Search

Supplementary Figure from Enhancing Radioiodine Incorporation into Radioiodine-Refractory Thyroid Cancer with MAPK Inhibition (ERRITI): A Single-Center Prospective Two-Arm Study

Purpose:Restoration of iodine incorporation (redifferentiation) by MAPK inhibition was achieved in previously radioiodine-refractory, unresectable thyroid carcinoma (RR-TC). However, results were unsatisfactory in BRAFV600E-mutant (BRAF-MUT) RR-TC. Here we assess safety and efficacy of redifferentiation therapy through genotype-guided MAPK-modulation in patients with BRAF-MUT or wildtype (BRAF-WT) RR-TC.Patients and Methods:In this prospective single-center, two-arm phase II study, patients received trametinib (BRAF-WT) or trametinib + dabrafenib (BRAF-MUT) for 21 ± 3 days. Redifferentiation was assessed by 123I-scintigraphy. In case of restored radioiodine uptake, 124I-guided 131I therapy was performed. Primary endpoint was the redifferentiation rate. Secondary endpoints were treatment response (thyroglobulin, RECIST 1.1) and safety. Parameters predicting successful redifferentiation were assessed using a receiver operating characteristic analysis and Youden J statistic.Results:Redifferentiation was achieved in 7 of 20 (35%) patients, 2 of 6 (33%) in the BRAF-MUT and 5 of 14 (36%) in the BRAF-WT arm. Patients received a mean (range) activity of 300.0 (273.0–421.6) mCi for 131I therapy. Any thyroglobulin decline was seen in 57% (4/7) of the patients, RECIST 1.1 stable/partial response/progressive disease in 71% (5/7)/14% (1/7)/14% (1/7). Peak standardized uptake value (SUVpeak) < 10 on 2[18F]fluoro-2-deoxy-D-glucose (FDG)-PET was associated with successful redifferentiation (P = 0.01). Transient pyrexia (grade 3) and rash (grade 4) were noted in one patient each.Conclusions:Genotype-guided MAPK inhibition was safe and resulted in successful redifferentiation in about one third of patients in each arm. Subsequent 131I therapy led to a thyroglobulin (Tg) decline in more than half of the treated patients. Low tumor glycolytic rate as assessed by FDG-PET is predictive of redifferentiation success.See related commentary by Cabanillas et al., p. 4164

Supplementary Data from Enhancing Radioiodine Incorporation into Radioiodine-Refractory Thyroid Cancer with MAPK Inhibition (ERRITI): A Single-Center Prospective Two-Arm Study

123/131I-MIBG scintigraphy has shown a high specificity for imaging pheochromocytoma and paraganglioma however with low sensitivity due to low spatial resolution. 124I-MIBG PET may overcome this limitation to improve the staging of patients with (suspected) pheochromocytoma. Methods: We analyzed the sensitivity, specificity, positive and negative predictive values (PPV, NPV) of 124I-MIBG PET in 43 consecutive patients with suspected (recurrence of) pheochromocytoma using histopathological (n = 25) and clinical validation (n = 18) as standard of truth. Furthermore, we compared 124I-MIBG PET versus contrast enhanced CT (CE-CT) per-patient and per-lesion detection rate of 124I-MIBG PET in 13 additional patients with known metastatic malignant pheochromocytoma (MMP). Results:124I-MIBG PET/CT was positive in 19/43 (44%) patients with suspected pheochromocytoma. Presence of pheochromocytoma was confirmed in 22/43 (51%). 124I-MIBG PET/CT sensitivity, specificity, PPV, NPV were 86%, 100%, 100%, 88%, respectively. 124I-MIBG PET was positive in 11/13 (85%) MMP patients. Combined 124I-MIBG PET and CE-CT detected 173 lesions, of which 166 (96%) and 118 (68%) were visible on 124I-MIBG PET and CE-CT, respectively. Discussion:124I-MIBG PET detects pheochromocytoma with high accuracy at initial staging and high detection rate at re-staging. Superior diagnostic performance aids guidance of surgical and medical management including personalized 131I-MIBG therapy.

Purpose The role of streptozocin-based chemotherapy (STZ CTx) in advanced, well-differentiated pancreatic neuroendocrine tumours (PanNET) and the best sequence of treatments in advanced PanNET are unclear. We examined the outcomes after STZ CTx in patients who had been selected according to the current therapeutic guidelines. Methods Data from 50 PanNET patients consecutively treated with STZ CTx between 2010 and 2018 were analysed. The endpoints of the study were the objective-response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results STZ CTx was the first-line treatment in 54% of patients. The PanNET grades were as follows: 6% G1, 88% G2, and 6% well-differentiated G3. The ORR was 38%. Stable disease was the best response in 38% of patients and 24% showed progressive disease. Treatment was discontinued because of toxicity in one patient. Median PFS and OS were 12 (95% confidence interval (CI), 8.5–15.5) and 38 months (95% CI, 20.4–55.6), respectively. In the Kaplan-Meier analysis, the median OS was 89 months (95% CI, 34.9–143.1) for STZ CTx as first-line therapy compared with 22 months (95% CI, 19.3–24.7; p = 0.001, log-rank test) for subsequent lines. Bone metastases negatively impacted survival (HR, 2.71, p = 0.009, univariate analysis, HR, 2.64, p = 0.015, multivariate analysis, and Cox regression). Conclusions In patients selected according to current guidelines, PFS, and OS after STZ CTx were lower than previously reported, whereas ORR was unchanged. First-line treatment was positively associated with OS and the presence of bone metastases was negatively associated with OS. Pre-treatment with targeted or peptide-receptor radionuclide therapy did not alter ORR, PFS, or OS.

Aims In contrast to all prior AJCC/TNM classifications for differentiated thyroid cancer (DTC) the 8th edition does not take minimal extrathyroidal extension (M-ETE) into consideration for local tumor staging. We therefore aimed to retrospectively assess the specific impact of M-ETE on the outcome of M-ETE patients treated in our clinic. Methods DTC patients with M-ETE and a follow-up time of ≥ 5 years were included and matched with an identical number of patients without M-ETE, but with equal histopathological tumor subtype and size. The frequency of initially metastatic disease among groups was compared using Fisher’s exact test, the recurrence rate by virtue of log-rank test. Fisher’s exact test and multivariate analysis were used to account for the presence of confounding risk factors. Results One hundred sixty patients (80 matching pairs) were eligible. With other confounding risk factors being equal, the prevalence of N1-/M1-disease at initial diagnosis was comparable among groups (M-ETE: 42.5 %; no M-ETE: 32.5 %; p = 0.25). No differences with regard to the recurrence rate were shown. However, M-ETE patients were treated with external beam radiation therapy more often (16.3 % vs. 1.3 %; p = 0.004) and received higher median cumulative activities of 131I (10.0 vs. 8.0 GBq; p Discussion Although having played a pivotal role for local tumor staging of DTC for decades M-ETE did not increase the risk for metastases at initial diagnosis and the recurrence rate in our cohort. Patients with M-ETE had undergone intensified treatment, which entails a possible confounding factor that warrants further investigation in randomized controlled trials.

