Hálfdánarson, Þorvarður R.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare, but increasingly recognized entity that primarily affects middle-aged and elderly women. It is characterized by abnormal proliferation of pulmonary neuroendocrine cells (PNECs) and is considered a preinvasive lesion for carcinoid tumorlets/tumors. Sometimes, DIPNECH is accompanied by constrictive bronchiolitis which usually manifests as chronic cough and/or dyspnea, along with airflow limitation on spirometry. The telltale imaging sign of DIPNECH is the presence of multiple noncalcified pulmonary nodules and mosaic attenuation on CT. However, these clinico-radiologic features of DIPNECH are characteristic but nonspecific; thus, histopathologic confirmation is usually necessary. DIPNECH has an indolent course and only rarely leads to respiratory failure or death; progression to overt neuroendocrine tumor (carcinoid) of the lung occurs in a minority of patients. Of available therapies, somatostatin analogs and mechanistic target of rapamycin inhibitors are the most promising. In this review, we provide an update regarding the diagnosis and management of DIPNECH and describe critical gaps in our understanding of this entity, including the central terms ‘diffuse’ and ‘idiopathic.’ We also summarize the inconsistencies in definitions employed by recent studies and discuss the pitfalls of the DIPNECH definitions proposed by the World Health Organization in 2021. In this context, we propose an objective and reproducible radio-pathologic case definition intended for implementation in the research realm and seeks to enhance homogeneity across cohorts. Furthermore, we discuss aspects of PNECs biology which suggest that PNEC hyperplasia may contribute to the pathogenesis of phenotypes of lung disease aside from constrictive bronchiolitis and carcinoid tumorlets/tumors. Finally, we steer attention to some of the most pressing and impactful research questions awaiting to be unraveled.

e18807 Background: CUP represents both a diagnostic and a management challenge. Despite improvements through sophisticated imaging modalities, specific and sensitive testing using immunohistochemistry, a concrete determination of the site of origin of the primary tumor can still be a diagnostic challenge Hereby, we described the genomic landscape of patients with CUP treated at our institution. Methods: Retrospective study of patients with CUP treated at Mayo Clinic Rochester MN from 2010 to 2021. Next generation sequencing (NGS) information was abstracted, and alterations were ranked into different levels of actionability following the Onco KB framework. All data were analyzed by the SPSS version 22.0 software (SPSS, Chicago, IL, United States). Results: From a total of 214 patients, we identified 67 (32%) patients in whom NGS was performed. Among patients with available NGS the median age was 64 years (range: 35-86) and 51% were female. the most prevalent histology included adenocarcinoma (39%), carcinoma NOS (31%), and neuroendocrine tumors (12%). NGS on tumor (t-NGS) was available in 56 (84 %) patients, circulating tumor NGS (b-NGS) was available in 12 (18%) patients, and only 1 patient had both testing available. Among the 56 patients with available t-NGS, MSI-high was detected in 9 patients, whereas among the 12 patients with available b-NGS, MSI-high was detected in 8 patients; yielding an MSI-high detection rate of 16% and 67% for t-NGS and b-NGS. In this cohort, there were a total of 474 genomic alterations detected from which 103 (22 %) were able to be ranked into one therapeutic level following the OncoKB framework. Genomic alterations were most observed among patients with carcinoma (n = 50, 48.53%) adenocarcinoma (n = 33, 32.03 %), squamous cell carcinoma (n = 3, 2.91 %) and neuroendocrine tumor (n = 2, 1.94%). Following the OncoKB framework, 39-level 1 genomic alterations were detected in a total of 14 genes. The most common level 1 genomic alterations comprised the BRCA2 (20.51%), NF1 ATM (17.95%) and HER2/NEU (ERBB2) (15.38%) genes. Therapeutic level 2 included 51 genomic alterations in 13 genes of which KRAS (17.65%), BRAF (15.69%), and BRCA2 (15.69%) were the most prevalent mutated genes. Additionally, level R comprised 13 genomic alterations in the following genes: KRAS (69.23) NRAS (23.08%) and PDGFRA (7.69%). Conclusions: CUP are malignancies rich in potentially actionable alterations, and NGS of tissue and blood samples can inform systemic therapy decisions. Alteration-specific targeted therapy may be an option for a substantial proportion of patients. NGS of tumor tissue or blood should be considered for all patients with CUP.

