[Phaeochromocytoma and paraganglioma]. / Phéochromocytome et paragangliome.

Phaeochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors that arise from the adrenal medulla or sympathetic and parasympathetic ganglia. These tumors produce most often catecholamines in excess, causing hypertension and sometimes severe acute cardiovascular complications. The diagnosis is based on plasma or urines metanephrines measurements and on conventional and nuclear medicine imaging. Catecholamines-producing PPGL is very unlikely if levels are normal. The diagnosis of PPGL cannot be made without visualization of a tumor. Therapeutic management consists mostly of surgical excision, after drug preparation, and should be done in referral centers. About 40% of pheochromocytomas and paragangliomas occur in the context of an autosomal inherited syndrome, making genetic testing essential. The follow-up must be prolonged because a metastatic evolution or a recurrence can be observed in about 15% of the cases.

European Society of Endocrinology Clinical Practice Guideline for long-term follow-up of patients operated on for a phaeochromocytoma or a paraganglioma.

Phaeochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours. Standard treatment is surgical resection. Following complete resection of the primary tumour, patients with PPGL are at risk of developing new tumoural events. The present guideline aims to propose standardised clinical care of long-term follow-up in patients operated on for a PPGL. The guideline has been developed by The European Society of Endocrinology and based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) principles. We performed a systematic review of the literature and analysed the European Network for the Study of Adrenal Tumours (ENS@T) database. The risk of new events persisted in the long term and was higher for patients with genetic or syndromic diseases. Follow-up in the published cohorts and in the ENS@T database was neither standardised nor exhaustive, resulting in a risk of follow-up bias and in low statistical power beyond 10 years after complete surgery. To inform patients and care providers in this context of low-quality evidence, the Guideline Working Group therefore prepared recommendations on the basis of expert consensus. Key recommendations are the following: we recommend that all patients with PPGL be considered for genetic testing; we recommend assaying plasma or urinary metanephrines every year to screen for local or metastatic recurrences or new tumours; and we suggest follow-up for at least 10 years in all patients operated on for a PPGL. High-risk patients (young patients and those with a genetic disease, a large tumour and/or a paraganglioma) should be offered lifelong annual follow-up.

Outcomes of adrenalectomy in patients with unilateral primary aldosteronism: a review.

Aldosterone hypersecretion in primary aldosteronism is unilateral (aldosterone producing adenoma and primary unilateral hyperplasia) or bilateral (idiopathic adrenal hyperplasia). Laparoscopic adrenalectomy is nowadays the preferred approach to treat patients with unilateral primary aldosteronism. We review the outcomes of this intervention in recently published series. Laparoscopic adrenalectomy has a morbidity of 5-14%, mortality below 1%, and a mean hospital stay around 3 days. It generally results in the normalization of aldosterone secretion and in a large decrease of blood pressure and antihypertensive medication, but normotension without treatment is only achieved in 42% of all cases. Normotension following adrenalectomy is more likely in young and lean women with recent low grade hypertension than in obese men with long-standing high grade hypertension or a family history of hypertension. However, individual prediction of the blood pressure outcome is not accurate and predictors of hypertension cure should not be used to select patients for surgery. Age, associated health conditions and preferences of the patient are more relevant to this end.

Long-term postoperative follow-up in patients with apparently benign pheochromocytoma and paraganglioma.

Patients with pheochromocytoma or paraganglioma are at risk of developing tumor recurrences or new tumors after successful resection of the primary tumor. This review summarizes current knowledge concerning the incidence and risk factors for such events. The overall incidence exceeds 15%. Patients with inherited tumors have a higher probability of recurrence or new tumors. Most recurrences are metastatic, particularly in patients with SDHB mutations or nonhereditary tumors. We recommend the determination of plasma or urinary metanephrines (normetanephrine and metanephrine) 1 month after surgery. In patients with sporadic, single tumors ≤5 cm in diameter, clinical and biochemical follow-up should be performed every 2 years. However, this follow-up period can be reduced to yearly, if it is more simple and more convenient for patients and physicians. Patients with larger or multiple but apparently benign tumors and/or inherited disease should be tested 6 months after surgery and then every year for the rest of their lives. Imaging follow-up is also required in patients with inherited or malignant tumors.

