Sporadic Tumors Research Articles

Pulmonary artery sarcoma: an unexpected settler in the right ventricular outflow tract

Pulmonary artery sarcoma (PAS) is a sporadic malignant tumor that mainly originates from the pulmonary arteries. However, PAS may also involve the right ventricular outflow tract (RVOT) and lead to obstruction, syncope, or sudden death. Early diagnosis and complete surgical resection are essential to prolong survival and improve the quality of life of patients with PAS. Herein, we report a case of a young female patient admitted for pulmonary malignancy and acute pulmonary embolism. The patient had a mass in the RVOT, which was detected by transthoracic echocardiography. Computed tomography and magnetic resonance imaging revealed the invasion depth and extent of the lesions. Surgical resection improved hemodynamics, while pathological and immunohistochemical tests confirmed the diagnosis of a pulmonary artery sarcoma. Local recurrence was detected in the adjacent tissues about two months after the surgery. Given the potential risk of reoperation, the patient was suggested to undergo conservative treatment.

High frequency of colorectal neoplasia in patients with sporadic adenomas or adenocarcinomas of the papilla of Vater: The same adenoma-carcinoma sequence?

Data on the frequency of colorectal neoplasia in sporadic ampullary tumors remains scarce. We retrospectively reviewed 135 patients undergoing endoscopic ampullectomy from January 2018 to July 2021, and identified 95 patients with sporadic ampullary adenoma who underwent total colonoscopy. Colonoscopy findings were compared with 380 asymptomatic controls using the chi-squared test. Whole-exome sequencing (WES) was performed on one patient with synchronous adenomas of the ampulla of Vater and ascending colon. Colorectal polyps were present in 60% of Cases vs. 34.7% of Controls (P=0.001), advanced adenoma in 20% vs. 5.5%, and adenocarcinoma in 4.2% vs. 0.8%. Cases tended to have larger polyps than Controls (P<0.001), while there was no difference in polyp location and histology between the two groups. The odds ratio of all the colorectal lesions, advanced colorectal adenoma and adenocarcinoma in Cases was 1.7, 4.2, and 4, respectively. WES in one patient revealed that both of ampullary adenoma and colonic adenoma shared somatic ABCB1 mutation. The frequency of colorectal polyps or neoplasia was significantly higher in Cases than Controls. We proposed that ampullary neoplasia is analogous to colon lesions and warrants total colonoscopy screening in patients diagnosed with ampullary tumors.

Interstitial deletion of the Apc locus in β-catenin-overexpressing cells is a signature of radiation-induced intestinal tumors in C3B6F1 ApcMin/+ mice†.

Recent studies have identified interstitial deletions in the cancer genome as a radiation-related mutational signature, although most of them do not fall on cancer driver genes. Pioneering studies in the field have indicated the presence of loss of heterozygosity (LOH) spanning Apc in a subset of sporadic and radiation-induced intestinal tumors of ApcMin/+ mice, albeit with a substantial subset in which LOH was not detected; whether copy number losses accompany such LOH has also been unclear. Herein, we analyzed intestinal tumors of C3B6F1 ApcMin/+ mice that were either left untreated or irradiated with 2Gy of γ-rays. We observed intratumor mosaicism with respect to the nuclear/cytoplasmic accumulation of immunohistochemically detectable β-catenin, which is a hallmark of Apc+ allele loss. An immunoguided laser microdissection approach enabled the detection of LOH involving the Apc+ allele in β-catenin-overexpressing cells; in contrast, the LOH was not observed in the non-overexpressing cells. With this improvement, LOH involving Apc+ was detected in all 22 tumors analyzed, in contrast to what has been reported previously. The use of a formalin-free fixative facilitated the LOH and microarray-based DNA copy number analyses, enabling the classification of the aberrations as nondisjunction/mitotic recombination type or interstitial deletion type. Of note, the latter was observed only in radiation-induced tumors (nonirradiated, 0 of 8; irradiated, 11 of 14). Thus, an analysis considering intratumor heterogeneity identifies interstitial deletion involving the Apc+ allele as a causative radiation-related event in intestinal tumors of ApcMin/+ mice, providing an accurate approach for attributing individual tumors to radiation exposure.

