Poorly Differentiated Neuroendocrine Carcinomas Research Articles

Treatment of poorly differentiated neuroendocrine carcinomas of rectum and anus with chemoradiotherapy: a single-centre evaluation

PurposePoorly differentiated neuroendocrine carcinoma (PDNEC) of the rectum and anus is a rare disease exhibiting aggressive biological behaviour, even if diagnosed early. Currently, there are no agreed standard treatment approaches and management of locally advanced (LA) and metastatic PDNEC usually follows treatments used in pulmonary neuroendocrine carcinomas because of the similarities with small cell lung cancer. The role of surgery in PDNEC is still debated and the benefit of chemoradiotherapy (CRT) is unknown. This report summarises the experiences of CRT application in anorectal PDNEC in a single Danish institution.MethodsAll patients with PDNEC treated with concomitant CRT between May 2019 and January 2021 at a University hospital in Denmark were evaluated. Demographics, treatment and survival outcomes were collected and analysed.ResultsSix patients were identified. Five patients received radiotherapy with 50.4 Gy/28 fractions, and four were eligible for curative resection after the CRT. Distant metastasis was observed in four patients at diagnosis. Two patients with synchronous liver metastases were treated with RFA, and one received a liver resection. The treatment was well tolerated with limited side effects. The median follow-up time was 17 months (range 10–36 months), and the median duration of response was 11.2 months (range 8.1 to 24.2 months). One patient achieved a complete response.ConclusionA multimodal treatment approach with CRT in advanced stages of PDNEC in a highly selected patient group is well tolerated and with a high chance of achieving local control and, combined with surgery, even complete response in a single case.

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)?

Review of Merkel cell carcinoma with solitary pancreatic metastases mimicking primary neuroendocrine tumor of the pancreas.

Merkel cell carcinoma (MCC) but metastases to the pancreas are very rare. There are only a few cases of isolated metastases of MCC to the pancreas. Because of this rarity, it can be wrongly diagnosed as a neuroendocrine tumor of the pancreas(pNET), especially the poorly differentiated neuroendocrine carcinoma (PNEC) subtype, in which the treatment is vastly different than that of MCC with isolated metastases of the pancreas. An electronic search of the PubMed and google scholar databases was performed to obtain the literature on MCC with pancreatic metastases, using the following search terms: Merkel cell carcinoma, pancreas, and metastases. Results are limited to the following available article types: case reports and case series. We identified 45 cases of MCC with pancreatic metastases from the PubMed and Google Scholar database search and examined their potential relevance. Only 22 cases with isolated pancreatic metastases were taken for review including one case that we encountered. The results from our review of cases of isolated pancreatic metastases of MCC were compared to the characteristics of the poorly differentiated pancreatic neuroendocrine tumor (PNEC). We found the following: (a) MCC with isolated pancreatic metastases occurred at an older age than PNEC and with male gender predominance (b) Most of the metastases occurred within 2years of initial diagnosis of MCC (c) Resection of pancreatic mass was the first line treatment in case of resectable PNECs whereas resection of metastases was infrequently performed in MCC with pancreatic metastases.

Urinary Neuroendocrine Neoplasms Treated in the "Modern Era": A Multicenter Retrospective Review.

Primary urinary neuroendocrine neoplasms (U-NENs) are extremely rare thus optimal treatment is unknown. Grading and treatment are typically extrapolated from other primary sites. Since 2010, the clinical landscape for NENs has changed substantially. We performed a retrospective review of U-NENs to assess treatment patterns and oncologic outcomes of patients treated in the recent era of NEN therapy. A multicenter retrospective review of patients diagnosed after 2005 and alive after 2010. Time to treatment failure (TTF) was used to evaluate progression and toxicity for systemic therapy. Tumors were categorized as having either well-differentiated neuroendocrine tumor (WDNET) or poorly differentiated neuroendocrine carcinoma (PDNEC) histology. A total of 134 patients from 6 centers were included in our analysis, including 94 (70%) bladder, 32 (24%) kidney, 2 (1.5%) urethra and 4 other urinary primaries (3.0%). Poorly-differentiated neuroendocrine carcinoma was more common in bladder (92%) than non-bladder tumors (8%). Median Ki-67 available in bladder primary was 90% (n=24), kidney 10% (n=23), ureter 95% (n=1), urethra 54% (n=2), and others 90% (n=3). Patients received a median of 2 therapies (range 0-10). Median time to death was not reached in locoregional WDNETs versus 8.2 years (95% CI, 3.5-noncalculable) in metastatic WDNETs (predominantly renal primary). Median time to death was 3.6 years (95% CI, 2.2-9.2) in locoregional PDNECs versus 1 year (95% CI, 0.8-1.3) in metastatic PDNECs (predominantly bladder primary). This is the most extensive series examining treatment patterns in patients with U-NENs in the recent era of NEN therapy. The apparent inferior survival for bladder NENs is likely due to the preponderance of PDNECs in this group. As predicted, treatments for U-NENs mirrored that of other more common NENs. In our retrospective cohort, we observed that patients with WD-UNETs treated with peptide receptor radionuclide therapy (PRRT) and everolimus suggested potential activity for disease control in WD-UNETs. Prospective studies are needed to assess the activity of new oncology drugs in UNENs.

