[Histopathologic diagnosis of solid and cystic pancreatic lesions with a focus on ductal adenocarcinoma : A vademecum for daily practice]. / Histopathologische Diagnostik von soliden und zystischen Pankreasläsionen mit Hauptaugenmerk auf dem duktalen Adenokarzinom : Ein Vademecum für den Alltag.

Pancreas pathology is constantly evolving and can present various challenges for pathologists. This paper is focused on providing helpful hints for daily routine diagnostics. During histopathological analysis of pancreas biopsies, pancreatic ductal adenocarcinoma must be distinguished not only from other solid neoplasms, but especially from its mimicker, autoimmune pancreatitis. This can be achieved by a systematic workup following clear diagnostic criteria. When analyzing samples from cystic pancreatic lesions, mucin-producing neoplasms must be detected due to their role as pancreatic cancer precursors; molecular analyses can help considerably with their detection and distinction. During frozen section examination, evaluation of the pancreatic neck margin and analysis of unclear lesions of the liver are two important tasks, which are explained further in this article. A special challenge is the evaluation of neoadjuvant treated pancreatic cancer, which requires a detailed macroscopic and microscopic workup. Finally, current advances in precision oncology and emerging approaches for pancreatic cancer within this field are discussed. With the advancement of technical possibilities and their increasingly broad implementation, the classification systems in pancreatic pathology will continue to gain in complexity, but also in accuracy.

Ultra-sensitive CTC-based liquid biopsy for pancreatic cancer enabled by large blood volume analysis.

The limited sensitivity of circulating tumor cell (CTC) detection in pancreatic adenocarcinoma (PDAC) stems from their extremely low concentration in the whole circulating blood, necessitating enhanced detection methodologies. This study sought to amplify assay-sensitivity by employing diagnostic leukapheresis (DLA) to screen large blood volumes. Sixty patients were subjected to DLA, with a median processed blood volume of ~ 2.8 L and approximately 5% of the resulting DLA-product analyzed using CellSearch (CS). Notably, DLA significantly increased CS-CTC detection to 44% in M0-patients and 74% in M1-patients, yielding a 60-fold increase in CS-CTC enumeration. DLA also provided sufficient CS-CTCs for genomic profiling, thereby delivering additional genomic information compared to tissue biopsy samples. DLA CS-CTCs exhibited a pronounced negative prognostic impact on overall survival (OS), evidenced by a reduction in OS from 28.6 to 8.5 months (univariate: p = 0.002; multivariable: p = 0.043). Additionally, a marked enhancement in sensitivity was achieved (by around 3-4-times) compared to peripheral blood (PB) samples, with positive predictive values for OS being preserved at around 90%. Prognostic relevance of CS-CTCs in PDAC was further validated in PB-samples from 228 PDAC patients, consolidating the established association between CTC-presence and reduced OS (8.5 vs. 19.0 months, p < 0.001). In conclusion, DLA-derived CS-CTCs may serve as a viable tool for identifying high-risk PDAC-patients and aiding the optimization of multimodal treatment strategies. Moreover, DLA enables comprehensive diagnostic profiling by providing ample CTC material, reinforcing its utility as a reliable liquid-biopsy approach. This high-volume liquid-biopsy strategy presents a potential pathway for enhancing clinical management in this malignancy.

Conventional Imaging, MRI and 18F-FDG PET/MRI for N and M Staging in Patients with Newly Diagnosed Breast Cancer.