Improving fine needle aspiration to predict the tumor biological aggressiveness in pancreatic neuroendocrine tumors using Ki-67 proliferation index, phosphorylated histone H3 (PHH3), and BCL-2

IntroductionSurgery is the only known cure for sporadic pancreatic neuroendocrine tumors (PNETs). Therefore, the prediction of the PNETs biological aggressiveness evaluated on endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) has a significant impact on clinical management. The proliferation rate of Ki-67 in PNETs can help to predict the biological aggressiveness of the tumor. In addition, there is a relatively new proliferation marker called phosphorylated histone H3 (PHH3) that can identify and quantify dividing cells in tissue samples, which is a marker highly specific to mitotic figures. Other markers such as BCL-2 also contribute to tumorigenesis and may be involved in the differentiation of neuroendocrine cells. Materials and methodsA retrospective observational study was performed on patients undergoing surveillance for PNETs from January 2010 to May 2021. Data collection included the patients' age, sex, tumor location, tumor size in the surgical specimen, and tumor grade in FNA. The 2019 World Health Organization (WHO) classification guideline was followed to diagnose PNETs, including grade and stage. Immunohistochemical stainings for Ki-67, PHH3 and BCL-2 in PNETs were performed. ResultsAfter excluding cell blocks containing fewer than 100 tumor cells, 44 patients with EUS-FNA and surgical resection specimens were included in this study. There were 19 cases of G1 PNETs, 20 cases of G2 PNETs, and 5 cases of G3 PNETs. The grade assigned based on the Ki-67 index was higher and more sensitive than that based on the mitotic count using H&E slides in some cases of G2 and G3 PNETs. However, there was no significant difference between the mitotic count using PHH3-positive tumor cells and the Ki-67 index to grade PNETs.All grade 1 tumors (19 cases) on surgical resection specimens were correctly graded on FNA (100 % concordance rate). Within the 20 G2 PNETs, 15 cases of grade 2 on surgical resection specimens were graded correctly on FNA based on the Ki-67 index only. Five cases of grade 2 PNETs on surgical resection specimens were graded as grade 1 on FNA when using only the Ki-67 index. Three of five grade 3 tumors on surgical resection specimens were graded as grade 2 on FNA based on the Ki-67 index only. Using only FNA Ki-67 to predict PNET tumor grade, the concordance (accuracy) rate was 81.8 % in total. However, all these eight cases (5 cases of G2 PNETs and 3 cases of G3 PNETs) were graded correctly by using the Ki-67 index plus mitotic rate (using PHH3 IHC stains).Four of 18 (22.2 %) patients with PNETs were positive for BCL-2 stain. In these 4 cases positive for BCL-2 stains, 3 cases were G2 PNETs and one case was G3 PNETs. ConclusionGrade and the proliferative rate in EUS-FNA can be used to predict the tumor grade in surgical resection specimens. However, when using only FNA Ki-67 to predict PNET tumor grade, about 18 % of cases were downgraded by one level. To solve the problem, immunohistochemical staining for BCL-2 and especially PHH3 would be helpful. Our results demonstrated that the mitotic count using PHH3 IHC stains not only improved the accuracy and precision of PNET grading in the surgical resection specimens, but also could reliably be used in routine scoring of mitotic figures of FNA specimens.

