Cornelia Dotzenrath

Differential loss of heterozygosity in familial, sporadic, and uremic hyperparathyroidism

Abstract Various genetic loci harboring oncogenes, tumor suppressor genes, and genes for calcium receptors have been implicated in the development of parathyroid tumors. We have carried out loss of heterozygosity (LOH) studies in chromosomes 1p, 1q, 3q, 6q, 11q, 13q, 15q, and X in a total of 89 benign parathyroid tumors. Of these, 28 were sporadic parathyroid adenomas from patients with no family history of the disease, 41 were secondary parathyroid tumors, 5 were from patients with a history of previous irradiation to the neck, 12 were from patients with a family history of hyperparathyroidism, and 3 were parathyroid tumors related to multiple endocrine neoplasia type 1 (MEN1). In addition, we determined the chromosomal localization of a second putative calcium-sensing receptor, CaS, for inclusion in the LOH studies. Based on analysis of somatic cell hybrids and fluorescent in situ hybridization to metaphase chromsomes, the gene for CaS was mapped to chromosomal region 2q21-q22. The following results were obtained from the LOH studies: (1) out of the 24 tumors that showed LOH, only 4 had more than one chromosomal region involved, (2) in the tumours from uremic patients, LOH of chromosome 3q was detected in a subset of the tumors, (3) LOH of the MEN1 region at 11q13 was the most common abnormality found in both MEN1-related and sporadic parathyroid tumours but was not a feature of the other forms of parathyroid tumors, (4) LOH in 1p and 6q was not as frequent as previously reported, and (5) tumor suppressor genes in 1q and X might have played a role, particularly on the X chromosome, in the case of familial parathyroid adenomas. We therefore conclude that the tumorigenesis of familial, sporadic, and uremic hyperparathyroidism involves different genetic triggers in a non-progressive pattern.

Long-term Biochemical Results after Operative Treatment of Primary Hyperparathyroidism Associated with Multiple Endocrine Neoplasia Types I and IIa: Is a More or Less Extended Operation Essential?

OBJECTIVE To analyse our long term results in patients operated on for primary hyperparathyroidism associated with multiple endocrine neoplasia types I and IIa. DESIGN Retrospective (data collection) and prospective (follow-up) analysis. SETTING University hospital, Germany. SUBJECTS 39 patients with MEN type I-associated and 7 patients with MEN-type-IIa-associated primary hyperparathyroidism. INTERVENTIONS Subtotal parathyroidectomy (n = 25 with MEN I and 1 with MEN IIa), total parathyroidectomy and autotransplantation (one in each group) and removal of only enlarged glands (13 with MEN type I and 5 with MEN type IIa). MAIN OUTCOME MEASUREMENTS Recurrence rate of hyperparathyroidism and permanent hypocalcaemia postoperatively. RESULTS Subtotal parathyroidectomy in patients with MEN type I gave a significantly lower recurrence rate than removal of only enlarged glands (3/25 compared with 3/13, log rank, p = 0.04). Permanent hypocalcaemia developed in 3/25 compared with 3/13, respectively. 2/5 patients with MEN type IIa developed recurrences after removal of only enlarged glands and the rate was higher than expected. CONCLUSIONS A more extensive operation is essential for patients with MEN type I; the rate of permanent hypocalcaemia is not increased, but the recurrence rate is reduced. Patients with MEN type IIa should be treated by excision of enlarged glands alone, but this may be extended to subtotal parathyroidectomy in patients with severe symptoms.

Neuropsychiatric and Cognitive Changes after Surgery for Primary Hyperparathyroidism

IntroductionNeuropsychiatric symptoms and cognitive impairment are mental manifestations of primary hyperparathyroidism (pHPT). The aim of our study was to determine if surgical treatment results in a long-lasting full recovery from these symptoms.MethodsIn a prospective case-control study with matching pairs, mental changes were examined preoperatively and 6 months postoperatively in 30 patients with primary hyperparathyroidism and 30 patients with nontoxic nodular goiter using the Hamilton depression score and four cognitive tests: DEM Tect, MWT (multiple word test), ZVT, and Benton test.ResultsPatients with pHPT demonstrated significantly more cognitive changes (P < 0.0001) with significant improvement 6 months postoperatively (P < 0.0001). Patients with pHPT presented more psychopathologic symptoms than patients of the control group (P = NS), and there was a tendency towards recovery in the pHPT group postoperatively. There was no correlation between biochemistry and psychopathologic or cognitive changes in the pHPT group.ConclusionsPatients with pHPT often present with neuropsychiatric symptoms and cognitive impairment. A successful parathyroid operation improves cognitive disorders in particular.