e18803 Background: CUPs are a heterogeneous group of metastatic cancers for which a standardized diagnostic work-up fails to identify the site of origin at the time of diagnosis. CUP accounts for 3%-5% of all cancer diagnoses worldwide, and the natural history of patient with CUP differs from that of patients (pts) with cancer with known primary tumor. Here we report and summarize the clinical features of patients with CUP treated at Mayo Clinic. Methods: Retrospective study of patients treated at Mayo Clinic Rochester MN from 2010 to 2021. Patient demographics, tumor-related variables, treatment-related variables, and clinical data were extracted. Descriptive statistics were used, and all data were analyzed by the SPSS version 22.0 software (SPSS, Chicago, IL, United States). Results: From a total of 214 pts, 207 pts were included, as primary tumor site was identified in 7 patients after initial evaluation. The pts in this study were predominantly white (87%) of female (50.2%) gender with a mean age of 63 (SD: 13) without history of smoking (51%) and either private or public insurance (82.6%). The predominant histology was adenocarcinoma (30%), followed by neuroendocrine neoplasms (27%), and carcinoma NOS (not otherwise specified) (25%). The most prevalent grade in this cohort was grade III with poorly differentiated tumor cells. All pts had diagnostic imaging and the most used imaging modalities included CT (81.2%), and PET-CT (43.5%). In our cohort, the 3 most common sites of metastases included lymph nodes (57.5%), liver (37.8%), lung (34.3%), and bone (23.7%); and in 64% of pts, there was a specific presentation pattern including liver-predominant (24.6%), lymph node-predominant (24.6%), bone-predominant (7.7%), and peritoneal carcinomatosis (7.7%). The majority of pts received systemic therapy (69%) as first line of therapy and the most frequent first line regimens included platinum-doublet (26.5%), gemcitabine-based regimen (20.7%), 5FU-based regimens (18%) and somatostatin analogs (16.7%); whereas salvage radiation and ablation were offered to 11% of pts and surgery to 17%. The median follow-up time was 22 months (IQR: 45) with a median survival time of 23 months and the 3-year cumulative survival rate was 30%. Conclusions: The heterogenous nature of CUPs and lack of specific immunohistochemical signature prevents primary tissue of origin diagnoses in CUP pts. Without the identification of a primary origin site, treatment is restricted to generic chemotherapy with limited benefit as demonstrated in this cohort.

e18802 Background: CUP is a rare cancer with an incidence of 7–12 cases per 100,000/year. CUP is defined as metastatic cancer with no identifiable primary tumor despite comprehensive evaluation. Despite its heterogeneous clinicopathological presentation, the treatment of CUP has primarily been with platinum-based combination chemotherapies but results are poor and survival is short. Here, we describe survival outcomes in real-world dataset of patients with CUP seen at a tertiary referral center. Methods: Retrospective study of patients treated at Mayo Clinic, Rochester MN, from 2010 to 2021. Survival probabilities were estimated with the Kaplan-Meier method. We used Cox proportional hazard regression with forward modeling to explore the association between each variable and death. Overall survival (OS) analysis was conducted in the entire cohort, and it was stratified by histological subtype. For the hypothesis test, we considered p < 0.05 to be statistically significant; all tests were two-sided. All data were analyzed by the SPSS version 22.0 software (SPSS, Chicago, IL, United States). Results: From a total of 214 patients, 198 patients were included in the survival analysis. The patients were predominantly white (87%), female (50.2%), with a mean age of 63 (SD: 13) without history of smoking (51%). The predominant histology was adenocarcinoma (30%), followed by neuroendocrine neoplasms (NEN) (27%), carcinoma NOS (25%), squamous cell carcinoma (SCC) (10%) and non-classifiable tumors (7%). The median follow-up time was 23 months, and medial OS was 23 months in the entire cohort. OS by histology was as follows: 51 months for NEN, 34 months for SCC, 18 months for carcinomas NOS and 11 months for adenocarcinomas (p < 0.001) (fig.1). Similar OS trends were observed when we restricted the analysis to poorly differentiated tumors. The 3- and 5-year cumulative survival by histology were as follows: 7% and 0% for adenocarcinoma, 25% and 8% for carcinoma NOS, 39% and 17% for SCC, and 56% and 22% for NEN. In Cox regression models we did not identify any prognostic factors among patients with adenocarcinoma. Conclusions: Patients with adenocarcinoma of unknown primary possess a considerable challenge and the OS is short. CUP of other histologies have higher OS. This study highlights the need of accurate tumor identification and better treatment, perhaps as a multiomics therapeutic approach.

