Katrin Brauckhoff

Multiple endocrine neoplasia 2B syndrome due to codon 918 mutation: Clinical manifestation and course in early and late onset disease

More than 50% of patients with typical MEN-2B have a de novo M918T germline mutation of the RET protooncogene. However, even in typical MEN-2B, extrathyroidal manifestations of MEN-2B can be found to be differently expressed. We analyzed the clinical manifestation and course in 21 patients harboring a de novo RET M918T mutation. Mean age at MEN-2B diagnosis was 14.2 years (range: 1–31 years). All patients had medullary thyroid carcinoma (MTC). At the time of syndrome diagnosis, oral manifestations (bumpy lips, ganglioneuroma), ocular manifestations (corneal fibers, conjunctivitis sicca), intestinal dysfunctions, musculoskeletal manifestations, and pheochromocytoma were found in 86%, 90%, 74%, 79%, and 19% of the patients, respectively. At the time of follow-up examination, the symptoms were found at higher frequency. Severe intestinal manifestation was predominantly found in patients with prepubertal onset (≤ 12 years) of MTC (n = 4/10) compared with patients with late onset (> 12 years) of MTC (n = 0/11) (40% versus 0%; p = 0.019). Although biochemical cure was found only in four patients with early onset of MTC, the long-term prognosis for patients with early onset of MTC was poorer than for patients presenting with late onset of MTC (p = 0.005). During mean follow-up of 55.8 months (range: 3–161 months), seven patients (33%) died from MTC. In conclusion, whereas most typical MEN-2B symptoms were found to be age-related, severe intestinal manifestation was found to be predominantly expressed in patients with early onset of MTC. Furthermore, in patients with early onset of MTC who could not be biochemically cured, the long-term prognosis was found to be worse than that of non-cured patients with late onset of MTC, suggesting an additional pathological process in the younger subgroup reinforcing the very high transforming in vitro activity of the M918T RET mutation.

Identification of the non-recurrent inferior laryngeal nerve using intraoperative neurostimulation

Introduction: The non-recurrent inferior laryngeal nerve occurs at a frequency of about 0.5% and usually on the right side. The identification of a non-recurrent laryngeal nerve may be difficult. We describe a new method for its identification using intraoperative neurostimulation. Methods: We examined nine patients with a non-recurrent inferior laryngeal nerve and five patients with a normal inferior laryngeal nerve anatomy who were operated on trans-sternally. Neurostimulation of the vagal nerve producing electromyographic signal in the intrinsic laryngeal musculature was performed at different points proximally and distally. Results: Electromyographic signals were found proximally but not distally of the separation of the inferior laryngeal nerve from the vagus in 14 patients. In nine patients with a non-recurrent inferior laryngeal nerve, we performed neurostimulation of the vagus opposite the lower and the upper thyroid poles. In all patients we found no electromyographic signals at the distal stimulation point. In contrast, proximal neurostimulation of the vagus opposite the upper thyroid pole produced positive electromyographic signals. Conclusion: Neurostimulation of the vagal nerve distally of the separation of the inferior laryngeal nerve did not produce electromyographic signals in the intrinsic laryngeal musculature, perhaps due to the different modalities in the vagal fascicles. Negative electromyographic signals following neurostimulation of the distal vagal nerve opposite the lower thyroid pole should lead to proximal neurostimulation of the vagus opposite the upper thyroid pole. Positive electromyographic signals proximally and negative electromyographic signals distally predict the occurrence of a non-recurrent inferior laryngeal nerve which allows its diagnosis before surgical dissection of the thyroid gland and may prevent nerve palsy.

Papillary Thyroid Carcinoma in Patients with RET Proto-Oncogene Germline Mutation

The occurrence of papillary thyroid carcinoma in patients with RET germline mutations has been described in only eight cases since 1993. We report three women with a RET germline mutation in exon 13 and 14, affecting codon 790, 791, and 804, respectively, who underwent prophylactic thyroidectomy at the age of 29, 39, and 24 years, respectively. Histologic examination revealed C-cell hyperplasia and a small medullary thyroid carcinoma in the first patient and no pathologic changes of the C-cells in either of the other patients. However, all patients had papillary thyroid carcinoma (PTC). Concerning the frequency of PTC in patients with RET germline mutations who underwent surgery at our center (n = 104), it was found in 9.1% of all patients with RET mutation in codon 790, 791, and 804 (n = 33) but in none of the 104 patients with RET germline mutations not affecting codon 790, 791, or 804 (p = 0.0015). Our data and the data from the literature suggest a possible pathogenesis of PTC caused by exon 13 and 14 RET mutations that affect the intracellular domain of the encoded protein. Further investigation is necessary to confirm a potential pathogenetic role of exon 13 and 14 RET mutations with regard to the development of PTC.

