Medullary thyroid carcinoma (MTC) is a rare neuroendocrine malignancy with limited therapeutic options in advanced disease. While selective RET inhibitors have expanded systemic treatment strategies, disease progression frequently occurs over time. Antibody–drug conjugates (ADCs) have shown efficacy in the treatment of solid tumors but require suitable cell-surface targets, which have not yet been systemically characterized in MTC. This study aimed to identify therapeutically relevant surface antigens in MTC using immunohistochemical profiling. In this retrospective exploratory study, tumor specimens of 41 patients with histologically confirmed MTC were analyzed. Formalin-fixed paraffin-embedded tissues from primary tumors were subjected to immunohistochemical staining for six therapeutically relevant cell-surface antigens. Surface expression was assessed and categorized as strong, weak, or absent. Statistical analyses were conducted using descriptive statistics and Fisher’s exact test. The study included 41 patients with MTC, representing different tumor stages and clinicopathological characteristics with lymph node involvement in 45%. B7-H3 showed membranous expression in 91% of the included cases with strong expression in 82%, which was consistent across tumor stages and clinical subgroups. In contrast, no expression was detected for Nectin-4, Trop-2, c-Met, PD-L2, and Claudin 18.2 in any evaluable samples. B7-H3 was identified as the only consistently and strongly expressed surface antigen in a clinically heterogeneous MTC cohort. These findings identify B7-H3 as a potential therapeutic opportunity for advanced MTC and underscore the limited number of targetable surface antigens in this disease.

Sporadic primary hyperparathyroidism is most commonly caused by a single parathyroid adenoma. Traditionally, bilateral neck exploration with assessment of all four glands was the gold standard, achieving cure rates up to 98%. This approach has largely been replaced by limited exploration (LE), in which a prelocalized hyperfunctioning gland is selectively removed using a small open, video-assisted, or endoscopic approach.Successful LE relies on accurate preoperative localization of single-gland disease. First-line imaging consists of high-resolution ultrasound combined with 99mTc-sestamibi scintigraphy with single-Photon Emission Computerized Tomograph (SPECT/CT). When results are negative or discordant, 18F-choline PET/CT is recommended, significantly improving localization and enabling targeted surgery..Because multiglandular disease cannot be definitively excluded preoperatively, intraoperative parathyroid hormone (IOPTH) monitoring has become an important adjunct. IOPTH confirms complete excision of hyperfunctioning tissue and aids detection of additional abnormal glands. Several interpretive criteria exist, including Miami, Vienna, Halle, and Rome, with Miami and Vienna most commonly used. Although routine IOPTH use in concordantly localized single-gland disease remains debated, evidence suggests it reduces persistent disease and reoperation rates, particularly when imaging is inconclusive.Endoscopic, extracervical, and robotic approaches offer superior cosmetic outcomes but involve greater dissection, higher costs, and increased technical demands, limiting widespread use. Overall, advances in imaging and intraoperative adjuncts have enabled minimally invasive parathyroidectomy to replace bilateral exploration while maintaining excellent long-term outcomes.

Sporadic primary hyperparathyroidism is most commonly caused by a single parathyroid adenoma. Traditionally, bilateral neck exploration with assessment of all four glands was the gold standard, achieving cure rates up to 98

Background:Patients with rearranged-during-transfection (RET) mutations may develop aggressive medullary thyroid carcinoma (MTC), pheochromocytoma (PCC) and primary hyperparathyroidism (PHPT) within the multiple endocrine neoplasia 2 (MEN2) syndrome, depending on the specific genotype. The Y791F variant has been subject to studies over time but opinions on how to deal with it differ. Pathogenicity could never be proven, nor entirely ruled out. This study aims to contribute to the assessment of its importance and necessity for clinical surveillance. Methods:Thirty-six patients with a pathogenic variant in codon Y791F were analysed in this retrospective clinical and biochemical follow-up study in terms of their clinical manifestation. The patients were diagnosed within a prospective calcitonin screening program of individuals with thyroid nodules, PCC and/or PHPT. Results:MTC was diagnosed in three index cases of patients aged between 56 and 69 years. Beside thyroid nodules, neoplastic C-cell hyperplasia (nCCH) was diagnosed in five index cases, aged between 48 and 69 years. One index patient presented with unilateral PCC at the age of 68 years and another with PHPT at the age of 54 years. The patients were longitudinally monitored for a median [min-max] of 101.5 [0-263] months from the time of mutation diagnosis to the last follow-up, thereby encompassing observation until reaching a median [min-max] age of 56.5 [18-82] years, assuming a lifelong condition. Conclusions:Despite perceptions of clinical insignificance, ongoing uncertainties regarding potential clinical manifestations of MEN2 continue to surround the Y791F variant. There is an ambiguity between sporadic cases and MEN2 associated manifestations leaving the role of regular monitoring open for consideration.