Mixed Poorly-Differentiated Neuroendocrine Carcinoma and Well-Differentiated Neuroendocrine Tumor in the Extrahepatic Common Bile Duct: A Unique Rare Case

Mixed Poorly-Differentiated Neuroendocrine Carcinoma and Well-Differentiated Neuroendocrine Tumor in the Extrahepatic Common Bile Duct: A Unique Rare Case

S3411 Extensive Hepatic Lesions From a Primary Duodenal Neuroendocrine Carcinoma in a Young Male

Introduction: Neuroendocrine neoplasms (NEMs) are relatively rare, accounting for 0.5% of newly diagnosed malignancies. NEMs can be found throughout the body with two-thirds arising in the GI tract and incidence increasing among duodenal NEMs. These malignancies have a female predominance and generally occur in the 6th decade of life. This is a case of advanced metastatic disease from an unexpected duodenal neuroendocrine carcinoma in a healthy young male. Case Description/Methods: A 29-year-old male, with no PMH, acutely developed sharp RUQ abdominal pain. Prior to this, he was in his usual state of health. In the ED, the patient was hemodynamically stable with tenderness to palpation in the RUQ. Initial labs showed WBC 12.10 × 103/uL, Hgb 11.7 g/L, AST 55 U/L, ALT 173 U/L, ALP 127 U/L, and TBIL 0.8 mg/dL. CT A/P showed multiple well-circumscribed liver lesions, largest measuring 8.6 × 7.8 cm, with portal venous invasion (Figure A). CA 19-9 and CEA were negative. There was elevation of AFP 1,577 ng/mL and LDH 817 U/L, but negative hCG. A1AT, ANA, AMA, ASMA, ALKM, and ceruloplasmin were negative. Liver biopsy showed a poorly-differentiated malignant neoplasm of unknown primary. EGD was performed revealing a fungating mass in the second portion of the duodenum (Figure B). Pathology favored a high-grade poorly-differentiated neuroendocrine carcinoma (Figure C). He was discharged with palliative cisplatin/irinotecan initiation. Discussion: Gastrointestinal NEMs have been increasing in prevalence due to improved awareness. When carcinoid symptoms are absent, detection is dependent on imaging and endoscopy after the patient presents with complications from metastasis or mass effect. Following biopsy, GI NEMs are classified by WHO 2010 criteria into 3 groups based on mitotic count and Ki-67 index. Group 3 tumors are classified as poorly-differentiated neuroendocrine carcinomas with Ki-67 >20% with higher rates of angioinvasion and metastatic potential. Lymph node metastasis occurs in 60% of duodenal NETs, while liver mets occur in < 10%. In our case, the patient’s Ki-67% index was >90%, characterizing it as a Group 3 NEM. Characterization is important given the impact on prognosis and treatment. Group 3 NEMs have the overall worst prognosis. Since >90% of duodenal NEMs do not cause a clinical syndrome and are not associated with metastatic disease, surgical or endoscopic resection is preferred. However, if there is metastatic disease or high-grade histologic features, chemotherapy is the mainstay of treatment.Figure 1.: A, CT A/P with multiple large heterogeneously enhancing liver lesions concerning for metastatic malignancy of unknown primary (B) Large fungating mass located in the second portion of the duodenum (C) Duodenal mass, H&E stain, 20×, high-grade poorly differentiated epithelial malignancy composed of nested cells with indistinct nucleoli, moderate eosinophilic cytoplasm, and brisk mitosis.

