Clinical Presentation, Treatment, and Outcome of Parathyroid Carcinoma: Results of the NEKAR Retrospective International Multicenter Study.

OBJECTIVE: In this retrospective cohort study, we describe the clinical presentation and workup of parathyroid carcinoma (PC) and determine its clinical prognostic parameters. Primary outcome was recurrence free survival. SUMMARY BACKGROUND DATA: PC is an orphan malignancy for which diagnostic workup and treatment is not established. METHODS: Eighty-three patients were diagnosed with PC between 1986 and 2018. Disease-specific and recurrence-free survivals were estimated with the Kaplan-Meier method. Risk factors for recurrence were identified by binary logistic regression with adjustment for age and sex. Thirty-nine tumors underwent central histopathological review. RESULTS: Renal (39.8%), gastrointestinal (24.1%), bone (22.9%), and psychiatric (19.3%) symptoms were the most common symptoms. Surgical treatment was heterogeneous [parathyroidectomy [PTx)] alone: 22.9%; PTx and hemithyroidectomy: 24.1%; en bloc resection 15.7%; others 37.3%] and complications of surgery were frequent (recurrent laryngeal nerve palsy 25.3%; hypoparathyroidism 6%). Recurrence of PC was observed in 32 of 83 cases. In univariate analysis, rate of recurrence was reduced when extended initial surgery had been performed (P = 0.04). In multivariate analysis low T status [odds ratio (OR) = 2.65, 95% confidence interval (CI) 1.02-6.88, P = 0.045], N0 stage at initial diagnosis (OR = 6.32, 95% CI 1.33-30.01, P = 0.02), Ki-67 <10% (OR = 14.07, 95% CI 2.09-94.9, P = 0.007), and postoperative biochemical remission (OR = 0.023, 95% CI 0.001-0.52, P = 0.018) were beneficial prognostic parameters for recurrence-free survival. CONCLUSION: Despite a favorable overall prognosis, PC shows high rates of recurrence leading to repeated surgery and postoperative recurrent laryngeal nerve palsy and hypoparathyroidism. In view of the reduced recurrence rate in cases of extended surgery, ipsilateral completion surgery may be considered when PC is confirmed.

Questionable value of [99mTc]-sestamibi scintigraphy in patients with pHPT and negative ultrasound.

PURPOSE: A successful focused surgical approach in primary hyperparathyroidism (pHPT) relies on accurate preoperative localization of the parathyroid adenoma (PA). Most often, ultrasound is followed by [99mTc]-sestamibi scintigraphy, but the value of this approach is disputed. Here, we evaluated the diagnostic approach in patients with surgically treated pHPT in our center with the aim to further refine preoperative diagnostic procedures. METHODS: A single-center retrospective analysis of patients with pHPT from 01/2005 to 08/2021 was carried out followed by evaluation of the preoperative imaging modalities to localize PA. The localization of the PA had to be confirmed intraoperatively by the fresh frozen section and significant dropping of the intraoperative parathyroid hormone (PTH) levels. RESULTS: From 658 patients diagnosed with pHPT, 30 patients were excluded from the analysis because of surgery for recurrent or persistent disease. Median age of patients was 58.0 (13-93) years and 71% were female. Neck ultrasound was carried out in 91.7% and localized a PA in 76.6%. In 23.4% (135/576) of the patients, preoperative neck ultrasound did not detect a PA. In this group, [99mTc]-sestamibi correctly identified PA in only 25.4% of patients. In contrast, in the same cohort, the use of [11C]-methionine or [11C]-choline PET resulted in the correct identification of PA in 79.4% of patients (OR 13.23; 95% CI 5.24-33.56). CONCLUSION: [11C]-Methionine or [11C]-choline PET/CT are superior second-line imaging methods to select patients for a focused surgical approach when previous ultrasound failed to identify PA.

Suppurative thyroiditis caused by ingested fish bone in the thyroid gland: a case report on its diagnostics and surgical therapy.

BACKGROUND: Accidental ingestion of fish bone is a common cause of otolaryngological emergency. Migration of the ingested bone into the thyroid gland, however, occurs very rarely. The associated clinical presentation, symptoms and duration of discomfort are also highly variable between patients and can be diagnostically challenging. CASE PRESENTATION: Here, we report the case of a 71-year-old female patient presenting with an ingested fish bone that migrated into the right thyroid lobe as a rare cause of suppurative thyroiditis with the clinical features of sepsis. We outline the diagnostic approach, peri- and intraoperative management as well as complications. It is proposed that besides endoscopy, imaging methods such as ultrasound or computed tomography may be necessary to verify the diagnosis and location of an ingested fish bone. Prompt surgical removal of the foreign body and resection of the infectious focus is recommended to minimize the risk of local inflammation, recurrent nerve lesions and septic complications arising from the spread of infection. CONCLUSION: Fish bone migration into the thyroid gland is an extremely rare event, the successful detection and surgical management of which can be achieved through a careful interdisciplinary approach.