e16242 Background: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare cancers with highly heterogeneous growth rates, yielding very broad ranges of radiographic imaging intervals in standard guidelines, with a multitude of risk for patients. Better tools are needed to reduce risks for these patients. Chromogranin A (CgA) is released by GEP-NET cells and has been associated with increased tumor burden. The European Neuroendocrine Tumor Society (ENETS) considers CgA to be the most practical and useful general serum tumor marker in patients with NETs. However, clinical utility has been limited by the lack of prospective validation studies and by different sensitivity of CgA according to NET tumor type and volume. Accordingly, expert consensus guidelines have offered varying advice regarding the use of CgA to practicing clinicians. The aim was to evaluate the performance of the B·R·A·H·M·S CgA II KRYPTOR immunoassay to monitor the course of disease in patients with well-differentiated GEP-NETs (grade 1 and grade 2). This is the first prospective validation of a clinical algorithm for the interpretation of CgA values in patients with advanced GEP-NETs. Methods: This prospective, multi-center, observational study was designed to validate the performance of the B·R·A·H·M·S CgA II KRYPTOR assay in monitoring disease progression in a defined population of GEP-NET patients with minimal confounding from end organ dysfunction or concomitant medications (e.g. PPIs). Patients were followed for up to 36 months including the evaluation of tumor burden with RECIST 1.1 categorization by imaging (CT/MRI scans). A clinical cut-off for changes in CgA levels over time to indicate the risk that a tumor progression occurred was derived from a retrospective, bicentric observational pilot study. A change in CgA levels between visits was considered positive, if the CgA concentration increased by more than 50% to an absolute value of >100 ng/ml. Results: A total of 175 adult patients were enrolled, and 153 patients had measurable disease at baseline and ≥1 follow-up visit. Using the cut-off for CgA increase defined above resulted in a sensitivity of 34.4% (95%-CI: 25.6% - 44.3%, p < 0.001) and a specificity of 93.4% (95%-CI: 90.4% – 95.5%, p < 0.001). Positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (LR+) and negative likelihood ratio (LR-) to diagnose whether a tumor progression occurred according RECIST 1.1 criteria were 57.9% (95% CI: 45.0-69.8), 84.3% (95% CI: 80.5-87.6), 5.20 (95% CI: 3.23-8.36), and 0.70 (95% CI: 0.61-0.81), respectively. The AUC was estimated at 0.731 (95% CI: 0.670-0.793). Conclusions: B·R·A·H·M·S CgA II KRYPTOR can be used in conjunction with other clinical methods as an aid in monitoring of disease progression during the course of disease and treatment in patients with gastroentero-pancreatic neuroendocrine tumors (GEP-NETs, grade 1 and grade 2).

