Henning Dralle

Allelic deletion of the MEN1 gene in duodenal gastrin and somatostatin cell neoplasms and their precursor lesions

Background: Patients with a multiple endocrine neoplasia type 1 (MEN1)-associated Zollinger–Ellison syndrome (ZES) show multifocal duodenal gastrinomas and precursor lesions. Aims: To test these lesions for loss of heterozygosity (LOH) of the MEN1 gene locus on chromosome 11q13, and to investigate whether the MEN1-related endocrine cell changes also involved somatostatin cells. Material and methods: Tissue specimens from six patients with MEN1 and ZES were analysed by immunohistochemistry and immunofluorescence. LOH analysis was performed by fluorescence in situ hybridisation (FISH), using probes containing the MEN1 gene locus and the centromere 11 (C11) region. For simultaneous analysis of hormones and allelic deletions, a combined FISH/immunofluorescence protocol was established. Results: 28 of a total of 33 duodenal neuroendocrine tumours (NETs) were gastrin-producing tumours; 13/28 (46.4%) revealed LOH on 11q13 and/or C11. Five of the NETs were somatostatin-expressing tumours, two revealing LOH. Allelic loss was detected in tumours as small as 300 μm (gastrin) and 400 μm (somatostatin) in diameter. The gastrin-producing tumours showed different deletion/retention patterns. Hyperplastic somatostatin cell lesions, similar to those of the gastrin cells, were present in all patients. The hyperplastic lesions of both cell lines consistently retained both 11q13 alleles. Conclusions: Allelic deletion of the MEN1 gene may reflect a pivotal event in the development of multifocal gastrin and somatostatin cell neoplasms in the duodenum of patients with MEN1. The observation of distinct deletion patterns in small synchronous tumours supports the concept that each gastrin-producing tumour in an individual MEN1 patient arises from an independent cell clone.

Somatostatin receptor subtype expression in human thyroid tumours.

Somatostatin receptors (SSTR) are expressed in various endocrine tumours. The expression of SSTR at the tumour cell surface confers the possibility for diagnostic imaging and therapy of tumours using radiolabeled somatostatin analogues. The majority of currently available somatostatin analogues show a higher binding affinity for the SSTR2 subtype. To date, the precise expression pattern of the SSTR subtypes 1-5 in thyroid epithelial tumours remains to be determined. We investigated the mRNA expression of SSTR1-5 in benign and malignant epithelial thyroid tumours [20 cold thyroid nodules (CTNs), 20 toxic thyroid nodules (TTNs), 20 papillary, 20 follicular, and 5 anaplastic carcinomas (PTCs, FTCs, ATCs, respectively)] and compared them to normal surrounding thyroid tissues. Four out of five SSTR subtypes were detected in malignant thyroid tumours, benign neoplasia, and normal surrounding tissue with a predominant expression of SSTR2 and SSTR5, and a weak expression of SSTR1 and SSTR3. Weak SSTR4 mRNA expression was detected in some PTCs. Compared to normal thyroid tissue, SSTR2 was significantly upregulated in PTC and ATC. In addition significant upregulation of SSTR3 was found in PTC. SSTR5 mRNA expression was increased in PTC and FTC and significantly decreased in CTN and TTN compared to normal thyroid tissue. SSTR2 is the predominant subtype in thyroid epithelial tumours with a high expression pattern, in particular, in PTC . Perspectively, the expression of distinct SSTR in thyroid epithelial tumours might represent a promising avenue for diagnostics and therapy of advanced thyroid cancer with somatostatin analogues.

