Differentiated thyroid cancer is a malignant tumour that has a fairly good prognosis, with patients surviving for many years. Multimodal therapy with surgery, radioiodine therapy and TSH suppressive medication is of proven efficacy. However, loss of differentiation is observed in up to one-third of patients with differentiated thyroid cancer, paralleled by an increase in tumour grading and loss of thyroid-specific functions (thyrotropin receptor, iodine accumulation). Such tumours may no longer be amenable to standard treatment protocols, including TSH suppression and radioiodide therapy. Retinoic acids have been shown to exert re-differentiating effects on thyrocytes in various experimental studies and case reports, and it was on this basis that this pilot study was initiated. Patients with advanced thyroid cancer and without the therapeutic options of operation or radioiodide therapy were treated with 13- cis-retinoic acid at a dosage of 1.5 mg/kg body weight daily over 5 weeks. Parameters for assessment of the therapeutic effect were serum thyroglobulin (TG) levels, radioiodine uptake, and tumour size prior to and after retinoid treatment. Fifty patients were evaluated for response, classified as reduction in tumour size and TG levels, stable disease or disease progression. Thirteen patients showed a clear increase in radioiodine uptake, and eight a mild increase. TG levels were unchanged or decreased in 20 patients. Tumour size was assessable in 37 patients; tumour regression was observed in six, and there was no change in 22. In total, a response was seen in 19 patients (38%). Response to retinoid therapy did not always correlate with increased radioiodine uptake, so other direct antiproliferative effects have to be assumed. The encouraging results of the study and the low rate of side-effects with good tolerability of retinoids warrant further studies with altered inclusion criteria and employment of other redifferentiating drugs or combinations of agents.

Einleitung. In verschiedenen Untersuchungen liegt die Inzidenz differenzierter Schilddrüsenkarzinome bei Patienten mit primärem Hyperparathyreoidismus (pHPT) zwischen 3,5 und 21%. Patienten und Ergebnisse: Zwischen 4/86 und 12/99 wurden 963 Patienten mit pHPT operiert. Bei 390 Patienten (40%) erfolgte gleichzeitig eine Schilddrüsenresektion. Es fanden sich 21 papilläre und 4 follikuläre Schilddrüsenkarzinome, darunter 21 Zufallsbefunde. Die Inzidenz differenzierter Schilddrüsenkarzinome bei Patienten mit benignen Schilddrüsenerkrankungen lag im eigenen Krankengut bei 4,8%. Schlußfolgerung: Die Inzidenz zufällig entdeckter differenzierter Schilddrüsenkarzinome liegt bei pHPTPatienten mit simultaner Schilddrüsenresektion bei 5,4%. Vor pHPT-Operation ist eine Sonographie der Schilddrüse obligat, um benigne und maligne Schilddrüsenerkrankungen gleichzeitig mitbehandeln zu können.

Einleitung: Neuroendokrine Tumoren des Thymus kommen sporadisch und MEN1-assoziiert vor. Charakteristisch ist ihre Neigung zu Lokalrezidiven. Patienten und Ergebnisse: Zwischen 1984 und 1999 wurden 7 Patienten mit einem neuroendokrinen Tumor des Thymus identifiziert (5 Männer, 2 Frauen, Alter 19–58 Jahre). In 3 Fällen lag ein MEN1-Syndrom vor. In 3 Fällen fand sich ein Cushing-Syndrom. Insgesamt erfolgten 16 Operationen. In 13 Fällen gelang eine makroskopische Tumorentfernung. Es gab keine perioperative Letalität. Adjuvante Zusatztherapien (Bestrahlung, Chemotherapie, Somatostatin, Interferon) waren von begrenztem Wert. Die Überlebenszeit nach Resektion betrug 3–14,5 Jahre. Schlußfolgerung: Die chirurgische Therapie ist auch im Falle eines Rezidivs gerechtfertigt. Das komplexe Krankheitsbild des neuroendokrinen Thymustumors erfordert eine enge Kooperation von Thorax- und endokriner Chirurgie.