Survival in patients with neuroendocrine tumors of the colon, rectum and small intestine

BackgroundNeuroendocrine neoplasms (NENs) of the colon, rectum and small intestine (SI) are increasing in incidence and prevalence. We evaluated the 5-year overall survival (OS), and cancer-specific survival (CSS). MethodsThe Surveillance, Epidemiology, and End Results (SEER) 18 registry from 2000 to 2017 was accessed to identify patients with colonic, rectal, and SI NENs. Results46,665 patients were diagnosed with NENs of the colon (n = 10,518, 22.5%), rectum (18,063, 38.7%), and SI (18,084, 38.8%). By tumor site alone, patients with well-differentiated neuroendocrine tumors (NETs) of the rectum had improved 5-year OS (HR 0.72, 95% CI 0.68–0.77, p < 0.001). However, patients with rectal poorly-differentiated neuroendocrine carcinomas (NECs) who underwent oncologic resection had lower 5-year OS (35.1%) compared to colon (41.9%), and SI (72.5%). ConclusionsSurgical resection may improve 5-year OS for NECs of the SI and colon, except in the rectum where survival was reduced. More frequent surveillance and timely initiation of systemic therapy should be considered for rectal NECs.

Exploring Real World Outcomes with Nivolumab Plus Ipilimumab in Patients with Metastatic Extra-Pulmonary Neuroendocrine Carcinoma (EP-NEC).

Simple SummaryExtrapulmonary neuroendocrine carcinomas (EP-NEC) are a group of tumors which are often metastatic and characterized by poor outcomes. Platinum-etoposide chemotherapy is the current front-line therapy for metastatic EP-NEC, and has been adapted from small cell lung cancer. There are limited treatment options for patients with platinum-resistant EP-NEC, with no current established second-line standard of care. Recently, there has been mixed evidence for the role of immunotherapy in EP-NEC, with limited existing prospective data. In this multicenter retrospective analysis, we compared outcomes between patients with refractory EP-NEC who received single, dual immune check point inhibitors (ICPIs) and cytotoxic chemotherapy in the second-line setting. This real world experience suggests that utilizing ipilimumab and nivolumab in patients with second-line pretreated EP-NEC may be more effective than other existing treatment options.Background: Dual utilization of the immune checkpoint inhibitors (ICPIs) nivolumab plus ipilimumab has demonstrated clinical promise in the treatment of patients with refractory high-grade neuroendocrine neo-plasms (NENs) in phase II clinical trials (DART SWOG 1609 and CA209), while single agent ICPIs have largely been ineffective for these types of tumors. While both trials demonstrated promising results in high grade NENs, there was no adequate description of the association between tumor differentiation (high-grade well-differentiated neuroendocrine tumor vs poorly-differentiated extra-pulmonary neuroendocrine carcinoma (EP-NEC) and ICPI outcomes in the DART SWOG 1609 trial. Our study reports on the effectiveness and toxicity profile of dual ICPIs in a real world second-line EP-NEC patient population. Methods: Data on metastatic EP-NEC patients, treated with either ICPIs (single and dual ICPIs) or chemo-therapy in the second-line setting, were retrieved from databases of three comprehensive cancer centers. Associations between treatment characteristics and outcomes, including progression-free survival (PFS) and overall survival (OS), were evaluated. Results: From 2007 to 2020, we identified 70 patients with metastatic EP-NEC (predominantly of gastro-enteropancreatic origin), of whom 42 patients (23 males, 19 females, median age 62 years old) were eligible for the final analysis. All patients were refractory to platinum etoposide doublet chemotherapy in the first-line setting. The median PFS for patients who received dual ICPIs (11 patients), single agent ICPI (8 patients), and cytotoxic chemotherapy (23 patients) was 258 days, 56.5 days, and 47 days, respectively (p = 0.0001). Median overall survival (OS) for those groups was not reached (NR), 18.7 months, and 10.5 months, respectively (p = 0.004). There were no significant differences in treatment outcomes in patients according to tumor mismatch repair (MMR) or tumor mutational burden (TMB) status. Grade 3–4 adverse events (AEs) were reported in 11.1% of the patients who received dual ICPIs; however, none of these AEs led to permanent treatment discontinuation. Conclusions: In the second-line setting, patients with EP-NECs treated with dual ICPIs (nivolumab plus ipilimumab) experienced improved PFS and OS compared to patients treated with single agent ICPI or cytotoxic chemotherapy. These results echo some of the current evidence for ICPIs in grade 3 NENs and need to be validated in future prospective studies.