Hereditary thyroid cancer

ZusammenfassungHereditäre Schilddrüsenkarzinome werden in ca. 5% der differenzierten (DTC) und 25% der medullären Schilddrüsenkarzinome nachgewiesen. Sie kommen sowohl als Organkrebs innerhalb eines Tumorsyndroms vor (z.xa0B. differenzierte Karzinome bei FAP-Gardner-Syndrom, medulläre Karzinome beim MEN2-Syndrom), aber auch als alleiniger familiärer Organtumor. Unabhängig von der Manifestationsform treten hereditäre Schilddrüsenkarzinome häufig bei jüngeren Patienten und multifokal auf. Das Resektionsausmaß muss aufgrund der vorliegenden Keimbahnmutationen grundsätzlich in der Entfernung der gesamten Schilddrüse bestehen. Teilentfernungen der Schilddrüse, wie sie für frühe Tumorstadien der sporadischen Tumoren ausreichend sein können, sind daher unabhängig vom Tumorstadium beim hereditären Schilddrüsenkrebs nicht indiziert.Bei den meisten hereditären differenzierten Schilddrüsenkarzinomen ist die genetische Disposition unbekannt. Somit sind ein molekulargenetisches Screening und eine DNA-basierte prophylaktische Chirurgie nicht möglich. Auch bei den syndromal assoziierten DTC (FAP-Gardner-Syndrom, Cowden-Syndrom etc.) ist eine prophylaktische Chirurgie nicht begründet, da deren Prognose sich nicht von der sporadischer DTC unterscheidet.Beim hereditären medullären Karzinom ist die genetische Ursache der Punktmutationen im RET-Protoonkogen seit 15 Jahren bekannt. Es werden jedoch stets neue krankheitsauslösende Mutationen des RET-Protoonkogens berichtet, so dass eine abschließende Wertung aller bestehenden Mutationen derzeit nicht möglich ist. Grundsätzlich besteht eine Genotyp-Phänotyp-Korrelation mit mutationsspezifischen Risikogruppen (Risikogruppe 1–3), die eine mutationsorientierte prophylaktische Thyreoidektomie möglich machen. Aufgrund der erheblichen Variationen innerhalb der einzelnen Risikogruppen ist jedoch ein streng mutationsspezifisches Vorgehen hinsichtlich Operationszeitpunkt und -ausmaß (ohne oder mit Lymphknotendissektion) nicht möglich, so dass einem kombiniert molekulargenetisch-biochemischen Konzept unter gleichzeitiger Berücksichtigung der Ergebnisse des Pentagastrinstimulationstestes der Vorzug zu geben ist.AbstractHereditary thyroid carcinomas are present in about 5% of differentiated (DTC) and 25% of medullary thyroid carcinomas (MTC). They are part of a multiorgan tumour syndrome (e. g. FAP Gardner’s syndrome with DTC and MEN 2 syndrome with MTC) or confined to the thyroid gland. Hereditary thyroid carcinomas typically show multifocal growth and occur in young patients. Due to germ cell mutations as the underlying cause of disease, partial thyroidectomies that may be justified in early sporadic carcinomas are not indicated in this type of tumours. In the case of hereditary DTC, the genetic basis of the disease has been demonstrated only in syndromatic tumour variants. In most nonsyndromatic cases, specific genetic alterations have not yet been identified. In both types of hereditary DTC, prophylactic thyroidectomy is not warranted due to the favourable prognosis of tumours that do not differ from sporadic ones. Point mutations of the RET proto-oncogene have been known for 15xa0years to be the genetic basis of hereditary MTC. Recently several new mutations were discovered; however, final conclusions regarding their clinical significance are not possible at present. Basically it has been shown that the clinical aggressivity of tumour development follows a genotype-phenotype correlation (risk groups 1–3). However, in mutations of all risk classes there exists a wide spectrum of different stages of hereditary C-cell disease in individual risk groups. Regarding time and extent of prophylactic thyroidectomy (without or with lymph node dissection) a combined molecular-biochemical concept including the use of pentagastrin-stimulated calcitonin values is therefore recommended.Hereditary thyroid carcinomas are present in about 5% of differentiated (DTC) and 25% of medullary thyroid carcinomas (MTC). They are part of a multiorgan tumour syndrome (e. g. FAP Gardners syndrome with DTC and MEN 2 syndrome with MTC) or confined to the thyroid gland. Hereditary thyroid carcinomas typically show multifocal growth and occur in young patients. Due to germ cell mutations as the underlying cause of disease, partial thyroidectomies that may be justified in early sporadic carcinomas are not indicated in this type of tumours. In the case of hereditary DTC, the genetic basis of the disease has been demonstrated only in syndromatic tumour variants. In most nonsyndromatic cases, specific genetic alterations have not yet been identified. In both types of hereditary DTC, prophylactic thyroidectomy is not warranted due to the favourable prognosis of tumours that do not differ from sporadic ones. Point mutations of the RET proto-oncogene have been known for 15 years to be the genetic basis of hereditary MTC. Recently several new mutations were discovered; however, final conclusions regarding their clinical significance are not possible at present. Basically it has been shown that the clinical aggressivity of tumour development follows a genotype-phenotype correlation (risk groups 1-3). However, in mutations of all risk classes there exists a wide spectrum of different stages of hereditary C-cell disease in individual risk groups. Regarding time and extent of prophylactic thyroidectomy (without or with lymph node dissection) a combined molecular-biochemical concept including the use of pentagastrin-stimulated calcitonin values is therefore recommended.