The discovery of mutations of the menin gene in a few multiple endocrine neoplasma type 1 (MEN I)-associated lipomas and loss of heterozygosity (LOH) on chromosome 11q13 in some sporadic lipomas has stimulated the hypothesis that lipomas may belong to the group of sporadic tumors caused by defects of the gene responsible for MEN I. Since it is unclear if the above hypothesis applies to all patients with lipoma or just to specific subsets, we searched to enlarge the database on this topic. For this purpose, we identified two patients with multiple cutaneous lipomas. One had an additional pituitary adenoma and familial presentation of multiple lipomas, the other had recurrent goiter in the setting of a family history of adenomatous goiter. Deoxyribonucleic acid (DNA) was analyzed by complete direct DNA sequencing of all coding exons and splice junctions of the MEN I gene. No mutation was identified in the coding exons of the menin gene. In contrast to former data on sporadic lipomas, these data are the first to render evidence that mutations of the MEN I gene may not be responsible for the formation of multiple lipomas, even if they appear in the context of other endocrine tumors.

Adrenal cancer is a rare sporadic disease that has also been observed in the context of multiple endocrine neoplasia type I (MEN I). Adrenal lesions occur in up to 40% of MEN I patients. Loss of heterozygosity of the 11q13 band harboring the menin gene has been reported in more than 50% of patients with adrenal cancer. Despite this high index of suspicion, former screening studies did not reveal mutations of the MEN I gene in 28 patients. We identified loss of heterozygosity of 11q13 microsatellites in five of five patients (100%). In 40%, heterozygosity was retained in codon 418 of the MEN I gene. Complete direct DNA sequencing data of the entire coding region and adjacent splice sites of the MEN I gene were obtained in 14 patients with sporadic adrenal cancer. In only one of them a heterozygous missense mutation, R176Q (exon 3), was identified. Due to the heterozygous pattern and unknown biological effect of this mutation, it is not clear whether there is a causal relationship with adrenal cancer. The total mutation frequency in sporadic adrenal cancer is 1 of 14 (7%). Menin messenger RNA expression was identified in 14 of 14 patients (100%). Transcriptional inactivation of the menin gene is, hence, unlikely to cause loss of its tumor suppressor function in adrenal cancer. Furthermore, we examined three patients who presented adrenal cancer in the context of sporadic multiglandular endocrine tumor disease previously diagnosed on clinical grounds to be MEN I syndrome. An opal stop codon mutation was identified in codon 126 (exon 2) in the adrenal cancer of one of these patients. Formation of the adrenal cancer in this patient may be rather coincidental because the mutation was present in a heterozygous pattern. There was no mutation of the menin gene in the two other patients. This may mean that formation of adrenal cancer in the context of multiglandular endocrine disease denotes an entity different from MEN I in some patients.

Loss of heterozygosity (LOH) on chromosome 11q13 occurs in about 20% of sporadic adrenal neoplasms. Adrenal lesions, mostly benign, occur in up to 40% of patients from MEN I kindreds. The MEN I gene, positioned on 11q13, has been considered a primary candidate gene in these lesions. We studied a group of 15 patients with sporadic adrenal adenoma, and 1 patient with multinodular hyperplasia. Of the 16 patients, 4 had incidentally discovered masses, 5 had Conn's syndrome, 6 suffered from Cushing's syndrome, and 9 had high sex hormone production. Studies with the markers D11S480, PYGM, D11S449, and D11S987 in 13 patients (12 of whom were from our group of 16) revealed 4 losses of heterozygosity on D11 S480 on 11q13, but the deletion did not affect the MEN I gene in any case. We present complete direct DNA sequencing data of the menin gene in 14 sporadic adrenal adenomas and one with adrenal hyperplasia. We identified one heterozygous missense mutation, T552S, in a hormonally inactive adrenal adenoma. One base exchange was identified close to the intron-exon boundary in intron 9 of a nodular adrenal hyperplasia. mRNA expression studies found that MEN I was transcribed in all 13 samples analyzed. In summary, our study identified the second patient with sporadic benign adrenal tumor presenting a menin gene mutation. Our complete direct sequencing approach adds evidence that menin gene mutations may account only for a minority of benign adrenal tumors if at all. Another tumor-suppressor gene inactivated in sporadic adrenal neoplasms may be located on chromosome 11q13.

