Well-differentiated Tumors Research Articles

Bronchospasm Complicating A Small Intestine Neuroendocrine Tumor Resection: A Case Report

Small intestinal neuroendocrine tumors (SI-NETs) are rare neoplasms with increasing incidence, known for their diverse clinical presentations and potential hormonal complications. We present the case of a 65-year-old male with a history of chronic smoking and alcoholism, who presented with right iliac fossa pain, liquid diarrhea, and weight loss. Imaging revealed a neuroendocrine tumor of the small intestine, and the patient underwent surgical resection. However, postoperatively, he developed respiratory distress suggestive of bronchospasm, requiring intensive care management. Histopathological analysis confirmed a well-differentiated neuroendocrine tumor, Grade 2. This case underscores the importance of early recognition and management of hemodynamic complications following surgical resection of SI-NETs. Preoperative assessment for carcinoid syndrome and optimization of cardiac function are crucial to minimize perioperative risks. Surgical resection with meticulous attention to complete tumor removal and mesenteric dissection remains the mainstay of treatment for SI-NETs. Further research is needed to refine perioperative management strategies and improve long-term outcomes for patients with SI-NETs.

Pathogenesis, diagnosis and treatment of primary renal well-differentiated neuroendocrine tumors: a review of the literature.

Neuroendocrine tumors (NETs) are a rare type of neoplasm that originate from neuroendocrine cells and peptide neurons. Primary renal well-differentiated NETs are extremely rare, and only a few cases have been reported worldwide. In this study, we present a new case of primary renal well-differentiated NET at our institution, followed by a literature review. A systematic search was conducted using various search terms to identify relevant literature on primary renal well-differentiated NETs from 2021 to present. The study analyzed the clinical features, age, gender, tumor size, location, gross pathology, light microscopy, and immunohistochemical results of 32 cases of primary renal well-differentiated NETs. The findings suggest that these tumors are rare and have nonspecific clinical and imaging features. The diagnosis heavily relies on immunohistochemical analysis. Primary renal well-differentiated NETs are associated with low malignant potential and a favorable prognosis. Surgical resection is the preferred treatment, and long-term follow-up is necessary to monitor the patient's condition.

Rare renal well-differentiated neuroendocrine tumors: clinical and imaging characteristics in a series of three cases.

Rare renal well-differentiated neuroendocrine tumors: clinical and imaging characteristics in a series of three cases.

Tyrosine kinase inhibitors in patients with neuroendocrine neoplasms: a systematic literature review.

Several tyrosine kinase receptors inhibitors (TKIs) have demonstrated antiproliferative effects in well-differentiated neuroendocrine tumors (NETs). We aimed to summarize and appraise the current evidence of the efficacy of TKIs in patients with different types of NETs. We performed a systematic review of clinical trials of TKIs in patients with advanced gastroenteropancreatic or lung NETs (PROSPERO registration number: CRD42024507379). Population characteristics, efficacy, and safety results were summarized by type of NET. Twenty-eight studies were eligible, totaling 2284 patients. While sunitinib remains the only Food and Drug Administration-approved TKI in patients with NETs (for patients with pancreatic well-differentiated NETs), recent placebo-controlled randomized trials have demonstrated improved response rates and progression-free survival for patients with progressive and pre-treated well-differentiated pancreatic (cabozantinib or surufatinib) or gastrointestinal (GI) NETs (pazopanib, cabozantinib, or surufatinib). There is limited evidence to support the use of a TKI in patients with lung or grade 3 NETs. The toxicity associated with TKIs follows a class effect, with a significant proportion of patients experiencing fatigue, hypertension, and hand-foot skin reactions. TKIs are effective therapies in patients with pancreatic or GI well-differentiated NETs and should be part of the therapeutical sequencing of these patients.

Prevalence, distribution, and prognostic significance of morphological variants of neuroendocrine tumors of the gastrointestinal tract - a multicenter study.

The incidence and prevalence of neuroendocrine neoplasms (NENs) in many organs are increasing. Although such NENs have similar grades, they may exhibit quite different behaviors. In this multicenter study, we aimed to investigate the prevalence and distribution of different morphological NEN variants in the non-pancreatic gastrointestinal (GI) tract and determine whether they can guide prognosis prediction. Two hundred and fifty-six patients diagnosed with NENs originating from the GI tract from 7 different centers were included in the study. In 89 (36.6%) cases, different morphological variants were detected. When the variants were grouped according to their aggressiveness as described in the literature, a statistically significant relationship between aggressiveness and the variables organ and age was found ( p < 0.05). The oncocytic variant was found to metastasize more than the other aggressive types (42.9%). The paraganglioma-like variant was found to have a smaller size, lower proliferation index, and a more benign clinical course. This study demonstrated that well-differentiated GI neuroendocrine tumors (GI-NETs) have considerable morphological diversity. Generally, case reports of rare morphological variants of GI-NETs are available in the literature. We believe that our study contributes to a better understanding of the prevalence, localization, and significance of morphological variations in GI-NETs.