Molecular Profiling of Well-Differentiated Neuroendocrine Tumours: The Role of ctDNA in Real-World Practice.

Simple SummaryThe analysis of circulating tumour DNA (ctDNA) can help to identify genetic alterations present in cancer cells without the need to access tumour tissue, which can be an invasive approach. This study explored the feasibility of analysing ctDNA in patients with advanced well-differentiated neuroendocrine tumours (WdNETs). A total of 45 patients (15 with WdNETs) were included. Although feasible (with a non-evaluable sample rate of 27.8%), mutation-based ctDNA analysis was of limited clinical utility for patients with advanced WdNETs. While patients with WdNETs could still be offered genomic profiling (if available and reimbursed), it is important to manage patients’ expectations regarding the likelihood of the results impacting their treatment.Background: The role of tumour genomic profiling in the clinical management of well-differentiated neuroendocrine tumours (WdNETs) is unclear. Circulating tumour DNA (ctDNA) may be a useful surrogate for tumour tissue when the latter is insufficient for analysis. Methods: Patients diagnosed with WdNETs underwent ctDNA genomic profiling (FoundationLiquid®); non-WdNETs (paraganglioma, goblet cell or poorly-differentiated neuroendocrine carcinoma) were used for comparison. The aim was to determine the rate of: test failure (primary end-point), “pathological alterations” (PAs) (secondary end-point) and patients for whom ctDNA analysis impacted management (secondary end-point). Results: Forty-five patients were included. A total of 15 patients with WdNETs (18 ctDNA samples) were eligible: 8 females (53.3%), median age 63.2 years (range 23.5–86.8). Primary: small bowel (8; 53.3%), pancreas (5; 33.3%), gastric (1; 6.7%) and unknown primary (1; 6.7%); grade (G)1 (n = 5; 33.3%), G2 (9; 60.0%) and G3 (1; 6.7%); median Ki-67: 5% (range 1–30). A total of 30 patients with non-WdNETs (34 ctDNA samples) were included. Five WdNETs samples (27.78%) failed analysis (vs. 17.65% in non-WdNETs; p-value 0.395). Of the 13 WdNET samples with successful ctDNA analyses, PAs were detected in 6 (46.15%) (vs. 82.14% in non-WdNETs; p-value 0.018). In WdNETs, the PA rate was independent of concomitant administration anti-cancer systemic therapies (2/7; 28.57% vs. 4/6; 66.67%; p-value 0.286) at the time of the ctDNA analysis: four, one and one samples had one, two and three PAs, respectively. These were: CDKN2A mutation (mut) (one sample), CHEK2mut (one), TP53mut (one), FGFR2 amplification (one), IDH2mut (one), CTNNB1mut (one), NF1mut (one) and PALB2mut (one). None were targetable (0%) or impacted clinical management (0%). There was a lower maximum mutant allele frequency (mMAF) in WdNETs (mean 0.33) vs. non-WdNETs (mean 26.99), even though differences did not reach statistical significance (p-value 0.0584). Conclusions: Although feasible, mutation-based ctDNA analysis was of limited clinical utility for patients with advanced WdNETs. The rates of PAs and mMAFs were higher in non-WdNETs. While patients with WdNETs could still be offered genomic profiling (if available and reimbursed), it is important to manage patients’ expectations regarding the likelihood of the results impacting their treatment.

What Is the Status of Immunotherapy in Neuroendocrine Neoplasms?

Immunotherapy has changed the treatment of patients with advanced cancer, with different phase III trials showing durable responses across different histologies. This review focuses on the preclinical and clinical evidence of potential predictive biomarkers of response and efficacy of immunotherapy in neuroendocrine neoplasms (NENs) of gastro-entero-pancreatic origin. PD-L1 staining by immunohistochemistry has shown heterogeneous results across different studies in both well-differentiated neuroendocrine tumors (NETs) and poorly-differentiated neuroendocrine carcinomas (NECs). Tumor mutational burden in NENs is low, but seems to be higher in NECs. Immune infiltrate (CD3+ lymphocytes) at the tumor microenvironment (TME) is present in NETs and NECs. However, results from clinical trials with immunotherapy as monotherapy o combinations have shown limited efficacy. Further investigation into new strategies aside from anti-CTLA-4/PD-1/PD-L1 antibodies, validation of predictive biomarkers, and better population selection for clinical trials in NENs are more than needed in the near future.

