Low-grade Neuroendocrine Tumors Research Articles

ATP6AP2 is robustly expressed in pancreatic β cells and neuroendocrine tumors, and plays a role in maintaining cellular viability

ATP6AP2, also known as (pro)renin receptor, has been shown to be expressed in several tissues including pancreatic β cells. Whereas ATP6AP2 plays an important role in regulating insulin secretion in mouse pancreatic β cells, the expression profiles and roles of ATP6AP2 in human pancreatic endocrine cells and neuroendocrine tumor cells remain unclear. Here in this study, we investigated the expression profiles of ATP6AP2 in pancreatic endocrine cells, and found that ATP6AP2 is robustly expressed in pancreatic insulinoma cells as well as in normal β cells. Although ATP6AP2 was also expressed in low-grade neuroendocrine tumors, it was not or faintly detected in intermediate- and high-grade neuroendocrine tumors. Knockdown experiments of the Atp6ap2 gene in rat insulinoma-derived INS-1 cells demonstrated decreased cell viability accompanied by a significant increase in apoptotic cells. Taken together, these findings suggest that ATP6AP2 plays a role in maintaining cellular homeostasis in insulinoma cells, which could lead to possible therapeutic approaches for endocrine tumors.

Real world use of lanreotide in neuroendocrine tumors.

Treatment for metastatic neuroendocrine tumors (NETs) is often with somatostatin analogues (SSA) such as lanreotide in the first-line setting. Real world use of lanreotide in Canada is not well studied. We performed a retrospective chart review of 69 patients to study real world use of lanreotide at our centre. Lanreotide was the first-line of systemic treatment in 60 patients. Watch-and-wait was a common strategy and was seen in 31 patients. SSA switch strategy was seldom applied. Majority of patients on lanreotide had low-grade NETs. Standard starting dose of lanreotide 120 mg every 28 days was used in 66 patients. Dose escalation to 120 mg every 21 days occurred in 7 patients. The primary intention for treatment was tumor control in 32 patients, and both tumor and symptom control in 34 patients. Median time on treatment was 21.6 months. Overall, our findings were in keeping with current guidelines. It will be interesting to assess how clinical practice evolves in the future and to determine the role of dose escalation for disease control.

Video Presentation: Robotic Left Superior (S6) Segmentectomy and Bronchial Sleeve Resection

Recent guidelines advocate parenchymal preserving surgery, including bronchial sleeve lobectomy for low-grade neuroendocrine tumours. Segmentectomy and bronchoplasty may further improve parenchymal preservation, whilst respecting oncological principles. Robotic-assisted thoracic surgery (RATS) bronchial sleeve lobectomy has been shown to be safe and effective. This paper reports the second-in-man robotic segmentectomy with sleeve bronchoplasty.

Optimising Outcomes and Surveillance Strategies of Rectal Neuroendocrine Neoplasms.

Rectal neuroendocrine neoplasms are increasing in incidence, in part due to increased endoscopic procedures being performed for bowel cancer screening. Whilst most of these lesions are low-grade well-differentiated neuroendocrine tumours, they can have a varied clinical behaviour. Frequently, these lesions are incorrectly characterised at endoscopy and, therefore, incompletely excised using standard polypectomy techniques. Furthermore, some cases are not fully staged prior to or post resection. In this article we discuss the endoscopic and surgical options available to improve the likelihood of achieving an R0 resection and the staging procedures that should be used in these NETs. We also review factors that may suggest a higher risk of nodal involvement or recurrence. This information may help determine whether endoscopic or surgical resection techniques should be considered. In cases of R1 resection we discuss the management options available and the long-term surveillance options and when these should be offered to patients.