Background: This study compares the diagnostic potential of conventional staging (computed tomography (CT), axillary sonography and bone scintigraphy), whole-body magnetic resonance imaging (MRI) and whole-body 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET/)MRI for N and M staging in newly diagnosed breast cancer. Methods: A total of 208 patients with newly diagnosed breast cancer were prospectively included in this study and underwent contrast-enhanced thoracoabdominal CT, bone scintigraphy and axillary sonography as well as contrast-enhanced whole-body 18F-FDG PET/MRI. The datasets were analyzed with respect to lesion localization and characterization. Histopathology and follow-up imaging served as the reference standard. A McNemar test was used to compare the diagnostic performance of conventional staging, MRI and 18F-FDG PET/MRI and a Wilcoxon test was used to compare differences in true positive findings for nodal staging. Results: Conventional staging determined the N stage with a sensitivity of 80.9%, a specificity of 99.2%, a PPV (positive predictive value) of 98.6% and a NPV (negative predictive value) of 87.4%. The corresponding results for MRI were 79.6%, 100%, 100% and 87.0%, and were 86.5%, 94.1%, 91.7% and 90.3% for 18F-FDG PET/MRI. 18F-FDG PET/MRI was significantly more sensitive in determining malignant lymph nodes than conventional imaging and MRI (p < 0.0001 and p = 0.0005). Furthermore, 18F-FDG PET/MRI accurately estimated the clinical lymph node stage in significantly more cases than conventional imaging and MRI (each p < 0.05). Sensitivity, specificity, PPV and NPV for the M stage in conventional staging were 83.3%, 98.5%, 76.9% and 98.9%, respectively. The corresponding results for both MRI and 18F-FDG PET/MRI were 100.0%, 98.5%, 80.0% and 100.0%. No significant differences between the imaging modalities were seen for the staging of distant metastases. Conclusions:18F-FDG PET/MRI detects lymph node metastases in significantly more patients and estimates clinical lymph node stage more accurately than conventional imaging and MRI. No significant differences were found between imaging modalities with respect to the detection of distant metastases.

Treatment Pathways and Prognosis in Advanced Sarcoma with Peritoneal Sarcomatosis.

Sarcomas represent a heterogeneous group of mesenchymal malignancies that most commonly occur in the extremities, retroperitoneum, and head and neck. Intra-abdominal manifestations are rare and prove particularly difficult to treat when peritoneal sarcomatosis is present. Because of the overall poor prognosis of the disease, a tailored approach to surgical management is essential to achieve satisfactory outcomes with limited morbidity. We present the perioperative and long-term outcomes of 19 cases of sarcoma with peritoneal sarcomatosis treated surgically at our hospital. Treatment pathways were reviewed and clinical follow-up was performed. Patient characteristics, medical history, tumor subtype, surgical approach, hospital stay, complications, follow-up, and overall survival (OS) were assessed. Our patients were 9 women and 10 men with a median age of 45.9 years (18-88) and a median survival of 30 months (0-200). In most cases, peritoneal sarcomatosis was either discovered during surgery or the procedure was performed with palliative intent from the beginning. The surgical approach in these cases is very heterogeneous and should consider a variety of factors to tailor an approach for each patient. Sharing our experiences will help to increase knowledge about this rare disease and provide insight into the management of future cases.

Clinical Decision Support for Axillary Lymph Node Staging in Newly Diagnosed Breast Cancer Patients Based on 18F-FDG PET/MRI and Machine Learning.

In addition to its high prognostic value, the involvement of axillary lymph nodes in breast cancer patients also plays an important role in therapy planning. Therefore, an imaging modality that can determine nodal status with high accuracy in patients with primary breast cancer is desirable. Our purpose was to investigate whether, in newly diagnosed breast cancer patients, machine-learning prediction models based on simple assessable imaging features on MRI or PET/MRI are able to determine nodal status with performance comparable to that of experienced radiologists; whether such models can be adjusted to achieve low rates of false-negatives such that invasive procedures might potentially be omitted; and whether a clinical framework for decision support based on simple imaging features can be derived from these models. Methods: Between August 2017 and September 2020, 303 participants from 3 centers prospectively underwent dedicated whole-body 18F-FDG PET/MRI. Imaging datasets were evaluated for axillary lymph node metastases based on morphologic and metabolic features. Predictive models were developed for MRI and PET/MRI separately using random forest classifiers on data from 2 centers and were tested on data from the third center. Results: The diagnostic accuracy for MRI features was 87.5% both for radiologists and for the machine-learning algorithm. For PET/MRI, the diagnostic accuracy was 89.3% for the radiologists and 91.2% for the machine-learning algorithm, with no significant differences in diagnostic performance between radiologists and the machine-learning algorithm for MRI (P = 0.671) or PET/MRI (P = 0.683). The most important lymph node feature was tracer uptake, followed by lymph node size. With an adjusted threshold, a sensitivity of 96.2% was achieved by the random forest classifier, whereas specificity, positive predictive value, negative predictive value, and accuracy were 68.2%, 78.1%, 93.8%, and 83.3%, respectively. A decision tree based on 3 simple imaging features could be established for MRI and PET/MRI. Conclusion: Applying a high-sensitivity threshold to the random forest results might potentially avoid invasive procedures such as sentinel lymph node biopsy in 68.2% of the patients.