Evaluation of diagnostic efficacy for localization of parathyroid adenoma in patients with primary hyperparathyroidism undergoing repeat surgery.

PURPOSE: Repeat surgery in patients with primary hyperparathyroidism (pHPT) is associated with an increased risk of complications and failure. This stresses the need for optimized strategies to accurately localize a parathyroid adenoma before repeat surgery is performed. However, evidence on the extent of required diagnostics for a structured approach is sparse. METHODS: A retrospective single-center evaluation of 28 patients with an indication for surgery due to pHPT and previous thyroid or parathyroid surgery was performed. Diagnostic workup, surgical approach, and outcome in terms of complications and successful removement of parathyroid adenoma with biochemical cure were evaluated. RESULTS: Neck ultrasound, sestamibi scintigraphy, C11-methionine PET-CT, and selective parathyroid hormone venous sampling, but not MRI imaging, effectively detected the presence of a parathyroid adenoma with high positive predictive values. Biochemical cure was revealed by normalization of calcium and parathormone levels 24-48h after surgery and was achieved in 26/28 patients (92.9%) with an overall low rate of complications. Concordant localization by at least two diagnostic modalities enabled focused surgery with success rates of 100%, whereas inconclusive localization significantly increased the rate of bilateral explorations and significantly reduced the rate of biochemical cure to 80%. CONCLUSION: These findings suggest that two concordant diagnostic modalities are sufficient to accurately localize parathyroid adenoma before repeat surgery for pHPT. In cases of poor localization, extended diagnostic procedures are warranted to enhance surgical success rates. We suggest an algorithm for better orientation when repeat surgery is intended in patients with pHPT.

Impact of preoperative risk factors on outcome after gastrectomy.

BACKGROUND: Gastrectomy is associated with relevant postoperative morbidity. However, outcome of surgery can be improved by careful selection of patients. The objective of the current study was therefore to identify preoperative risk factors that might impact on patients' further outcome after surgical resection. METHODS: Preoperative risk factors having respectively different surgical risk scores for major complex surgery (including Cologne Risk Score, p-/o-POSSUM, and NSQIP risk score) of patients that underwent gastrectomy for AEG II/III tumors and gastric cancer were correlated with complications according to Clavien-Dindo and outcome. Patients who underwent surgery in palliative intention were excluded from further analysis. RESULTS: Subtotal gastrectomy was performed in 23%, gastrectomy in 59%, and extended gastrectomy in 18% in a total of 139 patients (mean age: 64 years old). Thirty six percent experienced a minor complication (Dindo I-II) and 24% a major complication (Dindo III-V), which resulted in a prolonged hospital stay (p < 0.001). In-hospital mortality (=Dindo V) was 2.5%. Besides age, type of surgical procedure impacted on complications with extended gastrectomy showing the highest risk (p = 0.005). The o-POSSUM score failed to predict mortality accurately. We observed a highly positive correlation between predicted morbidity respectively mortality and occurrence of complications estimated by p-POSSUM (p = 0.005), Cologne Risk (p = 0.007), and NSQIP scores (p < 0.001). CONCLUSION: The results demonstrate a significant association between different risk scores and occurrence of complications following gastrectomy. The p-POSSUM, Cologne Risk, and NSQIP score exhibited superior performance than the o-POSSUM score. Therefore, these scores might allow identification and selection of high-risk patients and thus might be highly useful for clinical decision making.

The time point of completion thyroidectomy has no prognostic impact in patients with differentiated thyroid cancer.