Multiple distant metastases arising from a single, low-grade rectal neuroendocrine tumor: an autopsy case report

BackgroundRectal neuroendocrine neoplasms are rare epithelial neoplasms of the rectum. The incidence of these tumors has increased over the past decades. However, many questions remain unanswered regarding their clinicopathology, including the possible mechanisms in which these tumors may grow and metastasize.Case presentationIn this case report, we report the findings of an autopsy of a 65-year-old Japanese woman diagnosed with multiple liver metastases from a single, low-grade rectal neuroendocrine tumor. The diagnosis was made in late 2018 to early 2019, and subsequently the patient underwent several rounds of standard chemotherapy. However, due to unfavorable side effects, she opted for palliative care at our hospital instead from December 2020. The patient’s condition was generally stable for the next 17 months, but in May 2022, she was hospitalized for increased abdominal pain. Despite enhanced pain control therapy, she eventually passed away. An autopsy was conducted to determine the exact cause of death. The primary rectal tumor was found to be small, but showed strong histological evidence of venous invasion. Metastases in the liver, pancreas, thyroid gland, adrenal glands, and vertebrae were also present. On the basis of the histological evidence obtained, we deduced that the tumor cells may have mutated and gained multiclonality as they spread vascularly to the liver, contributing to the distant metastases.ConclusionsThe results from this autopsy may provide an explanation for the possible mechanism by which small, low-grade rectal neuroendocrine tumors metastasize.

Gastric Neuroendocrine Tumor Type 1: A Case Report

33-year-old patient who is referred to Endocrinology Outpatient Consultation in March 2021 due to the finding in gastric polyp biopsy 9 mm sessile located in greater curvature, of low-grade neuroendocrine tumor (ki-67 < 3%) without infiltration of the muscularis layer own. It is followed jointly with the Digestive Service, performing mucosectomy in April 2021 on carcinoid in major curvature of the stomach, where there is no evidence of residual tumor in the anatomo-pathological study (A-P). After completing the study with other complementary tests, gastric neuroendocrine tumor type 1 is diagnosed against the background of chronic atrophic gastritis. At present, the patient continues with periodic gastroscopic check-ups scheduled by the Digestive Service.

Natural history study and tissue procurement of neuroendocrine neoplasms (NENs).

TPS659 Background: Neuroendocrine neoplasms (NENs) are a rare spectrum of malignant neoplasms originating from neuroendocrine cells, most commonly affecting the gastrointestinal tract, pancreas, and lungs. Tumors may vary from low grade neuroendocrine tumors (NET) to high grade neuroendocrine carcinomas (NEC). The annual occurrence of NENs is increasing worldwide and currently the incidence in the US is about 6 cases per 100,000 people per year. A variety of therapeutic options are available for advanced NENs, however, when to apply a given option, what combination therapeutic approach should be used, how long treatment should be continued is unclear and controversial. Moreover, unlike common cancers, pre-clinical models for NENs are sorely limited. Without robust pre-clinical models our understanding of tumor pathophysiology and novel drug development can be challenging. Methods: A prospective study to evaluate the natural history and sample acquisition of NENs comprehensively and longitudinally. Patients ≥ 18 years old with histological confirmation of NENs, biochemical evidence of NENs, or by imaging studies of NENs are eligible. Participants are invited to NIH for biannual evaluations or as clinically indicated. Patients complete individual medical history, family history, and laboratory assessments including blood, saliva, and tumor for RNA/DNA analysis. A tumor analysis via a 500+ gene panel (Illumina TruSight Oncology 500 Panel) is performed for comprehensive genomic and epigenomic analysis. When feasible, fresh tissue is collected to develop pre-clinical models for drug testing. If clinically indicated, anatomic and functional imaging is performed. We aim to 1) create a repository of biological samples and conduct future investigations to understand the basic biology of NENs with the goal to develop novel treatment approaches, biomarkers of treatment response, and new prognostic and diagnostic models, 2) acquire clinical data so that the overall genomic, proteomic, and metabolomic alternations can be correlated to clinical parameters, 3) establish organoid cultures, cell line models, and xenograft models corresponding to NENs of various grades for drug screening. This protocol will evaluate the natural history of NENs, allow tissue acquisition, and study this heterogenous group of neoplasms with unique tumor biology, and current clinical management to stabilize correlations with clinical outcomes and develop novel therapies. Clinical trial information: NCT05237934 .

