011.

Role of the endothelin axis in the proliferation of human thyroid cancer cells.

OBJECTIVE: Endothelin-1 (ET-1) may play a role in carcinogenesis. ET-1 axis is overexpressed in thyroid carcinoma. We investigated the expression and the production of ET-1 by thyroid cancer cells as well as the effect of ET-1 receptor antagonism on cell proliferation. DESIGN: Human papillary and follicular thyroid carcinoma cell lines were cultured. MEASUREMENTS: (i) Prepro-ET-1, ET-1 receptors (ETA R and ETB R) and ET-1 converting enzyme (ECE) by reverse transcriptase polymerase chain reaction (RT-PCR); (ii) the presence of ETA R by western blot; (iii) ET-1 concentrations in medium by an enzyme immunometric assay; (iiii) the proliferation of cells by BrdU and tritiated thymidine incorporation. RESULTS: RT-PCR detected the presence of mRNA for prepro-ET-1, ETA R and ECE in papillary and follicular carcinoma cells. ETB R was only expressed by follicular cells. ETA R was also detected in both cell types by western blot. Measurements of ET-1 concentrations demonstrated a secretion of active ET-1 by the cells. ETA R antagonism with atrasentan reduced cell proliferation by 16% in papillary carcinoma cells (P < 0.05) and by 51% in follicular carcinoma cells (P < 0.001). CONCLUSIONS: Papillary and follicular carcinoma cells express all components of the ET-1 axis. ETA R antagonism exerts antiproliferative effects, which opens up new therapeutic perspectives in thyroid carcinoma.

Interrelated overexpression of endothelial and inducible nitric oxide synthases, endothelin-1 and angiogenic factors in human papillary thyroid carcinoma.

OBJECTIVE: Nitric oxide (NO) and endothelin-1 (ET-1) are involved in carcinogenesis. Overexpression of the ET-1 axis has been demonstrated in papillary thyroid carcinoma (PTC). This study investigated the expression of NO synthases (NOS) and their relationship with expression of ET-1 and angiogenic markers in PTC. DESIGN AND PATIENTS: Expression of NOS, angiogenic markers [vascular endothelial growth factor (VEGF), angiopoietin-1 and angiopoietin-2] and their receptors was studied in surgical thyroid samples obtained from 22 patients aged 15-68 years. Three groups were constituted: normal thyroid (n = 5), Hashimoto's thyroiditis (n = 9) and PTC (n = 8). RESULTS: Immunohistochemistry disclosed NOS2 and NOS3 immunoreactivity in PTC cells, the percentage of positive cells being greater than normal (P < 0.02). Real-time quantitative polymerase chain reaction (RTQ-PCR) showed that NOS2 and NOS3 mRNA levels were, respectively, increased (P < 0.02) by 2.6 +/- 0.6 and 4.2 +/- 1.1 times in PTC. RTQ-PCR demonstrated that VEGF, its receptors VEGFR-1 and VEGFR-2, and angiopoietin-2 and its receptor (Tie2) were also overexpressed (P < 0.05) in PTC. Correlations were found between ET-1 expression and that of NOS2, angiopoietin-1 and -2 (P < 0.05). NOS2 mRNA levels also correlated with those of NOS3 and angiopoietin-2 (P < 0.05). In thyroiditis, NOS2 immunoreactivity was observed in inflammatory cells whereas NOS2 mRNA levels were 12.1 +/- 1.6 times higher than normal (P < 0.005). CONCLUSIONS: This study revealed an activation of the NO pathway in thyroid carcinoma, which is interrelated to the ET-1 axis, both systems being overexpressed in concert with angiogenic factors. This global system might play a role in carcinogenesis and constitutes a potential target for anticancer therapy.

Endoscopic and microscopic paraseptal transsphenoidal approach to the sella turcica.

