Evaluation of the clonidine suppression test in the diagnosis of phaeochromocytoma.

The aim of this study is to review the experience of the clonidine suppression test in a regional endocrine centre and to compare the diagnostic sensitivity and specificity using various previous published criteria. The design used is retrospective study. The subjects include 56 patients in whom clonidine suppression tests had been performed from 1995 to 2000: 15 with phaeochromocytoma and 41 patients in whom the diagnosis was excluded using a combination of biochemical testing, abdominal computed tomography scanning and clinical follow-up. Plasma catecholamines were measured by high pressure liquid chromatography on basal samples and at hourly intervals for 3 h after the administration of clonidine 300 µg orally and the following diagnostic criteria were applied: plasma noradrenaline+adrenaline>2.96 nmol l(-1) at 3 h post-clonidine or a baseline plasma adrenaline plus noradrenaline>11.82 nmol l(-1); plasma noradrenaline>2.96 nmol l(-1) at 3 h post-clonidine and plasma noradrenaline>2.96 nmol l(-1) and <50% fall in noradrenaline at 3 h post-clonidine. The results obtained is that mean plasma noradrenaline plus adrenaline fell across the test in 40/41 patients in the non-phaeochromocytoma patients and was lowest at 3 h (basal 2.28 ± 0.14 vs 1.36 ± 0.11 nmol l(-1), P<0.001). In the phaeochromocytoma group, clonidine had a variable effect on adrenaline plus noradrenaline levels with increases in 7/15. Using an abnormal result as a 3 h level of noradrenaline plus adrenaline>2.96 mmol l(-1) gave a sensitivity of 93% and specificity of 95%. When a 3 h noradrenaline>2.96 mmol l(-1) was used, sensitivity was 87% and specificity 95%. Using the former criteria, noradrenaline plus adrenaline>2.96 mmol l(-1), 1/15 in the phaeochromocytoma group had a normal result after clonidine suppression testing. Two of 41 in the non-phaeochromocytoma group had a false-positive result. Under carefully controlled conditions, the clonidine suppression test is well tolerated, safe and accurate for use in the investigation of patients with suspected phaeochromocytoma.

Cyclooxygenase-2 expression correlates with phaeochromocytoma malignancy: evidence for a Bcl-2-dependent mechanism.

AIMS: Phaeochromocytomas are rare but potentially life-threatening neuroendocrine tumours of the adrenal medulla or sympathetic nervous system ganglia. There are no histological features which reliably differentiate benign from malignant phaeochromocytomas. The aim of the study was to evaluate cyclooxygenase (COX)-2 and Bcl-2 as tissue-based biomarkers of phaeochromocytoma prognosis. METHODS AND RESULTS: COX-2 and Bcl-2 expression were examined immunohistochemically in tissue from 41 sporadic phaeochromocytoma patients followed up for a minimum of 5 years after diagnosis. There was a statistically significant association between COX-2 histoscore (intensity x proportion) and the development of tumour recurrence or metastases (P = 0.006). A significant relationship was observed between coexpression of COX-2 and Bcl-2 in the primary tumour and the presence of recurrent disease (P = 0.034). A highly significant association was observed between (i) tumour-associated expression of these two oncoproteins (P = 0.001) and (ii) COX-2 histoscore and the presence of Bcl-2 expression (P = 0.002). COX regression analysis demonstrated no significant relationship between (i) the presence or absence of either COX-2 or Bcl-2 and patient survival or (ii) COX-2 histoscore and patient survival. CONCLUSIONS: COX-2 and Bcl-2 may promote phaeochromocytoma malignancy, and these oncoproteins may be valuable surrogate markers of an aggressive tumour phenotype.

Laparoscopic adrenalectomy versus open adrenalectomy: results from a retrospective comparative study.

The relatively new operation of laparoscopic adrenalectomy has now become the procedure of choice for the management of most benign adrenal tumours. We have reviewed the data relating to the first 25 patients on whom we performed laparoscopic adrenalectomy and have made comparison with a group of 25 diagnosis-matched individuals on whom we had previously carried out open adrenalectomy. The patients who underwent laparoscopic adrenalectomy had a significantly shorter hospital stay and experienced significantly less postoperative morbidity than those who had an open operation, but the operation time was significantly longer for the laparoscopic group of patients. There is now good potential and sound evidence base for extending the indications for laparoscopic adrenalectomy.

Randomized clinical trial comparing scan-directed unilateral versus bilateral cervical exploration for primary hyperparathyroidism due to solitary adenoma.