Successful Treatment with <sup>177</sup>Lutetium-Dotatate and Maintenance Octreotide in a Patient with Esthesioneuroblastoma with Central Nervous System Invasion: Case Report and Review of the Literature

This article presents a case of a patient with relapsed esthesioneuroblastoma (ENB), an aggressive rare tumor that arises from the specialized sensory epithelial olfactory cells in the skull base area, which was initially treated with endoscopic surgery, followed by adjuvant radiotherapy. After local relapse, new surgical approaches and subsequent lines of platin-based chemotherapy were performed. A PET-CT with 68GALIUM DOTATATOC (PET-DOTATOC) showed intense uptake of disease, compatible with the presence of somatostatin receptors, in the face, nodes, liver, bones, and meningeal area. Treatment with 4 cycles of 177Lutetium-Dotatate was performed, followed by maintenance octreotide, with a major radiological and clinical response that is lasting more than 1 year after treatment. This article describes a rare case of a skull-base tumor, with multiple recurrences, in which disease control was achieved with a targeted Peptide Receptor Radionuclide Therapy (PRRT) with 177Lutetium-Dotatate, and discusses factors that could influence the incorporation of this form of therapy. Previous case reports proved the potential efficacy of this therapy usually given for low-grade neuroendocrine tumors and will be carefully reviewed.

A multidisciplinary approach to the work up and management of pulmonary carcinoid tumors and DIPNECH: a narrative review.

Low and intermediate grade neuroendocrine tumors of the lung are uncommon malignancies representing 2% of all lung cancers. These are termed typical and atypical pulmonary carcinoid tumors. These can arise in the setting of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). The presentation, workup, management and outcomes of patients with these tumors can overlap with more common lung cancers but differ in that many of these patients have a prolonged clinical course. The objective of this narrative review is to summarize the literature and provide evidence and expert-based algorithms for work up and treatment of pulmonary carcinoids and DIPNECH. A search of PubMed and Web of Science databases ending April 15, 2022, with the following keywords "lung carcinoid", "DIPNECH", "lung neuroendocrine," and "bronchopulmonary carcinoid". Pulmonary carcinoid tumors benefit from a multidisciplinary approach. Pre-treatment imaging with contrast-enhanced computed tomography, and DOTATATE positron emission tomography is required. Surgical resection is the gold standard for curative intent, and possibly including sublobar resections. Patients can recur or develop new primaries thus emphasizing the importance of surveillance; national guidelines recommend at least a 10-year follow up. A growing body of literature support the use of endobronchial therapy, with long responses documented. Systemic therapy consists of everolimus, somatostatin analogs, peptide receptor radionuclide therapy, and chemotherapy. Diffuse idiopathic pulmonary neuroendocrine tumor cell hyperplasia is rare, but series suggest somatostatin analogs may confer clinical benefit. Pulmonary carcinoid tumors and DIPNECH are rare. Despite lack of regulatory approvals for advanced disease, multiple options are available but should be sequenced according to the clinical status and disease biology. Each patient should be discussed in a multidisciplinary setting and clinical trials should be considered if available.

Two Cases of Duodenal Neuroendocrine (Carcinoid) Tumor Concurrent with Invasive Gastric Adenocarcinoma and Pancreatic Intraductal Papillary Mucinous Neoplasm