Domain landscapes of somatic NF1 mutations in pheochromocytoma and paraganglioma

Pheochromocytoma and paraganglioma (PPGL), are rare neuroendocrine tumors arising from the adrenal medulla and extra-adrenal paraganglia, respectively. Up to about 60% are explained by germline or somatic mutations in one of the major known susceptibility genes e.g., inNF1,RET,VHL, SDHx,MAXandHRAS. Targeted Next Generation Sequencing was performed in 14 sporadic tumors using a panel including 26 susceptibility genes to characterize the mutation profile. A total of 6 germline and 8 somatic variants were identified. The most frequent somatic mutations were found in NF1(36%), four have not been reported earlier in PCC or PGL. Gene expression profile analysis showed that NF1 mutated tumors are classified into RTK3 subtype, cluster 2, with a high expression of genes associated with chromaffin cell differentiation, and into a RTK2 subtype, cluster 2, as well with overexpression of genes associated with cortisol biosynthesis. On the other hand, by analyzing the entire probe set on the array and TCGA data, ALDOC was found as the most significantly down regulated gene in NF1-mutated tumors compared to NF1-wild-type. Differential gene expression analysis showed a significant difference between Nt - and Ct-NF1 domains in mutated tumors probably engaging different cellular pathways. Notably, we had a metastatic PCC with a Ct-NF1 frameshift mutation and when performing protein docking analysis, Ct-NF1 showed an interaction with Nt-FAK suggesting their involvement in cell adhesion and cell growth. These results show that depending on the location of the NF1-mutation different pathways are activated in PPGLs. Further studies are required to clarify their clinical significance.

The Progress of Colorectal Polyposis Syndrome in Chinese Population.

The pathogenesis, clinical phenotype, treatment strategy, and family management of hereditary tumor syndromes are different from those of sporadic tumors. Nearly a quarter of patients with colorectal cancer show significant familial aggregation and genetic predisposition, and 5 to 10% are associated with definite genetic factors. According to the clinical phenotype, it can be divided into nonpolyposis syndrome and polyposis syndrome. Among the polyposis syndrome patients with definite clinical symptoms, there are still some patients with unknown etiology (especially attenuated familial adenomatous polyposis), which is a difficult problem in clinical diagnosis and treatment. Therefore, for this rare disease, it is urgent to carry out multicenter studies, complete the gene variation spectrum, explore new pathogenic factors, and accumulate clinical experience. This article mainly introduces the research progress and related work of colorectal polyposis syndrome in China.

Abstract 15: Investigating the spectrum of brain tumors associated with Adgrb3 and Tp53 loss in a mouse model of Li-Fraumeni syndrome

Abstract Adhesion G protein-coupled receptor 3 (ADGRB3), also known as brain specific angiogenesis inhibitor (BAI3) is a member of the ADGRB1-3 subfamily of adhesion transmembrane proteins, which are highly expressed in the brain specifically in cerebellum and hippocampal neurons. ADGRB3 has been shown to play diverse roles under physiological and pathological conditions which include dendritic morphogenesis, synaptic plasticity, synaptogenesis, and myogenesis. Loss of ADGRB3 expression and point mutations in the gene have been observed in sporadic tumors, including brain tumors, but the significance of this observation has not been investigated. Moreover, no mouse models to understand the role of ADGRB3 in brain tumor susceptibility and pathobiology have been developed thus far. Li-Fraumeni syndrome (LFS) is a rare inherited autosomal dominant disorder caused by a germline mutation in one TP53 allele, predisposing patients to the development of a variety of tumors from a pediatric age, including gliomas and medulloblastoma. The secondary molecular alterations that predispose LFS patients to brain tumors are currently unknown. Interestingly, a LFS patient was reported to carry a translocation in ADGRB3 and HGMLL genes. To investigate the molecular mechanisms underlying brain tumor formation in LFS patients and the role of p53 and ADGRB3 in the process, we have generated a LFS mouse model. The mice harbor a germline p53 deleted allele and a second floxed allele. Loss of the second allele is induced in the brain by crossing with mice harboring a Nestin promoter driven Cre recombinase, since Nestin is expressed along the craniospinal axis and in glial precursor cells. We observed that the majority of nestin-Cre p53m/f mice all died between 8 and 10 months of age while nestin-Cre p53m/+ mice did not. About 20% of the mice developed hind leg paralysis and harbored large gliomas, which likely caused their demise. The remainder mice lacked brain tumors, but had other malignancies (sarcomas, etc.) as observed in patients. Remarkably, the addition of Adgrb3 deletion to the genotype led to a dramatic increase (from 20% to 60%??) in the number of brain tumors, including medulloblastoma formation, which are also reported in LFS patients. The Adgrb3-/- p53+/- Nestin-Cre mouse model constitutes a useful tool to understand the tumorigenic landscape caused by the loss of Adgrb3. We are now performing genomic analyses on the excised tumors and derived neurosphere cultures to further study the transformation process and the molecular changes induced by Adgrb3 loss. Citation Format: Alex B. Torrelli-Diljohn, Svetlana Komarova, Vipul Sheth, Benjamin Lin, Paran Goel, Ryan Miller, Robert Welner, Erwin G. Van Meir. Investigating the spectrum of brain tumors associated with Adgrb3 and Tp53 loss in a mouse model of Li-Fraumeni syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 15.