BACKGROUND: It was shown in a previous retrospective study that scan-directed unilateral cervical exploration for primary hyperparathyroidism (HPT) can be carried out without an increase in the incidence of persistent or recurrent hypercalcaemia. This randomized clinical trial was conducted to test the hypothesis that focused unilateral operation leaves the patient no more vulnerable to persistent HPT than standard bilateral neck exploration. METHODS: Patients with HPT routinely underwent preoperative dual-isotope subtraction scintigraphy in an attempt to localize the presumed solitary parathyroid adenoma. Individuals with a positive scan (one residual focus of activity following subtraction) were deemed suitable for focused unilateral cervical exploration. At operation, if a single tumour was identified at the site suggested by the scan, the patient was randomized to unilateral or bilateral neck exploration. RESULTS: Between April 1998 and December 2003, 190 patients underwent first-time cervical exploration for HPT. Of these, 100 qualified for randomization. Fifty-four patients were randomized to unilateral neck exploration and 46 to bilateral operation. All 100 patients were cured following operation, as assessed by return of the serum calcium level to normal. Two patients randomized to bilateral exploration were found to have an unsuspected additional enlarged parathyroid on the contralateral side. CONCLUSION: Scan-directed unilateral cervical exploration for HPT does not significantly increase the incidence of persistent hypercalcaemia compared with standard bilateral operation.

Pre-operative sestamibi-technetium subtraction scintigraphy in primary hyperparathyroidism: experience with 156 consecutive patients.

AIM: The aim of this study was to assess the usefulness of pre-operative sestamibi-technetium subtraction scintigraphy in a large cohort of patients with primary hyperparathyroidism (HPT). MATERIALS AND METHODS: A group of 156 consecutive patients with biochemically proven HPT underwent sestamibi-technetium subtraction scintigraphy before cervical exploration. Images were interpreted and reported prospectively and influenced the extent of surgical exploration. The intraoperative findings were compared retrospectively with the pre-operative scintigram reports in 154 individuals with technically satisfactory scintigrams. RESULTS: Of the 154 patients with satisfactory scintigrams, 122 (78.2%) demonstrated a single focus of activity following subtraction, 31 (19.9%) had negative findings and the remaining scintigram showed four foci of activity. At operation 138 (89.6%) solitary adenomas were removed, 13 patients (8.4%) had multi-gland disease and in three individuals (2.0%) no abnormal parathyroid tissue was found. The pre-operative scintigram accurately localized 91 of 98 (92.9%) solitary tumours weighing > 500 mg but only 18 of 35 (51.4%) adenomas weighing < 500 mg, (P < 0.0001). Overall sensitivity of sestamibi-technetium scintigraphy for localizing single parathyroid adenomas was 83.7%. CONCLUSION: Sestamibi-technetium subtraction scintigraphy will accurately localize a high proportion of solitary parathyroid adenomas but its usefulness is diminished by its inability to consistently identify smaller tumours.

Medullary thyroid carcinoma in Northern Ireland, 1967-1997.

BACKGROUND: The experience of managing medullary thyroid carcinoma (MTC) in a specialist endocrine surgery unit was reviewed. METHODS: The case records of 38 patients (19 male, 19 female) treated over a 30 year period were studied. RESULTS: There were 23 (60.5%) patients with sporadic MTC while the remainder had familial MTC--12 multiple endocrine neoplasia (MEN) type 2A, two MEN type 2B, one non-MEN familial medullary thyroid carcinoma (FMTC). Sporadic MTC patients were significantly older at presentation (median 56 years, interquartile range 41.5-61.3 years) compared to MEN 2A patients (median 26 years interquartile range 17.5-34 years) and had more advanced stage of disease. Survival of MTC patients was significantly worse in sporadic disease than in those with MEN 2A (P < 0.0001). All familial cases had bilateral multifocal tumour whereas in sporadic patients only unilateral disease was seen. The availability of genetic testing now allows early identification of affected members of familial MTC kindreds. This has led to total thyroidectomy being performed on the basis of positive genetic screening alone in three patients (two MEN 2A, one FMTC), in all of whom widespread C-cell hyperplasia and microscopic multifocal invasive MTC were identified histologically. CONCLUSIONS: The management of MTC has changed during the study period with total thyroidectomy recommended as the primary procedure of choice for all patients. In the familial setting, positive genetic testing now allows thyroidectomy to be performed at an early pre-clinical stage, with the hope of permanent cure.

Epithelioid Hemangioendothelioma of the Spermatic Cord.