Abstract Introduction/Objective Neuroendocrine (carcinoid) tumors of the duodenum are extremely rare and account for only 2-4% of gastrointestinal tract neuroendocrine tumors. We report two cases of incidentally discovered duodenal neuroendocrine tumor which respectively occurred in a patient with invasive gastric adenocarcinoma and in a patient with pancreatic intraductal papillary mucinous neoplasm (IPMN). Methods/Case Report The first case involved a 60-year old male who presented with melena and symptomatic anemia and was found on EGD to have a large circumferential mass at the gastric antrum/pylorus, which was revealed to be an invasive gastric adenocarcinoma on biopsy. At the time of distal gastrectomy for this malignancy, a concurrent, 0.6 cm-sized, low grade neuroendocrine tumor was incidentally discovered at the duodenal margin. The duodenal tumor consisted of nests and trabeculae of monotonous cells with ovoid/round nuclei, finely speckled “salt and pepper” chromatin, and low mitotic rate (< 2 mitoses/2 mm2), and invaded only into submucosa. The tumor cells were strongly and diffusely positive for neuroendocrine markers chromogranin, synaptophysin, and CD56, positive for CK7 and CDX2, negative for CK20, and with low Ki67 proliferation index (< 3%). The second case involved a 69-year old female who presented with epigastric pain and was found on abdominal CT to have a 4 cm-sized cystic mass in the pancreatic head. While biopsy of the pancreatic mass revealed an IPMN, a separate biopsy of an incidentally discovered, 1 cm-deep ulcer in the duodenum bulb revealed a low-grade neuroendocrine tumor with similar morphologic features, mitotic rate, and immunohistochemical staining pattern as the prior case while also negative for IMP3 stain. The patient had normal serum gastrin and urine HIAA levels, but elevated serum chromogranin-A levels. Results (if a Case Study enter NA) NA. Conclusion Duodenal carcinoids are rare (1-3% of primary duodenal tumors) and are mostly non-functional and unifocal. The duodenum is also the least common site (2-4%) for GI tract neuroendocrine tumors. The pathophysiology of these tumors is still poorly understood, with the majority occurring sporadically and a minority in the setting of hereditary cancer syndromes. This report documents two very rare instances of duodenal neuroendocrine tumor incidentally discovered with invasive gastric adenocarcinoma and pancreatic IPMN.

68Ga-DOTATATE PET/BT görüntülemede somatostatin analogları ile tedavi normal hedef organların ve malign lezyonların alımında farklılık gösterir mi?

Abstract
 Objective: 
 Somatostatin analogs (SSA) are used in treating low-grade neuroendocrine tumors, mainly because of their antiproliferative effect. 68Ga tetraazacyclododecantetraacetic acid-DPhe1-Tyr3-octreotate (DOTATATE) PET/CT as somatostatin receptor imaging has been widely used in recent years. However, there are conflicting publications in the literature, although there are guidelines for discontinuing the use of SSA before imaging. This study aims to investigate the effect of SSAs on Somatostatin receptor imaging.
 Material and Method: We retrospectively analyzed 253 patients who underwent 68Ga-DOTATATE PET/CT imaging between 2018 and 2022. Among these patients, those with low grades (Grade 1 and Grade 2) using SSA were included in the study. SUVmax (maximum standard uptake volume) of normal target organs, primary tumors, and metastases with the highest SUVmax in each organ were compared before and after SSA treatment. 
 Results: 28 patients (16 females; 12 males, age [mean±SD], 54.82±14.27, range 18-78) with low-grade (Grade 1 and 2) NET and 68Ga-DOTATATE PET/CT imaging with SSA therapy were included in the study. Although SUVmax was decreased in the values measured after SSA application in the liver and spleen, it was not statistically significant (p>0.05). There was no significant difference between SUVmax values in primary tumors and metastatic lesions in the liver, bone, lung, or lymph nodes before and after SSA application (P> 0.05).
 Conclusion: In conclusion, these drugs do not need to be discontinued before 68Ga-DOTATATE PET/CT imaging for treatment follow-up in neuroendocrine tumor patients using somatostatin analogs. In addition, these drugs may help report interpretation by increasing the intensity of metastatic lesions in the liver and spleen.

Demographic trends in the incidence of malignant appendiceal tumours in England between 1995 and 2016: Population-based analysis.

