[Hemithyroidectomy or total thyroidectomy for low-risk papillary thyroid cancer? : Surgical criteria for primary and secondary choice of treatment in an interdisciplinary treatment concept]. / Hemithyreoidektomie oder totale Thyreoidektomie beim papillären Niedrigrisikokarzinom der Schilddrüse? : Chirurgische Kriterien der primären und sekundären Therapiewahl im interdisziplinären Behandlungskonzept.

The increase in small intrathyroid papillary thyroid cancer (PTC) observed worldwide over the past two decades, with no increase in cancer-specific mortality, has challenged the previous concept of total thyroidectomy as a one-size-fits-all panacea. After exclusion of papillary microcarcinomas, a systematic review of 20 clinical studies published since 2002, which compared hemithyroidectomy (HT) to total thyroidectomy (TT), found comparable long-term oncological outcomes for low-risk papillary thyroid cancer (LRPTC) 1-4 cm in diameter, whereas postoperative complication rates were markedly lower for HT. To refine individual treatment plans, HT should be combined with ipsilateral central lymph node dissection and intraoperative frozen section analysis for staging. Based on recent evidence from studies and in consideration of individual risk factors, patients with LRPTC can be offered the concept of HT as an alternative to the standard TT. A prerequisite for the treatment selection and decision is a comprehensive patient clarification of the possible advantages and disadvantages of both approaches.

[Medicolegal aspects of primary and renal hyperparathyroidism]. / Medikolegale Aspekte der Chirurgie des primären und renalen Hyperparathyreoidismus.

BACKGROUND: Compared with malpractice claims in thyroid surgery, expert medico-legal reviews of surgery performed for hyperparathyroidism (HPT) that aim to prove or rebut surgical malpractice are rare. The aim of this analysis was to describe typical risk patterns for possible treatment errors and to generate recommendations for avoiding these treatment errors. MATERIAL AND METHODS: A total of 12 surgical expert medico-legal reviews, which were carried out by order of 9 arbitration boards and 3 courts between 1997 and 2020 were evaluated. RESULTS: If the indications for surgical treatment of hyperparathyroidism were present, the failure to identify a parathyroid adenoma or hyperplastic parathyroid glands was in the majority of cases not rated as a surgical treatment error, especially in atypical localizations. Unilateral recurrent laryngeal nerve palsy and postoperative bleeding cannot always be prevented, despite maximum diligence. In contrast, bilateral recurrent laryngeal nerve palsy can be prevented when intraoperative neuromonitoring is correctly applied. A lack of patient information regarding postoperatively persistent HPT, postoperative hypoparathyroidism following the removal of inconspicuous parathyroid glands and nonindicated lobectomy or total thyroidectomy, mostly performed under the assumption of an intrathyroid parathyroid adenoma, represented avoidable malpractice issues. CONCLUSION: Advanced knowledge of the pathophysiology of the disease and the anatomy of the parathyroid glands as well as the establishment of intraoperative and perioperative standards can prospectively greatly reduce avoidable errors in the surgical treatment and postoperative care of HPT.

Superiority of continuous over intermittent intraoperative nerve monitoring in preventing vocal cord palsy.

BACKGROUND: Continuous intraoperative nerve stimulation (IONM) with uninterrupted monitoring is likely better than intermittent IONM in preventing vocal cord palsy after thyroid surgery. METHODS: This was a comparative study of intermittent versus continuous IONM in patients with benign and malignant thyroid disease treated at a tertiary centre over 10 years. Early postoperative and permanent vocal cord palsy rates were estimated. Multivariable logistic regression analysis was used to quantify the contributions of clinical and histopathological variables to early postoperative and permanent vocal cord palsy. RESULTS: A total of 6029 patients were included, of whom 3139 underwent continuous and 2890 intermittent IONM. Based on nerves at risk (5208 versus 5024 nerves), continuous IONM had a 1·7-fold lower early postoperative vocal cord palsy rate than intermittent monitoring (1·5 versus 2·5 per cent). This translated into a 30-fold lower permanent vocal cord palsy rate (0·02 versus 0·6 per cent). In multivariable logistic regression analysis, continuous IONM independently reduced early postoperative vocal cord palsy 1·8-fold (odds ratio (OR) 0·56) and permanent vocal cord palsy 29·4-fold (OR 0·034) compared with intermittent IONM. One permanent vocal cord palsy per 75·0 early vocal cord palsies was observed with continuous IONM, compared with one per 4·2 after intermittent IONM. Early postoperative vocal cord palsies were 17·9-fold less likely to become permanent with continuous than intermittent IONM. CONCLUSION: Continuous IONM is superior to intermittent IONM in preventing vocal cord palsy.