BACKGROUND: After partial resection of the thyroid gland, a second operation referred to as "completion thyroidectomy" may be required if histopathological analysis indicates the presence of differentiated thyroid cancer (DTC). Although there is little evidence, it is assumed that the time point of completion thyroidectomy is not critical for oncological prognosis of patients with DTC. We assessed whether patients with total thyroidectomy (TTx) in a two-step procedure have an equal long-term prognosis with regard to disease-specific survival (DSS) compared to patients immediately undergoing total thyroidectomy in a one-step procedure. METHODS: A database study using the Würzburg thyroid cancer database with 2258 patients with pT1a-pT4b tumours DTC who were operated between 1980 and 2016 was carried out. RESULTS: A total of 277 patients with papillary microcarcinoma pT1aN0M0 were treated by hemithyroidectomy. TTx as one-step procedure was performed in 1114 patients compared to 867 with TTx as a two-step procedure. Patients with papillary thyroid cancer more frequently had a TTx as one-step procedure than follicular thyroid cancer patients (59.4% vs 47%; P < 0.001). Compared to a one-step thyroidectomy, overall complication rate was not different compared to patients undergoing a single operation. Multivariate analysis showed that the presence of distant metastases, T-stage and age at diagnosis were the only independent determinants for DTC-specific survival, regardless of a one- or two-time thyroidectomy. CONCLUSION: The present study on the largest of such patient collectives provides evidence that a delayed completion operation does not affect DSS in DTC, nor does it lead to a significant increase in complication rates.

Procalcitonin--a Marker for Anastomotic Insufficiency after Pancreatoduodenectomy?

BACKGROUND: Anastomotic insufficiency after pancreatoduodenectomy (PD) represents a major complication in pancreatic surgery. Early detection and treatment of pancreatic fistulas (PF) are essential for the outcome of affected patients. Procalcitonin (PCT) is a biochemical marker which allows detection of bacterial infections. The aim of this study was to evaluate if PCT is suitable for early detection of PF after PD. METHODS: In this prospective study patients undergoing PD from 08/2010 to 09/2012 were included into three groups: (1) patients without complications (n = 19), (2) patients with postoperative infections (n = 14) and (3) PF (n = 7). Using a defined study protocol, clinical (e.g., vital signs, drain fluid, etc.) and laboratory parameters (full blood count, inflammatory markers) were assessed daily for the first ten postoperative days. RESULTS: 76 patients were assessed. 40 (52.6%) patients underwent PD and were included. CRP and PCT demonstrated an initial peak at the 1st to 3rd postoperative day with subsequent normalization. Patients with postoperative infections and PF showed a significant increase of PCT and CRP (p < 0.05) compared to patients without complications. Leucocyte counts demonstrated a variance in all three groups and clinical use for detection of complications was not evident. CONCLUSIONS: Patients with a postoperative complication revealed significantly increased levels of PCT and CRP without the expected normalization. PCT and/or CRP did not enable a distinction between patients with PF or postoperative infections. Thus, PCT does not seem to be suitable for detecting PF after PD and its use in the postoperative course after PD cannot be recommended.

Preoperative ¹¹C-methionine PET/CT enables focused parathyroidectomy in MIBI-SPECT negative parathyroid adenoma.

BACKGROUND: Precise preoperative localization is essential for focussed parathyroidectomy. The imaging standard consists of cervical ultrasonography (cUS) and (99m)Tc-MIBI-SPECT (MIBI-SPECT). (11)C-methionine positron emission tomography/computed tomography (Met-PET/CT) is a promising method for localizing parathyroid adenomas. The objective of our study was to elucidate whether additional Met-PET/CT increases the rate of focussed parathyroidectomy. METHODS: Fourteen patients with primary hyperparathyroidism (HPT) and three patients with tertiary HPT underwent cUS and MIBI-SPECT. Met-PET/CT was carried out in patients with negative MIBI results. Subsequent surgical strategy was adapted according to imaging results. RESULTS: cUS localized a single parathyroid adenoma in 10/17 patients (59 %), while MIBI-SPECT/CT identified 11/17 single adenomas (65 %). In the remaining six patients, Met-PET/CT identified five single adenomas. This step-up approach correctly identified single adenomas in 16/17 patients (94 %). CONCLUSION: Met-PET/CT raises the rate of correctly localized single parathyroid adenomas in patients with negative cUS and MIBI-SPECT/CT and increases the number of focussed surgical approaches.

Targeted therapy of advanced parathyroid carcinoma guided by genomic and transcriptomic profiling.