[Endocrine hypertension]. / Hypertension artérielle endocrine.

Endocrine hypertension represents more than half of the causes of secondary hypertension. This entity encompasses several diseases including primary aldosteronism, paraganglioma/pheochromocytoma and Cushing's syndrome. The screening of endocrine hypertension should be performed in all the patients presenting with: (1) a resistant hypertension; (2) a severe hypertension; (3) the coexistence of hypertension with an adrenal adenoma, clinical or biological abnormalities. Clinical signs and symptoms, whenever present, lack specificity, especially for primary aldosteronism where hypertension is usually the unique symptom. Screening is performed by the measurement of several hormones and by a tomodensitometry to study the morphology of the adrenals: the presence of a solitary or multiples adenomas, or hyperplasia. Pheochromocytoma and Cushing's syndrome are very uncommon and should be referred to specialized centres. Primary aldosteronism is a frequent cause of secondary hypertension. Once the diagnosis is obtained, it is essential to differentiate whether it is a surgically correctable form or not. The patients with a bilateral adrenal hyperplasia can be managed effectively by mineralocorticoids receptor antagonist. The adrenalectomy will cure or improve hypertension for the majority of the patients with a lateralized secretion of aldosterone. The diagnosis and the treatment of these disorders can be challenging. However, the diagnosis of endocrine hypertension allows diagnosing surgical correctable form of hypertension, which is not possible in essential hypertension.

Video-assisted thoracoscopic surgery as a first-line treatment for mediastinal parathyroid adenomas: strategic value of imaging.

OBJECTIVE: To present first-line thoracic surgery made possible by localization studies in three patients with ectopic parathyroid adenomas. DESIGN AND METHODS: Three patients with ectopic parathyroid tissue in the mediastinum were examined by ultrasound, technetium-99m sestamibi scintigraphy, computed tomography (CT), and venous catheterization with measurement of parathyroid hormone. Without previous cervical exploration, video-assisted thoracic surgery (VATS) was used in all cases to avoid the need for thoracic open surgical procedures. RESULTS AND CONCLUSIONS: The mediastinal parathyroid glands were all detected at scintigraphy, and CT and venous catheterization were helpful in anatomic and functioning characterization. All pathologic glands were successfully resected, with only one minor complication. VATS can safely remove a deep mediastinal parathyroid adenoma and avoid more aggressive open approaches. In an experienced referral center, systematic and sophisticated imaging studies may accurately identify and localize rare ectopic parathyroid adenomas, and avoid cervical surgery.

[Diagnosis of ectopic mediastinal parathyroid adenomas: value of cardiac MRI]. / Diagnostic des adénomes parathyroïdiens ectopiques médiastinaux: apport de l'IRM cardiaque.

Primary hyperparathyroidism is due to an adenoma in 85% of cases. In 10% of cases, the parathyroid adenoma may be in an ectopic location. Ten per cent of these ectopic adenomas are located in the mediastinum. Imaging modalities performed in persistent or recurrent hyperparathyroidism include ultrasound, MIBI scintigraphy, venous blood sampling, helical CT and MRI. The authors report 3 cases of ectopic adenoma located in the mediastinum, where pre-operative diagnosis was confirmed using cardiac MRI sequences.

Desmosomes are regulated by protein kinase C in primary rat epithelial cells.