Prophylactic parathyroidectomy for familial parathyroid carcinoma

ZusammenfassungIm Gegensatz zum primären Hyperparathyreoidismus (pHPT) sind Nebenschilddrüsenkarzinome (NSD-Ca) sehr selten. Bei Patienten mit einem Hyperparathyreoidismus-Jaw-Tumor (HPT-JT-)Syndrom, welches durch Keimbahnmutationen in HRPT2 verursacht wird, muss in 10–15% der Patienten mit der Entstehung eines NSD-Ca gerechnet werden. In der vorliegenden Übersicht werden die klinischen und molekulargenetischen Angaben von knapp 100xa0Patienten aus der Literatur sowie 3 eigenen Patienten zusammengefasst. Leider treten die typischen Osteofibrome (Jaw-Tumor), welche eine frühzeitige Diagnose ermöglichen könnten, erst relativ spät sowie in nur ca. 30% der Patienten auf. In ca. 80% liegt eine Eindrüsenerkrankung vor. Eine generelle Empfehlung zur prophylaktischen Parathyreoidektomie kann derzeit nicht gegeben werden, ein engmaschiges Screening der Betroffenen ist indiziert. Wichtig ist, dass auch bei vermeintlich sporadischem NSD-Ca in bis zu 20% Keimbahnmutationen in HRPT2 nachgewiesen wurden, d.h., dass Patienten mit einem NSD-Ca auf eine entsprechende Mutation hin untersucht werden sollten.AbstractIn contrast to primary hyperparathyroidism, parathyroid carcinoma is a rare disease. In patients with hyperparathyroidism jaw tumor (HPT-JT) syndrome, caused by germline mutations in HRPT2, the development of parathyroid carcinoma is estimated to be 10–15%. This review summarizes the clinical and molecular genetic data of about 100 patients in the literature and three of our own cases. Unfortunately, osteofibromas, which might enable timely diagnosis of HPT-JT syndrome, occur in only about 30% of patients; about 80% have uniglandular disease. Based on the current data, a general recommendation to perform prophylactic parathyroidectomy cannot be given. However, thorough screening of patients at risk is mandatory. Of note in patients thought to have sporadic parathyroid carcinoma, germline HRPT2 mutations are found in up to 20%. Hence, any patient with parathyroid carcinoma should undergo HRPT2 mutation analysis.

[Vocal cord paralysis after thyroid surgery : Current medicolegal aspects of intraoperative neuromonitoring].

