Analysis of genotype-phenotype correlations and survival outcomes in patients with primary hyperparathyroidism caused by multiple endocrine neoplasia type 1: the experience at a single institution.

PURPOSE: To examine the clinical characteristics and survival outcomes of patients with primary hyperparathyroidism (PHPT) in multiple endocrine neoplasia type 1 (MEN1) in relation to the MEN1 gene mutation. METHODS: The study population included the patients, positive for the MEN1 gene mutation, who underwent parathyroidectomy between 1983 and 2009 at a single tertiary referral center. Manifestations of the syndrome, other tumors and causes of death were retrospectively correlated with the specific types and locations of MEN1 gene mutations. RESULTS: Thirty-two patients from 19 families were diagnosed as having MEN1 on genetic examinations. Mutations were most common in exons 2, 7 and 10. A phenotypic analysis of the main MEN1 tumor types among the 32 patients revealed that PHPT was the most common (100 %), followed in order by pancreatic neuroendocrine tumors (PNETs) (53 %) and pituitary tumors (38 %). Death due to MEN1-related disease occurred in five patients (16 %), including malignant PNET in three cases (exons 2, 3), pituitary crisis in one case (exon 2) and thymic cancer in one case (large deletion). CONCLUSIONS: Premature deaths related to MEN1 are due to the development of malignant PNET, pituitary crisis or thymic tumors associated with mutations in exons 2, 3 and a large deletion.

Thoracoscopic removal of mediastinal parathyroid lesions: selection of surgical approach and pitfalls of preoperative and intraoperative localization.

BACKGROUND: Thoracoscopic surgery has replaced conventional sternotomy or thoracotomy for resection of mediastinal parathyroid lesions. We review our experience with this type of surgery with reference to selection of the appropriate approach and the pitfalls of lesion localization before and during surgery. METHODS: During a 14-year period, we treated 14 patients with hyperparathyroidism, in whom a mediastinal lesion had been localized preoperatively by sestamibi scan. Primary hyperparathyroidism was present in 12 patients (single adenoma in 11, associated with MEN 1 in one) and secondary hyperparathyroidism in 2. Thoracoscopic procedures were performed by the three-port method. RESULTS: The thoracoscopic procedure was successful in eight patients who were shown preoperatively to have a deep-seated (5 anterior, 3 middle) mediastinal lesions. Intraoperative visual confirmation of parathyroid adenoma was difficult only in a 19-year-old patient with a tumor embedded in the thymus, necessitating partial thymectomy. One of the eight mediastinal lesions resected thoracoscopically was a sestamibi-positive thymoma. Secondary hyperparathyroidism recurred 4 years after thoracoscopic mediastinal parathyroidectomy in one patient, necessitating additional thoracoscopic removal of this supernumerary lesion. However, seven patients with mediastinal parathyroid lesions localized at the aortic arch or upper region were treated successfully via a cervical approach. None of the patients suffered any surgical complications. CONCLUSIONS: Thoracoscopic surgery is safe and feasible for resection of deep mediastinal parathyroid lesions. Such lesions localized preoperatively at the aortic arch or upper region can be treated via a cervical approach. Preoperative sestamibi scan can sometimes give a false-positive result in cases of concurrent thymoma.

A large deletion in the succinate dehydrogenase B gene (SDHB) in a Japanese patient with abdominal paraganglioma and concomitant metastasis.

Recently, mutations in nuclear genes encoding two mitochondrial complex II subunit proteins, Succinate dehydrogenase D (SDHD) and SDHB, have been found to be associated with the development of familial pheochromocytomas and paragangliomas (hereditary pheochromocytoma/paraganglioma syndrome: HPPS). Growing evidence suggests that the mutation of SDHB is highly associated with abdominal paraganglioma and the following distant metastasis (malignant paraganglioma). In the present study, we used multiplex ligation dependent probe amplification (MLPA) analysis to identify a large heterozygous SDHB gene deletion encompassing sequences corresponding to the promoter region, in addition to exon 1 and exon 2 malignant paraganglioma patient in whom previously characterized SDHB mutations were undetectable. This is the first Japanese case report of malignant paraganglioma, with a large SDHB deletions. Our present findings strongly support the notion that large deletions in the SDHB gene should be considered in patients lacking characterized SDHB mutations.