Gastric epithelial neoplasm of fundic-gland mucosa lineage: representative of the low atypia differentiated gastric tumor and Ki67 may help in their identification.

Gastric epithelial neoplasm of the fundic-gland mucosa lineages (GEN-FGMLs) are rare forms of gastric tumors that encompass oxyntic gland adenoma (OGA), gastric adenocarcinoma of the fundic-gland type (GA-FG), and gastric adenocarcinoma of the fundic-gland mucosa type (GA-FGM). There is no consensus on the cause, classification, and clinicopathological features of GEN-FGMLs, and misdiagnosis is common because of similarities in symptoms. 37 cases diagnosed with GEN-FGMLs were included in this study. H&E-stained slides were reviewed and clinicopathological parameters were recorded. Immunohistochemical staining was conducted for MUC2, MUC5AC, MUC6, CD10, CD56, synaptophysin, chromograninA, p53, Ki67, pepsinogen-I, H+/K+-ATPase and Desmin. The patients' ages ranged from 42 to 79years, with a median age of 60. 17 were male and 20 were female. Morphologically, 19 OGAs, 16 GA-FGs, and two GA-FGMs were identified. Histopathological similarities exist between OGA, GA-FG, and GA-FGM. The tumors demonstrated well-formed glands, expanding with dense growth patterns comprising pale, blue-grey columnar cells with mild nuclear atypia. These cells resembled fundic gland cells. None of the OGA invaded the submucosal layer. The normal gastric pit epithelium covered the entire surface of the OGA and GA-FG, but the dysplasia pit epithelium covered the GA-FGM. Non-atrophic gastritis was observed in more than half of the background mucosa. All cases were diffusely positive for MUC6 and pepsinogen-I on immunohistochemistry. H+/K+-ATPase staining was negative or showed a scattered pattern in most cases. MUC5AC was expressed on the surface of GA-FGMs. p53 was focally expressed and the Ki67 index was low (1%-20%). Compared with OGA, GA-FG and GA-FGM were more prominent in the macroscopic view (p < 0.05) and had larger sizes (p < 0.0001). Additionally, GA-FG and GA-FGM exhibited higher Ki67 indices than OGA (p < 0.0001). Specimens with Ki-67 proliferation indices >2.5% and size >4.5mm are more likely to be diagnosed with GA-FG and GA-FGM than OGA. GEN-FGMLs are group of well-differentiated gastric tumors with favourable biological behaviours, low cellular atypia, and low proliferation. Immunohistochemistry is critical for confirming diagnosis. Compared with OGA, GA-FG and GA-FGM have larger sizes and higher Ki67 proliferation indices, indicating that they play a critical role in the identification of GEN-FGML. Pathologists and endoscopists should be cautious to prevent misdiagnosis and overtreatment, especially in biopsy specimens.

Identification of patients at high risk for recurrence in carcinoma of the ampulla of Vater: Analysis in 460 patients.

Carcinoma of the ampulla of Vater (CAV) shows a favorable prognosis compared to that with the other periampullary tumors, while some cases have a poor prognosis. The aims of the present study are to clarify the clinicopathological factors associated with poor recurrence-free survival (RFS) in patients with CAV after curative resection and to validate the usefulness of adjuvant chemotherapy (AC). The study design is a multicenter retrospective cohort study. Patients with CAV who underwent pancreaticoduodenectomy between January 2008 and December 2020 at 26 hospitals were analyzed. The 30 clinicopathological factors were evaluated. A propensity score matching (PSM) was used to compare between patients with and without AC. Finally, 460 patients were analyzed. Median duration of follow-up was 47.2 months. Twenty-one prognostic factors associated with poor RFS were identified by univariate analysis. In multivariate analysis, aged ≥71, tumor diameter ≥12 mm, pT2 or higher stage (pT≥2), portal vein invasion (PV+), venous invasion(V+), and node positive disease (pN+) were independent prognostic factors for poor RFS. Out of 80 patients who received AC, 63 patients were assigned to analysis for PSM. The results showed no beneficial effect of AC on RFS. The preoperative factors potentially predicting pT≥2, V+, and/or N+ were at least one of following; (1) CA19-9 > 37 IU/mL, (2) ulcerative or mixed type appearance, (3) except for well-differentiated tumor, or (4) except for intestinal subtype of histology. Aged ≥71, tumor diameter ≥12 mm, pT≥2, PV+, V+, and pN+ were independent prognostic factors for poor RFS in patients with CAV. An additional therapeutic strategy may be desirable in CAV patients at high risk for recurrence.

