Background
Grade 3 (G3) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs) are aggressive tumors with poor survival outcomes for which medical management is generally recommended. This ...study sought to evaluate outcomes of surgically treated G3 GEP-NEN patients.
Methods
A single-institutional prospective NEN database was reviewed. Patients with G3 GEP-NENs based on World Health Organization (WHO) 2019 definitions included well-differentiated neuroendocrine tumors (G3NET) and poorly differentiated neuroendocrine carcinomas (G3NEC). Clinicopathologic factors were compared between groups. Overall survival from G3 diagnosis was assessed by the Kaplan-Meier method.
Results
Surgical resection was performed for 463 patients (211 G1, 208 G2, 44 G3). Most had metastatic disease at presentation (54% G1, 69% G2, 91% G3;
p
< 0.001). The G3 cohort included 39 G3NETs and 5 G3NECs, 22 of pancreatic and 22 of midgut origin. Median overall survival (mOS; in months) was 268.1 for G1NETs, 129.9 for G2NETs, 50.5 for G3NETs, and 28.5 for G3NECs (
p
< 0.001). Over the same period, 31 G3 patients (12 G3NETs, 19 G3NECs) were treated non-surgically, with mOS of 19.0 for G3NETs and 12.4 for G3NECs.
Conclusions
Surgical resection of G3 GEP-NENs remains controversial due to poor prognosis, and surgical series are rare. This large, single-institutional study found significantly lower mOS in patients with resected G3NENs than those with G1/G2 tumors, reflecting more aggressive tumor biology and a higher proportion with metastatic disease. The mOS for resected G3NETs and G3NECs exceeded historical non-surgical G3NEN series (mOS 11–19 months), suggesting surgery should be considered in carefully selected patients with G3NENs, especially those with well-differentiated tumors.
This report describes a rare case of hepatocellular carcinoma (HCC) concurrent with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) without traditional risk factors, such as hepatic ...fibrosis or chronic hepatitis. Initially presenting with hematuria, incidental imaging revealed a liver lesion, later diagnosed as moderately differentiated HCC. Notably, the patient had no history of well-established risk factors of HCC including viral hepatitis or liver cirrhosis. CLL/SLL was unexpectedly discovered in the surgical specimen during the hepatectomy. This case challenges traditional perceptions of HCC etiology, suggesting a potential link between HCC and CLL/SLL even without established risk factors.
We recently encountered a patient with unexplained hyperleukocytosis (105.4 K/μL at presentation), subsequently found to have colon cancer with a marked tumor-associated neutrophilic infiltrate; the ...leukocytosis abruptly improved after tumor removal. Paraneoplastic leukemoid reaction (PLR) is a rare entity, occurring due to tumor cytokine secretion (typically granulocyte-colony stimulating factor G-CSF). We describe a case and aggregate results of previously published cases.
We reviewed the English-language literature for all prior reports of PLR, recording age, gender, histologic diagnosis, WBC count, G-CSF level, and overall survival. We analyzed clinicopathologic variables’ impact on survival.
We identified 179 cases (mean age 64; 72 % M). Adeno-, squamous cell, sarcomatoid, and undifferentiated carcinomas accounted for >70 %. Esophagus, gallbladder, lung, liver, and pancreas were the most common primaries. At time of publication 81 % of patients had died, with mean overall survival of 4 months. There was no correlation between WBC count and G-CSF level. On univariate analysis, WBC count was the only variable associated with survival (P = 0.03). Patients with WBC counts >100 K/μL were twice as likely to die as those with counts from 11 K to 40 K/μL.
PLR, typically carcinoma-associated, is characterized by dismal prognosis. The WBC count is inversely related to survival. Knowledge of this phenomenon militates against protracted, expensive work ups. In malignant neoplasms with prominent neutrophilic stroma, the pathologist should correlate with the WBC count and, if markedly elevated (>40 K/μL), raise consideration for PLR.
Background
The small bowel (SB) is the most common site of neuroendocrine tumors (NETs) of the GI tract. These are described as being predominantly jejunoileal, but their exact locations within the ...SB have not been well defined. We sought to determine prospectively the spectrum of SBNET locations.
Methods
Patients undergoing exploration for SBNET primaries had measurement of bowel length, tumor locations, and resection length recorded. Correlations of clinicopathologic factors were performed, and analysis done utilizing Welch’s
t
test, Chi square test, and the Kaplan–Meier method.