202 Molecular Signature of Malignant Peripheral Nerve Sheath on Tumor Site

INTRODUCTION: Malignant peripheral nerve sheath tumors (MPNSTs) are rare, highly aggressive soft tissue sarcomas that may occur sporadically, in association with neurofibromatosis type I (NF1) or after radiotherapy (RT). High recurrence rates and distant metastases are common, with lung and bone being the most common sites, yet the anatomic distribution of molecular changes is largely unknown. METHODS: Using the cBioPortal platform and systematic bioinformatical-analysis of the Cancer Genome Atlas (MSKCC) Nature Genetics 2014 dataset, we screened the dataset for the ADAM3A gene in the completed gene panel and twelve MPNST patients [pulmonary (6), neck (1), chest-wall (2), calf (1), arm (2)] with were included in the study. Broadly, these twelve patients were categorized as primary-pulmonary MPNST (6) and non-pulmonary MPNST (6) subgroups. RESULTS: The putative copy-number alteration pattern involving the ADAM3A gene based on the primary site was distinct (p &lt;0.0001). All six patients with primary-pulmonary MPNST showed ADAM3A amplification while all six patients with non-pulmonary MPNST demonstrated ADAM3A homodeletion. Remarkably, regardless of the underlying etiology and pathogenesis, ADAM3A amplification in primary-pulmonary MPNST was invariably noted across the board in sporadic (3), NF1-associated (2), and RT-associated (1) tumor samples (p &lt;0.0001). CONCLUSIONS: The findings in this study highlight the site-specificity of the MPNST molecular landscape. Further studies are essential for understanding the underlying molecular implications, pathways, and the specific role of ADAM3A in pulmonary and non-pulmonary MPNSTs.

Molecular and Clinical Spectrum of Primary Hyperparathyroidism.

Recent data suggest an increase in the overall incidence of parathyroid disorders with primary hyperparathyroidism (PHPT) being the most prevalent parathyroid disorder. PHPT is associated with morbidities (fractures, kidney stones, chronic kidney disease) and increased risk of death. The symptoms of PHPT can be non-specific, potentially delaying the diagnosis. Approximately 15% of patients with PHPT have an underlying heritable form of PHPT which may be associated with extra-parathyroidal manifestations, requiring active surveillance for these manifestations as seen in multiple endocrine neoplasia type 1 and 2A. Genetic testing for heritable forms should be offered to patients with multi-glandular disease, recurrent PHPT, young onset PHPT (age ≤ 40 years) and those with a family history of parathyroid tumors. However, the underlying genetic cause of majority of patients with heritable forms of PHPT remains unknown. Distinction between sporadic and heritable forms of PHPT is useful in surgical planning for parathyroidectomy and has implications for family. The genes currently known to be associated with heritable forms of PHPT account for approximately half of the sporadic parathyroid tumors. But the genetic cause in approximately half of the sporadic parathyroid tumors remains unknown. Furthermore, there is no systemic therapy for parathyroid carcinoma, a rare but potentially fatal cause of PHPT. Improved understanding of the molecular characteristics of parathyroid tumors will allow us to identify biomarkers for diagnosis and novel targets for therapy.