BRAF Exon 15 Mutations in the Evaluation of Well-Differentiated Epithelial Nephroblastic Neoplasms in Children: A Report From the Children's Oncology Group Study AREN03B2.

The distinction between well-differentiated epithelial favorable-histology Wilms tumor (EFHWT) and metanephric adenoma (MA) in children has historically been determined by the required absence of both a fibrous pseudocapsule and mitotic activity in MA. More recently these features have been allowed in adult MA. Mutations in exon 15 of the BRAF gene are reported in up to 88% of MAs but have not been reported in EFHWTs in children lacking MA features. To clarify the pathologic and molecular features used to distinguish between pediatric MA and EFHWT. Stage I epithelial tumors classified as EFHWT on central review (36 patients) were identified from the Children's Oncology Group AREN03B2 study. Thirteen tumors had morphologic features overlapping those of MA and 23 lacked such features; 35 of 36 had tissue available for sequencing of BRAF. Patients with EFHWTs with MA features (13) were older (mean, 8.4 versus 1.9 years; P < .001), had smaller tumor diameters (mean, 6.0 versus 9.7 cm; P < .001), and had fewer mitoses (mean, 1 versus 48 mitoses per 10 high-power fields; P < .001) than patients with EFHWT lacking MA features (23). All EFHWTs with MA features contained at least a partial fibrous pseudocapsule; 7 of 12 (58%) had a BRAF exon 15 mutation. No BRAF exon 15 mutations were identified in 23 EFHWTs lacking MA features. None of the 13 EFHWT patients with MA features have experienced relapse (median follow-up 5.9 years). Pediatric epithelial neoplasms with features of MA that show partial encapsulation and/or modest mitotic activity may be classified as MAs. Although BRAF mutation supports the diagnosis of MA, it is not required for the diagnosis.

Prevalence of Differentiated High-Grade Thyroid Carcinoma Among Well-Differentiated Tumors: A Systematic Review and Meta-Analysis.

Background: The current edition of the World Health Organization (WHO) classification of endocrine tumors introduced grading for follicular cell-derived thyroid cancer. Tumors with necrosis and/or high mitotic count but not fulfilling the Turin criteria for poorly differentiated carcinoma will be reclassified as differentiated high-grade thyroid carcinoma (DHGTC). However, the impact of this reclassification has not been evaluated. In this study, we performed a systematic review and meta-analysis to estimate the prevalence of this new entry across thyroid tumor subtypes. Methods: In this systematic review and meta-analysis, studies reporting data on necrosis and/or mitoses in well-differentiated thyroid carcinoma (WDTC) were used to estimate the prevalence of DHGTC. Heterogeneity and potential publication bias were also evaluated. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed, and quality assessment was performed using a modification of the Newcastle-Ottawa scale. The study has been registered in the International Prospective Register of Systematic Reviews (PROSPERO, ID: CRD42022378716). Results: In clinically unselected patients, the prevalence of DHGTC in WDTC was 0.072 [95% confidence interval, CI, = 0.045-0.113]. The proportion of high-grade tumors greatly varied across growth patterns and subtypes. Overall, the prevalence of DHGTC was higher in follicular thyroid carcinoma (FTC; 0.146 [CI = 0.101-0.205]) than in papillary thyroid carcinoma (PTC; 0.059 [CI = 0.036-0.097]). Diffuse sclerosing, follicular, and classic subtype PTC had the lowest rates of high-grade features (i.e., 0.018 [CI = 0.004-0.084]; 0.036 [CI = 0.010-0.124]; and 0.042 [CI = 0.027-0.066], respectively), while a greater proportion of solid trabecular and histologically aggressive PTC could be reclassified as DHGTC (i.e., 0.154 [CI = 0.067-0.314] and 0.168 [CI = 0.108-0.252], respectively). Similar proportions were obtained for minimally and widely invasive FTC (i.e., 0.136 [CI = 0.058-0.287] and 0.152 [CI = 0.086-0.254], respectively). Finally, in a cohort of patients with poor prognosis (i.e., fatal cases, metastatic and radioiodine resistant tumors, cases with biochemical recurrence), the proportion of DHGTC was 0.287 [CI = 0.155-0.469]. Conclusions: Following the current WHO indications, some tumors will be reclassified as DHGTC. The proportion of tumors with high-grade features is relevant in FTC, solid trabecular, and histologically aggressive PTC subtypes. A remarkable enrichment in DHGTC among patients with poor prognosis confirms the negative impact of high-grade features on outcome.