AimsRecent data suggest that the incidence of malignant appendiceal tumours is increasing. This study aimed to determine temporal trends in the incidence of malignant appendiceal tumours within England and a possible influence by demographic factors.MethodsAll incident cases of appendiceal tumours in patients aged 20 years and above were identified from the National Cancer Registration and Analysis Service database between 1995 and 2016 using ICD-9/10 codes. Cancers were categorized according to histology. Joinpoint regression analysis was used to investigate changes in age-standardized incidence rates by age, sex, histological subtype and index of multiple deprivation quintiles, based on socioeconomic domains (income, employment, education, health, crime, barriers to housing and services and living environment). Average annual per cent changes (AAPCs) were estimated by performing Monte-Carlo permutation analysis.ResultsA total of 7333 tumours were diagnosed and 7056 patients were analysed, comprising 3850 (54.6 per cent) neuroendocrine tumours (NETs), 1892 (26.8 per cent) mucinous adenocarcinomas and 1314 (18.6 per cent) adenocarcinoma (not otherwise specified). The overall incidence of appendiceal tumours increased from 0.3 per 100 000 to 1.6 per 100 000 over the study interval. Incidence rate increases of comparable magnitude were observed across all age groups, but the AAPC was highest among patients aged 20–29 years (15.6 per cent, 95 per cent c.i 12.7–18.6 per cent) and 30–39 years (14.2 per cent, 12.2–16.2 per cent) and lowest among those aged 70–79 years (6.8 per cent, 5.7–8.0 per cent). Similar incidence rate increases were reported across all socioeconomic deprivation quintiles and in both sexes. Analysis by grade of NET showed that grade 1 tumours accounted for 63 per cent between 2010 and 2013, compared with 2 per cent between 2000 and 2003.ConclusionsThe incidence rate of malignant appendiceal tumours has increased significantly since 1995 and is mainly attributed to an increase in NETs. The increased diagnosis of low-grade NETs may in part be due to changes in pathological classification systems.

Bone metastases from neuroendocrine tumors: clinical and biological considerations.

We considered 351 patients affected by neuroendocrine tumors (NETs), followed at the University Hospital of Padua and at the Veneto Oncological Institute. Of these, 72 (20.5%) suffered from bone metastases. The sample was divided according to the timing of presentation of bone metastases into synchronous (within 6 months of diagnosis of primary tumor) and metachronous (after 6 months). We collected data on the type and grading of the primary tumor and on the features of bone metastases. Our analysis shows that the group of synchronous metastases generally presents primary tumors with a higher degree of malignancy rather than the ones of the metachronous group. This is supported by the finding of a Ki-67 level in GEP-NETs, at the diagnosis of bone metastases, significantly higher in the synchronous group. Moreover, in low-grade NETs, chromogranin A values are higher in the patients with synchronous metastases, indicating a more burden of disease. The parameters of phospho-calcium metabolism are within the normal range, and we do not find significant differences between the groups. Serious bone complications are not frequent and are not correlated with the site of origin of the primary tumor. From the analysis of the survival curves of the total sample, a cumulative survival rate of 33% at 10 years emerges. The average survival is 80 months, higher than what is reported in the literature, while the median is 84 months. In our observation period, synchronous patients tend to have a worse prognosis than metachronous ones with 52-months survival rates of 58 and 86%.

Abstract No. 247 Transarterial radioembolization (TARE) versus transarterial chemoembolization (TACE) for the treatment of low-grade neuroendocrine tumors

For patients with unresectable hepatic metastases caused by low-grade neuroendocrine tumors (carcinoid), liver-directed arterial therapies have the potential to provide disease control and/or symptom palliation with a low risk of complications. Although carcinoid has long been regarded as a radioresistant tumor type, more recent studies have shown radiation to be effective in significantly decreasing carcinoid tumor burden and controlling carcinoid syndrome. The goal of this study was to use the TriNetX platform to determine if Y-90 trans-arterial radioembolization (TARE) treatment of carcinoid tumors is noninferior to trans-arterial chemoembolization (TACE).

Primary ovarian carcinoid arising in associated mature cystic teratoma

BackgroundPrimary ovarian carcinoid is a very rare ovarian low-grade neuroendocrine tumor, accounting for about 0.1% of all ovarian neoplasms.Case presentationWe reported a case of primary ovarian carcinoid arising from a mature cystic teratoma in a 50-year-old woman. Intraoperative frozen section of left ovarian mass was assessed and a malignant epithelial tumor was considered. Morphologically, the main tumor was composed of cells forming trabeculae, and mature cystic teratoma was observed adjacent to the main part. Immunohistochemistry revealed that the trabecular cells were diffuse positive for pan Cytokeratin, CD56 and synaptophysin with low Ki-67 index (about 1%).ConclusionsCareful morphological observation combined with appropriate accessory examination are essential for the diagnosis of primary ovarian carcinoid arising from mature cystic teratoma. In addition, the classification criteria of the primary ovarian neuroendocrine tumor are discussed.