Treatment response and clinical outcomes of neuroendocrine neoplasms treated with immune checkpoint inhibitors: A single-institution experience.

506 Background: Immune checkpoint inhibitors (ICIs) have antitumor activity in some solid tumors, however a role for ICI’s in the treatment of neuroendocrine neoplasms (NENs) is uncertain. We analyzed response and outcomes of NENs, both well differentiated neuroendocrine tumors (WDNET) and poorly differentiated neuroendocrine carcinomas (PDNEC), treated with ICIs at Memorial Sloan Kettering Cancer Center during the past decade. Methods: Patients with NENs who received ICIs between 2010-2021 were identified. Demographics, pathology characteristics, treatment response and outcomes were recorded. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier methods. Analysis of next-generation sequencing (NGS) results from archival tumor tissue was performed. Results: 57 patients with NENs treated with ICIs were identified (WDNET-16; PDNEC-41). All patients had heavily-treated metastatic disease (median number of prior systemic treatments, WDNET-4, PDNEC-2). Median time from diagnosis to ICI treatment was 41.5 months in WDNET, 8 months in PDNEC. WDNET response: 1 (6%) partial response (PR), 4 (25%) stable disease (SD), 10 (63%) progressive disease (PD). PDNEC response: 6 (15%) PR (5 microsatellite stable, 1 unknown), 3 (7%) SD, 32 (78%) PD. Median duration of ICI treatment: 2 months (range 0-27) in WDNET, 1 month (range 0-16) in PDNEC; median duration of treatment for the 7 responders was 11 months (range 2-27). While receiving ICIs, 3 PDNEC responders developed PD in an escape lesion (2 brain, 1 nodal) after response in all other disease sites and successfully continued ICI treatment post-RT of escape lesion. Six-month PFS was 20% [95%CI: 7%-55%] and 9.8% [95%CI: 4%-25%], OS 60% [95%CI: 40%-91%] and 37% [95%CI: 25%-56%], respectively in WDNET and PDNEC. NGS results were available in archival tumor tissue of 35 patients (61%); most common alterations were TP53 (20/26, 77%) and RB1 (14/26, 54%) in PDNEC versus ATM, SMAD4, CREBBP, and IRS2 (all 1/9, 11%) in WDNET. Conclusions: We observed limited activity for ICI’s in NEN treatment, primarily restricted to a subset of PDNEC. PFS/OS findings were consistent with historical data, reflecting the pathogenesis of distinct NEN subtypes.

SATB.2 is a sensityive for well differentiated neuroendocrine tumors

Introduction: Neuroendocrine tumors (NET) constitute a heterogeneous group of rare neoplasms, with a sustained increase in incidence in recent years. They originate in neuroendocrine cells, the most common are those of the gastrointestinal system and most are sporadic, although they can be part of hereditary syndromes. Neuroendocrine neoplasms are divided into well-differentiated neuroendocrine tumors (WDNET) and poorly differentiated neuroendocrine carcinomas (PDNEC). Material and methods: We retrospectively evaluated 78 WDNET of the anterior, middle and posterior intestine, in a period of 20 years (01/01/2000 to 07/31/2020), with the SATB2 antibody, in which it is considered a diagnostic marker for WDNET of the hindgut tract. Results: Of the 40 WDNET of the anterior intestine, 2 (5%) tumors showed reactivity with SATB 2. Positive staining with SATB2 was observed in 1/17 (5.88%) of WDNET of the midgut. Among the 21 WDNET of the hindgut, we observed SATB2 staining in 19 (90.57%) of the tumors. Conclusion: Our results indicate that SATB2 is a sensitive marker for hindgut WDNET, although it is not specific. Keywords: STAB2 protein; Carcinoid tumors; Gastroenteropancreatic neuroendocrine tumors; Neuroendocrine tumor; Colorectal neuroendocrine tumors.

Immunotherapy for gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs): a 2021 update.