BACKGROUND Follow-up after pediatric liver transplantation (LTX) is challenging and needs to be refined to extend graft survival as well as general functional health and patients´ quality of life. Strategies towards individual immunosuppressive therapy seem to play a key role. Our aim was to evaluate protocol liver biopsies (PLB) as a tool in personalized follow up after pediatric LTX. PATIENTS AND METHODS Our retrospective analysis evaluates 92 PLB in clinically asymptomatic pediatric patients after LTX between 2009 and 2019. Histological findings were characterized using the Desmet scoring system. In addition to PLB, other follow-up tools like laboratory parameters, ultrasound imaging and transient elastography were evaluated. Risk factors for development of fibrosis or inflammation were analyzed. RESULTS PLB revealed a high prevalence of graft fibrosis (67.4%) and graft inflammation (47.8%). Graft inflammation was significantly (P = 0.0353*) more frequent within the first 5 years after transplantation compared to later time points. Besides conventional ultrasound, the measurement of liver stiffness using transient elastography correlate with stage of fibrosis (r = 0.567, P =

Introduction: Primary squamous cell carcinoma (PSCC) of the thyroid is an exceptionally rare malignancy accounting for 12 months. Case Presentation: A 78-year-old male patient presented with a 3-week history of dysphonia and dyspnoea. Laryngoscopy revealed a mechanical obstruction by a right-sided, subglottical mass, which on cervical ultrasound was highly suggestive of anaplastic thyroid carcinoma. Additional workup including esophagogastroduodenoscopy showed compression of the oesophagus but no oesophageal infiltration by the tumour. Immunohistochemistry displayed CK19-positive cells indicating epithelial origin of the tumour. CK5/6 and P40 immunohistochemistry confirmed the morphological impression of squamous cell differentiation while staining with thyroid markers TTF-1 and TPO was negative and PAX8 showed a nuclear positive signal. Based on immunohistopathology, presence of TP53 and BRAF V600E mutations, and exclusion of metastatic squamous cell carcinoma of other origin, the diagnosis of a PSCC of the thyroid was established. As an individualized treatment concept, we decided to advocate combined BRAF V600E targeting by the multikinase inhibitors dabrafenib and trametinib. This led to drastic improvement in patient’s quality of life without severe side effects over a period of >12 months. Conclusion: In this case, molecular diagnosis allowed a highly individualized treatment concept with combined dabrafenib and trametinib therapy.

Nuclear inclusions (NI) are a common finding in hepatocytes from patients with liver disease especially in diabetes mellitus and non-alcoholic fatty liver disease (NAFLD) but studies examining the shape and content of these inclusions in detail are lacking. In this study we define two distinct types of NI in NAFLD: inclusions bounded by the nuclear membrane, containing degenerative cell organelles and heterolysosomes (type1) and inclusions with deposits of glycogen but without any kind of organelles and delimiting membrane (type2). NI in 77 paraffin-embedded patients of NAFLD including NAFL and non-alcoholic steatohepatitis (NASH) were analyzed. In 4–12% of type1 NI immunopositivity for the autophagy-associated proteins LC3B, ubiquitin, p62/sequestosome1, cathepsin D and cathepsin B were detected with co-localizations of ubiquitin and p62; type2 NI showed no immunoreactivity. Three-dimensional reconstructions of isolated nuclei revealed that NI type1 are completely enclosed within the nucleus, suggesting that NI, although probably derived from cytoplasmic invaginations, are not just simple invaginations. Our study demonstrates two morphologically different types of inclusions in NAFLD, whereby both gained significantly in number in advanced stages. We suggest that the presence of autophagy-associated proteins and degenerated organelles within type1 NI plays a role in disease progression.

Die Lebertransplantation ist eine etablierte Therapieoption zur Behandlung von Patienten mit einer irreversiblen Lebererkrankung im Endstadium. Das Therapiemanagement der Patienten erfolgt interdisziplinar und verlangt von den Pathologen Kenntnisse sowohl der Klinik wie auch der Immunologie. Stetige Fortschritte in der Behandlung und die zunehmende klinische Erfahrung gehen mit der Weiterentwicklung der pathologischen Transplantationsdiagnostik einher. Im vorliegenden Artikel werden die neueste Klassifikation der T‑Zell-mediierten Abstosung (TCMR), der antikorpermediierten Abstosung (AMR) sowie Aspekte der Pratransplantationsdiagnostik vorgestellt und diskutiert.

Neuroendokrine Neoplasien (NEN) des Verdauungstrakts stellen eine heterogene Erkrankung mit variabler klinischer Manifestation dar. Sie machen etwa 1 % aller Malignome aus. Die funktionell aktiven NEN stellen aufgrund ihrer Hormonexzesssyndrome besondere Anforderungen an Diagnostik und Therapie. Die einzig kurative Therapie der NEN ist ihre vollstandige Entfernung. Weitere Optionen sind Somatostatinanaloga, molekular-zielgerichtete Therapien, Peptid-Radiorezeptor-Therapie und systemische Chemotherapie. Die Zahl der Phase-III-Studien ist limitiert, komparative Studien fehlen fur die meisten Situationen. Eine etablierte Therapiesequenz ist daher nur selten vorhanden, die Masnahmen werden individualisiert eingesetzt. Therapieziel bei fortgeschrittenen, differenzierten neuroendokrinen Tumoren ist eine Wachstumsstabilisierung. Bei undifferenzierten neuroendokrinen Karzinomen ist die objektive Ansprechrate auf eine systemische Chemotherapie hoher, jedoch statistisch von kurzer Dauer.