[Therapeutic strategy for pheochromocytoma].

Pheochromocytoma is the most common type of neuroendocrine tumor arising from the adrenal gland. Pheochromocytoma has been termed a 10% tumor because roughly 10% of such tumors are malignant, multifocal, bilateral, and arise in extra-adrenal sites. During the last decade, laparoscopic adrenalectomy has been the standard method to remove pheochromocytomas. Adrenal-sparing laparoscopic surgery is a treatment of choice for bilateral pheochromocytomas. Cyclophosphamide, vincristine and dacarbazine combined chemotherapy and (131)I-MIBG therapy are required for the treatment of metastatic or unresectable malignant pheochromocytoma.

Parathyroid carcinoma: etiology, diagnosis, and treatment.

BACKGROUND: The goal of the present study was to make our medical practice evidence-based for patients with parathyroid carcinoma. METHODS: We posed six clinical questions relevant to the management of parathyroid cancer. A comprehensive search and critical appraisal of the literature was then carried out. RESULTS: Most of the literature retrieved was retrospective in design and differed in the definition of carcinoma. The distinction between unequivocal and equivocal carcinoma (or atypical adenoma) was not always made for the study populations. None of the studies indicated reproducibility of outcome measures. Of the histopathological features described in the literature based on the description of Schantz and Castleman, capsular/vascular invasions and trabecular growth pattern were the most specific, and fibrous bands were the most sensitive. None of the patients with "atypical adenoma" developed recurrence, whereas 25% of those with "equivocal carcinoma" did. Mutations in HRPT2, the gene responsible for hereditary hyperparathyroidism with jaw-tumor syndrome, were strongly associated with sporadic parathyroid carcinoma. Severe hypercalcemia and its related clinical symptoms, extremely high levels of parathyroid hormone, osteitis fibrosa cystica, a palpable neck mass, and a relatively large depth-width ratio on ultrasonography, are the important features of parathyroid carcinoma. Disease-specific survival rates reported in the literature were varied, reflecting the differences in the definitions of carcinoma, study populations, and interventions. CONCLUSIONS: To establish valid evidence for patient management in the future, a collaboration of endocrine specialists is essential to conduct well-designed clinical studies for this rare disease.

Bone mineral density before and after surgical cure of Cushing's syndrome due to adrenocortical adenoma: prospective study.

Osteoporosis is a major complication of Cushing's syndrome. The aim of the present study was to assess the chronologic effect of surgical cure on bone mineral density (BMD) in patients with Cushing's syndrome due to adrenal adenoma. BMD was examined in 28 patients before laparoscopic adrenalectomy; 17 patients with reduced BMD were then included in the longitudinal evaluation. BMD was determined using dual energy X-ray absorptiometry (DXA) before and at 3, 6, 12, 18, and 24 months after adrenalectomy. The prevalence of osteoporosis was 64% (95% confidence interval 44-81%). Preoperative BMD of the lumbar spine in the lateral projection was significantly lower than that of the femoral neck (mean+/-SD score: -3.53+/-0.75 vs. -1.54+/-0.22, p=0.003). A significant increase in BMD was observed at 3 months after surgery in the lumbar spine (p=0.0004). Improvement at both sites was maintained at 24 months after surgery. The postoperative percentage change in BMD of the lumbar spine was significantly higher than that of the femoral neck (mean+/-SD 36.7%+/-26.5% vs. 11.2%+/-12.1%, p=0.01). The change in the seven premenopausal patients was significantly higher than that in the three postmenopausal patients (p=0.0006). Surgical cure of hypercortisolism provides significant improvement in BMD in patients with Cushing's syndrome due to adrenal adenoma. The improvement is particularly apparent in the lumbar spine measured in the lateral projection. Premenopausal women are more likely to benefit from surgery in terms of secondary osteoporosis.

Functional parathyroid carcinoma: Long-term treatment outcome and risk factor analysis.