Targeted use of intraoperative frozen-section analysis lowers the frequency of completion thyroidectomy.

BACKGROUND: The impact of intraoperative frozen section (iFS) analysis on the frequency of completion thyroidectomy for the management of thyroid carcinoma is controversial. Although specialized endocrine centres have published their respective results, there are insufficient data from primary and secondary healthcare levels. The aim of this study was to analyse the utility of iFS analysis. METHODS: In the Prospective Evaluation Study Thyroid Surgery (PETS) 2 study, 22 011 operations for benign and malignant thyroid disease were registered prospectively in 68 European hospitals from 1 July 2010 to 31 December 2012. Group 1 consisted of 569 patients from University Medical Centre (UMC) Mainz, and group 2 comprised 21 442 patients from other PETS 2 participating hospitals. UMC Mainz exercised targeted but liberal use of iFS analysis for suspected malignant nodules. iFS analysis was compared with standard histological examination regarding the correct distinction between benign and malignant disease. The percentage of completion thyroidectomies was assessed for the participating hospitals. RESULTS: iFS analysis was performed in 35.70 per cent of patients in group 1 versus 21.80 per cent of those in group 2 (risk ratio (RR) 1.6, 95 per cent c.i. 1.5 to 1.8; P < 0.001). Sensitivity of iFS analysis was 75.0 per cent in group 1 versus 63.50 per cent in group 2 (RR 1.2, 1.2 to 1.3; P = 0.040). Completion surgery was necessary in 8.10 per cent of patients in group 1 versus 20.8 per cent of those in group 2 (RR 0.4, 0.2 to 0.7; P = 0.001). CONCLUSION: iFS analysis is a useful tool in determining the appropriate surgical management of thyroid disease. Targeted use of iFS was associated with a significantly higher sensitivity for the detection of malignancy, and with a significantly reduced necessity for completion surgery.

Management of primary and renal hyperparathyroidism: guidelines from the German Association of Endocrine Surgeons (CAEK).

BACKGROUND AND AIMS: The purpose of this review is to provide updated recommendations for the surgical management of primary (pHPT) and renal (rHPT) hyperparathyroidism, formulating a new guideline of the German Association of Endocrine Surgeons (CAEK). METHODS: Evidence-based recommendations for the diagnosis and therapy of pHPT and rHPT were assessed by a multidisciplinary panel using PubMed for a comprehensive literature search together with a structured consensus dialogue (S2k guideline of the Association of the German Scientific Medical Societies, AWMF). RESULTS: During the last 20 years, a variety of new preoperative localization procedures, such as sestamibi-SPECT, 4D-CT, and various PET/CT procedures, were established for pHPT. High-resolution imaging, together with intraoperative parathyroid hormone (IOPTH) measurement, enabled focused or minimally invasive surgery to become the most favored surgical technique. Patients with pHPT and nonlocalizing imaging have a higher risk of multiglandular disease. Surgical therapy provides very high cure rates, with a clear relation to the surgeon's experience in parathyroid procedures. Reoperative parathyroidectomy, children with pHPT or familial forms, and parathyroid carcinoma are addressed and require special surgical expertise. A multidisciplinary team of experienced nephrologists, transplant, and endocrine surgeons should assess the diagnosis and treatment of renal HPT. CONCLUSION: Surgery is the only curative treatment for pHPT and should be considered for all patients with pHPT. For rHPT, a more selective approach is required, and parathyroidectomy is indicated only when conservative treatment options fail. In parathyroid carcinoma, the adequacy of local resection influences local disease control.

DLL3 (delta-like protein 3) expression correlates with stromal desmoplasia and lymph node metastases in medullary thyroid carcinomas.