While papillary thyroid cancer (PTC) has largely favorable prognosis, anaplastic thyroid cancer (ATC) is a rare but extremely aggressive malignancy with grim clinical outcome. Even though new therapeutic options are emerging for ATC, additional preclinical models and novel combinations are needed for specific subsets of patients. We established a novel cell line (PF49) from the malignant pleural effusion of a 68-year-old male patient with ATC that rapidly transformed from a BRAF and TERT promoter mutant PTC. PF49 cells demonstrated a robust migratory activity in vitro and strong invasive capacity in vivo in a pleural carcinosis model. Combined BRAF and MEK inhibition decreased the proliferation and migration of PF49 cells, however could not induce cell death. Importantly, HDAC inhibitor treatment with SAHA or valproic acid induced cell cycle arrest and strongly increased PD-L1 expression of the tumor cells. Induction of PD-L1 expression was also present when paclitaxel-cisplatin chemotherapeutic treatment was combined with HDAC inhibitor treatment. Increased PD-L1 expression after HDAC inhibition was recapitulated in an international ATC cell model. Our data suggest that HDAC inhibition alone or in combination with standard chemotherapy may potentiate anaplastic thyroid cancer cells for immunotherapy. Electronic supplementary material The online version of this article (10.1007/s12253-020-00834-y) contains supplementary material, which is available to authorized users.

Clostridium perfringens enterotoxin (CPE) can be used to eliminate carcinoma cells that overexpress on their cell surface CPE receptors – a subset of claudins (e.g., Cldn3 and Cldn4). However, CPE cannot target tumors expressing solely CPE‐insensitive claudins (such as Cldn1 and Cldn5). To overcome this limitation, structure‐guided modifications were used to generate CPE variants that can strongly bind to Cldn1, Cldn2 and/or Cldn5, while maintaining the ability to bind Cldn3 and Cldn4. This enabled (a) targeting of the most frequent endocrine malignancy, namely, Cldn1‐overexpressing thyroid cancer, and (b) improved targeting of the most common cancer type worldwide, non‐small‐cell lung cancer (NSCLC), which is characterized by high expression of several claudins, including Cldn1 and Cldn5. Different CPE variants, including the novel mutant CPE‐Mut3 (S231R/S313H), were applied on thyroid cancer (K1 cells) and NSCLC (PC‐9 cells) models. In vitro, CPE‐Mut3, but not CPEwt, showed Cldn1‐dependent binding and cytotoxicity toward K1 cells. For PC‐9 cells, CPE‐Mut3 improved claudin‐dependent cytotoxic targeting, when compared to CPEwt. In vivo, intratumoral injection of CPE‐Mut3 in xenograft models bearing K1 or PC‐9 tumors induced necrosis and reduced the growth of both tumor types. Thus, directed modification of CPE enables eradication of tumor entities that cannot be targeted by CPEwt, for instance, Cldn1‐overexpressing thyroid cancer by using the novel CPE‐Mut3., Clostridium perfringens enterotoxin (CPE) is used to target carcinomas overexpressing a claudin subset serving as CPE receptors. CPE‐based pores in membrane cause cell death. Structure‐guided CPE modifications (CPE‐S231R/S313H) enabled also claudin‐1 binding and growth reduction of claudin‐1‐expressing papillary thyroid carcinoma (mouse xenotransplants) that could not be targeted by CPEwt. Furthermore, CPE‐S231R/S313H improved targeting of lung cancer (NSCLC) expressing multiple claudins.

Purpose: Restoration of iodine incorporation (redifferentiation) by MAPK inhibition was achieved in previously radioiodine-refractory, unresectable thyroid carcinoma (RR-TC). However, results were unsatisfactory in BRAFV600E-mutant (BRAF-MUT) RR-TC. Here we assess safety and efficacy of redifferentiation therapy through genotype-guided MAPK-modulation in patients with BRAF-MUT or wildtype (BRAF-WT) RR-TC. Patients and Methods: In this prospective single-center, two-arm phase II study, patients received trametinib (BRAF-WT) or trametinib + dabrafenib (BRAF-MUT) for 21 ± 3 days. Redifferentiation was assessed by 123I-scintigraphy. In case of restored radioiodine uptake, 124I-guided 131I therapy was performed. Primary endpoint was the redifferentiation rate. Secondary endpoints were treatment response (thyroglobulin, RECIST 1.1) and safety. Parameters predicting successful redifferentiation were assessed using a receiver operating characteristic analysis and Youden J statistic. Results: Redifferentiation was achieved in 7 of 20 (35%) patients, 2 of 6 (33%) in the BRAF-MUT and 5 of 14 (36%) in the BRAF-WT arm. Patients received a mean (range) activity of 300.0 (273.0–421.6) mCi for 131I therapy. Any thyroglobulin decline was seen in 57% (4/7) of the patients, RECIST 1.1 stable/partial response/progressive disease in 71% (5/7)/14% (1/7)/14% (1/7). Peak standardized uptake value (SUVpeak) < 10 on 2[18F]fluoro-2-deoxy-D-glucose (FDG)-PET was associated with successful redifferentiation (P = 0.01). Transient pyrexia (grade 3) and rash (grade 4) were noted in one patient each. Conclusions: Genotype-guided MAPK inhibition was safe and resulted in successful redifferentiation in about one third of patients in each arm. Subsequent 131I therapy led to a thyroglobulin (Tg) decline in more than half of the treated patients. Low tumor glycolytic rate as assessed by FDG-PET is predictive of redifferentiation success. See related commentary by Cabanillas et al., p. 4164

(123/131)I-metaiodobenzylguanidine (MIBG) scintigraphy has shown a high specificity for imaging pheochromocytoma and paraganglioma, but with low sensitivity because of low spatial resolution. (124)I-MIBG PET may be able to overcome this limitation and improve the staging of patients with (suspected) pheochromocytoma. Methods: We analyzed the sensitivity, specificity, and positive and negative predictive values of (124)I-MIBG PET in 43 consecutive patients with suspected (recurrence of) pheochromocytoma using histopathologic (n = 25) and clinical validation (n = 18) as the standard of truth. Furthermore, we compared the detection rate of (124)I-MIBG PET versus contrast-enhanced (CE) CT on a per-patient and per-lesion basis in 13 additional patients with known metastatic malignant pheochromocytoma. Results: (124)I-MIBG PET/CT was positive in 19 (44%) of 43 patients with suspected pheochromocytoma. The presence of pheochromocytoma was confirmed in 22 (51%) of 43. (124)I-MIBG PET/CT sensitivity, specificity, and positive and negative predictive values were 86%, 100%, 100%, and 88%, respectively. (124)I-MIBG PET was positive in 11 (85%) of 13 patients with malignant pheochromocytoma. Combined (124)I-MIBG PET and CE CT detected 173 lesions, of which 166 (96%) and 118 (68%) were visible on (124)I-MIBG PET and CE CT, respectively. Conclusion: (124)I-MIBG PET detects pheochromocytoma with high accuracy at initial staging and a high detection rate at restaging. Future assessment of (124)I-MIBG PET for treatment guidance, including personalized (131)I-MIBG therapy, is warranted.