HGF (hepatocyte growth factor) has been characterised as an important mitogen and motogen in many epithelial cells. The biological and clinical significance of HGF and its receptor c-met in the thyroid is currently under study. Overexpression of c-met is an important feature of papillary thyroid cancer. We developed a quantitative differential RT-PCR method in order to examine HGF-receptor regulation using RNA of about 50 cells per analysis. Experiments were performed in three spontaneously transformed follicular thyroid cancer (FTC) cell lines FTC-133, 236, and 238, 7 primary cultures derived from multinodular goitres, one from Graves disease and 1 from papillary thyroid cancer (PTC). TGF-alpha and to a minor degree HGF were shown to induce a marked up-regulation of the receptor whereas bovine TSH, NaI, dbcAMP or basic FGF had no apparent effect. We conclude that expression of the HGF-receptor is under control of paracrine growth factors activating tyrosine-kinase-dependent pathways. We could demonstrate a minor stimulation of thyroid cell proliferation by HGF in presence but not in absence of 10% fetal calf serum.

Als Basisuntersuchung werden bei Schilddrüsenerkrankungen Anamnese und klinischer Befund durch bTSH und Ultraschall ergänzt. Das Szintigramm beantwortet spezielle Fragestellungen am ehesten für kalte und heiße Knoten bzw. für die thyreoidale Autonomie. Beweis für das Vorliegen des M. Basedow liefert die positive TRAK-Bestimmung. Bei supprimiertem TSH entsprechend Vorliegen einer Hyperthyreose sichert der T3-Wert den aktuell vorhandenen Funktionszustand.

Endocrine active islet cell tumors of the pancreas are rare and become clinically evident mainly by symptoms of hormone over-production (hypoglycemia, gastric ulcer disease, diarrhea etc.). The tumors may occur sporadically or in connection with the familial MEN-I syndrome. Diagnosis is verified biochemically and does not need further localization studies. Localization studies are important, however, intraoperatively and in detecting persistent or recurrent tumor disease. Principally endocrine pancreatic tumors are excised selectively with exception of MEN-I patients and patients suffering from "Nesidioblastosis", where subtotal resections of the pancreas are indicated. In case of malignant metastatic endocrine pancreatic tumors palliative therapies (surgery, embolization, chemotherapy, therapy of hormone excess etc.) are demanded to improve the quality of life in these patients, since they may survive for years despite their tumor burden.

A critical analysis of early and late postoperative complications is necessary to assure the quality of surgery for benign thyroid diseases. The 2 major complications are palsy of the recurrent laryngeal nerve and hypoparathyroidism. Yet, long-term and follow up studies. as well as pre and post operative investigations are rather scarce.

Bilateral versus unilateral or subtotal adrenalectomy in MEN II patients with associated pheochromocytoma is subject to controversial discussion. The aim of this study was to compare the two procedures with regard to surgical approach and postoperative recurrence rate.

Diagnosis and treatment of primary hyperparathyroidism has changed substantially during recent years. Routine serum calcium measurements and development of specific as well as sensitive PTH assays made primary hyperparathyroidism the most prevalent diagnosis of hypercalcaemia in the normal population. With increasing numbers of asymptomatic patients secondary complications are reduced but the demands made on surgeon's technical skill are much higher. In view of our experience in 329 patients with primary hyperparathyroidism during the last six years and a success rate of 98% we refrain from any localisation technique and advocate visualisation of all four glands.

Reoperation was performed in 110 of 185 patients with a differentiated thyroid carcinoma. In 25 patients (23 per cent) the indication for reintervention was a large thyroid remnant and in the other 85 (77 per cent) persistent or recurrent cancer was suspected. In 32 (29 per cent) of the 110 patients undergoing reoperation no evidence of cancer tissue was found. Tumour tissue in 33 patients (30 per cent) was resectable. Of 45 patients (41 per cent) with residual tumour after operation 24 showed only occult thyroid carcinoma with a raised serum thyroglobulin level. Eight of 21 patients with macroscopically persistent tumour died from the disease during a mean follow-up of 2.3 years. In 13 of 38 patients the investigated recurrent tumours were histologically less differentiated than the primary lesions, stressing the importance of total tumour clearance. The treatment of choice for persistent and recurrent differentiated thyroid carcinoma is surgical reintervention, if feasible, before radioiodine and radiation therapy are considered.