Medullary thyroid carcinomas (MTC) are rare and aggressive neuroendocrine tumors of the thyroid. About 70% of MTC are sporadic; approximately 50% of those harbor somatic RET mutation. DLL3 is widely expressed in many neuroendocrine tumors and has been evaluated as a potential therapeutic target. Since stromal desmoplasia in sporadic MTC has been identified as a reliable predictor of aggressive behavior and development of lymph node metastases, a possible correlation of DLL3 expression with the presence of stromal desmoplasia was of particular interest. 59 paraffin-embedded samples of sporadic MTC with (44 cases) and without (15 cases) stromal desmoplasia and known lymph node status were included. DLL3 expression was determined by immunohistochemistry; no expression (0%), low expression (1-49%) and high expression (≥50%) were correlated with clinicopathological data. The proportion of DLL3 positivity was significantly correlated with both stromal desmoplasia (P < 0.0001) and lymph node metastases (P < 0.0001). MTC without stromal desmoplasia consistently lack DLL3 expression. This is the first study to focus on MTC regarding DLL3 expression and the relationship to various factors. Our results demonstrate that expression of DLL3 in MTC represents a reliable surrogate marker for stromal desmoplasia and lymph node metastases and might be an indicator for aggressive clinical behavior. DLL3 expression in ≥50% of tumor cells virtually excludes MTC without stromal desmoplasia. DLL3 was discussed as a potential therapeutic target in malignant tumors of other locations with positive immunohistochemical reaction and might therefore be a new therapeutic option in MTC, as well.

[Case volume and complications after thyroid gland surgery in Germany: an analysis of routine data from 48,387 AOK patients]. / Fallvolumen und Komplikationen nach Schilddrüsenoperationen in Deutschland: eine Routinedatenanalyse von 48.387 AOK-Patienten.

BACKGROUND: Many studies showed that hospital and surgeon volume have a significant influence on the complication rates of thyroid surgery. The present study investigates whether this relationship applies in subtotal as well as total lobe resections. Furthermore, it is still unclear which threshold for the hospital-related case volume can be determined, above which the risk of complications lies below the current national average. MATERIAL AND METHODS: The study was based on nationwide routine data for persons insured with the Local General Sickness Fund (AOK) who had undergone thyroid surgery in 2014-2016. Permanent vocal cord palsy, bleeding and wound infection needing revision were recorded using indicators. The effect of the case volume on the indicators and the case number threshold was determined using logistic regression. RESULTS: Permanent vocal cord palsy was observed in 1.3% and bleeding or wound infections needing revision in 1.6% and 0.3% of the cases. Compared to hospitals with >450 surgeries per year, the risk of permanent vocal cord palsy in hospitals with fewer than 201, 101 and 51 surgeries was significantly increased (OR [95% CI]: 1.5 [1.1-2.1]; 1.5 [1.1-2.1]; 1.8 [1.3-2.5]). The threshold needed to achieve a risk for permanent vocal cord palsy below the national average (1.3%) was 265 thyroid surgeries per year (95% CI: 110-420). For bleeding or wound infection in need of revision, no association between volume and outcome was found. CONCLUSION: The present study showed that the risk of postoperative permanent vocal cord palsy decreased with increasing case volume. The broad confidence interval of the threshold makes clear case volume recommendation difficult. In order that the risk for a postoperative permanent vocal cord palsy is not likely above the national average, the annual case volume should reach 110 thyroid interventions.

[Extent of resection in intrathyroidal medullary thyroid cancer]. / Resektionsausmaß beim intrathyreoidalen medullären Schilddrüsenkarzinom.

Improvements in preoperative diagnostic modalities in conjunction with highly sensitive calcitonin assays, ultrasound and functional imaging modalities and differentiated genetic testing for detection of hereditary forms, have enabled detection and resection of medullary thyroid carcinoma at an increasingly earlier stage. These developments open up possibilities to deescalate primary surgery adapted to these stages and avoid surgical overtreatment in locally limited tumor growth: thus, promoting a shift from routinely recommended total thyroidectomy with bilateral central lymph node dissection in favor of limited unilateral thyroid resection. Prerequisites for limited thyroid resection include clinical evidence that the tumor is sporadic, unifocal and confined to the thyroid. Corresponding calcitonin levels should also indicate that a biochemical cure will be achieved after unilateral resection. A decisive structural prerequisite for such a limited concept is the low threshold availability of intraoperative frozen section analysis that reliably detects and evaluates a medullary thyroid carcinoma and can assess a breach of the thyroid capsule and desmoplasia with certainty.