In the present study, we addressed the possible relevance of protein kinase C (PKC) in the regulation of intracytoplasmic desmosome assembly. Treatment of cultured rat lingual and epidermal keratinocytes with a potent and highly selective PKC inhibitor (GF109203X) induced an increase in granular labelling for major desmosomal proteins, desmoplakins, desmoglein and plakoglobin, both intracellularly and at the cell surface. This was associated with the formation of ultrastructurally recognizable desmosomes deep in the cytoplasm and increase in intercellular desmosome number. In contrast, PKC activation upon short exposure to 12-O-tetradecanoylphorbol 13-acetate (TPA) resulted in altered cell morphology, loss of intercellular contact and accumulation of desmosomal proteins in the juxtanuclear zone. On the other hand, PKC depletion by long term TPA treatment re-established cell-cell contact, where desmosomal markers were exclusively redistributed. Taken together, these results suggest that inhibition of PKC is required for intracytoplasmic as well as intercellular desmosome assembly, whereas its activation may regulate disassembly process.

Cytoplasmic desmosome formation by H-7 and EGF treatment in cultured fetal rat keratinocytes.

Cytoplasmic desmosomes (CD) are classically found in dyskeratotic cells of many epithelial tumors. Their significance and mechanism of formation remain largely speculative. Recently, we have reported the induction of these structures in rat keratinocytes following a brief treatment with acrylamide, and proposed that protein kinase inhibition may be implicated in their formation. In the present study, we show that protein kinase inhibitor H-7 in the presence of EGF is able to induce CD in rat keratinocytes within half an hour. In serum free medium containing 20 ng/ml of EGF, desmosomal structures at different stages of assembly were obtained using H-7 at concentrations ranging between 20 and 80 microM. No such structures were found at lower concentrations. The plaque diameters were significantly small in comparison with plasma membrane plaques. EGF induced plakoglobin positive membrane invaginations and in the presence of H-7, desmosomal plaques assembled on these membranes as either half desmosomes or as symmetric ones. The present results implicate protein kinase inhibition in CD formation and suggest that EGF provides tubular membrane structures in the cytoplasm on which desmosomes may assemble.

Structural status of the int loci in women showing high incidence of breast cancer.

Mammary carcinomas in certain mice strains are induced following infection by the MMTV. Insertion of MMTV provirus into the int-1 and int-2 loci results in transcriptional activation of these two proto-oncogenes and is thought to be a key step in breast tumorigenesis in mice. A viral etiology for human breast cancers, though proposed several years ago, is far from proven. However, morphological structures resembling Bittner's particles have been observed earlier in about 39% samples of breast tumor and milk sediments of Parsi women. We therefore investigated in the Parsis, the structural integrity of two potential sites of integration (int-1 and int-2) of the hypothetical human mammary tumor virus and have used for this purpose a large number of patient DNA. The results obtained however failed to distinguish any major structural change existing at the int-1 or the int-2 sites that may point to a proviral integration event having occured in human breast cancers. We have, however, observed differences in the physical structure of the int-1 map, compared to the one reported and sequenced, and have therefore felt it necessary to present a new one indicating our findings, notably, the polymorphic PvuII sites. In addition, we report a single case of Parsi woman, with infiltrating grade 3 ductal carcinoma, whose DNA contains an alteration in the int-2 structure.

The XLR sequence family: dispersion on the X and Y chromosomes of a large set of closely related sequences, most of which are pseudogenes.

The XLR sequence family encodes RNA transcripts specific to late-stage T and B cells and their neoplasms. Only one apparently functional mRNA has been identified thus far and this encodes a novel 25 kDa nuclear protein. In this report, we find that the XLR gene family is composed of 50-75 copies per haploid genome which localize to at least two different portions of the mouse X chromosome. Neither of these locations are near the xid mutation that earlier work had correlated with XLR. In addition, some members of this family are also on the Y chromosome. Another surprising finding is that while the fourteen genomic clones examined to date have the same exon-intron structure and are closely related with respect to sequence conservation (90%), all appear (in most cases by multiple criteria) to be non-functional, raising the possibility that all but one of the members of this large semi-dispersed family are pseudogenes.