A pilot study of pembrolizumab and embolization or 90Y radioembolization for patients with metastatic well-differentiated neuroendocrine tumors

A pilot study of pembrolizumab and embolization or 90Y radioembolization for patients with metastatic well-differentiated neuroendocrine tumors

Do Pancreatic Well-differentiated Neuroendocrine Tumor (NET) Progress to Poorly-differentiated Neuroendocrine Carcinoma (NEC)?

Do Pancreatic Well-differentiated Neuroendocrine Tumor (NET) Progress to Poorly-differentiated Neuroendocrine Carcinoma (NEC)?

ETCTN 10450: A phase I trial of peposertib and lutetium 177 DOTATATE in well-differentiated somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs).

ETCTN 10450: A phase I trial of peposertib and lutetium 177 DOTATATE in well-differentiated somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs).

A pilot study of pembrolizumab and peptide receptor radionuclide therapy for patients with metastatic well-differentiated neuroendocrine tumors

A pilot study of pembrolizumab and peptide receptor radionuclide therapy for patients with metastatic well-differentiated neuroendocrine tumors

ETCTN 10388: A first in human Phase I Trial of Triapine and Lutetium Lu 177 DOTATATE in Well-Differentiated Somatostatin Receptor-Positive Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs)

ETCTN 10388: A first in human Phase I Trial of Triapine and Lutetium Lu 177 DOTATATE in Well-Differentiated Somatostatin Receptor-Positive Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs)

Use and perceived utility of [18 F]FDG PET/CT in neuroendocrine neoplasms: A consensus report from the European Neuroendocrine Tumor Society (ENETS) Advisory Board Meeting 2022.

Somatostatin receptor (SST) PET/CT is the gold standard for well-differentiated neuroendocrine tumours (NET) imaging. Higher grades of neuroendocrine neoplasms (NEN) show preferential [18F]FDG (FDG) uptake, and even low-grade NET may de-differentiate over time. FDG PET/CT's prognostic role is widely accepted; however, its impact on clinical decision-making remains controversial and its use varies widely. A questionnaire-based survey on FDG PET/CT use and perceived decision-making utility in NEN was submitted to the ENETS Advisory Board Meeting attendees (November 2022, response rate = 70%). In 3/15 statements, agreement was higher than 75%: (i) FDG was considered useful in NET, irrespective of grade, in case of mis-matched lesions (detectable on diagnostic CT but negative/faintly positive on SST PET/CT), especially if PRRT is contemplated (80%); (ii) in NET G3 if curative surgery is considered (82%); and (iii) in NEC prior to surgery with curative intent (98%). FDG use in NET G3, even in the presence of matched lesions, as a baseline for response assessment was favoured by 74%. Four statements obtained more than 60% consensus: (i) FDG use in NET G3 if locoregional therapy is considered (65%); (ii) in neuroendocrine carcinoma before initiating active therapy as a baseline for response assessment (61%); (iii) biopsy to re-assess tumour grade prior to a change in therapeutic management (68%) upon detection of FDG-positivity on the background of a prior G1-2 NET; (iv) 67% were in favour to reconsider PRRT to treat residual SST-positive lesions after achieving complete remission on FDG of the SST-negative disease component. Multidisciplinary opinion broadly supports the use of FDG PET/CT for characterisation of disease biology and to guide treatment selection across a range of indications, despite the lack of full consensus in many situations. This may reflect existing clinical access due to lack of reimbursement or experience with this investigation, which should be addressed by further research.

Tumour cells can escape antiproliferative pressure by interferon-β through immunoediting of interferon receptor expression