Therapy of suspected intrathoracic parathyroid adenomas

Background and aims: Ectopic mediastinal parathyroid adenoma as a cause of primary hyperparathyroidism (pHPT) can normally be resected from conventional collar incision. In rare cases with adenomas deeper in the chest, a transthoracic approach is necessary. Patients/methods: We report our experience of 19 patients with suspected mediastinal parathyroid adenomas from a total of 1035 patients with pHPT who were operated on between 1986 and 2000 using an open approach (sternotomy or thoracotomy) or video-assisted mediastinal or thoracoscopic surgery (VAMS/VATS). Results: Fourteen patients underwent an open approach with a success rate of 71% (10 of 14). Four patients remained hypercalcaemic. There were four complications in three patients: three permanent recurrent nerve palsies and one chylus fistula, requiring further surgery. VATS was successful in three of four patients with conversion to sternal splitting because of a false-negative frozen section in one patient. Another patient had parathyroid adenoma retrosternally which could not be resected by means of VAMS and had to be excised using a transsternal approach. There were no complications of minimal invasive procedures. All five patients were normocalcaemic after the operation. Conclusion: Ectopic parathyroid adenomas not resectable by means of a collar incision are rare causes of pHPT and comprise 1.25% of all patients with pHPT in our series. For these patients, VATS revealed an alternative to conventional open procedures. In questionable cases, however, the collar incision should precede the VATS procedure.

Genetic and Biochemical Screening for Endocrine Disease

AbstractThe development of biochemical and genetic screening tests for inherited endocrine diseases has dramatically changed our approach to surgical patients with endocrine tumors. Among more than 1800 patients with endocrine tumors and a possible inherited disease operated on between 1986 and 1997, there were 6.1% to 7.3% who were found to have a familial disease associated with familial medullary thyroid cancer, (MTC), multiple endocrine neoplasia type IIa (MEN-IIa), MEN-IIb, or MEN-I. Genetic testing for the RET proto-oncogene is therefore recommended for all patients with MTC, and testing for the MEN-I gene is recommended in patients with suspected MEN-I and in specific clinical subgroups with an increased probability of endocrine tumor heredity. Early treatment based on early diagnosis by genetic testing appears to improve survival and to decrease morbidity in these patients.

Growth Regulation of Thyroid and Thyroid Tumors in Humans

In a study of growth regulation of the human thyroid gland and thyroid tumors we investigated the impact of iodine and that of the thyroid-specific growth-stimulating hormone TSH. Further studies included locally active growth factors such as the epidermal growth factor, insulin-like growth factor, and tissue transforming growth factors alpha and beta. In addition to studies of growth regulation by the various growth factors in mostly normal thyrocytes, the impact of tumor-specific mutations in oncogenes and tumor-suppressor genes was investigated. The results demonstrated distinct changes in tissue specificity and sensitivity to external stimuli. This rather complex view on thyrocyte growth regulation may be confusing, but it describes the biologic reality more precisely. Increased knowledge of the regulatory processes may lead to the development of new tumor- and patient-specific therapeutic approaches, especially for preventing benign goiter recurrence and for treating follicular and papillary thyroid cancers.

Primary hyperparathyroidism in the young age group: Particularities of diagnostic and therapeutic schemes

Primary hyperparathyroidism (pHPT) is a rare endocrine disease in children and young adults. The widespread use of new developments in pHPT surgery (i.e., unilateral and minimally invasive approaches) is based on the assumption that the solitary adenoma is the predominant intraoperative finding, but it has not been evaluated in the subgroup of young patients. From April 1986 to December 2002, a total of 1219 patients with pHPT have been operated on in our institution. The records of 64 patients (5.3%) younger than 30 years were extracted and compared to those of the older patients. The study group (median age 25 years, range 11–30 years) had significantly less bone pain, fewer signs of bone demineralization, and fewer neuropsychiatric symptoms. Eleven patients had hereditary disease. We found a solitary adenoma in only 32 of the 64 juvenile patients (p < 0.001), multiple gland disease in 25 patients (p < 0.001), and two suspected carcinomas. No adenoma could be identified in five patients. Follow-up of 54 patients after a median of 6.1 years revealed 42 normocalcemic patients, 5 hypocalcemic patients, and 7 patients with hypercalcemia. Altogether, 16 juvenile patients underwent parathyroid reoperations (25%) compared to 105 older patients (9%) (p = 0.003). Problems and difficulties with parathyroid surgery are pronounced in younger patients. The high rate of multiple gland disease requires bilateral cervical exploration as the standard procedure in pHPT patients younger than 30 years of age.

Therapeutic experience of 65 cases with organic hyperinsulinism.