BACKGROUND: This study was conducted to evaluate the long-term outcome of surgical treatment in patients with functional parathyroid carcinoma and to clarify factors determining prognosis. METHODS: A retrospective review of 38 patients with parathyroid carcinoma was performed. The Ki-67 index was evaluated in 29 cases. Disease-free survival and cause-specific survival estimated using the Kaplan-Meier method were analyzed, and the median follow-up period was 119 months. RESULTS: Fifteen patients developed persistent or recurrent parathyroid carcinoma, and 9 patients died of the disease. Twenty-one of 41 reoperations normalized the serum calcium level for at least 6 months. Univariate and multivariate analyses showed that locoregional tumor extension at initial operation and Ki-67 index >or=5% were significant factors affecting cause-specific survival (P = .0008, P = .05) and disease-free survival (P = .0005, P = .005), respectively. Five of 6 patients whose tumor showed a Ki-67 index >or=10% developed recurrence within 3 years after initial operation, and 4 died of the disease. CONCLUSIONS: Parathyroid carcinomas with locoregional extension at initial surgery have potential for recurrence. Our data suggest that aggressive surgical resection of recurrent parathyroid carcinoma is beneficial for palliation of hypercalcemia in selected patients. Ki-67 staining may be a valuable prognostic factor for patients with parathyroid carcinoma, especially as tumors with indices greater than 10% are more likely to recur in the early postoperative period.

Water-clear cell parathyroid adenoma causing primary hyperparathyroidism in a patient with neurofibromatosis type 1: report of a case.

Water-clear cell parathyroid adenoma is an exceedingly rare tumor, composed exclusively of tumor cells with abundant foamy cytoplasm. A combination of hyperparathyroidism and neurofibromatosis type 1 (NF1) is also a rare phenomenon. We report an 18-year-old woman with primary hyperparathyroidism caused by water-clear cell parathyroid adenoma in association with NF1. She had renal stones, hypercalcemia, and an elevated plasma level of intact parathyroid hormone. Physical examination revealed a palpable tumor in the right neck, and café-au-lait spots distributed over her entire body. An ultrasound examination showed an isoechoic mass in the right thyroid lobe. Thallium-technetium subtraction scintigraphy showed high thallium accumulation in the right thyroid lobe area. A surgical exploration revealed the palpable mass to be a parathyroid tumor. The pathological features were consistent with water-clear parathyroid adenoma. This is the first reported case of water-clear cell parathyroid adenoma associated with NF1.

Preoperative localization of pancreatic insulinoma by super selective arterial stimulation with venous sampling.

Although most insulinomas are small, they have been successfully detected by computed tomography and magnetic resonance imaging recently. However, preoperative localization of the insulinomas by arterial stimulation with venous sampling is crucial when they show atypical findings on these imaging modalities. We report a case of a large benign insulinoma located at the pancreatic tail; this tumor was diagnosed correctly by super selective arterial stimulation with venous sampling.

Probability of axillary lymph node metastasis when sentinel lymph node biopsy is negative in women with clinically node negative breast cancer: a Bayesian approach.

BACKGROUND: Although sentinel lymph node biopsy(SLNB)is highly accurate in predicting axillary nodal status in patients with breast cancer, it has been shown that the procedure is associated with a few false negative results. The risk of leaving metastatic nodes behind in the axillary basin when SLNB is negative should be estimated for an individual patient if SLNB is performed to avoid conventional axillary lymph node dissection(ALND). METHODS: A retrospective analysis of 512 women with T1-3N0M0 breast cancer was conducted to derive a prevalence of nodal metastasis by T category as a pre-test(i.e., before SLNB)probability and to examine potential confounders on the relationship between T category and axillary nodal involvement. Probability of nodal metastasis when SLNB was negative was estimated by means of Bayes' theorem which incorporated the pre-test probability and sensitivity and specificity of SLNB. RESULTS: Axillary nodal metastasis was observed in 6.1% of T1a-b, 25.1% of T1c, 28.7% of T2, 35.0% of T3 tumors. Point estimates for the probability of nodal involvement when SLNB was negative ranged from 0.3-1.3% for T1a-b, 1.6-6.3% for T1c, 2.0-7.5% for T2, and 2.6-9.7% for T3 tumors with representative sensitivities of 80%, 85%, 90% and 95%, respectively. The risk may be higher when the tumor involves the upper outer quadrant of the breast, while it may be lower for an underweight woman. CONCLUSIONS: The probability of axillary lymph node metastasis when SLNB is negative can be estimated using a Bayesian approach. Presenting the probability to the patient may guide the decision of surgery without conventional ALND.