Multiparametric 18F-FDG PET/MRI-Based Radiomics for Prediction of Pathological Complete Response to Neoadjuvant Chemotherapy in Breast Cancer.

BACKGROUND: The aim of this study was to assess whether multiparametric 18F-FDG PET/MRI-based radiomics analysis is able to predict pathological complete response in breast cancer patients and hence potentially enhance pretherapeutic patient stratification. METHODS: A total of 73 female patients (mean age 49 years; range 27-77 years) with newly diagnosed, therapy-naive breast cancer underwent simultaneous 18F-FDG PET/MRI and were included in this retrospective study. All PET/MRI datasets were imported to dedicated software (ITK-SNAP v. 3.6.0) for lesion annotation using a semi-automated method. Pretreatment biopsy specimens were used to determine tumor histology, tumor and nuclear grades, and immunohistochemical status. Histopathological results from surgical tumor specimens were used as the reference standard to distinguish between complete pathological response (pCR) and noncomplete pathological response. An elastic net was employed to select the most important radiomic features prior to model development. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were calculated for each model. RESULTS: The best results in terms of AUCs and NPV for predicting complete pathological response in the entire cohort were obtained by the combination of all MR sequences and PET (0.8 and 79.5%, respectively), and no significant differences from the other models were observed. In further subgroup analyses, combining all MR and PET data, the best AUC (0.94) for predicting complete pathologic response was obtained in the HR+/HER2- group. No difference between results with/without the inclusion of PET characteristics was observed in the TN/HER2+ group, each leading to an AUC of 0.92 for all MR and all MR + PET datasets. CONCLUSION: 18F-FDG PET/MRI enables comprehensive high-quality radiomics analysis for the prediction of pCR in breast cancer patients, especially in those with HR+/HER2- receptor status.

[Pancreatic cystic space-occupying lesions-Diagnostics, treatment and follow-up care : Current recommendations taking the current German S3 guidelines on pancreatic cancer into account]. / Zystische Pankreasraumforderungen ­ Diagnostik, Therapie und Nachsorge : Aktuelle Empfehlungen unter Berücksichtigung der aktuellen S3-Leitlinie zum Pankreaskarzinom.

Due to their increased detection pancreatic cystic space-occupying lesions are becoming increasingly relevant in the clinical routine and represent a morphologically and biologically heterogeneous and thus clinically demanding as well as potentially (pre)malignant entity. As a result, recommendations for the diagnostics and treatment of pancreatic cystic tumors have now been incorporated into the current German S3 guidelines on pancreatic cancer. The diagnostics of pancreatic cystic space-occupying lesions are based on the following three elements: collection of relevant clinical information, performance of high-resolution imaging procedures and if diagnostic uncertainty persists, puncture diagnostics. Differentiated diagnostics are of essential importance as these represent the basis for an adequate treatment decision. Pancreatic cystic lesions with a relevant risk of malignant transformation, e.g., main duct intraductal papillary mucinous neoplasms (IPMN), followed by mucinous cystic neoplasms (MCN), solid pseudopapillary neoplasms (SPN) and generally pancreatic cystic lesions with risk factors independent of the entity, should be resected, whereas a differentiated and individualized approach is necessary, especially for branch-duct IPMNs. The serous cystic neoplasms (SCN) have no malignant potential and do not require any treatment if they are asymptomatic. Important principles in surgery of pancreatic cancer, such as adequate surgical resection taking oncological standards into account and standardized appropriate histopathological processing of the specimens as well as intraoperative frozen section analysis also play an important role in pancreatic cystic space-occupying lesions. An annual follow-up seems to be meaningful, especially for IPMNs.