Abstract. Introduction: The treatment for insulinoma is enucleation or resection, which are associated with various degrees of morbidity, including fistulas, pseudocysts, and necessity for reoperations. Patients: We evaluated the outcome of 65 patients operated on for organic hyperinsulinism at an experienced university hospital (Department of Surgery, Heinrich-Heine University, Düsseldorf, Germany) between 1990 and 1998. Procedures included enucleation (n=37), left-sided resection (n=19), combination of enucleation from the head and left-sided resection (n=4), subtotal left pancreatectomy (n=2), and pancreaticoduodenectomy (n=3). Results: In 47 out of the 65 patients (72%), the expected benign solitary insulinoma was found. Seven patients had malignant tumors and another eight had multiple tumors (including two with multiple endocrine neoplasia type 1 (MEN-1)), and three had nesidioblastosis. In total, 20 patients (31%) developed postoperative drainage of high amylase containing fluid, which in all but three cases resolved with conservative therapy. The three patients who developed fistulas and the three patients who developed pseudocysts underwent reoperative surgery. Seventeen (41%) of the patients who underwent enucleation (10 from the pancreatic head; 50%) and six (25%) of the resected patients demonstrated these complications. Postoperative glucose metabolism was normalized in all patients. Conclusion: Resection, especially in the head of the pancreas, demonstrates lower complication rates than enucleation. We propose resection for tumors that are large, malignant, situated close to pancreatic duct, and are multiple, including in MEN-1. For tumors in the head, pancreaticoduodenectomy may be an occasional choice.

Operative therapie des sekundaren hyperparathyreoidismus nach nierentransplantation

Between April 1986 and January 1992, a tota of 22 patients with chronic renal failure were operated on for secondary hyperparathyroidism after kidney trans plantation, and 21 of these patients were normocalcemi, postoperatively. In 1 patient three reductions of auto transplantated parathyroid tissue were performed an this patient was still hypercalcemic postoperatively, with a serum calcium of 2.65 mmol/1. The renal function wa not impaired by parathyroidectomy. In 9 of the 22 patients subtotal parathyroidectomy was indicated within months after renal transplantation because of serum calcium levels over 3.0 mmol/1 or severe clinical symptoms. Subtotal parathyroidectomy is indicated in patients with secondary hyperparathyroidism after renal transplantation with a serum calcium over 3.0 mmol/1 and sever, clinical symptoms and also in patients with slightly elevated serum calcium levels after an observation period of up to 12 months.ZusammenfassungZwischen dem 1.4.1986 und dem 1.1.1992 wurden 22 Patienten mit einem sekundären Hyperparathyreoidismus (HPT) nach Nierentransplantation (NTP) operiert. 21 Patienten waren postoperativ normokalzämisch und 1 Patient zeigte trotz der 3maligen Reduktion des Autotransplantats weiterhin einen Serumkalziumwert von 2,65 mmol/1. In keinem Fall wurde die Nierenfunktion durch die Operation beeinträchtigt. In 9 Fällen wurde die subtotale Parathyreoidektomie (SPTX) innerhalb der ersten 4 Monate nach der NTP notwendig. Die Indikation zur subtotalen Parathyreoidektomie wird bei alien Patienten mit Serumkalziumwerten > 3,0 mmol/1 and schweren klinischen Symptomen sofort gestellt. Bei Serumkalziumwerten < 3,0 mmol/1 kann ein Beobachtungszeitraum von bis zu 12 Monaten ohne akute Gefährdung des Transplantats akzeptiert werden.Between April 1986 and January 1992, a total of 22 patients with chronic renal failure were operated on for secondary hyperparathyroidism after kidney transplantation, and 21 of these patients were normocalcemic postoperatively. In 1 patient three reductions of autotransplanted parathyroid tissue were performed and this patient was still hypercalcemic postoperatively, with a serum calcium of 2.65 mmol/l. The renal function was not impaired by parathyroidectomy. In 9 of the 22 patients subtotal parathyroidectomy was indicated within 4 months after renal transplantation because of serum calcium levels over 3.0 mmol/l or severe clinical symptoms. Subtotal parathyroidectomy is indicated in patients with secondary hyperparathyroidism after renal transplantation with a serum calcium over 3.0 mmol/l and severe clinical symptoms and also in patients with slightly elevated serum calcium levels after an observation period of up to 12 months.

Is there any consensus in diagnostic and operative strategy with respect to medullary thyroid cancer

Abstract. Background: The purpose of this investigation was to analyze the individual diagnostic and operative strategy in the treatment of medullary thyroid carcinoma (MTC) in international specialized centers and to assess whether standard procedures are carried out in practice everywhere. Methods: A questionnaire concerning diagnosis and treatment of patients with primary, persistent, or recurrent sporadic or familial MTC was sent to 263 members of the International Association of Endocrine Surgeons. Results: Primary treatment of MTC does not show significant differences for patients with sporadic or familial disease (Chi-square, n.s.), and standard procedures are performed in only 25–40% of patients. Computed tomography scan is the most common localization procedure in persistent or recurrent disease (52–72%), followed by scintigraphy (43–71%), ultrasonography (41–56%), and magnetic resonance imaging (31–49%). In case of negative localization studies, 68–86% of colleagues do not recommend reoperation. In symptomatic patients with stage-IV tumors, however, 84% of colleagues advocate reoperation to provide relief from the tumor burden. Conclusions: Even with experienced endocrine surgeons, a consensus to uni- and/or bilateral neck dissection in primary MTC is lacking. The majority of authors supports at least total thyroidectomy with central lymph-node dissection. In recurrent disease, there is a general tendency to reoperate in case of positive localization studies and in case of symptomatic disease.