Repeat Adrenocortical-Sparing Adrenalectomy for Recurrent Hereditary Pheochromocytoma

PurposeMany endocrine surgeons advocate subtotal adrenalectomy for patients with bilateral hereditary pheochromocytoma despite the risk of recurrence. However, as the effectiveness of this procedure for locally recurrent pheochromocytoma is not well known, we investigated two patients who underwent this operation.MethodsWe performed repeat subtotal adrenalec-tomy for recurrent hereditary pheochromocytoma in two patients who had undergone primary subtotal adrenalectomy.ResultsPatient 1 was a 23-year-old woman with multiple endocrine neoplasia type 2A, in whom about 25% of the right adrenal gland was left in situ. Patient 2 was a 22-year-old man with von-Hippel-Lindau syndrome, in whom about 25% of both normal adrenal glands was left in situ. No steroid replacement was required postoperatively, and adrenocorticotropic hormone stimulation revealed sufficient adrenocortical function in both patients. No sign of recurrent pheochromocytoma has been found in 96 months and 11 months of follow-up, respectively.ConclusionRecurrent hereditary benign pheochromocytoma after subtotal adrenalectomy may be treated successfully by repeated subtotal adrenalectomy. However, the risk of recurrence and malignancy must be weighed carefully against the risk of lifelong steroid replacement and potential Addisonian crisis. Thus, repeated subtotal adrenalectomy should be considered for selective patients who want to avoid steroid replacement.

Functional Results After Endoscopic Subtotal Cortical-Sparing Adrenalectomy

Abstract.Purpose: We examined the required amount of residual adrenal tissue and whether an intact adrenal vein are necessary to achieve sufficient function after endoscopic subtotal adrenalectomy. Method: Endoscopic subtotal adrenalectomy was performed in 14 patients. Two patients underwent unilateral subtotal and contralateral total adrenalectomy and another two patients underwent unilateral subtotal adrenalectomy after contralateral total adrenalectomy several years earlier. We analyzed the postoperative serum levels of cortisol and adrenocorticotropic hormone (ACTH). Patients with bilateral tumors underwent an ACTH test. Results: We had to cut the main adrenal vein in ten patients, and less than one third of the adrenal gland was left in situ in four patients. Subtotal adrenalectomy was performed unilaterally in two patients with bilateral tumors. One third of the adrenal gland was preserved in these patients, and also in the two patients with unilateral subtotal adrenalectomy after previous contralateral total adrenalectomy. The postoperative ACTH test confirmed satisfactory adrenocortical function. During the follow-up period of about 24 months no recurrent tumors have been found. Conclusion: Subtotal cortical-sparing adrenalectomy can be successfully performed laparoscopically. The venous drainage of the main adrenal vein does not seem to be crucial for sufficient adrenocortical function. We estimate that leaving about one third of the entire adrenal gland as remnant adrenal tissue will result in sufficient function.

MEDULLARY THYROID CARCINOMA

Medullary thyroid carcinoma (MTC) is subdivided into sporadic (75%) and hereditary (25%) forms. Several germline mutations in the RET proto-oncogene are the source of distinct clinical phenotypes in hereditary MTC including familial MTC (FMTC) and multiple endocrine neoplasia 2A (MEN 2A) and 2B (MEN 2B). The higher the penetrance of the MEN 2 phenotype the earlier the progression of MTC which forms the basis for the currently recommended codon-related concept of prophylactic thyroidectomy. In patients with sporadic MTC, routine calcitonin (CT) measurement in nodular goiter patients has been shown to reduce the frequency of advanced tumor stages. Patients with CT levels over 100 pg/ml after pentagastrin stimulation are recommended for total thyroidectomy. In patients with unexpected sporadic MTC after histological examination, completion thyroidectomy is currently only recommended when CT levels remain elevated. The extent of lymph node dissection in patients with MTC is controversial. However, with respect to lymphonodal micrometastases, systematic compartment-oriented microdissection has been shown to reduce the frequency of lymphonodal recurrence. On the other hand, to avoid unnecessary lymph node dissection, a more individualized concept is required in the future. New chemotherapeutic agents (tyrosine kinase inhibitors), therapeutic nuclids (90Yttrium-labeled octreotide), and chemoembolization of liver metastases are currently the most promising therapeutical concepts in patients with distant metastases.