Neuroendocrine neoplasms (NENs) are a group of heterogeneous malignancies, arising from the neuroendocrine system. These neoplasms are divided into two distinct groups, the low-proliferating, well-differentiated neuroendocrine tumors (NETs), and the highly-proliferating, poorly-differentiated neuroendocrine carcinomas (NECs). Recent data demonstrate that the incidence of gastroenteropancreatic (GEP) neuroendocrine neoplasms, GEP-NETs and GEP-NECs, has increased exponentially over the last three decades. Although surgical resection is considered the best treatment modality, patients with GEP-NETs often present with advanced disease at diagnosis associated with a 5-year survival rate of 57% for well-differentiated tumors, and only 5.2% for small-cell tumors. Immunotherapy is a novel treatment approach, which has demonstrated effective and promising therapeutic results against several types of cancers. In the present study, we review the current ongoing clinical trials and to evaluate the efficacy of immunotherapy in GEP-NENs. Furthermore, we analyze the importance of tumor genetic profiling and its clinical implications in immunotherapy response.

Progress in diagnosing and treating gastroenteropancreatic neoplasms

<p indent=0mm>Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a group of highly heterogeneous malignancies originating from the diffuse neuroendocrine system, and their incidence has gradually increased in the past <sc>30 years.</sc> The results of molecular biological studies indicate that NENs of different grades and primary sites have distinct molecular characteristics and are responsible for the heterogeneity of clinical manifestations. Surgery remains the method to cure localized GEP-NENs, and prospective clinical study results support no adjuvant therapy. Treating advanced GEP-NENs requires multidisciplinary collaboration, including symptom and tumor proliferation control. Systemic treatment options for patients with metastatic well-differentiated neuroendocrine tumors (NETs) have expanded considerably. However, treating advanced poorly-differentiated neuroendocrine carcinomas (NECs) lacks prospective randomized controlled study outcomes. Platinum-based chemotherapy is the preferred first-line treatment, and the role of immune checkpoint inhibitors still needs to be confirmed by further studies. The present report reviews the recent research progress in GEP-NENs.

Breast cancer with neuroendocrine differentiation: an update based on the latest WHO classification.

Breast cancers with neuroendocrine (NE) differentiation are very heterogeneous, comprising broadly cancers that are morphologically similar to NE tumors (NET) of other anatomic sites, infiltrating breast carcinomas, no special type (IBC-NST) and other special subtypes with NE morphology and/or NE markers expression. Depending on the classification schemes, they are variably included into "NE breast cancers". The latest WHO classification harmonized NE breast cancers with NE neoplasms (NEN) of other organ systems, defined NEN into well-differentiated NET (low Nottingham grade) and poorly-differentiated NE carcinoma (NEC) (high Nottingham grade). Other IBC with NE differentiation are diagnosed based on solely the non-NEN component. Due to the changes in diagnostic criteria, variable results were obtained in the previous studies on NE breast cancers. Hence, the clinical value of NE differentiation in breast cancers is not well investigated and understood. In this review, the current understanding in the pathogenesis, clinical, prognostic, immunhistochemical, and molecular features of "NE breast cancers" is summarized. Controversial issues in their diagnosis and classification are also discussed.

Clinicopathological Features of Primary Neuroendocrine Tumors of Gastrointestinal/Pancreatobiliary Tract With Emphasis on High-Grade (Grade 3) Well-Differentiated Neuroendocrine Tumors.

IntroductionThe two broad subcategories of neuroendocrine neoplasms (NENs) are well-differentiated neuroendocrine tumors (WDNETs) and poorly differentiated neuroendocrine carcinomas (PDNECs), based on tumor architecture and cytology. Grade 3 WDNETs are a subset of WDNETs that not only are high grade by mitotic activity or proliferative index but exhibit a well-differentiated histology. In this study, we evaluated the clinicopathological features of primary neuroendocrine tumors of the gastrointestinal (GI)/pancreatobiliary tract with emphasis on high-grade WDNETs, as it is a newly defined entity.MethodsWe conducted a retrospective observational study, including a total number of 122 cases of primary GI and pancreatobiliary tract NENs. Slides and blocks of all cases were retrieved from the departmental archives. Immunohistochemical stains including Ki67 were applied to selected tissue blocks of all cases. Tumors were then evaluated for their histological differentiation and tumor grade.ResultsOur results showed that the mean age of patients was 46.8 ± 17.1 years. Majority of the NENs were GI tract origin (86.9%). The most common site of tumor in gastroenteropancreatic tract was the small bowel (31.1%), followed by the stomach (26.2%). Ninety five percent of the tumors were WDNETs, of which the most common grade was G2. The mean Ki67 index was 15.8 ± 23.8. Grade 3 WDNETs were noted to have an older mean age than grades 1 and 2 WDNETs. Ten out of 102 (9.8%) WDNETs of GI tract were grade 3, compared with four out of 14 (28.6%) of pancreatobiliary tract. ConclusionIn this study, we found that high-grade (grade 3) WDNETs were more frequent in pancreatobiliary tract than GI tract. Moreover, high-grade WDNETs were associated with a higher mean age than low-grade (grade 1-2) WDNETs. It is extremely important to recognize this subset (high grade) of WDNETs and to distinguish it from PDNECs, as the latter are known to be associated with a worse overall survival. Despite high mitotic rate/proliferative index, high-grade WDNETs are characterized by organoid architecture and monomorphic cell population.