Molecular alterations and therapeutic targets in pancreatic neuroendocrine tumors

Human pancreatic neuroendocrine tumors (PanNETs) are a rare, deadly tumor type that is sporadic or arises in the background of a hereditary syndrome. A critical genetic event in sporadic tumors is inactivation of the gene menin 1 (MEN1) on chromosome 11, and indeed, PanNETs occur in patients with the hereditary syndrome multiple endocrine neoplasia type 1 (MEN1) due to germline mutations in the gene. Here, we review the recent progress in the field of molecular genetics and therapeutic targets of PanNETs. The key genomic alterations, including MEN1, ATRX/DAXX, mammalian target of rapamycin (mTOR), DNA damage and repair associated genes, vascular endothelial growth factor receptor (VEGFR) and SSTRs, and epigenetic aberrations in PanNETs are discussed. In addition, the commonly used preclinical models for PanNETs are enumerated.

Cellular mechanisms of heterogeneity in NF2-mutant schwannoma

Schwannomas are common sporadic tumors and hallmarks of familial neurofibromatosis type 2 (NF2) that develop predominantly on cranial and spinal nerves. Virtually all schwannomas result from inactivation of the NF2 tumor suppressor gene with few, if any, cooperating mutations. Despite their genetic uniformity schwannomas exhibit remarkable clinical and therapeutic heterogeneity, which has impeded successful treatment. How heterogeneity develops in NF2-mutant schwannomas is unknown. We have found that loss of the membrane:cytoskeleton-associated NF2 tumor suppressor, merlin, yields unstable intrinsic polarity and enables Nf2−/− Schwann cells to adopt distinct programs of ErbB ligand production and polarized signaling, suggesting a self-generated model of schwannoma heterogeneity. We validated the heterogeneous distribution of biomarkers of these programs in human schwannoma and exploited the synchronous development of lesions in a mouse model to establish a quantitative pipeline for studying how schwannoma heterogeneity evolves. Our studies highlight the importance of intrinsic mechanisms of heterogeneity across human cancers.

Tumeurs neuroendocrines digestives bien différenciées: focus sur les tumeurs pancréatiques

Pancreatic neuroendocrine tumors are rare tumors showing a rising incidence. They are well-differentiated tumors, classified by grade according to their Ki67 index value (grade 1 to 3). Pancreatic neuroendocrine tumors are mainly sporadic tumors but about 10% arise within endocrine tumor syndromes such as multiple endocrine neoplasia type 1. They can be responsible for functional syndromes or non-specific clinical symptoms depending on tumor extension. However, there is also an increase of incidental diagnoses of nonfunctional pancreatic neuroendocrine tumors with the widespread use of high-quality imaging techniques. About 50% of pancreatic neuroendocrine tumors are diagnosed at a metastatic stage, with metastases often located in the liver. Chromogranin A, CT-scan and often an abdominal MRI, and functional imaging should be performed for tumor staging and follow-up. Imaging with PET/CT with68Ga-labeled somatostatin analogues has the highest sensitivity for the diagnosis of pancreatic neuroendocrine tumors, while 18fluorodeoxyglucose PET/CT can sometimes be useful. Overall, they are rather indolent tumors with prolonged survival. Surgery is the recommended treatment in the localized setting, with the exception of small<2cm nonfunctional tumors that can be monitored with imaging techniques. For advanced tumors, there are several available treatments such as somatostatine analogues, chemotherapy, targeted therapies (sunitinib, everolimus), locoregional ablative therapies and Peptide Receptor Radiolabelled Therapy. The treatment strategy will depend on the initial tumor staging, tumor grade, aggressiveness and patient's choice.

Pancreatic resections or observation in management of sporadic non-functioning stage T1 neuroendocrine tumors of the pancreas (PNET) (literature review)

Pancreatic resections or observation in management of sporadic non-functioning stage T1 neuroendocrine tumors of the pancreas (PNET) (literature review)

Impact of concurrent tumour events on the prostate cancer outcomes of germline BRCA2 mutation carriers