[Diagnosis and surgical treatment of adrenal tumors].

Adrenal surgery is necessary for the management of functioning adrenal tumors, such as aldosterone-producing adenoma, cortisol-producing adenoma, and pheochromocytoma. The role of adrenal imaging in primary hyperaldosteronism is to separate the surgically resectable unilateral aldosteronoma from bilateral hyperplasia. Once the clinical diagnosis of primary hyperaldosteronism is confirmed, adrenal computed tomography (CT) with 3-mm sections should be the first imaging study. If the results of CT and NP-59 scintigraphy are equivocal, adrenal venous sampling is necessary. Cortisol-producing adrenocortical adenomas are seen as adrenal masses 2.5 cm or larger in diameter in CT scanning. When an adrenal mass measures more than 5 cm in diameter, a functioning adrenal carcinoma should be considered. Symptomatic pheochromocytomas are almost always 2 cm or larger. On MR scanning, pheochromocytomas are extremely bright on T2-weighted images. In patients with ectopic pheochromocytomas, 131I-MIBG scintigraphy should be mandatory. In the past decade, laparoscopic adrenalectomy has replaced open adrenalectomy as a standard operative procedure for benign adrenal tumors. Adrenal-sparing laparoscopic surgery has recently become a feasible option in patients with hereditary bilateral pheochromocytomas.

[Diagnosis and treatment for adrenocortical carcinoma].

Adrenocortical carcinomas frequently hypersecrete multiple adrenocortical steroids and their precursors. CT scan and MRI usually demonstrate necrotic lesions or areas of calcification in this uncommon tumor. Therapy in patients with adrenocortical carcinoma is less satisfactory. Surgical excision is the primary mode of therapy. Up to the present, mitotane (o, p'-DDD) treatment combined with chemotherapy has been the only palliative measure for patients with nonresectable or extensively recurrent tumors.

Adrenal-preserving laparoscopic surgery in selected patients with bilateral adrenal tumors.

BACKGROUND: There have been few reports of laparoscopic adrenal-sparing surgery for bilateral adrenal tumors. We review our experience with this type of surgery with the aim of evaluating its feasibility and safety. METHODS: Over a 4-year period, we treated 9 patients with bilateral benign adrenal tumors. Seven patients had bilateral pheochromocytomas (MEN 2: 5, VHL: 1, sporadic: 1), and 2 patients had Cushing's syndrome caused by bilateral adrenocortical adenomas. Laparoscopic procedures were performed by a flank approach. The mean diameter of the tumors was 3.7 cm (range, 2.0-8.5 cm). RESULTS: All the tumors were removed laparoscopically. Four patients with hereditary pheochromocytomas underwent bilateral total adrenalectomy because of the large tumor size and multiplicity. The other 5 patients were treated successfully with preservation of adrenocortical function. In 4 of these 5 patients, the adrenal tumors were 3 cm or less in diameter. None of the patients experienced surgical complications. At a mean follow-up of 16 months (range, 4-40 months), none of the 5 patients who were treated by adrenal-sparing surgery required corticosteroid replacement. CONCLUSION: Laparoscopic surgery is feasible for the treatment of bilateral adrenal tumors. Adrenal-preserving laparoscopic surgery may be practicable for the removal of these tumors, if the tumor on either side is 3 cm or less in diameter; however, our follow up is short (mean, 16 months).

Adult-type ganglioneuroblastoma in the adrenal gland treated by a laparoscopic resection: report of a case.

A case of ganglioneuroblastoma in the adrenal gland of a 50-year-old man is reported. The patient was incidentally found to have a nonfunctioning tumor in the right adrenal gland. The tumor, measuring 4.5 cm, was successfully removed using laparoscopy. Histologically, the tumor was diagnosed to be a ganglioneuroblastoma. Immunohistochemically, a few MIB-1-positive cells and no S-100 protein-positive cells were observed. There has been no evidence of recurrence for 2.5 years to date after the operation. Adrenal ganglioneuroblastoma is extremely rare in adults, and only seven such cases have been previously reported in the literature.