Type I interferons (IFNs) play a central role not only in innate immunity against viral infection, but also in the antitumour response, e.g. through a direct impact on cell proliferation. Particularly for cancer arising in the context of chronic inflammation, constant exposure to IFNs may constitute a strong selective pressure during tumour evolution. Expansion of neoplastic subclones resistant to the antiproliferative effects of IFNs may contribute to immunoediting of tumours, leading to more aggressive disease. Experimental evidence for this development of IFN-insensitivity has been scarce and its molecular mechanism is unclear. In this study we demonstrate that six weeks exposure of cells to IFN-β in vitro reduces their sensitivity to its antiproliferative effects, and that this phenotype was stable for up to four weeks. Furthermore, we observed substantial differences in cellular sensitivity to growth inhibition by IFN-β in a panel of ten different liver cancer cell lines, most prominently in a pair of highly dedifferentiated cell lines, and least in cells from well-differentiated tumours. In both, long-term IFN selection and in dedifferentiated tumour cell lines, we found IFNAR2 expression to be substantially reduced, suggesting the receptor complex to be a sensitive target amenable to immunoediting. Beyond new insights into possible molecular processes in tumour evolution, these findings might prove valuable for the development of biomarkers allowing to stratify tumours for their sensitivity to IFN treatment in the context of patient tailored therapies.

Recent Advances in The Diagnosis of Well-Differentiated Colon Neuroendocrine Tumors

Neuroendocrine tumors (NETs) are rare tumors that appear with secondary symptoms based on the release of vasoactive peptides and hormones into the blood as an answer to a signal from the nervous system. Neuroendocrine neoplasms of the colon are epithelial neoplasms with neuroendocrine differentiation and are classified in step with the foremost recent WHO 2022 classification as well- differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinoma- mas (NECs. NETs can be divided into serotonin-producing enterochromaffin-cell neuroendocrine tumor and glicentin-PYY-producing L-cell neuroendocrine tumor. Compared to NECs, NETs are often idle lesions occurring as incidental findings, being generally characterized by indolent course and relatively frequent ab- since of specific symptoms, which underscores the significance of establishing a prompt and accurate diagnosis, colonic neuroendocrine tumors generally presenting as a large tumor with local or distant metastasis (generally liver) at the time of diagnosis. While utmost colon NETs are considered non-aggressive tumors, a few cases may show a more aggressive clinical course. Clinical/pathological characteristics to select cases at high threat of recurrence/metastases are sadly inadequately consolidated. Diagnosis is based on the combination of clinical presentation, biochemical markers, endoscopy, imaging and confirmed by histopathology. Differential diagnostic for NETs can cause various problems: the rare appendiceal tubular and clear cell variants (which may be confused with non-neuroendocrine cancers). This review presents the updates in established diagnostic tests and tests that require further development, investigation, and validation before use [1,7].

Challenges of cytopathological pancreas diagnostics

The cytologic diagnostics of solid and cystic pancreatic lesions with endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is an integral part of the clinical workup and the decision of asurgical versus aconservative approach. Cystic lesions are increasingly being diagnosed due to improved imaging and represent numerous neoplastic as well as non-neoplastic epithelial and non-epithelial entities, which differ in biological behavior and prognosis. In particular, the differentiation of mucinous and non-mucinous cysts is significant for further clinical management. Regressive cellular changes, gastrointestinal contaminants, and overlapping morphologic changes of reactively altered ductal epithelial cells and cells of well-differentiated neoplasms and preneoplasms are special challenges of cytological diagnostics. For auniform cytological classification of findings, an internationally developed seven-level classification system has been published and co-published by the World Health Organization (WHO). This classification system takes into account both morphological findings and further procedures on cytological material such as next-generation sequencing and immunocytochemistry and is based on the WHO classification for pancreatic tumors. Against this background, important cytologic diagnostic criteria of various solid and cystic lesions relevant in clinical practice are presented in this article, considering diagnostic possibilities and pitfalls as well as differential diagnoses.

Intraoperative Radioguided Localization of an Occult Neuroendocrine Tumor of the Ileum.

We report the intraoperative radioguided localization of an occult well-differentiated neuroendocrine tumor of the ileum in a patient with a known neuroendocrine lymphonodal metastasis in the mesentery. Preoperative imaging included CT, PET/CT with 68 Ga-DOTATOC, and SPECT/CT with 99m Tc-HYNICTOC. These scans revealed morphological and functional properties of the primary tumor localized in the ileum. The day after IV 99m Tc-HYNICTOC injection, the patient underwent surgery, and the target lesion was intraoperatively detected by a collimated handheld γ-probe. Postoperative pathology examination confirmed the target lesion to be a neuroendocrine tumor of the ileum.

PP047 Concomitant 177Lu-DOTATATE and low dose capecitabine versus 177Lu-DOTATATE alone in patients with advanced well-differentiated gastroenteropancreatic neuroendocrine tumours – a randomized controlled trial

PP047 Concomitant 177Lu-DOTATATE and low dose capecitabine versus 177Lu-DOTATATE alone in patients with advanced well-differentiated gastroenteropancreatic neuroendocrine tumours – a randomized controlled trial