BackgroundSeveral studies have reported the association of germline BRCA2 (gBRCA2) mutations with poor clinical outcomes in prostate cancer (PCa), but the impact of concurrent somatic events on gBRCA2 carriers survival and disease progression is unknown. Patients and methodsTo ascertain the role of frequent somatic genomic alterations and histology subtypes in the outcomes of gBRCA2 mutation carriers and non-carriers, we correlated the tumour characteristics and clinical outcomes of 73 gBRCA2 and 127 non-carriers. Fluorescent in-situ hybridisation and next-generation sequencing were used to detect copy number variations in BRCA2, RB1, MYC and PTEN. Presence of intraductal and cribriform subtypes was also assessed. The independent impact of these events on cause-specific survival (CSS), metastasis-free survival and time to castration-resistant disease was assessed using cox-regression models. ResultsSomatic BRCA2-RB1 co-deletion (41% versus 12%, p < 0.001) and MYC amplification (53.4% versus 18.8%, p < 0.001) were enriched in gBRCA2 compared to sporadic tumours. Median CSS from diagnosis of PCa was 9.1 versus 17.6 years in gBRCA2 carriers and non-carriers, respectively (HR 2.12; p = 0.002), Median CSS in gBRCA2 carriers increased to 11.3 and 13.4 years in the absence of BRCA2-RB1 deletion or MYC amplification, respectively. Median CSS of non-carriers decreased to 8 and 2.6 years if BRCA2-RB1 deletion or MYC amplification were detected. ConclusionsgBRCA2-related prostate tumours are enriched for aggressive genomic features, such as BRCA2-RB1 co-deletion and MYC amplification. The presence or absence of these events modify the outcomes of gBRCA2 carriers.

Clinical Prediction Models for Recurrence in Patients with Resectable Grade 1 and 2 Sporadic Non-Functional Pancreatic Neuroendocrine Tumors: A Systematic Review.

Recurrence after resection in patients with non-functional pancreatic neuroendocrine tumors (NF-pNET) has a considerable impact on overall survival. Accurate risk stratification will tailor optimal follow-up strategies. This systematic review assessed available prediction models, including their quality. This systematic review followed PRISMA and CHARMS guidelines. PubMed, Embase, and the Cochrane Library were searched up to December 2022 for studies that developed, updated, or validated prediction models for recurrence in resectable grade 1 or 2 NF-pNET. Studies were critically appraised. After screening 1883 studies, 14 studies with 3583 patients were included: 13 original prediction models and 1 prediction model validation. Four models were developed for preoperative and nine for postoperative use. Six models were presented as scoring systems, five as nomograms, and two as staging systems. The c statistic ranged from 0.67 to 0.94. The most frequently included predictors were tumor grade, tumor size, and lymph node positivity. Critical appraisal deemed all development studies as having a high risk of bias and the validation study as having a low risk of bias. This systematic review identified 13 prediction models for recurrence in resectable NF-pNET with external validations for 3 of them. External validation of prediction models improves their reliability and stimulates use in daily practice.

The Impact of the COVID-19 Pandemic on the Prognosis of Laryngeal Adenoid Cystic Carcinoma: A Case Report and a Literature Review

Laryngeal adenoid cystic carcinoma (LACC) is a sporadic neoplasm, especially if supraglottic. The COVID-19 pandemic worsened the presenting stage of many cancers and impacted their prognosis negatively. Here, a case of a patient with adenoid cystic carcinoma (ACC) with delayed diagnosis and a rapid deterioration with distant metastasis due to the COVID-19 pandemic is illustrated. Next, we present a literature review of this rare glottic ACC. The COVID-19 pandemic worsened the stage of presentation of many cancers and adversely affected their prognosis. The present case had a rapidly lethal course, undoubtedly due to the diagnosis delay caused by the COVID-19 pandemic, which impacted the prognosis of this rare glottic ACC. Strict follow-up is recommended for any suspicious clinical findings, as an early diagnosis will improve the disease prognosis, and to consider the influence of the COVID-19 pandemic, especially on the timing of common diagnostic and therapeutic procedures for oncological diseases. In the post-COVID-19 era, it is important to generate new diagnostic scenarios to achieve an increasingly rapid diagnosis of oncological diseases, especially the rare ones, through screening or similar procedures.