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.

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.

The current edition of the WHO classification of thyroid tumors (2017) contains a number of very relevant changes with considerable consequences for the diagnostic assessment of thyroid specimens. This applies to both the histomorphological examination of surgical specimens and the preoperative fine needle biopsy (FNB). In addition, molecular pathological examinations are becoming increasingly important in the diagnosis of thyroid tumors. Changes affect practically all areas of thyroid tumor diagnostics. Some of these changes have far-reaching consequences that justify a comprehensive commentary and query of the knowledge acquired in the form of this CME article.Die aktuelle Fassung der WHO-Klassifikation der Tumoren der Schilddrüse (2017) enthält eine Reihe sehr relevanter Änderungen mit beträchtlicher Konsequenz für die diagnostische Beurteilung von Schilddrüsenpräparaten. Dies betrifft sowohl die histomorphologische Untersuchung von Operationspräparaten als auch die präoperative Feinnadelbiopsie (FNB); darüber hinaus erlangen molekularpathologische Untersuchungen auch in der Diagnostik von Schilddrüsentumoren einen immer wichtigeren Stellenwert. Änderungen betreffen praktisch alle Bereiche der Schilddrüsentumordiagnostik; einige dieser Änderungen haben weitreichende Konsequenzen, die eine zusammenfassende Kommentierung und Abfrage des erworbenen Wissens in Form des vorliegenden CME-Beitrags rechtfertigen.

To investigate a correlation betweenA total of 26 patients with newly diagnosed, therapy-naive neuroendocrine neoplasms (NEN) were enrolled in this prospective study and underwentThere was a moderate negative correlation between arterial contrast enhancement and tumor grading (r=-0.35, p = 0.005), while portal venous enhancement showed a weak positive correlation with the Ki-67 index (r = 0.28, p = 0.008) and a non-significant positive correlation with tumor grading (r = 0.19, p = 0.063). Features that were significantly associated with an aggressive tumor biology were the presence of liver metastases (OR 2.6, p = 0.042), T1w hyperintensity in comparison to muscle (OR 12.7, p = 0.0001), arterial phase hyperenhancement (OR 1.4, p = 0.001), diffusion restriction (OR 2.8, p = 0.02) and SUVmax above the hepatic level (OR 7.0, p = 0.001).The study reveals that PET/MRI features might be useful for prediction of NEN grading and thus provide a preliminary assessment of tumor aggressiveness.

We report the case of a 27-year-old Syrian patient who came to the emergency department with a syncopal episode. No medical history could be raised due to a language barrier and so the clinical presentation was leading.The patient exhibited signs of shock, accompanied by an exanthema as well as perioral hematin. In an ultrasound sonography free intraabdominal fluid and an obscure change in the upper abdomen could be visualized. An esophagogastroduodenoscopy showed evidence of an ulcer, however did not explain all symptoms. In a CT abdomen, signs of a ruptured cyst could be demonstrated.The patient stabilized under the treatment protocol for anaphylaxis. Due to the clinical course and country of origin the patient received albendazole and a partial liver resection for a suspected echinococcus cyst.Obscure clinical symptoms alongside signs of shock, should always considered to be an allergic reaction in absence of sepsis or hemorrhage. In anaphylaxis, echinococcosis should always be included in the differential diagnosis.Wir berichten über eine 27-jährige syrische Patientin, die aufgrund eines Kollapses in die Notaufnahme kam. Die Anamnese war praktisch nicht zu erheben, sodass die klinische Symptomatik führend war.Es bestand ein Schock, mit einem Exanthem einhergehend. Zusätzlich fiel perioral Hämatin auf. Es erfolgte eine Sonografie mit Nachweis freier intraabdomineller Flüssigkeit sowie einer unklaren Veränderung im Oberbauch. Eine Ösophagogastroduodenoskopie erbrachte einen Ulkusnachweis, erklärte aber nicht das Geschehen. Die Computertomografie des Abdomens zeigte eine rupturierte Zyste.Durch eine antiallergische Therapie erfolgte die Stabilisierung. Unter dem Verdacht einer Echinokokkuszyste aufgrund der Herkunft der Patientin und des Verlaufs wurde nach Gabe von Albendazol die Leberteilresektion durchgeführt. Der makroskopische Befund sowie die Histologie bestätigten den Verdacht.Eine unklare klinische Symptomatik, die mit einem Schock einhergeht, sollte bei Ausschluss einer Sepsis oder Blutung immer eine allergische Reaktion berücksichtigen. Kommt es zu einer Anaphylaxie, so ist immer eine Echinokokkose differenzialdiagnostisch miteinzubeziehen.

Aim: β-catenin activation is known to promote liver regeneration and play a role in the pathogenesis of liver cancer. Recently, we detected intranuclear inclusions (NI) in hepatocellular carcinoma (HCC) containing degenerated cell organelles and lysosomal proteins and delimited by a completely closed nuclear membrane. The presence of NI was positively associated with patient survival. The aim of the current study was to investigate a possible association between proteins of the Wnt/β-catenin pathway with NI morphology and survival. Methods: We examined NI in 72 paraffin-embedded specimens of HCC. Immunohistochemistry (IHC) and immunofluorescence (IF) were performed to investigate the content and shape of NI. β-catenin gene (CTNNB1 ) mutations were analyzed by next generation sequencing. Results: We detected the accumulation of β-catenin and glutamine synthetase (a target gene of β-catenin) proteins within NI. Further, we found immunopositivity for the lysine demethylase KDM2A in NI. KDM2A is known to be involved in β-catenin degradation. We detected significant associations between the presence of β-catenin and autophagy-associated proteins in NI. Double-IF revealed co-localization of β-catenin and p62 in the same NI. Kaplan-Meier survival analysis showed that the presence of NI containing KDM2A protein accumulations displayed a significant benefit in overall survival. Conclusion: We detected accumulations of β-catenin and proteins associated with the Wnt/β-catenin pathway partly together with autophagy-associated proteins in the same inclusion. Our finding that KDM2A immunopositivity within NIs was associated with favorable clinical outcomes and suggests a biological significance of NI. CA Baba