OBJECTIVES: To establish the feasibility of the paraseptal approach to the sella and to demonstrate the superiority of the endoscopic over the microscopic vision during pituitary surgery. STUDY DESIGN: Prospective monocentric study. METHODS: Nine consecutive patients with a pituitary tumour were operated since November 2002. The surgical procedure consisted of a paraseptal approach of the sella with use of a rigid endoscope. Pre- and postoperative (3 months after surgery) symptoms, Magnetic Resonance Imaging (MRI) findings, endocrine and ophthalmic assessment, and intraoperative findings were recorded. RESULTS: One patient presented a CSF leak with a successful peroperative repair. Regarding symptom resolution, headache disappeared during the early postoperative period in case of pituitary apoplexy. All cases of preoperative hemianopsia and diplopia but one improved significantly. Two patients recovered preoperative deficient hormonal functions and six patients did not require substitution therapy any more. No nasal packing was needed except in one case. Considering the healing course, the mucosa repair inside the sphenoid sinus was quicker with Surgicel removal at week 4. Postoperative MRI demonstrated a residual parasellar nodule in 3 out of 6 cases of macroadenoma. Only one required radiation therapy. These results are commented through comparison with the transseptal approach and with surgery exclusively using the microscope. CONCLUSIONS: The paraseptal transsphenoidal approach to the sella turcica using the telescope is at least as effective as the conventional transseptal approach using the operating microscope only. It provides a wide access to the pituitary fossa and an optimal vision of the critical areas. The absence of postoperative nasal packing improves significantly the comfort of the patient during the first postoperative hours.

Increased expression of endothelin-1 and its mitogenic receptor ETA in human papillary thyroid carcinoma.

OBJECTIVE: Since the isolation of endothelin-1 (ET-1) in 1988, there has been tremendous interest in the pathophysiological roles of ET-1 as a vasoconstrictive and mitogenic peptide. Whereas ET-1 is mainly released by vascular endothelial cells, it also proved to be produced by various tissues including the thyroid. Because of its mitogenic properties in malignancy and its role as an inflammatory modulator, ET-1 could be involved in thyroid carcinogenesis and thyroiditis. DESIGN AND PATIENTS: Studies were performed in human thyroid samples obtained at the time of surgery from 39 men and women aged 15-72 years. Thyroid samples were classified in four groups according to conventional histology: normal thyroid (n = 7) papillary thyroid carcinoma (n = 12), Hashimoto's thyroiditis (n = 9) and benign nontoxic nodular goitres (n = 11). Immunohistochemistry and real-time quantitative polymerase chain reaction were used to determine the expression of ET-1 and its receptors (ETAR and ETBR). RESULTS: ET-1 and ETAR mRNA levels were, respectively, 3.8 +/- 1.3 and 4.1 +/- 1.5 times greater (P < 0.001) in papillary thyroid carcinoma than in normal thyroid. Expression of ETBR was unaltered. In Hashimoto's thyroiditis, ET-1 and ETAR were also overexpressed (P < 0.005). Furthermore, immunohistochemistry demonstrated a greater percentage of ET-1-positive follicular cells in these conditions (P < 0.001). In nodular goitres, the expression was increased by 1.7 +/- 0.7 times (P < 0.05) but expression of receptors remained unchanged. CONCLUSIONS: ET-1 and ETAR overexpression observed in thyroid carcinoma suggest a mitogenic role of ET-1 that theoretically could be countered by ETAR antagonists. ET-1 and ETAR overexpression in thyroiditis supports a role of ET-1 in the inflammatory process.

Intraoperative gamma probe detection of insulinoma in an elderly patient with pancreatic cystic lesions.

Insulinoma is a rare endocrine tumour in the elderly. We report the case of an 81-year-old woman suffering from grand mal seizures. Insulinoma was suspected because plasma glucose and insulin levels were 1.5 mmol/l and 80.4 pmol/l, respectively. A pancreatic computerized tomography (CT) scan, magnetic resonance imaging (MRI) and arteriography were normal but (111)In-DTPA-octreotide scintigraphy detected a hotspot in the pancreatic tail. Intraoperative pancreatic ultrasonography and palpation were non-contributory due to multiple pancreatic cysts and nodular lesions. However, a gamma-detecting probe localized a small tumour, labelled preoperatively with (111)In-DTPA-octreotide. Intraoperative insulin measurements in portal venous blood confirmed the successful removal of an insulinoma that was 6 mm in diameter histologically. Pancreatic cystic lesions increase with age and make the intraoperative localization of the insulinoma difficult. Intraoperative gamma probe detection of the tumour labelled with (111)In-DTPA-octreotide might therefore constitute a useful surgical tool.