Since the late sixties standard total thyroidectomy with or without selective radical neck dissection depending on the extent of the disease has become the routine surgical procedure for differentiated thyroid carcinoma (DTC;-papillary, follicular). This strategy has contributed remarkably to the increase of cure rates for various reasons. Only recently, in the last decade, has limited radicality with only unilateral lobectomy (= hemithyroidectomy) with or without partial contralateral resection been advocated as being sufficient for selected early tumor stages. We have analyzed a series of 252 patients, 174 (69%) being papillary and 78 (31%) follicular. Primary operation was done in 117 patients (46%) while 135 patients (54%) underwent reoperative surgery at this institution for either completion of radicality or because of loco-regional recurrence. From our evaluation we draw the conclusion that limited radicality (unilateral operation or subtotal) is justified only in pT-1-tumors in younger age (< 45 yrs) in order to avoid recurrence and unnecessary reoperation. On the other hand generous indication for reoperation is justified with the overall chance of almost 60% cure rate. All adjuvant treatment, mainly radioiodine should be applied thereafter.

BACKGROUND:Up to 80% of patients with adrenocortical tumors comprising Conn's or Cushing's syndrome and patients with pheochromocytomas suffer from hypertension. Its implications in cardiovascular disease and its impact on quality of life make it the most important aim in therapeutic efforts. The aim of our study was to assess the long-term results in postoperative blood pressure after adrenalectomy and to evaluate potential risk factors for persistent hypertension.METHODS:Forty four patients with adrenal hypertension operated on between April 1986 and April 1991 underwent follow-up consisting of exact history, hormonal analysis, and adrenal imaging.RESULTS:Forty three patients were reexamined, which showed 11 patients (26%) with hypertension at dismissal from hospital and 17 patients (40%) with hypertension after a median of 2 years. Except for two recurrent tumors in adrenocortical carcinoma all patients were surgically cured. Antihypertensive medication could be reduced in 13 of 17 patients with persistent hypertension. Persistent hypertension did not correlate with the degree of preoperative blood pressure elevation, age, and gender, but it did correlate strongly with history of hypertension. Patients with normal blood pressure level after operation had a mean history of 5.7 years versus 11.5 years in patients with persistent hypertension (p < 0.03).CONCLUSIONS:The success of surgical treatment for adrenal hypertension strongly depends on early diagnosis and surgical intervention.

Rezidive differenzierter Schilddrüsenkarzinome (papilläres und follikuläres Karzinom) können mittels Radiojod-, perkutaner Strahlentherapie oder operativ behandelt werden. Am ehesten wird ein dauerhafter Erfolg jedoch durch die Kombination verschiedener Therapiemodalitäten, wie z. B. der Chirurgie in Verbindung mit der Radiojodtherapie gewährleistet [7, 10]. Die Bedeutung interdisziplinärer Kooperation kann deshalb kaum genügend unterstrichen werden [13]. Im Gegensatz dazu ist die Therapiemöglichkeit von Patienten mit C-Zellkarzinomen der Schilddrüse (medulläres Karzinom) allein auf die effektive operative Entfernung aller Tumorgewebe angewiesen, da weder nuklearmedizinische Behandlungskonzepte existieren noch die perkutane Strahlentherapie eine nachweisliche Verlängerung der Lebenserwartung dieser Patienten erbringt [13].

Der hypercalcämische oder auch tertiäre Hyperparathryreoidismus, unabhängig, ob er nun unter Behandlung mit Vitamin D auftritt oder nicht.

Maligne Nebennierentumoren stellen eine Seltenheit dar. Sie präsentieren sich entweder unter dem klinischen Bild der hormonellen Überfunktion entsprechend den gutartigen Erkrankungen oder als große raumfordernde Tumormasse. Bildgebende Verfahren schließen ein den Ultraschall, das CT und mit selektiver Anwendung das MIBG- oder Jod-Norcholesterol-Szintigramm. Für die Operation empfiehlt sich prinzipiell der transabdominelle, in ausgewählten Fällen der abdominothorakale Zugang. Lokale Radikalität erfordert eine großzügige Exzision im Sinne einer en-bloc-Extirpation. Die Erfahrungen aus 3,5 Jahren mit 10 malignen Tumoren von insgesamt 64 Nebennierentumoren (16%) werden unter verschiedenen Aspekten dargelegt.