Fatty liver disease is a rising problem worldwide, particularly due to metabolic syndrome. The current prevalence is 20-30%, but a further increase is expected whereby children will also be increasingly affected. The presence of fat in hepatocytes is known as steatosis or, in the case of nonalcoholic origin, nonalcoholic fatty liver (NAFL). It is basically reversible, but can progress to steatohepatitis (NASH) as an active and progressive form of fatty liver disease due to continuous cell damage. This leads to progressive liver fibrosis up to end-stage liver cirrhosis. The gold standard of diagnosis is liver biopsy, in which obesity, inflammation, and hepatocellular damage (hepatocellular ballooning) are assessed for the distinction between NAFL and NASH. The extent of fibrosis indicates the progress of the disease. Childhood and adult fatty liver diseases differ morphologically, particularly in the location and amount of fat, inflammation, and fibrosis. Alcoholic and nonalcoholic fatty liver disease/steatohepatitis cannot be reliably differentiated by histology. Clinical parameters must also be taken into consideration for the differential diagnosis of other diseases associated with fatty liver. The main therapeutic goal is to reduce insulin resistance, which can be achieved through weight loss and lifestyle changes. Recently, however, drug therapies have also become available as a promising therapeutic option.

Strumal carcinoid is an extraordinary rare tumor of the ovary consisting of thyroid tissue intermixed with neuroendocrine tumor component. The cellular origin of strumal carcinoids has been an area of debate. There is also little data on detailed immunohistochemical and molecular characteristics of these neoplasms. For this reason, this series investigated the characteristics of a series of 13 strumal carcinoids using immunohistochemical markers and a 47-gene next-generation sequencing (NGS) solid tumor panel analysis. Both cellular components showed thyroglobulin expression in all tumors. TTF-1 expression was noted in both cellular components of 11 cases. Chromogranin A was positive in both components of most tumors (n = 12, 92.3% in the neuroendocrine component and n = 10, 76.9% in the thyroid follicular component). Synaptophysin stained the neuroendocrine component of all cases, and it was also identified in the follicular thyroid component of a single case. All tumors were negative for CDX2 and calcitonin. ISLET1 was positive in the neuroendocrine component of 8 cases (6.5%). With the exception of one case, all tumors were positive for SSTR2a. The tumors were associated with a low Ki67 labeling index. All cases were microsatellite stable and no pathogenic mutations were identified using a 47-gene NGS solid tumor analysis. This series underscored that strumal carcinoids are distinct neuroendocrine tumors. The synchronous expression for thyroid follicular epithelial and neuroendocrine differentiation biomarkers may suggest a precursor cell origin displaying mixed-amphicrine differentiation. While strumal carcinoids can be diagnosed by their typical morphology and immunohistochemical profile, frequent SSTR expression may serve as a potential theranostic biomarker in the management of affected patients. In addition, the absence of common driver mutations in the NGS solid tumor panel may suggest that these neoplasms seem to be genetically unrelated to follicular epithelial–derived thyroid tumors and potentially different than other commonly identified well-differentiated neuroendocrine neoplasms. Therefore, further studies focusing on molecular characteristics of this entity are still needed.

Introduction Medullary thyroid carcinoma (MTC) is an aggressive neuroendocrine neoplasia of the thyroid with 10 year overall survival of 50% and limited therapeutic options. High tumor mutational burden because of microsatellite instability (MSI) seems to be a predictor of response to immune checkpoint inhibitor therapy in different tumors. Therefor in 2017 the U.S. Food and Drug Administration (FDA) permitted the therapy of solid tumors with proven Microsatellite instability (MSI) with PD1 antibody Pembrolizumab independently of their origin. As little is known about MSI in MTC and new therapeutic strategies would be eligible we tried to find out, if therapy with PD1-inhibitors could be promising. Material and methods We performed MSI-analyses of 38 cases of MTC. Included were MTCs with and without stromal desmoplasia and with/without lymph node metastases. We also checked the immunhistochemical expression of PD-L-1 and performed next generation sequencing for genetic alterations. Results All cases revealed stable conditions of the microsatellites and showed immunohistochemically positive staining of the four mismatch repair proteins. PD-L-1- Immunostaining was negative in all cases. Discussion Our data show there is no MSI in MTCs, irrespectively of their status of desmoplasia, metastases and/or ret-mutation. Therefore a positive effect of PD1 inhibitors, because of MSI-associated high tumor mutational burden, seems to be unlikely.

Zusammenfassung Anamnese und klinischer Befund Wir berichten über eine 27-jährige syrische Patientin, die aufgrund eines Kollapses in die Notaufnahme kam. Die Anamnese war praktisch nicht zu erheben, sodass die klinische Symptomatik führend war. Untersuchungen und Diagnose Es bestand ein Schock, mit einem Exanthem einhergehend. Zusätzlich fiel perioral Hämatin auf. Es erfolgte eine Sonografie mit Nachweis freier intraabdomineller Flüssigkeit sowie einer unklaren Veränderung im Oberbauch. Eine Ösophagogastroduodenoskopie erbrachte einen Ulkusnachweis, erklärte aber nicht das Geschehen. Die Computertomografie des Abdomens zeigte eine rupturierte Zyste. Therapie und Verlauf Durch eine antiallergische Therapie erfolgte die Stabilisierung. Unter dem Verdacht einer Echinokokkuszyste aufgrund der Herkunft der Patientin und des Verlaufs wurde nach Gabe von Albendazol die Leberteilresektion durchgeführt. Der makroskopische Befund sowie die Histologie bestätigten den Verdacht. Folgerung Eine unklare klinische Symptomatik, die mit einem Schock einhergeht, sollte bei Ausschluss einer Sepsis oder Blutung immer eine allergische Reaktion berücksichtigen. Kommt es zu einer Anaphylaxie, so ist immer eine Echinokokkose differenzialdiagnostisch miteinzubeziehen.