ZusammenfassungDas intraoperative Neuromonitoring (IONM) ist eine seit ca. 15 Jahren kommerziell zur Verfügung stehende Technik, die es erlaubt, bei Schilddrüsenoperationen bereits intraoperativ mit hoher Wahrscheinlichkeit bei regelrechtem Muskelaktions-Elektromyogramm(EMG) eine postoperativ intakte (>u200999u2009% richtig-negativer Befund) oder bei Signalausfall eine postoperativ gestörte (>u200970u2009% richtig-positiver Befund) Stimmlippenfunktion vorherzusagen. Das IONM hat die intraoperative Erkennung des Nervenverlaufes verbessert, wegen seines hohen prädiktiven Wertes hinsichtlich der postoperativ zu erwartenden Stimmlippenfunktion ist es jedoch gleichzeitig erforderlich, das Ergebnis der Nervenfunktionstestung in das operative Vorgehen einzubeziehen. Einseitige Funktionsverluste des N.xa0recurrens können auch bei standardgerechtem Einsatz nicht gänzlich verhindert werden. Gleichwohl ist es möglich, bei geplant bilateraler Resektion eine bilaterale Stimmlippenparese sicher auszuschließen, wenn bei einem Funktionsverlust des N.xa0recurrens auf der erstoperierten Seite auf die Resektion der zweiten Seite verzichtet wird (Strategiewechsel). Der Patient muss bei geplantem Einsatz über die Grenzen des IONM und einen möglichen Strategiewechsel bei geplant bilateraler Resektion präoperativ informiert werden. Der Operateur soll sicherstellen, dass nach den aktuellen Anwendungsstandards und -empfehlungen des IONM vorgegangen und bei intraoperativem Funktionsausfall des Nerven risikoorientiert reagiert wird.AbstractIntraoperative neuromonitoring (IONM) has been commercially available for approximately 15 years and is highly predictive in thyroid gland surgery concerning either postoperative vocal fold mobility in the case of an intact signal for muscle action electromyogram (EMG, >u200999u2009% right negative) or vocal fold dysfunction in the case of loss of signal (>u200970u2009% right positive). The use of IONM improves the intraoperative identification of recurrent laryngeal nerve function and due to the high predictive value with respect to the expected vocal cord function the result of IONM has to be integrated into the surgical concept of thyroidectomy. Unilateral loss of function of the recurrent laryngeal nerve cannot be completely avoided despite correct application of IONM; however, bilateral vocal fold palsy can be safely avoided when contralateral surgery is cancelled after a loss of signal occurs during resection of the first side in planned bilateral surgery (alternative strategy). Patients have to be informed preoperatively about the limitations of IONM and potential strategy changes during planned bilateral surgery. Surgeons should apply IONM according to the published current recommendations and by selecting a risk-oriented intraoperative strategy in the case of loss of signal from the recurrent laryngeal nerve.Intraoperative neuromonitoring (IONM) has been commercially available for approximately 15 years and is highly predictive in thyroid gland surgery concerning either postoperative vocal fold mobility in the case of an intact signal for muscle action electromyogram (EMG, >u200999u2009% right negative) or vocal fold dysfunction in the case of loss of signal (>u200970u2009% right positive). The use of IONM improves the intraoperative identification of recurrent laryngeal nerve function and due to the high predictive value with respect to the expected vocal cord function the result of IONM has to be integrated into the surgical concept of thyroidectomy. Unilateral loss of function of the recurrent laryngeal nerve cannot be completely avoided despite correct application of IONM; however, bilateral vocal fold palsy can be safely avoided when contralateral surgery is cancelled after a loss of signal occurs during resection of the first side in planned bilateral surgery (alternative strategy). Patients have to be informed preoperatively about the limitations of IONM and potential strategy changes during planned bilateral surgery. Surgeons should apply IONM according to the published current recommendations and by selecting a risk-oriented intraoperative strategy in the case of loss of signal from the recurrent laryngeal nerve.

Distinct regulation of intrinsic apoptosis in benign and malignant thyroid tumours.

Aberrations in the control of apoptosis represent a central feature of thyroid carcinogenesis. However, little is known about the regulation of components of the intrinsic apoptosis pathway in the thyroid. Using a real-time PCR approach we investigated the mRNA expression levels of Caspase3, Caspase3 s, xIAP, Bad, and beta-actin in a panel of 79 thyroid tumours. Additionally, we assessed the activation status of Caspase3 by immunohistochemistry. In the present study, we provide first evidence for a deregulation of the intrinsic apoptosis pathway on the transcriptional and post-transcriptional level. Thus, malignant thyroid tumours revealed a significant downregulation of the proapoptotic Bad. In contrast Caspase3 s, an alternative splice variant of Caspase3 with anti-apoptotic characteristics, was upregulated in follicular and anaplastic cancers. Moreover, papillary thyroid tumours revealed a significant upregulation of Caspase3 mRNA. On the post-translational level, thyroid malignancies featured an impairment in the activation of Caspase3, since activated Caspase3 accumulated exclusively in the cytoplasm of thyroid cancer cells, whereas follicular adenoma and normal thyroid tissues showed no cytoplasmatic but nuclear Caspase3 distribution. Further knowledge on apoptosis-deregulation during thyroid carcinogenesis might confer diagnostic and therapeutic benefits in the management of thyroid cancer.