Clinicopathological Spectrum of Primary and Metastatic Neuroendocrine Neoplasms.

IntroductionNeuroendocrine neoplasms (NENs) are a heterogeneous group of tumors with histological features varying from well-differentiated neuroendocrine tumors (WDNETs) to poorly differentiated neuroendocrine carcinomas (PDNECs). In this study, we investigated the clinicomorphological spectrum of NENs including tumor grade, site of origin, and metastasis.MethodsWe retrospectively studied 125 cases of NENs (at the Department of Histopathology, Liaquat National Hospital and Medical College, Karachi) between the years 2014 and 2020. Slides of these cases were retrieved from the departmental archives and were evaluated for the tumor type, grade, and site of origin.ResultsThe mean age of the patients was 51.25±16.10 years. Overall, the liver was the most common site of the tumor (27.2%), followed by the small bowel (15.2%). Grade 2 was the most common tumor grade (40.8%), and most of the tumors were primary (68.8%). A total of 84.8% of the tumors were WDNETs/carcinoids, while 15.2% were PDNEC. The small bowel was the most common site of primary NENs, followed by the stomach and lung. Among primary neuroendocrine tumors, patients with PDNEC were significantly noted to have a higher mean age than WDNET/carcinoid. Similarly, PDNEC had a higher ki67 index than WDNET/carcinoid. For metastatic NENs, the liver was the most common site of metastasis (71.8%) with the GI/pancreatobiliary tract being the most common primary site of origin (51.3%). Tumors with primary lung origin were found to have a higher tumor grade than primary GI/pancreatobiliary tract origin NENs (p<0.0001).ConclusionIn this study, we found that the small intestine and liver were the most common sites for primary and metastatic NENs, respectively. Moreover, primary PDNECs were associated with a higher mean age than WDNETs. Alternatively, metastatic NENs with primary lung origin had a higher tumor grade than primary GI/pancreatobiliary tract origin.

Alterations in Ki67 Labeling Following Treatment of Poorly Differentiated Neuroendocrine Carcinomas: A Potential Diagnostic Pitfall.

Assessment of the Ki67 index is critical for grading well-differentiated neuroendocrine tumors (WD-NETs), which can show a broad range of labeling that defines the WHO grade (G1-G3). Poorly differentiated neuroendocrine carcinomas (PD-NECs) have a relatively high Ki67 index, >20% in all cases and commonly exceeding 50%. After anecdotally observing PD-NECs with an unexpectedly low and heterogeneous Ki67 index following chemotherapy in 5 cases, we identified 15 additional cases of treated high-grade neuroendocrine neoplasms (HG-NENs). The study cohort comprised 20 cases; 11 PD-NECs, 8 mixed adenoneuroendocrine carcinomas, and 1 WD-NET, G3 from various anatomic sites (gastrointestinal tract, pancreas, larynx, lung, and breast). The Ki67 index was evaluated on pretreatment (when available) and posttreatment samples. Topographic heterogeneity in the Ki67 index was expressed using a semi-quantitative score of 0 (no heterogeneity) to 5 (>80% difference between maximal Ki67 and minimal Ki67 indices). Relative to the pretreatment group (n=9, mean Ki67 of 86.3%, range 80% to 100%), the neoplasms in the posttreatment group (n=20, mean Ki67 of 47.7%, range 1% to 90%) showed a significantly lower Ki67 index (18/20 cases). Of the 18 cases with a relatively low Ki67 index, 15 showed heterogeneous labeling (mean heterogeneity score of 2.3, range 1 to 5) and in 3 cases it was a homogeneously low. This phenomenon was observed in all subtypes of HG-NENs. In 6 cases, the alterations in Ki67 index following treatment were sufficient to place these HG-NENs in the WHO G1 or G2 grade, erroneously suggesting a diagnosis of WD-NET, and in 9 cases there was sufficient heterogeneity in the Ki67 index to suggest that a limited biopsy may sample an area of low Ki67, even though hotspot regions with a Ki67 index of >20% persisted. In 7 cases, the alterations in the Ki67 index were accompanied by morphologic features resembling a WD-NET. These observations suggest that there is a potential for misinterpretation of previously treated PD-NECs as WD-NETs, or for assigning a lower grade in G3 WD-NETs. While the prognostic significance of treatment-associated alterations in Ki67 index is unknown, awareness of this phenomenon is important to avoid this diagnostic pitfall when evaluating treated NENs.