Fettlebererkrankungen nehmen weltweit, insbesondere ernahrungsbedingt, zu. Die Pravalenz liegt bereits bei 20–30 %. Ein weiterer Anstieg der Fallzahlen wird erwartet, wobei auch zunehmend Kinder betroffen sein werden. Die reine Einlagerung von Fett in die Hepatozyten bezeichnet man als Steatose bzw. bei nichtalkoholischer Genese als nichtalkoholische Fettleber (NAFL). Dabei handelt es sich um eine prinzipiell reversible Erkrankung, die sich aber durch fortwahrende Zellschadigung zu einer nichtalkoholischen Steatohepatitis (NASH) als aktive und progrediente Form der Fettlebererkrankung weiterentwickeln kann. Dabei entsteht eine fortschreitende Leberfibrose bis hin zur Leberzirrhose im Endstadium. Goldstandard der Diagnostik ist die Leberbiopsie, in der Verfettung, Entzundung und hepatozellularer Schaden (hepatozellulare Ballonierung) fur die Unterscheidung NAFL/NASH beurteilt werden. Das Ausmas der Fibrose bezeichnet dabei den Fortschritt der Erkrankung. Fettlebererkrankungen bei Kindern und Erwachsenen unterscheiden sich morphologisch insbesondere in Lokalisation und Ausmas von Verfettung, Entzundung und Fibrose. Alkoholische und nichtalkoholische Fettlebererkrankung/Steatohepatitis konnen histopathologisch nicht zuverlassig voneinander unterschieden werden. Auch zur Differenzialdiagnostik anderer Grunderkrankungen, die mit einer Einlagerung von Fett in die Leber einhergehen konnen, mussen zumeist klinische Parameter mitberucksichtigt werden. Therapeutisch ist das Hauptziel die Verringerung der Insulinresistenz, die durch Gewichtsreduktion und Lebensstilanderung erreicht werden kann. Neuerdings stehen aber auch medikamentose Therapien als vielversprechende Option zur Verfugung.

The morphological differentiation between benign and malignant adrenocortical tumors is an ongoing problem in diagnostic pathology. In recent decades the complex scoring systems have been widely used to calculate the probability of malignancy in adrenocortical tumors on the basis of a variety of histomorphological parameters. We herewith present a substantially simplified method to diagnose adrenocortical carcinoma by a single histomorphological parameter on a consecutive series of more than 800 adrenocortical tumors. Between January 2000 and May 2019, altogether 2305 adrenalectomies for of all types of diseases were removed, approximately 98% by minimally invasive approaches. After exclusion of pheochromocytomas, adrenal ganglioneuromas, adrenal metastases, Cushing’s disease related specimens, and Conn’s adenomas, the present series finally consisted of 837 adrenocortical tumors. All tumors were analyzed by experienced pathologists of a single institution using standard histopathological methods (Hematoxylin-Eosin and Ki67 stained sections). Clinical and histopathologic data were prospectively collected and retrospectively analyzed. Clinically, 385 patients had 420 functioning tumors (FT), and 417 had non-functioning adrenal tumors (NFT). The mean size of FT was 3.8 ± 1.4 cm (range 0.5–16 cm) and for NFT 4.5 ± 1.6 cm (range 1.5–18 cm). Histomorphologically, 32 adrenal tumors were classified as adrenocortical carcinoma (ACC; 3.8%). In all 32 cases (tumor size 9.1 ± 4.0 cm, range 3–18 cm), confluenting tumor necrosis could be demonstrated. The remaining 805 tumors (control group) completely lacked this highly reproducible single morphological feature. Ki67 levels above 10% were found in 31 of 32 ACCs and never in adrenocortical adenomas (ACA). With a mean follow-up of 8.2 years, 24 out of 32 patients primarily diagnosed as ACC developed distant metastases (75.0%), whereas all patients in the control group remained free of local or distant recurrence. We conclude that a single morphological parameter (confluenting tumor necrosis) is sufficient to predict a poor clinical course in adrenocortical tumors. The histomorphological diagnosis of this parameter is straightforward and highly reproducible.

Der klinische Begriff „differenziertes Schilddrusenkarzinom“ (DTC) umfasst das follikulare (FTC) und papillare Karzinom (PTC). In der diagnostischen Schilddrusenpathologie wird der Begriff „differenziertes Karzinom (NOS)“ nur sehr selten bei Tumoren mit morphologischen Merkmalen sowohl des FTC und als auch des PTC verwendet. In der derzeit gultigen WHO-Klassifikation der Schilddrusentumoren wurde die Entitat der nichtinvasiven follikularen Neoplasie mit PTC-aquivalenten Kernmerkmalen (NIFTP) eingefuhrt; dadurch mussten die Diagnosekriterien des papillaren Karzinoms angepasst werden (zwingender histologischer Nachweis der Invasion und/oder von Papillen), was auch das diagnostische Potenzial der Feinnadelbiopsie (FNB) der Schilddruse deutlich limitiert hat. Das FTC wird nunmehr in drei Subgruppen unterteilt. Ebenso etablierte die WHO-Klassifikation die diagnostischen Kriterien des gering differenzierten Schilddrusenkarzinoms (PDTC), dessen Abgrenzung von differenzierten Karzinomen, aber auch vom gutartigen Adenom von eminenter Bedeutung ist. Der vorliegende Artikel stellt auch den gegenwartigen diagnostischen Stellenwert molekularpathologischer Analysen von Schilddrusentumoren dar.

Background & Aims: Primary sclerosing cholangitis (PSC) is characterized by chronic cholestasis and inflammation, which promotes cirrhosis and an increased risk of cholangiocellular carcinoma (CCA). The transcription factor Krueppel-like-factor-6 (KLF6) is a mediator of liver regeneration, steatosis, and hepatocellular carcinoma (HCC), but no data are yet available on its potential role in cholestasis. Here, we aimed to identify the impact of hepatic KLF6 expression on cholestatic liver injury and PSC and identify potential effects on farnesoid-X-receptor (FXR) signalling. Methods: Hepatocellular KLF6 expression was quantified by immunohistochemistry (IHC) in liver biopsies of PSC patients and correlated with serum parameters and clinical outcome. Liver injury was analysed in hepatocyte-specific Klf6-knockout mice following bile duct ligation (BDL). Chromatin-immunoprecipitation-assays (ChIP) and KLF6-overexpressing HepG2 cells were used to analyse the interaction of KLF6 and FXR target genes such as NR0B2. Results: Based on IHC, PSC patients could be subdivided into two groups showing either low (80%) hepatocellular KLF6 expression. In patients with high KLF6 expression, we observed a superior survival in Kaplan-Meier analysis. Klf6-knockout mice showed reduced hepatic necrosis following BDL when compared to controls. KLF6 suppressed NR0B2 expression in HepG2 cells mediated through binding of KLF6 to the NR0B2 promoter region. Conclusion: Here, we show an association between KLF6 expression and the clinical course and overall survival in PSC patients. Mechanistically, we identified a direct interaction of KLF6 with the FXR target gene NR0B2.