Lymphadenectomy for thyroid and lymph node carcinomas

ZusammenfassungGenerell wird beim Schilddrüsenkarzinom neben der totalen Thyreoidektomie initial eine zervikozentrale Lymphadenektomie empfohlen. Ausnahmen hiervon sind papilläre Mikrokarzinome sowie so genannte prophylaktische Operationen aufgrund des Vorliegens einer multiplen endokrinen Neoplasie Typxa02A.xa0Über das zervikozentrale Kompartiment hinaus ist eine kompartimentorientierte Lymphadenektomie stets dann indiziert, wenn Lymphknotenmetastasen nachweisbar sind. Da das klinisch nachgewiesene medulläre Schilddrüsenkarzinom oft beidseits zervikolateral metastasiert, ist bei diesen Patienten stets auch ohne präoperativen Metastasennachweis eine bilaterale zervikolaterale Lymphadenektomie indiziert.Beim Nebenschilddrüsenkarzinom sollte die ipsilaterale zervikozentrale Lymphadenektomie stets en bloc mit der Parathyreoidektomie und Hemithyreoidektomie durchgeführt werden.Die Lymphadenektomie eines jeden Kompartiments sollte generell systematisch durchgeführt werden, weil sich Lymphknotenmetastasen aufgrund ihrer geringen Größe oft erst histologisch nachweisen lassen.AbstractIn general, primary surgery of thyroid carcinoma should consist of total thyroidectomy and lymph node dissection of the cervicocentral compartment. Exceptions are cases of papillary microcarcinoma and prophylactic surgery due to multiple type 2A endocrine neoplasia. Lymph node dissection beyond the cervicocentral compartment also should be compartment-oriented. It is generally indicated if lymph node metastases have been proven. Concerning clinically proven medullary thyroid carcinoma, bilateral cervicolateral lymph node dissection is generally indicated, since lymph node metastases may be missed preoperatively but are often found histologically. In patients with parathyroid carcinoma, en bloc ipsilateral cervicocentral lymph node dissection should be performed in addition to parathyroidectomy and hemithyroidectomy. Lymph node dissection should always be performed systematically, since lymph node metastases may be missed both clinically and by imaging techniques.

Chirurgie der Schilddrüsenkarzinome@@@Surgery of thyroid carcinoma

The 5 main types of thyroid cancer (papillary, PTC, follicular, FTC, poorly differentiated, PDTC undifferentiated, UTC, medullary, MTC) not only differ regarding morphology, pathogenesis, genetics,and pathophysiology (iodine metabolism, thyroglobulin and calcitonin production), but also concerning tumor biology, metastatic behavior (lymphogenous, locally invasive and hematogenous routes) and prognosis. Knowledge of these features is the basis of the surgical concept of one or two-stage thyroidectomy, the exceptions and the concept of locoregional lymph node dissection. Lymph node surgery plays an important role in those cancers exhibiting mainly lymph node metastases (PTC, MTC) not only due to frequent recurrences but also due to its potential curative intent. Differentiated carcinomas may have an acceptable prognosis despite local invasion of the cervical aerodigestive system, thus resections are justified when technical prerequisites are given.ZusammenfassungDie 5 Haupttypen des Schilddrüsenkarzinoms (papillär [PTC], follikulär [FTC], wenig differenziert [PDTC], undifferenziert [UTC], medullär [MTC]) unterscheiden sich nicht nur hinsichtlich ihrer Morphologie, Pathogenese, Genetik und Pathophysiologie (Jodmetabolismus, Thyreoglobulin- bzw. Kalzitoninproduktion), sondern vor allem hinsichtlich ihrer Tumorbiologie, Metastasierung (dominant-lymphogen bzw. lokal-invasiv und hämatogen) und Prognose. Die Kenntnis dieser Charakteristika ist Grundlage des operativen Konzepts der ein- bzw. zweizeitigen Thyreoidektomie und deren Ausnahmen sowie des Konzepts der lokoregionären Lymphknotendissektion. Der Lymphknotenchirurgie kommt bei den dominant-lymphogen metastasierenden Schilddrüsenkarzinomen (PTC, MTC) nicht nur wegen der beträchtlichen Rezidivrate, sondern vor allem wegen der potenziell kurativen Zielsetzung im Gegensatz zu vielen anderen viszeralen Organtumoren eine eigenständige Bedeutung zu. Differenzierte Schilddrüsenkarzinome können auch bei Infiltration des zervikalen Aerodigestivtraktes noch eine gute Prognose haben, sodass Resektionen unter Beachtung der besonderen operationstechnischen Bedingungen vertretbar sind.AbstractThe 5 main types of thyroid cancer (papillary, PTC, follicular, FTC, poorly differentiated, PDTC undifferentiated, UTC, medullary, MTC) not only differ regarding morphology, pathogenesis, genetics,and pathophysiology (iodine metabolism, thyroglobulin and calcitonin production), but also concerning tumor biology, metastatic behavior (lymphogenous, locally invasive and hematogenous routes) and prognosis. Knowledge of these features is the basis of the surgical concept of one or two-stage thyroidectomy, the exceptions and the concept of locoregional lymph node dissection. Lymph node surgery plays an important role in those cancers exhibiting mainly lymph node metastases (PTC, MTC) not only due to frequent recurrences but also due to its potential curative intent. Differentiated carcinomas may have an acceptable prognosis despite local invasion of the cervical aerodigestive system, thus resections are justified when technical prerequisites are given.