Large benign chondroid syringoma of the lower limb-an uncommon presentation of a rare disease

Chondroid syringoma (CS) is a sporadic skin appendage tumor that manifests as slow-growing, subcutaneous, non-tender, non-ulcerating dermal nodules, most often in the head and neck. The tumor is more common in men, has a biphasic age distribution, and usually attains a size of 0.5 to 3 cm. Larger lesions up to 9 cm in size have been recorded in the literature, with the majority of them containing malignancies. Rare cases of malignant CS have been described, with local recurrence and metastasis. We report a case of an 85-year-old man presenting with complaints of a significantly large swelling in the inner aspect of his right thigh for the past 25 years. Clinical and radiological differential diagnoses of a large uncomplicated dermoid cyst, sebaceous cyst, epidermal inclusion cysts, neurogenic tumours, or myxoid tumours with cystic degeneration were suggested. Under general anaesthesia, the lesion was completely excised with a 1 cm margin of healthy surrounding tissue. The histopathological examination of the complete surgical specimen was consistent with CS. Patient has been on regular follow-up and has shown excellent response to treatment, with no evidence of recurrence, metastasis, or disfigurement. With this paper, we report a case of benign CS in an unusual location, attaining a huge size (&gt;10 cm) and, even then, not turning malignant. We hope to add to the current knowledge on CS, allowing for early and accurate diagnosis and successful disease management.

Immune Microenvironment in Sporadic Early-Onset versus Average-Onset Colorectal Cancer

The incidence of left-sided colon and rectal cancer in young people are increasing worldwide, but its causes are poorly understood. It is not clear if the tumor microenvironment is dependent on age of onset, and little is known about the composition of tumor-infiltrating T cells in early-onset colorectal cancer (EOCRC). To address this, we investigated T-cell subsets and performed gene expression immune profiling in sporadic EOCRC tumors and matched average-onset colorectal cancer (AOCRC) tumors. Left-sided colon and rectal tumors from 40 cases were analyzed; 20 EOCRC (<45 years) patients were matched 1:1 to AOCRC (70-75 years) patients by gender, tumor location, and stage. Cases with germline pathogenic variants, inflammatory bowel disease or neoadjuvant-treated tumors were excluded. For T cells in tumors and stroma, a multiplex immunofluorescence assay combined with digital image analysis and machine learning algorithms was used. Immunological mediators in the tumor microenvironment were assessed by NanoString gene expression profiling of mRNA. Immunofluorescence revealed no significant difference between EOCRC and AOCRC with regard to infiltration of total T cells, conventional CD4+ and CD8+ T cells, regulatory T cells, or γδ T cells. Most T cells were located in the stroma in both EOCRC and AOCRC. Immune profiling by gene expression revealed higher expression in AOCRC of the immunoregulatory cytokine IL-10, the inhibitory NK cell receptors KIR3DL3 and KLRB1 (CD161), and IFN-a7 (IFNA7). In contrast, the interferon-induced gene IFIT2 was more highly expressed in EOCRC. However, in a global analysis of 770 tumor immunity genes, no significant differences could be detected. T-cell infiltration and expression of inflammatory mediators are similar in EOCRC and AOCRC. This may indicate that the immune response to cancer in left colon and rectum is not related to age of onset and that EOCRC is likely not driven by immune response deficiency.

Association Between Survival and Metastatic Site in Mismatch Repair–Deficient Metastatic Colorectal Cancer Treated With First-line Pembrolizumab