This report describes an epithelioid hemangioendothelioma arising on the spermatic cord of a 50-year-old man who presented with a nodule in the right hemiscrotum. Histologic examination showed a cellular tumor composed of epithelioid cells, many of which had intracytoplasmic lumina containing red blood cells. Immunohistochemistry showed focal positivity of tumor cells with the endothelial markers CD34, factor VIII-related antigen, and Ulex and with the anticytokeratin antibodies CAM5.2 and AE1/AE3. Ultrastructural examination revealed polygonal tumor cells forming vascular spaces and intracytoplasmic lumina containing red blood cells. This is the second documented occurrence of epithelioid hemangioendothelioma at this site. The case illustrates the value of immunohistochemistry and electron microscopy in establishing a diagnosis. Int J Surg Pathol 8(1):75-78, 2000

Accuracy of CT scanning and adrenal vein sampling in the pre-operative localization of aldosterone-secreting adrenal adenomas.

In primary hyperaldosteronism, it is important to distinguish between unilateral and bilateral disease, as management strategies differ. In the period 1983-95, we identified 34 patients with primary hyperaldosteronism. Following further investigations, a diagnosis of aldosterone-secreting adenoma was made in 17 patients, and surgery was performed. Computed tomography clearly localized an apparent adenoma (discrete adenoma=1 cm diameter; normal contralateral gland) in only 10 of these patients (59%); two of these 'adenomas' were subsequently shown to be hyperplastic glands without adenomas. Histological examination showed adrenal adenomas in the remaining 15 patients. An 'adenoma' also appeared to be clearly localized in 3/17 patients later classified as having bilateral adrenal hyperplasia by adrenal vein sampling. CT scanning, therefore clearly localizes adenomas in only 50% of histologically proven cases, and can also produce misleading results. Adrenal vein sampling results altered our management approach in one third of cases. On the basis of our detailed results we would recommend surgery if there is clear evidence of unilateral aldosterone secretion along with CT findings which may not be strictly localizing but are in keeping with the dominant side on adrenal vein sampling. The decision to refer for surgery in primary hyperaldosteronism can be difficult, and we would caution against too heavy a reliance on CT results when recommending adrenalectomy, and suggest that adrenal vein sampling should remain a routine part of the investigation of patients with primary hyperaldosteronism.

Median sternotomy for parathyroid adenoma.

Most mediastinal parathyroid tumours lie within the thymus gland and may be retrieved when cervical thymectomy is carried out in the course of neck exploration for primary hyperparathyroidism (HPT). We report 4 patients, each of whom required sternotomy for removal of a true mediastinal parathyroid adenoma. Subtraction isotope scintigraphy suggested the presence of a mediastinal tumour prior to cervical exploration in 2 individuals and prior to re-exploration in a third. When localisation before initial exploration for HPT suggests a parathyroid tumour within the chest, consideration should be given to proceeding to sternotomy, at first operation if a comprehensive neck exploration, including cervical thymectomy, fails to uncover the adenoma. Uniquely, one of our patients underwent sternotomy for HPT when 23 weeks pregnant.

Cure of hyperparathyroidism in pregnancy by sternotomy and removal of a mediastinal parathyroid adenoma.

Primary hyperparathyroidism is rarely reported during pregnancy but can cause significant maternal and neonatal morbidity. We report a case of hyperparathyroidism during pregnancy requiring a median sternotomy for resection of a mediastinal parathyroid adenoma. Surgery resulted in normalisation of serum calcium, resolution of symptoms, and prevented neonatal hypocalcaemia.

Management of thyroid tumours.

True tumours of the thyroid gland, both benign and malignant, are uncommon. Most present as solitary thyroid nodules and can be readily diagnosed by fine-needle aspiration and cytology. Surgical resection is the only appropriate treatment for the majority of thyroid tumours.

Expression of the apoptosis-suppressing gene BCL-2 in pheochromocytoma is associated with the expression of C-MYC.

It has become increasingly clear that deregulation of programmed cell death is a critical component in multistep tumorigenesis. Previous studies have demonstrated a high frequency of Bcl-2 expression in tumors arising from cells derived from the neural crest and in tumor cell lines of neural origin. The present investigation was undertaken to determine whether similar molecular events occur in human pheochromocytoma. With the aim of determining the potential role of apoptosis in the pathogenesis of this tumor, we assessed proto-oncogene Bcl-2 and c-myc protein products as well as Bcl-2 messenger RNA levels in a collection of such tumors. Western blot analysis revealed that such tumors expressed the 26 kDa Bcl-2 (5 of 8 cases) and the 64 kDa c-Myc (7 of 8 cases) proteins. Northern blot analysis detected the Bcl-2 transcripts in 6 of 8 tumors. Immunoperoxidase staining, using a monoclonal anti-Bcl-2 antibody, was positive in 18 (82%), including 5 malignant tumors, of the 22 specimens examined. This Bcl-2 immunoreactivity was seen in 14 of 18 (78%) sporadic tumors, including 2 that were extra-adrenal, and all familial tumors. Of the 22 tumor samples examined for c-Myc protein, 20 (91%) tumors were positive. Our results suggest that deregulation of programmed cell death may be a critical component in the multistep tumorigenesis of human pheochromocytoma. The genetic complementation of simultaneously deregulated Bcl-2 and c-myc may be implicated in this process.