Is there a diagnostic benefit of late-phase abdomino-pelvic PET/CT after urination as part of whole-body 68 Ga-PSMA-11 PET/CT for restaging patients with biochemical recurrence of prostate cancer after radical prostatectomy?

BACKGROUND: To assess the diagnostic value of an additional late-phase PET/CT scan after urination as part of 68 Ga-PSMA-11 PET/CT for the restaging of patients with biochemically recurrent prostate cancer (BCR). METHODS: This retrospective trial included patients with BCR following radical prostatectomy, who underwent standard whole-body early-phase PET/CT performed 105 ± 45 min and an additional late-phase PET/CT performed 159 ± 13 min after injection of 68 Ga-PSMA-11. Late-phase PET/CT covered a body volume from below the liver to the upper thighs and was conducted after patients had used the bathroom to empty their urinary bladder. Early- and late-phase images were evaluated regarding lesion count, type, localisation, and SUVmax. Reference standard was histopathology and/or follow-up imaging. RESULTS: Whole-body early-phase PET/CT detected 93 prostate cancer lesions in 33 patients. Late-phase PET/CT detected two additional lesions in two patients, both local recurrences. In total, there were 57 nodal, 28 bone, and 3 lung metastases, and 7 local recurrences. Between early- and late-phase PET/CT, lymph node metastases showed a significant increase of SUVmax from 14.5 ± 11.6 to 21.5 ± 17.6 (p = 0.00007), translating to a factor of + 1.6. Benign lymph nodes in the respective regions showed a significantly lower increase of SUVmax of 1.4 ± 0.5 to 1.7 ± 0.5 (p = 0.0014, factor of + 1.2). Local recurrences and bone metastases had a SUVmax on late-phase PET/CT that was + 1.7 and + 1.1 times higher than the SUVmax on early-phase PET/CT, respectively. CONCLUSION: In patients with BCR following radical prostatectomy, an additional abdomino-pelvic late-phase 68 Ga-PSMA-11 PET/CT scan performed after emptying the urinary bladder may help to detect local recurrences missed on standard whole-body 68 Ga-PSMA-11 PET/CT. Lymph node metastases show a higher SUVmax and a stronger increase of SUVmax than benign lymph nodes on late-phase PET/CT, hence, biphasic 68 Ga-PSMA-11 PET/CT might help to distinguish between malignant and benign nodes. Bone metastases, and especially local recurrences, also demonstrate a metabolic increase over time.

Comparison of nodal staging between CT, MRI, and [18F]-FDG PET/MRI in patients with newly diagnosed breast cancer.