Metastatic colorectal cancer (mCRC) with deficient DNA mismatch repair (dMMR) shows frequent and durable responses to programmed cell death 1 blockade. While most of these tumors are sporadic and observed in older patients, first-line pembrolizumab data are limited to findings from the KEYNOTE-177 trial (A Phase III Study of Pembrolizumab [MK-3475] vs Chemotherapy in Microsatellite Instability-High [MSI-H] or Mismatch Repair Deficient [dMMR] Stage IV Colorectal Carcinoma). To investigate outcome with first-line pembrolizumab monotherapy in mostly older patients with dMMR mCRC at a multisite clinical practice. This cohort study included consecutive patients with dMMR mCRC who received pembrolizumab monotherapy between April 1, 2015, and January 1, 2022, at Mayo Clinic sites and the Mayo Clinic Health System. Patients were identified from review of electronic health records at the sites, which included the evaluation of digitized radiologic imaging studies. Patients with dMMR mCRC received first-line pembrolizumab, 200 mg, every 3 weeks. The primary study end point was progression-free survival (PFS), which was analyzed using the Kaplan-Meier method and a multivariable stepwise Cox proportional hazards regression model. Clinicopathological features, including metastatic site and molecular data (BRAF V600E and KRAS), were also analyzed along with tumor response rate, which was determined using Response Evaluation Criteria in Solid Tumors, version 1.1. The study cohort included 41 patients (median [IQR] age at treatment initiation, 81 [76-86] years; 29 females [71%]) with dMMR mCRC. Of these patients, 30 (79%) had the BRAF V600E variant and 32 (80%) were classified as having sporadic tumors. Median (range) follow-up was 23 (3-89) months. Median (IQR) number of treatment cycles was 9 (4-20). Overall response rate was 49% (20 of 41 patients), including 13 patients (32%) with complete responses and 7 (17%) with partial responses. Median (IQR) PFS was 21 (95% CI, 6-39) months. Liver as a site of metastasis was associated with significantly poorer PFS vs nonliver metastasis (adjusted hazard ratio, 3.40; 95% CI, 1.27-9.13; adjusted P = .01). Complete and partial responses were observed in 3 patients (21%) with liver metastasis vs 17 patients (63%) with nonliver metastases. Treatment-related grade 3 or 4 adverse events were observed in 8 patients (20%), 2 of whom discontinued therapy; there was 1 treatment-related death. This cohort study found a clinically significant prolongation of survival in older patients with dMMR mCRC who were treated with first-line pembrolizumab in routine clinical practice. Furthermore, liver vs nonliver metastasis was associated with poorer survival in this patient population, which suggests that the metastatic site has implications for survival outcome.

DICER1 RNase IIIb domain mutations trigger widespread miRNA dysregulation and MAPK activation in pediatric thyroid cancer.

DICER1 is a highly conserved RNase III endoribonuclease essential for the biogenesis of single-stranded mature microRNAs (miRNAs) from stem-loop precursor miRNAs. Somatic mutations in the RNase IIIb domain of DICER1 impair its ability to generate mature 5p miRNAs and are believed to drive tumorigenesis in DICER1 syndrome-associated and sporadic thyroid tumors. However, the DICER1-driven specific changes in miRNAs and resulting changes in gene expression are poorly understood in thyroid tissue. In this study, we profiled the miRNA (n=2,083) and mRNA (n=2,559) transcriptomes of 20 non-neoplastic, 8 adenomatous and 60 pediatric thyroid cancers (13 follicular thyroid cancers [FTC] and 47 papillary thyroid cancers [PTC]) of which 8 had DICER1 RNase IIIb mutations. All DICER1-mutant differentiated thyroid cancers (DTC) were follicular patterned (six follicular variant PTC and two FTC), none had lymph node metastasis. We demonstrate that DICER1 pathogenic somatic mutations were associated with a global reduction of 5p-derived miRNAs, including those particularly abundant in the non-neoplastic thyroid tissue such as let-7 and mir-30 families, known for their tumor suppressor function. There was also an unexpected increase of 3p miRNAs, possibly associated with DICER1 mRNA expression increase in tumors harboring RNase IIIb mutations. These abnormally expressed 3p miRNAs, which are otherwise low or absent in DICER1-wt DTC and non-neoplastic thyroid tissues, make up exceptional markers for malignant thyroid tumors harboring DICER1 RNase IIIb mutations. The extensive disarray in the miRNA transcriptome results in gene expression changes, which were indicative of positive regulation of cell-cycle. Moreover, differentially expressed genes point to increased MAPK signaling output and loss of thyroid differentiation comparable to the RAS-like subgroup of PTC (as coined by The Cancer Genome Atlas), which is reflective of the more indolent clinical behavior of these tumors.