[Completion thyroidectomy after less than total resection for postoperatively diagnosed follicular thyroid cancer]. / Komplettierungsoperation nach nichttotaler Thyreoidektomie beim postoperativ diagnostizierten follikulären Schilddrüsenkarzinom.

As there are no reliable preoperative or intraoperative markers to identify follicular thyroid cancer (FTC), the postoperative histopathological diagnosis frequently raises the question of completion surgery. The oncological necessity must not be questioned by an allegedly increased morbidity. The operation is particularly indicated if there is evidence of distant or lymph node metastasis, the presence of a broadly invasive FTC, or evidence of extensive angioinvasion. Prophylactic lymphadenectomy is not indicated. There are no clear data that minimally invasive oncocytic FTC poses a special risk. Risk factors such as tumor size and age must be assessed as a biological continuum and require an individual assessment. Utilizing the technical options and thorough planning enables a completion thyroidectomy to be performed without increased risk.

Prediction of biochemical cure in patients with medullary thyroid cancer.

BACKGROUND: The impact of number of node metastases versus metastatic lymph node ratio versus AJCC node category on biochemical cure in medullary thyroid cancer (MTC) is not well defined. METHODS: Multivariable logistic regression analysis was used to determine clinical and histopathological variables that contribute to biochemical cure in node-positive MTC. RESULTS: Some 584 of 1026 patients with MTC underwent systematic lymph node dissections for node-positive disease; 27·4 per cent (54 of 197) were biochemically cured after the initial operation and 13·5 per cent (42 of 310 patients) after repeat surgery. Cured patients had significantly less extrathyroid extension (11-14 versus 33·2-55·6 per cent), fewer lymph node metastases (median 2-4 versus 12-16), a lower metastatic lymph node ratio (median 0·05-0·08 versus 0·23-0·28), and were less likely to have AJCC pN1b disease (56-76 versus 89·9-91·6 per cent) and distant metastases (0 versus 28·4-37·1 per cent) than patients who were not cured. Biochemical cure curves advanced steadily up to 7-12 node metastases and a metastatic lymph node ratio of 0·33, eventually levelling off after 16-17 node metastases and metastatic lymph node ratios of 0·45-0·65. In logistic regression analysis, number of lymph node metastases (odds ratio (OR) 17·24 for more than 20 metastases, OR 5·28 for 11-20 metastases, OR 2·22 for 6-10 metastases), preoperative basal serum calcitonin (OR 6·24 for over 1000 pg/ml), reoperation (OR 5·34) and extrathyroid extension (OR 2·42) independently predicted failure to reach biochemical cure. CONCLUSION: Number of lymph node metastases, unlike metastatic lymph node ratio or AJCC node category, determines likelihood of biochemical cure after initial and repeat surgery for node-positive MTC.