PURPOSE: To compare CT, MRI, and [18F]-fluorodeoxyglucose positron emission tomography ([18F]-FDG PET/MRI) for nodal status, regarding quantity and location of metastatic locoregional lymph nodes in patients with newly diagnosed breast cancer. MATERIALS AND METHODS: One hundred eighty-two patients (mean age 52.7 ± 11.9 years) were included in this prospective double-center study. Patients underwent dedicated contrast-enhanced chest/abdomen/pelvis computed tomography (CT) and whole-body ([18F]-FDG PET/) magnet resonance imaging (MRI). Thoracal datasets were evaluated separately regarding quantity, lymph node station (axillary levels I-III, supraclavicular, internal mammary chain), and lesion character (benign vs. malign). Histopathology served as reference standard for patient-based analysis. Patient-based and lesion-based analyses were compared by a McNemar test. Sensitivity, specificity, positive and negative predictive values, and accuracy were assessed for all three imaging modalities. RESULTS: On a patient-based analysis, PET/MRI correctly detected significantly more nodal positive patients than MRI (p < 0.0001) and CT (p < 0.0001). No statistically significant difference was seen between CT and MRI. PET/MRI detected 193 lesions in 75 patients (41.2%), while MRI detected 123 lesions in 56 patients (30.8%) and CT detected 104 lesions in 50 patients, respectively. Differences were statistically significant on a lesion-based analysis (PET/MRI vs. MRI, p < 0.0001; PET/MRI vs. CT, p < 0.0001; MRI vs. CT, p = 0.015). Subgroup analysis for different lymph node stations showed that PET/MRI detected significantly more lymph node metastases than MRI and CT in each location (axillary levels I-III, supraclavicular, mammary internal chain). MRI was superior to CT only in axillary level I (p = 0.0291). CONCLUSION: [18F]-FDG PET/MRI outperforms CT or MRI in detecting nodal involvement on a patient-based analysis and on a lesion-based analysis. Furthermore, PET/MRI was superior to CT or MRI in detecting lymph node metastases in all lymph node stations. Of all the tested imaging modalities, PET/MRI showed the highest sensitivity, whereas CT showed the lowest sensitivity, but was most specific.

[Intraductal neoplasms of the pancreas]. / Intraduktale Pankreasneoplasien.

The latest WHO classification of tumors of the digestive system (2019) has introduced new concepts for the stratification of intraductal neoplasms of the pancreas, mostly based on molecular genetics and malignant potential. Among them, pancreatic intraepithelial neoplasias (PanINs) and intraductal papillary mucinous neoplasms (IPMN) are both precursors of pancreatic ductal adenocarcinoma, whereas intraductal oncocytic papillary neoplasms (IOPN) and intraductal tubulopapillary neoplasms (ITPN) are usually associated with less aggressive subtypes of pancreatic cancer and therefore have a much better prognosis. Hence, it is of utmost importance to correctly classify these lesions and to distinguish them from each other as well as from other nonductal types of neoplasms, which can rarely display an intraductal growth, such as neuroendocrine tumors and acinar cell carcinomas. PanIN are microscopic lesions with limited clinical significance. In contrast, all other intraductal neoplasms can be identified as cystic processes and/or solid tumors by means of imaging, thereby setting an indication for a potential surgical resection. This review presents diagnostically relevant aspects of intraductal neoplasms of the pancreas, which are instrumental for the discussion within interdisciplinary tumor boards (resection vs. watch-and-wait strategies) as well as to determine the extent of resection intraoperatively.

[Standardized diagnosis of pancreatic head carcinoma]. / Standardisierte Befundung des Pankreaskopfkarzinoms.

Most pancreatic ductal adenocarcinomas are localized in the pancreatic head. Due to the complex anatomic relationships with the surrounding organs and vascular structures in the retroperitoneal space and to the presence of numerous transection margins and dissection planes, pancreatic head resections belong to the most complex specimens concerning grossing and sampling for histopathologic analysis.Here we discuss current guidelines for standardized grossing and reporting of pancreatic cancer, with special reference to the assessment of the resection margin status. The importance of standardized reporting for the sake of completeness, comprehensibility, comparability, and quality control as well as for the integration of pathology reports in interdisciplinary digital workflows and artificial intelligence applications will be emphasized.

[Preoperative diagnostics of pancreatic neoplasms]. / Punktionsdiagnostik von Pankreasneoplasien.