Retroperitoneoscopic adrenalectomy (RPA) has proven to be safe and feasible with favorable postoperative courses. The role of RPA for tumor sizes larger than 6 cm is still controversial. The aim of the study was to evaluate the postoperative outcome for removal of larger adrenal tumors via the retroperitoneoscopic route. In this retrospective study, from 105 conducted RPA procedures, thirteen patients with adrenal tumor sizes larger than 6 cm received RPA in our hospital between January 2017 and December 2020. Clinicopathological factors, length of hospital stay, operative time and postoperative outcomes were included in this analysis. From this patient cohort, six (46.15

BACKGROUND:Pretherapeutic sex-specific basal calcitonin (bCt) cutoff levels and intraoperative diagnosis of desmoplastic stroma reaction (DSR) by frozen section independently facilitate the prediction of lymph-node metastases (LNM) and long-term outcomes in patients with medullary thyroid cancer (MTC). The relevance of combining these two parameters to "tailor" lymph-node (LN) surgery has thus far not been analyzed. PATIENTS AND METHODS:This single-center analysis included 306 patients covered by a calcitonin screening program. A uniform surgical protocol [thyroidectomy, bilateral central neck dissection (CND), lateral neck dissection (LND)] was applied. Risk groups were subdivided on the basis of predefined bCt cutoffs ("minimal risk," "low risk," and "high risk"), and the intraoperative classification of DSR was correlated with LN involvement in each patient. Biochemical long-term outcomes (mean follow-up: 8.3 years) were documented with the endpoints "disease-free," "persistent," or "recurrent" disease. RESULTS:Patients in the "minimal risk" group (37.6%) and "low risk" group (16.3%) showed central but never lateral LNM in 2.6% and 6.0% of patients, respectively (cure rate: 98.2%). In the "high risk" group (46.1%), LNM (central and/or lateral) were found in 51.1% of the patients (cure rate: 60.9%). In all risk groups, DSR negativity (overall 20.6%) confirmed absence of LNM (cure rate:100%). CONCLUSIONS:The analysis facilitates the recommendation to individualize the extent of LND combining pretherapeutic bCt and the presence of DSR. Independent of bCt levels (risk groups), LND can be avoided following thyroidectomy in patients with DSR-negative tumors. Patients with DSR-positive tumors should undergo thyroidectomy and bilateral CND. In addition, in "high risk" patients, unilateral LND is recommended in those with bCt < 350 pg/mL. Bilateral LND should be discussed in patients with M0 status and bCt > 350 pg/mL.

We report a case of a woman in her mid-30s who developed severe cardiac shock hours after giving birth to her second child with the need for extracorporeal haemodynamic support. Initially, postpartum cardiomyopathy was suspected, and high-urgency heart transplantation was considered. However, the endocrine work-up and imaging revealed pheochromocytoma as the cause for acute heart failure that was completely reversible. Notably, the patient also developed Sheehan's syndrome with pituitary necrosis and sustained hypopituitarism, most likely as a consequence of the haemodynamic failure during pheochromocytoma crisis. While pheochromocytoma crisis is already an extremely rare peripartum complication, the current case is-to the best of our knowledge-the first report of pheochromocytoma associated with Sheehan's syndrome. This case also highlights the clinical conundrum that pheochromocytomas can be easily overlooked in pregnancy due to non-specific symptoms and confusion with pregnancy-related hypertension or hypertension-associated other diseases. Appropriate case detection is important, especially in pregnant women with early onset of hypertension.