ANTECEDENTES: El impacto del número de metástasis ganglionares versus la relación de ganglios linfáticos metastásicos (metastatic lymph node ratio, MLNR) versus el estadio ganglionar según el American Joint Committee on Cancer (AJCC) sobre la curación bioquímica en el cáncer medular de tiroides (medullary thyroid cancer, MTC) no está bien definido. MÉTODOS: Se utilizaron análisis de regresión logística multivariable y análisis estratificados de Kaplan-Meier para determinar las variables clínicas e histopatológicas que contribuyen a la curación bioquímica en el MTC con ganglios positivos. RESULTADOS: En total, 584 de 1.026 pacientes con MTC se sometieron a disecciones sistemáticas de los ganglios linfáticos en caso de enfermedad con ganglios positivos, el 27,4% (54 de 197 pacientes) de los cuales se curaron bioquímicamente después de la cirugía inicial y el 13,5% (42 de 310 pacientes) después de la reintervención quirúrgica. Los pacientes curados tuvieron una extensión extratiroidea significativamente menor (11,1-14% versus 33,2-55,6%), menos metástasis en los ganglios linfáticos (2-4 versus 12-16 metástasis), una MLNR más baja (0,05-0,08 versus 0,23-0,28), una menor frecuencia de estadio ganglionar AJCC pN1b (55,6-76 versus 89,9-91,6%) y no tenían metástasis a distancia (0% versus 28,4-37,1%), Las curvas de tiempo hasta la curación bioquímica avanzaron de manera constante hasta las metástasis de 7 a 12 ganglios y una MLNR de 0,33, y finalmente se nivelaron después de las metástasis de 16 a 17 ganglios y una MLNR de 0,45 a 0,65. En la regresión logística, el número de metástasis en los ganglios linfáticos (razón de oportunidades, odds ratio, OR 17,2 para > 20 metástasis, OR 5,3 para 11-20 metástasis y OR 2,2 para 6-10 metástasis), la calcitonina sérica basal preoperatoria (OR 6,2 para> 1000 pg/mL), la reoperación (OR 5,4) y la extensión extratiroidea (OR 2,4) predijeron de forma independiente el fracaso para alcanzar la curación bioquímica, CONCLUSIÓN: El número de metástasis en los ganglios linfáticos, a diferencia de la MLNR y del estadio ganglionar AJCC, determina la probabilidad de curación bioquímica después de la cirugía inicial y la reintervención para el MTC con ganglios positivos.

[Pheochromocytomatosis after adrenalectomy: metastasis or cell seeding?] / Phäochromozytomatose nach Adrenalektomie: Metastasierung oder Zellverschleppung?

Pheochromocytomatosis is defined as a multifocal cell dissemination limited to the operatively opened space with no signs of distant metastasis. After primary adrenalectomy due to a pheochromocytoma this is a rare and underrecognized manifestation of a tumor recurrence. Between 2010 and 2019 a total of 5 patients with the presentation of pheochromocytomatosis were treated in this center. Clinical and survival data were compared to 12 patients with a metastasized pheochromocytoma. Patients presenting with pheochromocytomatosis showed a better but not significant overall survival (136.8 vs. 107 months). Furthermore, patients with pheochromocytomatosis presented more often with a noradrenaline secretion type. Tumor recurrence in the pheochromocytomatosis group occurred on average 69.2 months after the initial diagnosis and was therefore much later than in patients with distant metastases from a pheochromocytoma (39 months, p = 0.13). This article outlines this special manifestation of recurrence of a pheochromocytoma based on this patient collective. Besides technical operative aspects there appears to be evidence for tumor-specific factors that promote the development of pheochromocytomatosis. Importantly, it seems that all patients with a pheochromocytoma should receive lifelong aftercare and that patients should be closely monitored during the first 5 years after surgery.

[Morphologic diagnostic criteria of noninvasive follicular neoplasia with papillary-like nuclear features (NIFTP) : A diagnostic challenge for the patient's benefit]. / Morphologische Diagnosekriterien der nichtinvasiven follikulären Neoplasie mit PTC-äquivalenten Kernmerkmalen (NIFTP) : Eine diagnostische Herausforderung zum Nutzen des Patienten.

The major goals of the introduction of the noninvasive follicular neoplasia with papillary-like nuclear features (NIFTP) are to spare patients with a biologically indolent subgroup of the follicular variant of papillary carcinoma (FV-PTC) both overtreatment and the psychologically burden of a cancer/carcinoma diagnosis. However, strict histological and molecular pathological criteria have been introduced for the diagnosis of NIFTP. NIFTP tumors may be a few millimeters in diameter, but may also measure more than 4 cm. Histologically, an encapsulated/clearly demarcated lesion with (>70%) follicular structure and the nuclear characteristics of PTC must be present as a prerequisite; invasion of capsule/vessels must be excluded as well as significant proportions (>30%) showing a solid/trabecular/insular growth pattern, psammoma bodies, tumor necrosis, an increased mitotic rate (>3/10 HPF), and/or a BRAF V600E mutation. The establishment of the NIFTP necessitated a redefinition of the diagnostic criteria of PTC and has implications on the evaluation of fine needle biopsy (FNB) of the thyroid gland. Although a prediction is difficult, the correct diagnosis of NIFTP could lead to a 10-20% reduction in thyroid carcinoma incidence.