While patients with clinico-radiologically diagnosed resectable pancreatic cancer usually undergo surgery without preoperative cytological or histopathological diagnostics, patients with inoperable tumors or ambiguous findings in imaging often undergo EUS-FNA or EUS-FNB (endoscopic ultrasound-guided fine-needle aspiration or endoscopic ultrasound-guided fine-needle biopsy). In many cases, this concerns pancreatic cystic lesions, which can range from benign inflammatory pseudocysts to invasive pancreatic cancer emerging from intraductal papillary mucinous neoplasms (IPMNs) or mucinous cystic neoplasms (MCNs). However, the evaluation of EUS-FNA material can be especially hampered by contamination with gastric or enteric cells or mucin, degenerative changes, or low or even no cellularity of the sample. Next-generation-sequencing-based molecular analyses, especially of cystic lesions, can significantly increase the accuracy of EUS-FNA diagnostics of the pancreas. Interpretation of morphological and molecular data considering each case's clinico-radiological context is crucial. While reliable molecular markers for the detection of mucinous and specific nonmucinous pancreatic neoplasms already exist, establishing valid markers for the detection of high-grade lesions is an urgent future goal.

Prospective Correlation of Prognostic Immunohistochemical Markers With SUV and ADC Derived From Dedicated Hybrid Breast 18F-FDG PET/MRI in Women With Newly Diagnosed Breast Cancer.

PURPOSE: The aim of this study was to correlate prognostically relevant immunohistochemical parameters of breast cancer with simultaneously acquired SUVs and apparent diffusion coefficient (ADC) values derived from hybrid breast PET/MRI. PATIENTS AND METHODS: Fifty-six women with newly diagnosed, therapy-naive, histologically proven breast cancer (mean age, 54.1 ± 12.0 years) underwent dedicated prone 18F-FDG breast PET/MRI. Diffusion-weighted imaging (b-values: 0, 500, 1000 s/mm2) was performed simultaneously with the PET acquisition. A region of interest encompassing the entire primary tumor on each patient's PET/MRI scan was used to determine the glucose metabolism represented by maximum and mean SUV as well as into corresponding ADC maps to assess tumor cellularity represented by mean and minimum ADC values. Histopathological tumor grading and prognostically relevant immunohistochemical markers, that is, Ki67, progesterone receptor, estrogen receptor, and human epidermal growth factor receptor 2 (HER2), were assessed. Pearson correlation coefficients were calculated to compare SUV and ADC values as well as the immunohistochemically markers and molecular subtype. For the comparison with the tumor grading, a Wilcoxon test was used. RESULTS: A significant inverse correlation between SUV and ADC values derived from breast PET/MRI (r = -0.49 for SUVmean vs ADCmean; r = -0.43 for SUVmax vs ADCmin; both P's < 0.001) was found. Tumor grading and Ki67 both showed a positive correlation with SUVmean from breast PET/MRI (r = 0.37 and r = 0.32, P < 0.01). For immunohistochemical markers, HER2 showed an inverse correlation with ADC values from breast PET/MRI (r = -0.35, P < 0.01). Molecular subtypes significantly correlate with SUVmax and SUVmean (r = 0.52 and r = 0.42, both P's < 0.05). In addition, estrogen receptor expression showed an inverse correlation with SUVmax and SUVmean from breast PET/MRI (r = -0.45 and r = -0.42, P < 0.001). CONCLUSIONS: The present data show a correlation between increased glucose metabolism, cellularity, tumor grading, estrogen and HER2 expression, as well as molecular subtype of breast cancer primaries. Hence, simultaneous 18F-FDG PET and diffusion-weighted imaging from hybrid breast PET/MRI may serve as a predictive tool for identifying high-risk breast cancer patients in initial staging and guide-targeted therapy.

Pathology assessment of pancreatic cancer following neoadjuvant treatment: Time to move on.

Neoadjuvant treatment has increasingly become an integral part of the multimodal management of patients with pancreatic cancer. In patients who are able to undergo surgery following preoperative therapy, tumour regression grading remains the diagnostic gold standard for the histomorphological assessment of the effect of neoadjuvant treatment. In recent years, however, there has been growing concern about inherent flaws of tumour regression grading systems as well as their imprecise and impractical criteria that result in divergence of practice and lack of interobserver agreement. Furthermore, existing tumour regression systems differ in their defining criteria and thresholds, leading to incomparability of data. In this review, the principles and limitations of the main existing tumour regression systems are discussed, and potential alternative assessment approaches and novel markers are presented.