Cushing's syndrome due to bilateral adrenocortical adenomas with unique histological features.

Cushing's syndrome due to bilateral cortisol-secreting adenomas rarely occurs. We present a case of Cushing's syndrome due to bilateral adenomas. Both adenomas had distinct cell compositions, and were compared with emphasis on immunohistochemical and enzyme histochemical analysis for cytochrome P450(11beta) and 3beta-hydroxysteroid dehydrogenase (3betaHSD). A 37 year-old female was diagnosed with ACTH-independent Cushing's syndrome based on physical findings and hormonal evaluation. High-resolution CT scan showed bilateral adrenocortical adenomas and atrophied glands. 131I-methylnorcholesterol incorporation into both glands suggested both adenomas were functional. Clinical diagnosis prior to surgery was ACTH-independent Cushing's syndrome due to functioning bilateral adenomas. The left adrenal gland was totally resected, while the right one was partially resected by laparoscopic approach. Both adenomas were black on cut sections, and were comparatively evaluated by immunohistochemical and enzyme histochemical analysis for P450(11beta) and 3betaSD. The left adenoma was 1.6 cm in diameter and had a complex cellular composition and enzyme expression similar to that of primary pigmented nodular adrenocortical disease (PPNAD), while the right adenoma was 1.8 cm in diameter with compact cells typical of a solitary cortisol-producing adenoma. Adjacent bilateral adrenal cortex showed marked atrophy, but contained several micronodules. Serum cortisol levels, both at basal and after a low dodexamethasone, normalized thirteen months after surgery. In conclusion, the present case of Cushing's syndrome with bilateral adrenal adenomas demonstrated for the first time the simultaneous occurrence of two distinct adenomas, an ordinary cortisol-producing adenoma and a PPNAD-like adenoma. Further case reports of multiple adrenal adenomas should be well-analyzed to clarify whether the results from this case represent a new subgroup of ACTH-independent Cushing's syndrome.

Recent advances in minimally invasive pancreatic surgery.

For curative resection of pancreatic endocrine tumours, minimally invasive methods of pancreatic surgery, such as laparoscopy, should be indicated only for benign tumours. Among these uncommon tumours, pancreatic insulinomas are mostly benign and solitary. Successful management of patients with insulinomas relies on accurate localization of the tumour and the use of appropriate surgical techniques. Because of the small size of these tumours, conventional intraoperative ultrasonography combined with palpation has been widely regarded as the best localization procedure. Because contact ultrasonography, a new technique for localization of pancreatic lesions, can be used laparoscopically, several surgeons have used laparoscopy not only for localization, but also for resection of insulinomas. In the era of minimally invasive surgery for benign pancreatic lesions, we attempted laparoscopic-focused exploration of the pancreas for resecting insulinomas based on preoperative localization. We describe the use of this technique for the detection and resection of insulinomas and the results obtained, with a review of previous reports.

Minimally invasive endocrine surgery: laparoscopic resection of insulinomas.

Pancreatic insulinomas are mostly benign and solitary tumors. Successful management of patients with insulinoma relies on accurate localization of the tumors and the use of appropriate surgical techniques. However, preoperative radiological imaging studies often fail to localize the insulinomas because of the small tumor sizes. Conventional intraoperative ultrasonography combined with palpation has been widely used as the best localization tool. Since contact ultrasonography, a new technique for localizing pancreatic lesions, became available as a laparoscopic study, several surgeons have utilized laparoscopy for not only localization but also resection of insulinomas. Previous reports of laparoscopic ultrasonography for intraoperative identification of insulinomas showed a 100% success rate in cases with insulinoma localized by preoperative imaging studies, but a less satisfactory rate in cases with occult insulinoma. Laparoscopic resection of insulinomas located in the head of the pancreas is often difficult because of its anatomical relationship with important adjacent structures such as pancreatic duct and mesenteric vessels. In contrast, insulinomas located in the body or tail of the pancreas are laparoscopically resectable even when they are in close proximity to the major pancreatic duct. Laparoscopic procedure is a feasible technique with low morbidity for surgical management of insulinomas. Accurate preoperative localization is essential for safe performance of this minimally invasive procedure.