The aim of this study was to compare the autofluorescence of parathyroid glands (PGs) in-vivo and ex-vivo using two near-infrared autofluorescence(NIRAF) overlay imaging devices with different wavelengths of 785 nm and 805 nm. This prospective study included six patients(five[83.3%] female and one[16.7%] male) who had undergone thyroid and/or parathyroid surgery and in whom NIRAF imaging of at least one PG was performed using two EleVision IR(Medtronic, Dublin, Ireland) devices with 785 nm and 805 nm excitation light with the same power of 3000mW in June 2023 in a tertiary referral care center. The PGs were first localized by the surgeon. Autofluorescence was subsequently imaged with both NIRAF overlay imaging devices. The distance, angle and automatic adjustment of infrared intensity(IR%) were documented using both NIRAF overlay imaging devices. Differences in autofluorescence patterns were noted. In total, 16 PGs were analyzed in surgeries of the thyroid glands(n=3; 50%) and in 3(50%) PG surgeries. The ideal distance for each measurement using either NIRAF overlay imaging device(wavelength 785 nm vs. 805 nm) was 10 cm with an angle of 90°. EleVision IR with a wavelength of 785nm and 805nm showed mean IR% values of 30.1±22.4(6-75) and 30.1±15.9(6-68). Stronger and homogeneous autofluorescence patterns of parathyroid adenoma were seen using the EleVision IR device with 805 nm compared to 785 nm wavelength. No other differences in autofluorescence were seen in-vivo or ex-vivo using either device. NIRAF-based overlay imaging with a wavelength of 805 nm shows similar results in the localization of PGs as the device with 785 nm excitation light. Thus, it represents an equally feasible intraoperative tool for PGs.

IntroductionPrimary hyperparathyroidism (PHPT) is the third most common endocrine disease. With parathyroidectomy, a cure rate of over 95% at initial surgery is reported. Localization of the abnormal parathyroid gland is critical for the operation to be successful. The aim of this study is to analyze data of patients with single gland disease (SGD) and positive concordant localization imaging undergoing minimally invasive parathyroidectomy (MIP) and intraoperative parathyroid hormone monitoring (IOPTH) to evaluate if IOPTH is still justified in patients with localized SGD.MethodsA retrospective database analysis of all minimally invasive operations with IOPTH for PHPT and positive concordant localization in ultrasound (US) and 99mTc-sestamibi scintigraphy (MIBI) between 2016-2021. When both US and MIBI were negative, patients underwent either choline or methionine PET-CT. The patients were also analyzed a second time without applying IOPTH.ResultsIn total, 198 patients were included in the study. The sensitivity of US, MIBI and PET-CT was 96%, 94% and 100%, respectively. Positive predictive value was 88%, 89% and 94% with US, MIBI and PET-CT, respectively. IOPTH was true positive in 185 (93.4%) patients. In 13 (6.6%) patients, no adequate IOPTH decline was observed after localizing and extirpating the assumed enlarged parathyroid gland. Without IOPTH, the cure rate decreased from 195 (98.5%) to 182 (92%) patients and the rate of persisting disease increased from 2 (1.0%) to 15 (7.5%) patients.ConclusionDiscontinuing IOPTH significantly increases the persistence rate by a factor of 7.5 in patients with concordantly localized adenoma. Therefore, IOPTH appears to remain necessary even for this group of patients.

Background The introduction of new surgical technologies inevitably requires scrutiny. With the increasing introduction of transoral endoscopic thyroidectomy via the vestibular access (TOETVA) in benign and malignant thyroid surgery, it is imperative to also define the procedure for the parathyroid glands to ensure the clinically safe introduction and use of the Transoral Endoscopic Parathyroidectomy Vestibular Approach (TOEPVA). The aim of this study was to evaluate this technique within the European Transoral Endoscopic Para-/Thyroidectomy Vestibular Approach Study Group. Methods This study included patients who underwent TOEPVA between February 2016 and February 2023 at seven European high-volume tertiary referral centres. The data were analysed regarding the use of preoperative localization procedures, success rates, duration of surgery, complications and type of specimen collection. Results Overall, 29 (90.6%) patients underwent pure TOEPVA. In 3 (9.4 %) patients TOEPVA was combined with hemithyroidectomy. Each European Center performed between 2 and 10 cases. Overall, none cases were identified as 'complex', i.e. including bilateral neck exploration. Cervical ultrasound was performed in all 32 (100 %) patients and yielded a positive result. Tc99mSestaMibi scintigraphy with single positron emission computed tomography (SPECT) was performed in 30 (93.8%) patients, with inconclusive results in two (6.7%) of these patients. Choline positron emission tomography (PET)/computed tomography (CT) was performed in 4 (12.5 %) patients with positive results. Magnetic resonance imaging was not used. The mean operative time was 102 ± 46.9 (range 40 - 260) minutes. The success rate (i.e. normocalcaemia) was 100% on the first postoperative day. One (3.1%) patient had recurrent laryngeal nerve palsy. Conversion to open surgery, revisions and local infections did not occur. The mean hospital stay was 1.75±3 (range 1-3) days. At discharge, 2 (6.3%) patients had local swelling, 3 (9.4%) patients suffered from discolouration in the chin area, one (3.1%) patient had local sensory disturbance but no motor deficit. Conclusion This is the first European report on TOEPVA showing favourable perioperative outcomes for localised pHPT. Further experience and studies are needed to confirm the clinical benefit.