e16259 Background: Patients with KRAS mutant (mt) pancreatic ductal adenocarcinoma (PADC) have worse survival outcomes compared to KRAS wild-type (wt) PDAC patients. However, the prognostic implication of the KRAS mutation subtype (e.g. G12D, G12R, G12V and Q61) remains unclear. Furthermore, the clinical and molecular characteristics associated with these mutation subtypes remain not well defined. Methods: A retrospective review was conducted on patients with KRAS PDAC who underwent Next Generation Sequencing at Mayo Clinic between December 1, 2018 and December 1, 2021. Their somatic mutations, RNA expression, demographics, disease characteristics, therapies offered, and clinical outcomes were collected via chart review. Results on KRAS wt were reported previously; KRAS mt are reported here. Results: A total of 158 KRAS mt patients (at diagnosis: average age 63.8 years, 57% male, 88 (56%) Stage IV) were included. 10% of patients had KRAS Q61 mutation, 14% G12R, 30% G12V and 46% G12D. G12R had a longer overall survival (OS) compared to the others (median 24.8 vs 17.5 months, unadjusted hazard ratio (HR) 0.68, p=0.05), particularly in patients with localized disease at diagnosis (median 35.4 vs 28.3 months, p=0.08). Among patients with metastatic disease at diagnosis, G12V had the lowest OS (median 9.8 vs 12.4 months, unadjusted HR 1.8, p=0.02). 137 (87%) patients had at least one pathogenic somatic variant, with statistically significant differences in SMAD4, TP53, MYC, RB1, KMT2D, RBM10, RNF43, KDM6A, KMT2C, RBM10, LRP1B, PIK3CA, and SMARC among the KRAS mt subtypes. 82 (52%) patients had at least one RNA expression variant, with statistically significant differences in CCND1, CCNE1, HRAS, MET, EGFR, and ERB3 among KRAS mt subtypes. Between these subtypes, there were no statistically significant differences in TMB value, location of PDAC or subsequent metastasis, lines of treatment (average 2.3), age at diagnosis, or gender. Conclusions: KRAS mt subtypes may confer different PDAC phenotypes. In our cohort, G12R is associated with improved OS while G12V correlates with worse prognosis in de novo metastatic disease. Additionally, there are differences in genomic variations and RNA expression between the KRAS mt subtypes. To further examine this, transcriptomic analysis is underway. [Table: see text]

High-grade neuroendocrine neoplasms are a rare disease entity and account for approximately 10% of all neuroendocrine neoplasms. Because of their rarity, there is an overall lack of prospectively collected data available to advise practitioners as to how best to manage these patients. As a result, best practices are largely based on expert opinion. Recently, a distinction was made between well-differentiated high-grade (G3) neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas, and with this, pathologic details, appropriate imaging practices and treatment have become more complex. In an effort to provide practitioners with the best guidance for the management of patients with high-grade neuroendocrine neoplasms of the gastrointestinal tract, pancreas, and gynecologic system, the North American Neuroendocrine Tumor Society convened a panel of experts to develop a set of recommendations and a treatment algorithm that may be used by practitioners for the care of these patients. Here, we provide consensus recommendations from the panel on pathology, imaging practices, management of localized disease, management of metastatic disease and surveillance and draw key distinctions as to the approach that should be utilized in patients with well-differentiated G3 neuroendocrine tumors vs poorly differentiated neuroendocrine carcinomas.

Objectives Somatostatin receptor (SSTR) PET imaging is utilized with increasing frequency in the clinical management of neuroendocrine tumors. Incidental PET-avid CNS lesions are commonly noted and presumed to be meningiomas. However, SSTR PET lacks specificity for meningioma identification. This study aimed to clarify the role of SSTR-based imaging in the classification of incidental CNS lesions based on current clinical practice. Methods Patients who underwent both Ga-68-DOTATATE PET and brain MRI and had an incidental CNS lesion identified with a radiographic prediction of meningioma via one (discordant prediction) or both (concordant prediction) imaging modalities were retrospectively analyzed. Imaging indication, semiquantitative measures, and clinical history were recorded. Results Among 48 patients with a CNS lesion identified on both imaging modalities, most scans were performed for a history of neuroendocrine tumor (64.6%). Cases with concordant lesion-type prediction of meningioma between imaging modalities (N = 24) displayed a significantly higher SUV max (median 7.9 vs. 4.0; P = 0.008) and Krenning score (median 3.0 vs. 2.0; P = 0.005) on Ga-68-DOTATATE PET compared with cases with a discordant prediction of meningioma (N = 24). In cases with lower SUV max values, Ga-68-DOTATATE was more likely to discordantly predict meningioma without agreement by the corresponding MRI. Prior cranial radiation or use of somatostatin mimetics did not affect quantitative radiographic measures, and MRI-based tumor size was similar across groups. Conclusion Lesions with increased avidity may be more confidently predicted as meningioma in Ga-68-DOTATATE PET scans, whereas there is more discrepancy in prediction among low SUV cases.