Outcomes after high-dose radiation in management of neuroendocrine neoplasms.

616 Background: In this study, we analyze outcomes after the use of high-dose radiation therapy (RT) in management of neuroendocrine neoplasms (NENs) at a high-volume center. Methods: We performed a retrospective review of patients who received high-dose RT (defined as biologically effective dose (BED) &gt;40, α/β = 10) for their NEN. Patients with small cell lung cancer and Merkel cell carcinoma were excluded, given their unique treatment paradigms. Results: 61 patients completed a radiation course with BED &gt;40 for their NEN (median BED 70, range 44-180). Most tumors were gastroenteropancreatic in origin (n = 20); additional primary sites included lung (n = 11), head and neck (n = 10), cervix (n = 6), other (n = 9) and unknown (n = 5). 56% (n = 34) had well-differentiated (WD) neuroendocrine tumors, and 44% (n = 27) had poorly-differentiated (PD) neuroendocrine carcinomas. Disease stage at the time of RT was localized/locally advanced (LLA, n = 27), or metastatic/recurrent (MR, n = 34). The intent of RT was definitive (n = 18), post-operative (n = 10), for oligoprogression (n = 18), or purely palliative (n = 15). 48 patients had follow-up imaging at a median follow-up of 20 months after radiation. Outcomes were grouped by differentiation and stage, with median time to progression (mTTP) in months (Table). 8% of patients had local progression, while 44% developed new metastases, including 38% of WD-LLA, 47% of PD-LLA, 37% of WD-MR, and 67% of PD-MR disease with progressively shorter median time to progression (26, 10, 8, and 3 months, respectively). Conclusions: These data suggest that focal, high-dose radiation has a role in the management of NENs. Local failure is rare in patients with both WD-LLA and PD-LLA disease. The predominant pattern of failure is development of new metastases, which appear to occur sooner and more frequently in patients with PD and MR disease. [Table: see text]

Poorly differentiated neuroendocrine carcinoma of the head and neck: human papillomavirus tumour status/p16 status and impact on overall survival

Poorly differentiated neuroendocrine carcinoma (PDNEC) of the head and neck is a rare high-grade neuroendocrine neoplasm. Human papillomavirus (HPV) status and p16 status are as yet unclear among PDNECs, owing to a lack of statistical analysis. The objective of the present study was therefore to evaluate their potential clinicopathological associations, and their prognostic impact on overall survival in PDNECs of the head and neck, regardless to HPV genotype. All cases of PDNEC of the head and neck between 1998 and 2019 were identified from the database of the Lyon university hospital pathology department (n=21); for these cases, p16 immunohistochemistry and HPV in-situ hybridisation were performed. Published cases of PDNEC of the head and neck with assessment of HPV status and p16 status were identified in PubMed (n=57). Local and published cases were pooled for analysis. HPV positive (HPV+) tumour status was found to be significantly associated with oropharyngeal localisation (P<0.001) and overexpression of p16 (P<0.001). Multivariate analysis, adjusted on tumour site, histological subtype, p16 status, HPV status, and source of the case, showed that oropharyngeal localisation [hazard ratio (HR) 3.031, 95% confidence interval (CI) 1.257-7.310] and being a small-cell variant (HR 2.859, 95% CI 1.150-7.109) were significant predictors of worse overall survival; HPV+ tumour status was associated with better overall survival (HR 0.388, 95% CI 0.146-0.995). HPV+ tumour status was associated with oropharyngeal PDNECs and with a better prognosis.