BACKGROUND:The aim of this study is to define standards for the use of near-infrared autofluorescence (NIRAF)-based overlay imaging via EleVision IR (Medtronic, Dublin, Ireland) and to evaluate its clinical applicability.PATIENTS AND METHODS:This prospective study included 189 patients who had undergone open thyroid and/or parathyroid surgery and in whom EleVision IR was applied to visualize at least one parathyroid gland (PG) between January 2021 and May 2022 in a tertiary referral care center. Whether the PGs were first localized by the surgeon or by overlay imaging was noted. Handling of the device, application time and duration, distance, infrared intensity (IR%), and the angle of each measurement were analyzed. In thyroidectomies, the specimens were subsequently scanned for further PGs. NIRAF patterns and intensities were described.RESULTS:Overall, 543 PGs were analyzed in 158 (83.6%) surgeries of thyroid glands (TGs) and in 49 (25.9%) surgeries for hyperparathyroidism. In 111 (58.7%) patients, identical numbers of PGs were detected by the surgeon and by overlay imaging. While a larger number of PGs was identified by the surgeon in 48 (25.4%) patients, overlay imaging served to detect more PGs in 30 (15.9%) cases. In four (2.1%) patients, PGs were visualized post-thyroidectomy due to their autofluorescence on the specimen. NIRAF-based overlay imaging was applied to depict the PGs early on after exposure by the surgeon. The ideal distance for the measurement ranged between 8 and 12 cm with an angle of 90° and a mean IR% of 34.5% (± 17.6).CONCLUSIONS:Considering the standard operating procedures, NIRAF-based overlay imaging can be used as an adjunct tool for intraoperative localization.

Background: The clinical relevance of clearly defined pretherapeutic basal calcitonin (bCt) cut-offs for predicting lymph node metastases (LNMs) and long-term outcomes (LOs) has so far not been tested in a large cohort of patients with medullary thyroid cancer included in a Ct screening program during the initial diagnostic workup of thyroid nodules. Material and Methods: Female (f) patients with a bCt level of ≤23 pg/mL and male (m) patients with a level of ≤43 pg/mL were assigned to Group 1 (minimal oncologic risk), patients with a bCt between 24 and 84 pg/mL (f) and 44–99 pg/mL (m) to Group 2 (low oncologic risk), and those with a bCt of ≥85 pg/mL (f) and ≥100 pg/mL (m) to Group 3 (high oncologic risk). All patients underwent surgery applying a uniform surgical protocol. The median follow-up was 100 months. Results: The study included 306 patients. In 3/115 (2.6%) patients in Group 1 and in 3/50 (6.0%) in Group 2, LNM in the central but not lateral neck and no distant metastases (DMet) were documented. In both groups, the biochemical long-term cure rate was 95.7% and the disease-specific-survival (DSS) rate was 100% at 10, 15 and 20 years. Lateral LNM and DMet were diagnosed only in Group 3. The bCt levels of N0 and N1 patients showed broadly overlapping ranges, thus impeding the differentiation between those patients through bCt. Both the cure rate and DSS were significantly worse in Group 3. The overall biochemical long-term cure rate was 78.2%. Conclusions: Within a Ct screening program, grouping patients upon pretherapeutic bCt provides a simple risk classification system for indicating surgery, predicting LN involvement, and LOs.