Lutetium-177 Dotatate-Induced Hemolytic Anemia and Myelodysplastic Syndrome

Lutetium-177 (177Lu) dotatate is a type of peptide receptor radioligand therapy (PRRT) using radiolabeled somatostatin for patients with progressive somatostatin receptor-positive gastrointestinal neuroendocrine tumors. While cases of therapy-related myeloid neoplasms (t-MN) have been described as a consequence of 177 Lu dotatate, there are no reports of hemolytic anemia associated with therapy. We present a case of a 68-year-old woman with metastatic low-grade neuroendocrine tumor who presented four weeks after the second dose of 177Lu dotatate with progressive fatigue and dyspnea. Laboratory workup was remarkable for hemolytic anemia. Lutetium-177 dotatate-induced hemolysis was suspected after ruling out other causes. Corticosteroid treatment was initiated with improvement in hemoglobin, and dose-reduced PRRT was planned upon discharge. Six months into the treatment course of 177Lu dotatate, macrocytic anemia was noticed on routine follow-up with normal vitamin B12 and folic acid levels. A bone marrow biopsy was done, revealing myelodysplastic syndrome (MDS) features. Given the temporal relationship between drug introduction and the objective findings, early-onset 177Lu dotatate-induced MDS was diagnosed with a plan for close hematologic follow-up. Myelodysplastic syndrome should be suspected when megaloblastic anemia develops in patients with previous 177Lu dotatate therapy. The latency period between initial treatment and MDS diagnosis reported in the literature ranges between 15 months to seven years. Apart from the unusually early onset of MDS, what is unique about our case is the development of hemolytic anemia after administration of PRRT. The clinical course and the brisk response to steroid therapy, suggest other mechanisms of PRRT toxicity besides DNA breaks, genetic mutations, and myelosuppression by an immune-mediated component that likely plays a role in 177Lu dotatate toxicity. Further investigation and monitoring are needed to identify the frequency of such adverse events and the pathophysiology of their occurrence.

Parenchyma-Sparing Hepatic Cytoreduction for Neuroendocrine Tumours Metastases

Background: Due to unique indolent biology, metastatic neuroendocrine tumours (NETs) can be managed for many years with prolonged survival. Goals of NETs therapy differ from other more common solid malignancies. Cytoreductive surgery plays an important role in the multidisciplinary management of low-grade NETs. It offers an opportunity to reduce both tumor burden and hormonal load to potentially prolong survival and improve quality of life. While parenchyma-sparing cytoreduction is the recommended technique, anatomical resections are still commonly performed because they are more familiar to liver surgeons. Methods: This video reviews parenchyma-sparing cytoreductive surgery of hepatic NETs metastases. Approaches and techniques, with their rationale are reviewed. Results: We focus on the management of hepatic metastases in grade 1 and 2 NETs. The video reviews the principles of parenchyma-sparing cytoreduction with enucleation, hepatotomy, and intra-operative ablation. Considering the goal of cytoreduction for an indolent disease, R1 or R2 resection is planned. We highlight the need to avoid anatomical resection to preserve parenchyma, which is critical in minimizing morbidity and optimizing long-term sequencing of therapies for a chronic cancer. Conclusion: We herein illustrate the rationale and principles for hepatic parenchyma-sparing cytoreduction for metastatic NETs. This approach can lead to significant tumoral and hormonal control, with favorable long-term outcomes. Using a parenchyma sparing approach rather than anatomic resections may improve long term function and preserve the ability to tolerate future liver directed therapy. Review and dissemination of the technique will contribute to safe surgical management of metastatic NETs by hepato-pancreatico-biliary surgeons.

Emerging Therapeutic Concepts and Latest Diagnostic Advancements Regarding Neuroendocrine Tumors of the Gynecologic Tract.