Papillary thyroid carcinomas (PTCs) account for 90% of human thyroid cancer cases, which represent 1% of all cancer cases. They are likely to develop from papillary thyroid microcarcinomas (PTMCs), found in up to 36% of healthy individuals, due to rare progression events (0.01%). Although the prognosis of PTCs is excellent, 5% to 10% of tumors display an unfavorable outcome. About 45% of PTCs exhibit activating BRAFV600E mutations. Rats of the inbred BD strains postnatally exposed to the carcinogen N-ethyl-N-nitrosourea developed PTMCs, which closely resembled their human counterparts judging from their histology, size, and marginal tendency to progress. DNA sequencing revealed mutations in exon 15 of the Braf gene identical to the human BRAFV600E mutation in 82% of the cases. Predominantly a 50:50 ratio of wild-type to mutant Braf alleles was seen regardless of tumor size or animal age, indicating that the Braf mutation is an early, if not the initial, event in rat PTMC development. Surprisingly, most PTMCs carrying a confirmed BrafV600E mutation did not display BrafV600E protein expression. As the BrafV600Egene is supposed to be the driver in PTC development, down-regulation of expression should contribute to the low risk for progression of PTMC. This model system will enable further insights into the molecular mechanisms of PTMC initiation and progression to PTC, further translating into targeted tumor prevention strategies/therapies.

A 67-year-old woman presented with malignant struma ovarii after radical bilateral salpingo-oophorectomy. The surgery revealed a 4.4 cm papillary thyroid carcinoma (follicular variant) within a right-sided ovarian teratoma. I sodium iodide positron emission tomography / computed tomography and cervical ultrasound showed 2 slightly hyperfunctional thyroid nodules and several metastases, including bone metastases with intense iodine uptake. Thyroidectomy was necessary in preparation for radioiodine therapy and proofed the thyroid nodules to be benign. Complete remission was achieved by single radioiodine therapy (30 months of follow-up).

Background: Radioiodine refractory dedifferentiated thyroid cancer is a major clinical challenge. Anaplastic lymphoma kinase (ALK) mutations with increased ALK activity, especially fusion genes, have been suggested to promote thyroid carcinogenesis, leading to development of poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma. To determine the oncogenic potential of increased ALK activity in thyroid carcinogenesis in vivo, we studied mice with thyrocyte-specific expression of a constitutively active ALK mutant. Methods: Mice carrying a Cre-activated allele of a constitutively active ALK mutant (F1174L) were crossed with mice expressing tamoxifen-inducible Cre recombinase (CreER(T2)) under the control of the thyroglobulin (Tg) gene promoter to achieve thyrocyte-specific expression of the ALK mutant (ALK(F1174L) mice). Survival, thyroid hormone serum concentration, and tumor development were recorded. Thyroids and lungs were studied histologically. To maintain euthyroidism despite dedifferentiation of the thyroid, a cohort was substituted with levothyroxine (LT4) through drinking water. Results: ALK(F1174L) mice developed massively enlarged thyroids, which showed an early loss of normal follicular architecture 12 weeks after tamoxifen injection. A significant decrease in Tg and Nkx-2.1 expression as well as impaired thyroid hormone synthesis confirmed dedifferentiation. Histologically, the mice developed a carcinoma resembling human PDTC with a predominantly trabecular/solid growth pattern and an increased mitotic rate. The tumors showed extrathyroidal extension into the surrounding strap muscles and developed lung metastases. Median survival of ALK(F1174L) mice was significantly reduced to five months after tamoxifen injection. Reduced Tg expression and loss of follicular structure led to hypothyroidism with elevated thyrotropin (TSH). To test whether TSH stimulation played a role in thyroid carcinogenesis, we kept ALK(F1174L) mice euthyroid by LT4 substitution. These mice developed PDTC with identical histological features compared with hypothyroid mice, demonstrating that PDTC development was due to increased ALK activity and not dependent on TSH stimulation. Conclusion: Expression of a constitutively activated ALK mutant in thyroids of mice leads to development of metastasizing thyroid cancer resembling human PDTC. These results demonstrate in vivo that increased ALK activity is a driver mechanism in thyroid carcinogenesis.

Papillary thyroid carcinomas (PTCs) account for 90% of human thyroid cancer cases, which represent 1% of all cancer cases. They are likely to develop from papillary thyroid microcarcinomas (PTMCs), found in up to 36% of healthy individuals, due to rare progression events (0.01%). Although the prognosis of PTCs is excellent, 5% to 10% of tumors display an unfavorable outcome. About 45% of PTCs exhibit activating BRAF

Thyroid hormones are important for physiology and homeostasis. In addition to nuclear thyroid hormone receptors, the plasma membrane protein integrin αvβ3 has been recognized as a receptor for both thyroxine (T4) and triiodothyronine (T3). Here, we studied whether thyroid hormone promotes growth of murine lung cancer via αvβ3 in vivo. Murine Lewis lung carcinoma cells (3LL), stably transfected with luciferase, were injected into mouse lungs. Tumor growth in untreated mice was compared to hypothyroid mice and hypothyroid mice treated with T3 or T4 with or without the αvβ3 inhibitor 3,5,3′,5′-tetraiodothyroacetic acid (Tetrac). Tumor progression was determined by serial in vivo imaging of bioluminescence emitted from the tumor. Tumor weight was recorded at the end of the experiment. Neoangiogenesis was determined by immunohistochemistry for CD31. Tumor growth was reduced in hypothyroidism and increased by T4 treatment. Strikingly, only T4 but not T3 treatment promoted tumor growth. This T4 effect was abrogated by the αvβ3 inhibitor Tetrac. Tumor weight and neoangiogenesis were also significantly increased only in T4-treated mice. The T4 effect on tumor weight and neoangiogenesis was abolished by Tetrac. In vitro, T4 did not stimulate 3LL cell proliferation or signaling pathway activation. We conclude that T4 promotes lung cancer growth in this orthotopic mouse model. The tumor-promoting effect is mediated via the plasma membrane integrin αvβ3 and increased neoangiogenesis rather than direct stimulation of 3LL cells. These data suggest that such effects of levothyroxine may need to be considered in cancer patients on T4 substitution.