The clinical manifestation of multiple endocrine neoplasia type 2 (MEN2) in terms of developing medullary thyroid cancer (MTC), pheochromocytoma (PCC), and/or primary hyperparathyroidism (PHPT) is related to the respective pathogenic variant of the RET proto-oncogene. The aim of this study is to retrospectively analyze the individual, genotype-dependent clinical manifestations of a large cohort of MEN2 patients. By comparing their clinical profile with currently existing evidence-based knowledge, an optimal therapy and prevention strategy in terms of prophylactic thyroidectomy and clinical follow-up could be ensured. This is a retrospective single-center study of 158 MEN2 patients who were diagnosed and/or surgically treated at a tertiary referral care center between 1990 and 2022. All participants were categorized according to their pathogenic variant of the RET proto-oncogene. Subsequently, the clinical manifestation of the disease and its time of occurrence was documented. Our analysis showed results in line with existing studies, except for a considerably lower-than-predicted occurrence of PCC in patients with V804M/L mutations. This study supports the current recommendation regarding the pathogenic variant-dependent management of this rare cancer-associated syndrome.

Background: Hemodynamic instability is common during adrenalectomy for pheochromocytoma and paraganglioma (PPGL). Most analyses focus on the risk factors for intraoperative hypertension, but hypotension is a frequent and undesirable phenomenon during PPGL surgery. This study aimed to analyze the risk factors for hypotensive episodes during the removal of PPGL, and whether these episodes are always associated with concomitant intraoperative hypertensive events. Methods: A consecutive series of 121 patients (91.7% receiving preoperative alpha-blockade) treated with transperitoneal endoscopic adrenalectomy at a university hospital were analyzed, and pre- and intraoperative risk factors for intraoperative hypotension with or without intraoperative hypertension were analyzed using univariable and multivariable logistic regression analyses. Results: In total, 58 (56.2%) patients presented with intraoperative hypotension. Of these, 25 (20.7%) patients showed only hypotensive episodes but no hypertensive episodes (group 1), and 43 (35.5%) patients had both intraoperative hypotension and hypertension (group 2). The remaining 53 patients did not present with hypotension at all (group 3). When comparing group 1 (hypotension only) to all other patients with incidental diagnosis, higher age and lower preoperative diastolic arterial blood pressure (ABP) were significant risk factors for intraoperative hypotension; only the latter two were still significant in multivariate analysis. The significant risk factors for hypotension independent of hypertension (group 1 + 2 vs. group 3) were age and incidental diagnosis, pre-existing diabetes mellitus, and intraoperative use of remifentanil. Incidental diagnosis and use of remifentanil reached the level of significance in multivariate analysis. Conclusions: Since older age, incidental diagnosis of PPGL, lower preoperative ABP, and diabetes mellitus are risk factors for intraoperative hypotension, preoperative alpha-blocker treatment should be individualized for those at risk for hypotension. In addition, remifentanil should be used cautiously in the risk group.

Background Well-differentiated neuroendocrine tumors (NET) are rare malignancies that are clinically very heterogeneous. Accordingly, their treatment is also complex and dependent on various factors. With currently available systemic therapies, the prognosis is often favorable. Objectives This article aims to provide an overview of current treatment strategies for NET, addressing the most important NET locations. Methods The current European guidelines and further relevant literature on the treatment of NET were reviewed for this purpose. Results The therapeutic spectrum for NET is extremely broad: For NET of the stomach/duodenum, appendix, and rectum, endoscopic or surgical resection is often sufficient, and metastatic tumors are rare. NET of the pancreas, small intestine and lung should also undergo potentially curative resection in the early stages. In the metastatic stage, locoregional treatments such as surgery and liver tumor embolization play a role. Major advances have been made in drug therapy, with somatostatin analogs (octreotide and lanreotide), an mTOR inhibitor (everolimus), and a tyrosine kinase inhibitor (sunitinib) being widely used. Peptide receptor radionuclide therapy (PRRT) is also an invaluable option. In some cases, classic chemotherapy is indicated. Conclusions Many effective therapies are now available for NET. It is important to select the right therapy at the right time for each patient through interdisciplinary management.