Parathyroid carcinoma (PC) is an ultra-rare malignancy with a high risk of recurrence after surgery. Tumour-directed systemic treatments for PC are not established. We used whole-genome and RNA sequencing in four patients with advanced PC to identify molecular alterations that could guide clinical management. In two cases, the genomic and transcriptomic profiles provided targets for experimental therapies that resulted in biochemical response and prolonged disease stabilization: (a) immune checkpoint inhibition with pembrolizumab based on high tumour mutational burden and a single-base substitution signature associated with APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) overactivation; (b) multi-receptor tyrosine kinase inhibition with lenvatinib due to overexpression of FGFR1 (Fibroblast Growth Factor Receptor 1) and RET (Ret Proto-Oncogene) and, (c) later in the course of the disease, PARP (Poly(ADP-Ribose) Polymerase) inhibition with olaparib prompted by signs of defective homologous recombination DNA repair. In addition, our data provided new insights into the molecular landscape of PC with respect to the genome-wide footprints of specific mutational processes and pathogenic germline alterations. These data underscore the potential of comprehensive molecular analyses to improve care for patients with ultra-rare cancers based on insight into disease biology.

Current practice of thyroid surgery in Germany: a nationwide survey.

BACKGROUND: Due to the lack of perioperative standards in thyroid surgery, this study aimed to evaluate the perioperative management and wound closure techniques used in a nationwide survey. METHODS: A questionnaire evaluating preferred technique in thyroid resection, postoperative management, and the occurrence of complications was sent to all hospitals in Germany performing more than 50 thyroid operations p.a. (N.=362, response rate 78% [N.=283]). Subsequently, hospitals were subdivided into university and maximum care hospitals (Category A, N.=54) and tertiary hospitals and basic care hospitals (Category B, N.=229). RESULTS: According to our results, 10.6% of the hospitals were certified as a center for thyroid surgery, with a significantly higher percentage in Category A (20.4% vs. 8.3%; P<0.01). Concerning the surgical techniques, Kocher's incision was the favored cervical approach in 96% of the hospitals. A minimally invasive approach was performed in 30.1%, with a significantly more common description in Category A; 97.8% of all clinics stated that they perform a platysma muscle suture, primarily as a single stitch interrupted. Skin closure was predominantly performed via intracutaneous suture in 84.5% using absorbable suture material in 63.1%. There was no difference in the technology used in terms of hospital size. The mean in-hospital stay was significantly shorter in Category A hospitals (P=0.035). CONCLUSIONS: The suture technique used in thyroid surgery in Germany is a simple interrupted suture technique for platysma and a continuous suture with absorbable skin closure material. Maximum care hospitals are characterized by shorter in-hospital stays and improved quality assurance.

Definition and diagnosis of postsurgical hypoparathyroidism after thyroid surgery: meta-analysis.

BACKGROUND: Postsurgical hypoparathyroidism (PH) is the most frequent complication after thyroid surgery. The aim of this systematic review and meta-analysis is to summarize a unifying definition of PH and to elucidate the best possible approach for early detection of PH. METHODS: A systematic review of the literature according to the PICO framework using Embase, PUBMED and the Cochrane library was carried out on 1 December 2021 followed by analysis for risk of bias, data extraction and meta-analysis. All studies addressing the definition of postoperative hypoparathyroidism and/or diagnostic approaches for early detection and diagnosis were included. Case reports, commentaries, non-English articles, book chapters and pilot studies and reviews were excluded. RESULTS: From 13 704 articles, 188 articles were eligible for inclusion and further analysis. These articles provided heterogeneous definitions of PH. Meta-analysis revealed that postoperative measurements of parathormone (PTH) levels have a higher sensitivity and specificity than intraoperative PTH measurements to predict PH after thyroid surgery. None of the timeframes analysed after surgery within the first postoperative day (POD1) was superior to predict the onset of PH. PTH levels of less than 15 pg/ml and less than 10 pg/ml are both reliable threshold levels to predict the postoperative onset of PH. A relative reduction of mean(s.d.) PTH levels from pre- to postoperative values of 73 (standard deviation 11) per cent may also be predictive for the development of PH. The estimation of calcium levels on POD1 are recommended. CONCLUSION: PH is best defined as an undetectable or inappropriately low postoperative PTH level in the context of hypocalcaemia with or without hypocalcaemic symptoms. PTH levels should be measured after surgery within 24 h. Both threshold levels below 10 and 15 pg/ml or relative loss of PTH before/after thyroid surgery are reliable to predict the onset of PH.

Case Report: Abdominal Lymph Node Metastases of Parathyroid Carcinoma: Diagnostic Workup, Molecular Diagnosis, and Clinical Management.