Neuroendocrine neoplasms (NENs) are particularly rare in all sites of the gynecological tract and include a variety of neoplasms with variable prognosis, dependent on histologic subtype and site of origin. Following the expert consensus proposal of the International Agency for Research on Cancer (IARC), the approach in the latest World Health Organization (WHO) Classification System of the Female Genital Tumours is to use the same terminology for NENs at all body sites. The main concept of this novel classification framework is to align it to all other body sites and make a clear distinction between well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). The previous WHO Classification System of the Female Genital Tumours featured more or less the same principle, but used the terms ‘low-grade neuroendocrine tumor’ and ‘high-grade neuroendocrine carcinoma’. Regardless of the terminology used, each of these two main categories include two distinct morphological subtypes: NETs are represented by typical and atypical carcinoid and NEC are represented by small cell neuroendocrine carcinoma (SCNEC) and large cell neuroendocrine carcinoma (LCNEC). High-grade NECs, especially small cell neuroendocrine carcinoma tends to be more frequent in the uterine cervix, followed by the endometrium, while low-grade NETs usually occur in the ovary. NENs of the vulva, vagina and fallopian tube are exceptionally rare, with scattered case reports in the scientific literature.

Extrapulmonary small cell carcinoma. Literature review

The review shows the features of rare tumors extrapulmonary small cell carcinomas (EPSCC). The possible approaches for the treatment of this unfavorable group of tumors are discussed. EPSCC can occur in every organ. The clinical course and morphology of EPSCC are similar to small lung cell carcinoma (SCLC). EPSCC belongs to the group of low-grade neuroendocrine tumors with high proliferative activity. There are a small number of publications in the literature concerning EPSCC. Basically, these publications concerning the various clinical cases with comments. Most often, EPSCC occurs in the female genital tract, gastrointestinal tract, genitourinary SCC and known cases of SCC of the head and neck. The cases concerning SCC in other organs are also described. For the treatment of EPSCC are usually applied guidelines developed for SCLC, and several publications on the use of immunotherapy in the treatment of EPSCC have already appeared. The analysis of the available literature let us suggest EPSCC is a big problem that requires a more in-depth study and consensus guidelines adoption for the management of these patients.

Prevalence of Delta-Like Protein 3 in a Consecutive Series of Surgically Resected Lung Neuroendocrine Neoplasms.

Delta-like protein 3 (DLL3) is a protein of the Notch pathway, and it is a potential therapeutic target for high-grade lung neuroendocrine tumors (NETs), i.e., small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC). However, DLL3 prevalence in lung NETs and its association with clinicopathological characteristics and prognosis remained unclear. We analyzed the immunohistochemical expression of DLL3 and its prognostic role in a consecutive series of 155 surgically resected lung NETs, including typical carcinoid (TC), atypical carcinoid (AC), LCNEC, and SCLC patients. The DLL3 expression was categorized as high (>50% positive tumor cells) or low (<50%). In addition, tumors were categorized by H-score (i.e., percentage of positive cells by staining intensity, ≥150 vs. <150). DLL3 staining was positive in 99/155 (64%) samples, and high DLL3 expression was frequently observed in high-grade tumors. In detail, 46.9% and 75% of SCLC and 48.8% and 53.7% of LCNEC specimens showed a high DLL3 expression by using H-score and percentage of positive tumor cells, respectively. Regarding low-grade NETs, only 4.9% and 12.2% TCs and 19.5% and 24.4% ACs had high DLL3 expression considering H-score and percentage of positive tumor cells, respectively. High DLL3 expression was associated with advanced American Joint Committee on Cancer (AJCC) stage, peripheral location, and chromogranin A expression in high-grade tumors (p < 0.05). In low-grade NETs, high DLL3 expression was associated with female sex, peripheral location, a higher number of mitoses, higher Ki-67 index, presence of necrosis, and pleural infiltration (p < 0.05). No association was observed between high DLL3 expression and overall survival (OS) and disease-free survival (DFS) in high-grade NETs, whereas high DLL3 expression was associated with lower DFS in ACs (p = 0.01). In conclusion, our study demonstrated a high prevalence of DLL3 expression in high-grade lung NET patients and its association with aggressive clinicopathological features. These findings confirm that DLL3 could represent a useful biomarker for target therapy in high-grade tumors. Our results also suggest that the DLL3 expression could identify a subset of AC tumors with more aggressive behavior, thus providing the basis for new therapeutic options in this group of patients.