Background: Since 2017, switching from laparoscopic transabdominal adrenalectomy (LTA), posterior retroperitoneoscopic adrenalectomy (RPA) is used as standard procedure in this institution. Aim of this retrospective study was to compare both techniques regarding operative time, length of stay and safety of the procedures. Methods: All patients operated in our institution for adrenal tumors were prospectively documented in the EUROCRINE-database and retrospectively analyzed. Sex, age, body mass index (BMI), indication, operative time, conversion and complication rates, hospital stay and tumor-size were analyzed by Z-score, chi-square test, t-test, Mann-Whitney U test and Pearson correlation. Results: A total of 105 RPAs and 132 LTAs were performed in an 8-year period. No difference was seen in age, sex and tumor localization. Adenoma (n=113) and pheochromocytoma (n=64) were the most common histopathological findings. Compared to the LTA group, the RPA group had significantly shorter operative time with a median of 50 (15-380) vs. 125 (25-420) min (P<0.001) and shorter hospital stay with a median of 3 vs. 9 days (P<0.001). The decrease of the median operative time in RPA group, visualizing the learning curve of the procedure, was from 60 min (2017) to 45 min (2020). Four conversions from RPA to open adrenalectomy had to be performed due to bleeding or adhesions, whereas 9 LTA procedures had to be converted due to bleeding (n=2), unclear anatomy (n=1), adhesions (n=1), difficult access (n=1) or planned Conclusions: RPA could be safely introduced with reduced operative times and shorter length of hospital stay compared to LTA.

Zusammenfassung Hintergrund Gut differenzierte neuroendokrine Tumoren (NET) sind seltene Malignome, die klinisch sehr heterogen sind. Entsprechend ist auch ihre Behandlung komplex und von diversen Faktoren abhängig. Mit den heute verfügbaren Therapien ist die Prognose oft günstig. Ziel der Arbeit Dieser Artikel soll einen Überblick über die aktuellen Therapiestrategien bei NET geben und dabei auf die wichtigsten NET-Lokalisationen eingehen. Methoden Zu diesem Zweck wurden die aktuellen europäischen Leitlinien und die einschlägige Literatur zur Behandlung von NET zusammengefasst. Ergebnisse Das Therapiespektrum ist ausgesprochen breit: Bei den NET des Magens/Duodenums, der Appendix und des Rektums ist oft die endoskopische respektive chirurgische Entfernung ausreichend, und metastasierte Tumoren sind selten. NET des Pankreas, des Dünndarms und der Lunge sollen in frühen Stadien auch einer potenziell kurativen Resektion zugeführt werden. Im metastasierten Stadium haben lokale Therapiemaßnahmen wie Chirurgie und Leber-Tumorembolisation ebenfalls einen Stellenwert. Zuletzt gab es viele Fortschritte hinsichtlich der medikamentösen Therapie, wobei insbesondere Somatostatin-Analoga (Octreotid und Lanreotid), ein mTOR-Inhibitor (Everolimus) und ein Tyrosinkinase-Inhibitor (Sunitinib) eingesetzt werden. Ferner stellt die Peptidrezeptor-Radionuklid-Therapie (PRRT) ein wichtiges Verfahren dar. Auch die klassische Chemotherapie ist in einigen Fällen indiziert. Diskussion Inzwischen gibt es viele effektive Therapien für NET. Es ist wichtig, im interdisziplinären Management für jeden Patienten und jede Patientin die richtige Therapie zum richtigen Zeitpunkt auszuwählen.

Primary hyperparathyroidism with parathyroid tumors is a typical manifestation of Multiple Endocrine Neoplasia Type 1 (MEN1) and is historically termed "primary hyperplasia". Whether these tumors represent a multi-glandular clonal disease or hyperplasia has not been robustly proven so far. Loss of Menin protein expression is associated with inactivation of both alleles and a good surrogate for a MEN1 gene mutation. The cyclin-dependent kinase inhibitor 1B (CDKN1B) gene is mutated in MEN4 and encodes for protein p27 whose expression is poorly studied in the syndromic MEN1 setting.Here, we analyzed histomorphology and protein expression of Menin and p27 in parathyroid adenomas of 25 patients of two independent, well-characterized MEN1 cohorts. The pattern of loss of heterozygosity (LOH) was assessed by fluorescence in situ hybridization (FISH) in one MEN1-associated parathyroid adenoma. Further, next-generation sequencing (NGS) was performed on eleven nodules of four MEN1 patients.Morphologically, the majority of MEN1 adenomas consisted of multiple distinct nodules, in which Menin expression was mostly lost and p27 protein expression reduced. FISH analysis revealed that most nodules exhibited MEN1 loss, with or without the loss of centromere 11. NGS demonstrated both subclonal evolution and the existence of clonally unrelated tumors.Syndromic MEN1 parathyroid adenomas therefore consist of multiple clones with subclones, which supports the current concept of the novel WHO classification of parathyroid tumors (2022). p27 expression was lost in a large fraction of MEN1 parathyroids and must therefore be used with caution in suggesting MEN4.