Technical aspects of subtotal endoscopic adrenalectomy

SummaryBackground: The frequency of subtotal adrenalectomy has increased since the introduction of endoscopic approaches. In this study, we examined technical aspects of endoscopic subtotal adrenalectomy with respect to postoperative adrenocortical function.Methods: Sixteen patients with endoscopic subtotal adrenalectomy were included in this study (10 inherited phaeochromocytomas, five adrenocortical tumours, and one bilateral adrenocortical hyperplasia). Unilateral tumours were found in 10 patients, and bilateral tumours were found in five patients. The five patients with bilateral tumours underwent unilateral subtotal adrenalectomy following contralateral total adrenalectomy. In these patients, the main adrenal vein was divided. Fifteen operations were performed laparoscopically. In one patient, the retroperitoneoscopic approach was used. In patients with bilateral operations, an ACTH test was performed postoperatively.Results: More than one-third of one adrenal gland was left in situ in four patients. In eight patients, an adrenal remnant of about one-third of an adrenal gland was preserved. In the remaining four patients, the adrenal remnant was smaller than one-third. There were no complications. During a mean follow-up of 27 months, no recurrence was observed. Four of the five patients with bilateral tumours had an intact ACTH test. Neither patient with bilateral operations required steroids. In all five patients, the adrenal remnant was about one-third of an adrenal gland.Conclusions: Endoscopic subtotal adrenalectomy has a similar success rate to the open approach. As regards recurrent adrenal tumours and influencing factors, no conclusions can be drawn due to the short follow-up. One-third of an adrenal gland on one side is enough for sufficient adrenocortical function even after division of the main vein. The impact of subtotal adrenalectomy in patients with unilateral tumours has to be exmained in future studies.ZusammenfassungGrundlagen: Nach Einführung des endoskopischen Zugangs zu den Nebennieren ist eine deutliche Zunahme subtotaler Nebennierenresektionen zu beobachten. In der vorliegenden Arbeit sollen technische Aspekte der subtotalen Adrenalektomie im Hinblick auf die postoperative adrenokortikale Funktion untersucht werden.Methodik: In die Untersuchung wurden 16 Patienten mit subtotaler Adrenalektomie eingeschossen (10 Patienten mit familiären Phäochromozytomen, fünf Patienten mit adrenokortikalen Tumoren, ein Patient mit bilateraler nodulärer Nebennierenrindhyperplasie). Bei zehn Patienten lagen unilaterale, bei fünf Patienten bilaterale Tumoren vor. Die Patienten mit bilateralen Tumoren wurden nach totaler Nebennierenentfernung kontralateral subtotal adrenalektomiert. Die Nebennierenvene wurde bei allen Patienten mit bilateralen Operationen durchtrennt. Fünfzehn Operation erfolgten laparoskopisch, eine Operation retroperitoneoskopisch. Patienten mit bilateralen Operationen wurden postoperativ einem ACTH-Test unterzogen.Ergebnisse: Bei vier Patienten verblieben mehr als ein Drittel, bei acht Patienten ein Drittel und bei vier Patienten weniger als ein Drittel einer normalen Nebenniere. In keinem Fall traten perioperativ Komplikationen auf. In einem mittleren Follow-up von 27 Monaten wurde kein Rezidiv beobachtet. Vier der fünf Patienten mit bilateralen Tumoren wiesen einen normalen ACTH-Test auf. Keiner dieser Patienten benötigte Glukokortikoide. Bei allen fünf Patienten verblieb unilateral ein Drittel einer normalen Nebenniere.Schlußfolgerungen: Die endoskopische subtotale Adrenalektomie weist eine ähnliche Erfolgsquote wie beim konventionell offenen Zugang auf. Hinsichtlich der Rezidivrate kann aufgrund des kurzen Follow-up keine Aussage zu Rezidivhäufigkeit und diese beeinflussende Faktoren getroffen werden. Auch bei Durchtrennung der Hauptvene ist ein unilateraler adrenaler Geweberest von einem Drittel einer normalen Nebenniere für eine suffiziente adrenokortikale Funktion ausreichend. Weitere Untersuchungen mit längerem Follow-up sind erforderlich.

International neural monitoring study group guideline 2018 part I: Staging bilateral thyroid surgery with monitoring loss of signal: INMSG LOS Part 1

This publication offers modern, state‐of‐the‐art International Neural Monitoring Study Group (INMSG) guidelines based on a detailed review of the recent monitoring literature. The guidelines outline evidence‐based definitions of adverse electrophysiologic events, especially loss of signal, and their incorporation in surgical strategy. These recommendations are designed to reduce technique variations, enhance the quality of neural monitoring, and assist surgeons in the clinical decision‐making process involved in surgical management of recurrent laryngeal nerve. The guidelines are published in conjunction with the INMSG Guidelines Part II, Optimal Recurrent Laryngeal Nerve Management for Invasive Thyroid Cancer–Incorporation of Surgical, Laryngeal, and Neural Electrophysiologic Data.