Intraorbitale Meningeome sind extrem seltene Tumoren und machen nur 4 % aller orbitalen Tumoren aus. Im Kindesalter sind sie Raritaten und nur in Einzelfallen beschrieben. Der hier vorgestellte Fall dokumentiert ein primares Meningeom des Nervus opticus mit intraokularer Ausdehnung bei einem 8 Monate alten Kind, das mit Strabismus und Nystagmus auffallig geworden war. Eine MRT-Untersuchung zeigte eine langstreckige Verdickung des Nervus opticus mit einem intraokularen Tumor. Bei unklarem Befund wurde das Auge zur Diagnosesicherung bzw. zum Tumorausschluss enukleiert. Histologisch zeigte sich das typische Bild eines meningothelialen Meningeoms (WHO Grad I) mit ausgedehnter Extension entlang des Nervus opticus und nach intraokular sowie zusatzlich eine Retinadysplasie und epiretinale Membranen. Da eine Assoziation zwischen kindlichen Meningeomen, Retinadysplasie und epiretinalen Membranen mit einer Neurofibromatose Typ 2 besteht, wurden bei dem Kind entsprechende humangenetische Untersuchungen eingeleitet, die schlussendlich zur Diagnose einer Neurofibromatose Typ 2 fuhrten. Dieser Fall dokumentiert eine ausergewohnlich fruhe Manifestation einer Neurofibromatose Typ 2 mit Entwicklung eines intraorbitalen Meningeoms.

Objectives To investigate a correlation between 68Ga-DOTATOC PET/MR imaging parameters such as arterial and venous contrast enhancement, diffusion restriction, and maximum standardized uptake value (SUVmax) with histopathological tumor grading in patients with neuroendocrine neoplasms (NEN). Material and methods A total of 26 patients with newly diagnosed, therapy-naive neuroendocrine neoplasms (NEN) were enrolled in this prospective study and underwent 68Ga-DOTATOC PET/MRI. Images were evaluated regarding NEN lesion number and location, predominant tumor signal intensity on precontrast T1w and T2w images and on postcontrast arterial and portal venous phase T1w images, apparent diffusion coefficient (ADC) and SUVmax. Histopathological tumor grading was assessed and related to PET/MRI features using Pearson’s correlation coefficient and Fisher’s exact t-test. A binary logistic regression analysis was performed to evaluate a potential relation with an aggressive tumor biology and odds ratios (OR) were calculated. Results There was a moderate negative correlation between arterial contrast enhancement and tumor grading (r=-0.35, p = 0.005), while portal venous enhancement showed a weak positive correlation with the Ki-67 index (r = 0.28, p = 0.008) and a non-significant positive correlation with tumor grading (r = 0.19, p = 0.063). Features that were significantly associated with an aggressive tumor biology were the presence of liver metastases (OR 2.6, p = 0.042), T1w hyperintensity in comparison to muscle (OR 12.7, p = 0.0001), arterial phase hyperenhancement (OR 1.4, p = 0.001), diffusion restriction (OR 2.8, p = 0.02) and SUVmax above the hepatic level (OR 7.0, p = 0.001). Conclusion The study reveals that PET/MRI features might be useful for prediction of NEN grading and thus provide a preliminary assessment of tumor aggressiveness.

Purpose To investigate whether potential differences in staging between a traditional staging imaging algorithm and 18F-FDG PET/MR lead to a change in patient management in breast carcinoma and to compare the diagnostic accuracy between the traditional staging algorithm and 18F-FDG PET/MR for the TNM classification. Method In this prospective cohort study from two university hospitals 56 women with newly diagnosed, therapy-naive breast cancer and increased pre-test probability for distant metastases were included. All patients were examined by a traditional staging imaging algorithm (X-ray mammography, breast ultrasonography, chest plain radiography, bone scintigraphy, and ultrasonography of the liver and axillary fossa) and whole-body 18F-FDG PET/MR including dedicated 18F-FDG PET/MR breast examinations. Each patient was discussed two times in a separate tumor board session to determine a total of three therapy recommendations based on histopathological data of the primary tumor and (1) traditional algorithm only, (2) traditional algorithm and 18F-FDG PET/MR, and (3) 18F-FDG PET/MR only. Major changes in therapy recommendations and differences between the traditional staging algorithm and 18F-FDG PET/MR for the TNM classification were evaluated. Results Staging by 18F-FDG PET/MR led to a difference in treatment compared the traditional staging algorithm in 8/56 cases (14%). Therapy changes included therapy of the breast, locoregional nodes and systemic therapy. A trend to staging superiority was found for 18F-FDG PET/MRI without statistical significance (p = 0.3827). Conclusion In conclusion, for breast cancer patients with elevated pre-test probability for distant metastases a change of the therapy regiment occurs in 14 % of patients when staged by 18F-FDG PET/MR and confirmed by histopathology compared to a traditional staging algorithm. In particular with regard to the amendment of the guideline further assessment of 18F-FDG-PET/MR in this setting is necessary to assess the true value of this modality.

Ektopes Schilddrusengewebe entsteht durch entwicklungsgeschichtliche Defekte der fruhen Stadien der Schilddrusenembryogenese, bei der es zu einem Deszensus der medianen Schilddrusenanlage vom Mundboden zu ihrer endgultigen pratrachealen Position kommt. Die haufigsten Lokalisationen ektopen Gewebes sind dementsprechend im Bereich des Mundbodens und im Verlauf des Ductus thyreoglossus; seltene Lokalisationen sind intrathorakal (mediastinal, kardial, pulmonal) und unterhalb des Zwerchfells (u. a. Nebennieren, Leber, Gallenblase, Gastrointestinaltrakt). Die wichtigste Differenzialdiagnose ist die Unterscheidung von Metastasen eines differenzierten Schilddrusenkarzinoms. Die Nebenschilddrusenektopie ist dagegen nicht einheitlich definiert. Ublicherweise werden die Positionen zervikal-zentral als „Lagevarianten“ bezeichnet (ausgenommen Kieferhohle, hoch parapharyngeal) und die zervikal-lateralen (Karotisscheide, N. vagus) und die unterhalb der V. brachiocephalica und mediastinalen (extraligamentar, aortopulmonales Fenster, paravagal) sowie seltenere Positionen als „ektope Lage“ eingeordnet. Nebenschilddrusenektopien sind haufig (in Autopsiestudien in 28–42,8 % aller Menschen). Im Rahmen eines primaren Hyperparathyreoidismus (pHPT) besteht eine Pravalenz von 6,3–16 % von ektopem hyperfunktionalem Nebenschilddrusengewebe (ganz uberwiegend Adenome), die bei der chirurgischen Therapie des pHPT eine wichtige Rolle spielen.