Regulatory peptides and other neuroendocrine markers in medullary carcinoma of the thyroid.

Medullary thyroid carcinoma (MTC) is an APUDoma (APUD refers to amine precursor uptake and decarboxylation) arising from the parafollicular cells. Diarrhoea has been reported in some 30% of patients, variously attributed to excess production of calcitonin (CT), serotonin (5-HT), vasoactive intestinal peptide (VIP) or other factors. The regulatory factors in MTC were examined employing immunocytochemistry and RIA to tumours and their extracts. The patients were followed up for more than 15 years. CT and calcitonin gene-related peptide were universally expressed in all the tumours. The neuroendocrine markers chromogranin A (and its fragments pancreastatin and WE-14), neurone-specific enolase, protein gene product 9.5 and carcino-embryonic antigen were found in the majority of MTCs and might be useful as immunocytochemical markers. 5-HT, substance P, neurokinin A, glucagon and VIP could not be detected, excluding them as candidates in the diarrhoea of MTC.

Phaeochromocytoma in Northern Ireland: a 21 year review.

OBJECTIVE: To report our experience of 41 patients with phaeochromocytoma. DESIGN: Retrospective study. SETTING: Teaching hospital, United Kingdom. SUBJECTS: Forty-one patients who presented with phaeochromocytoma 1970-1991. INTERVENTIONS: Removal of tumour (n = 38). MAIN OUTCOME MEASURES: Mortality, morbidity, and recurrence. RESULTS: Thirty-four patients had sporadic tumours, five had the multiple endocrine neoplasia (MEN) type 2 syndrome, and two had non-MEN familial phaeochromocytoma. Thirty-six patients (88%) presented with symptoms of catecholamine excess, and 37 (90%) were hypertensive. The diagnosis was confirmed biochemically in 37. Tumours were located using computed tomography (n = 26), vascular studies (n = 11), and ultrasonography (n = 3). Thirty-eight patients had their tumours resected, of whom 10 (27%) developed complications. There were no postoperative deaths. Two patients were managed conservatively, and one died before diagnosis. Six patients developed recurrent tumours a mean of five years after the initial operation, and another patient had an inoperable tumour at initial diagnosis; four of these seven died from metastatic disease. Metaiodobenzylguanidine (MIBG) scans were positive in three of the patients who developed recurrences. CONCLUSIONS: Patients with phaeochromocytoma can now be operated on safely but prolonged follow-up is essential.

Flow cytometric analysis does not reliably differentiate benign from malignant phaeochromocytoma.

BACKGROUND AND OBJECTIVE: The differentiation of benign from malignant phaeochromocytoma is difficult. We have examined whether the use of flow cytometric determination of nuclear DNA content would be useful as a predictor of malignant behaviour in patients with phaeochromocytoma as some previous studies had suggested that a diploid cytometric DNA pattern indicated benign disease. DESIGN AND PATIENTS: DNA flow cytometry was performed on phaeochromocytoma tissue from 36 patients (19 female, 17 male; mean age at presentation 39.5 years). The results were correlated with clinical outcome after prolonged follow-up. MEASUREMENTS: DNA histograms were constructed following nuclear suspension analysis. RESULTS: Of 26 patients followed up for more than 5 years after initial removal of primary phaeochromocytoma, three have died from malignant recurrence. In these patients a diploid DNA cytometric pattern was observed in two and an aneuploid pattern in one. Twenty-one patients are still alive. DNA cytometry showed a diploid pattern in the one patient who developed recurrent phaeochromocytoma 4 years after removal of a primary tumour. CONCLUSION: In this study, three of nine patients with an apparently benign diploid cytometric pattern subsequently developed recurrent disease. Routine use of DNA flow cytometry did not reliably differentiate benign from malignant phaeochromocytoma. Prolonged clinical and biochemical follow-up is still necessary for all patients with this condition.