Parathyroid carcinoma (PC) is an orphan malignancy accounting for only ~1% of all cases with primary hyperparathyroidism. The localization of recurrent PC is of critical importance and can be exceedingly difficult to diagnose and sometimes futile when common sites of recurrence in the neck and chest cannot be confirmed. Here, we present the diagnostic workup, molecular analysis and multimodal therapy of a 46-year old woman with the extraordinary manifestation of abdominal lymph node metastases 12 years after primary diagnosis of PC. The patient was referred to our endocrine tumor center in 2016 with the aim to localize the tumor causative of symptomatic biochemical recurrence. In view of the extensive previous workup we decided to perform [18F]FDG-PET-CT. A pathological lymph node in the liver hilus showed slightly increased FDG-uptake and hence was suspected as site of recurrence. Selective venous sampling confirmed increased parathyroid hormone concentration in liver veins. Abdominal lymph node metastasis was resected and histopathological examination confirmed PC. Within four months, the patient experienced biochemical recurrence and based on high tumor mutational burden detected in the surgical specimen by whole exome sequencing the patient received immunotherapy with pembrolizumab that led to a biochemical response. Subsequent to disease progression repeated abdominal lymph node resection was performed in 10/2018, 01/2019 and in 01/2020. Up to now (12/2020) the patient is biochemically free of disease. In conclusion, a multimodal diagnostic approach and therapy in an interdisciplinary setting is needed for patients with rare endocrine tumors. Molecular analyses may inform additional treatment options including checkpoint inhibitors such as pembrolizumab.

Evolutionary Distance Predicts Recurrence After Liver Transplantation in Multifocal Hepatocellular Carcinoma.

BACKGROUND: Liver transplantation (LTx) is a potentially curative treatment option for hepatocellular carcinoma (HCC) in cirrhosis. However, patients, where HCC is already a systemic disease, LTx may be individually harmful and has a negative impact on donor organ usage. Thus, there is a need for improved selection criteria beyond nodule morphology to select patients with a favorable outcome for LTx in multifocal HCC. Evolutionary distance measured from genome-wide single-nucleotide polymorphism data between tumor nodules and the cirrhotic liver may be a prognostic marker of survival after LTx for multifocal HCC. METHODS: In a retrospective multicenter study, clinical data and formalin-fixed paraffin-embedded specimens of the liver and 2 tumor nodules were obtained from explants of 30 patients in the discovery and 180 patients in the replication cohort. DNA was extracted from formalin-fixed paraffin-embedded specimens followed by genome wide single-nucleotide polymorphism genotyping. RESULTS: Genotype quality criteria allowed for analysis of 8 patients in the discovery and 17 patients in the replication set. DNA concentrations of a total of 25 patients fulfilled the quality criteria and were included in the analysis. Both, in the discovery (P = 0.04) and in the replication data sets (P = 0.01), evolutionary distance was associated with the risk of recurrence of HCC after transplantation (combined P = 0.0002). In a univariate analysis, evolutionary distance (P = 7.4 × 10) and microvascular invasion (P = 1.31 × 10) were significantly associated with survival in a Cox regression analysis. CONCLUSIONS: Evolutionary distance allows for the determination of a high-risk group of recurrence if preoperative liver biopsy is considered.

Challenges in pancreatic adenocarcinoma surgery - National survey and current practice guidelines.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most deadly cancers in Europe and the USA. There is consensus that radical tumor surgery is the only viable option for any long-term survival in patients with PDAC. So far, limited data are available regarding the routine surgical management of patients with advanced PDAC in the light of surgical guidelines. METHODS: A national survey on perioperative management of patients with PDAC and currently applied criteria on their tumor resectability in German university and community hospitals was carried out. RESULTS: With a response rate of 81.6% (231/283) a total of 95 (41.1%) participating departments practicing pancreatic surgery in Germany are certified as competence and reference centers for surgical diseases of the pancreas in 2016. More than 95% of them indicate to carry out structured and interdisciplinary therapies along with an interdisciplinary pre- and postoperative tumor board. The majority of survey respondents prefer the pylorus-preserving partial pancreatoduodenectomy (93.1%) with standard lymphadenectomy for cancer of the pancreatic head. Intraoperative histological evaluation of the resection margins is used regularly by 99% of the survey respondents. 98.7% of survey respondents carry out partial or complete vein resection, 126 respondents (54.5%) would resect tumor adjacent arteries, and 102 respondents (44.2%) would perform metastasectomy if complete PDAC resection (R0) is possible. CONCLUSION: Evidence-based and standardized pancreatic surgery is practiced by a large number of hospitals in Germany. However, a significant number of survey respondents support an extended radical tumor resection in patients with advanced PDAC even when not indicated by current clinical guidelines.