Results
Measurements were recorded in 123 patients, 107 of whom had complete information. Multifocal tumors (MTs) were found in 69 (56%) and unifocal (UTs) in 54 (44%) patients. Only 1 of 107 patients had a tumor within 100 cm of the ligament of Treitz (LT), whereas 77 of 107 (72%) had tumors within 100 cm of the ileocecal valve (ICV). No MTs were found within 100 cm of LT, whereas 41 of 60 (68%) patients had all (10) or at least one tumor (31) located within 100 cm of the ICV. MTs required a mean resection length of 108 versus 59 cm for UTs (
p
< 0.01). Seventy-seven percent of UTs (36/47) were within 100 cm of ICV. Tumors occurring only between > 100 cm from the LT and ICV were seen in 29 of 107 (27%) patients.
Conclusions
SBNETs are frequently multifocal and most commonly located within 100 cm of the ICV. SBNETs are less prevalent proximally in the small bowel, which may result from anatomic differences in enterochromaffin cell density, hormonal factors, or environmental exposures in the distal SB.
The assessment of the expression of programmed cell death ligand-1 (PD-L1) using immunohistochemistry (IHC) has been controversial since its introduction. The methods of assessment and the range of ...assays and platforms contribute to confusion. Perhaps the most challenging aspect of PD-L1 IHC is the combined positive score (CPS) method of interpretation of IHC results. Although the CPS method is prescribed for more indications than any other PD-L1 scoring system, its reproducibility has never been rigorously assessed. In this study, we collected a series of 108 gastric or gastroesophageal junction cancer cases, stained them using the Food and Drug Administration-approved 22C3 assay, scanned them, and then circulated them to 14 pathologists at 13 institutions for the assessment of interpretative concordance for the CPS system. We found that higher cut points (10 or 20) performed better than a CPS of <1 or >1. We used the Observers Needed to Evaluate Subjective Tests algorithm to assess how the CPS system might perform in the real-world setting and found that the cut points of <1 or >1 showed an overall percent agreement of only 30% among the pathologist raters, with a plateau occurring at 8 raters. The raters performed better at higher cut points. However, the best cut point of <20 versus that of >20 was still disappointing, with a plateau at an overall percent agreement of 70% (at 7 raters). Although there is no ground truth for CPS, we compared the score with quantitative messenger RNA measurement and showed no relationship between the score (at any cut point) and messenger RNA amount. In summary, we showed that CPS shows high subjective variability among pathologist readers and is likely to perform poorly in the real-world setting. This system may be the root cause of the poor specificity and relatively low predictive value of IHC companion diagnostic tests for PD-1 axis therapies that use the CPS system.
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) stress response protein that plays an important role in pancreatic functions. As both alcohol and ER stress ...response proteins are involved in the pathogenesis of pancreatitis, we sought to investigate the expression of MANF in chronic alcoholic pancreatitis (CAP) and chronic non-alcoholic pancreatitis (CNP).
A cohort of chronic pancreatitis tissues was gathered from routine surgical pathology (
= 77) and autopsy (
= 10) cases and tissue microarrays were created. Sampled tissues were reviewed and designated as representing CAP (
= 15), CNP (
= 58), or normal pancreatic tissue (NPT) (
= 27). MANF immunohistochemistry (IHC) and digital image analysis were performed to obtain an estimation of tissue fibrosis and an optical density (OD) of MANF IHC in ducts and acini for each case. The averaged values for these variables among histologic designations were compared.
The amount of fibrous tissue of the combined CAP and CNP group (chronic alcoholic and non-alcoholic pancreatitis, CANP) exceeded that of the NPT group (70% vs. 34%,
< 0.0001). The MANF OD in ducts of CANP was significantly higher than that of NPT (0.19 vs. 0.10,
< 0.05). The MANF OD in ducts of CAP was significantly higher than that of CNP (0.27 vs. 0.17,
< 0.05). The MANF OD in acini of CAP was significantly lower than that in CNP (0.81 vs. 1.05,
< 0.05). Finally, there was a statistically significant positive relationship between the amount of fibrosis and MANF OD in ducts (
< 0.001).
MANF expression was higher in ducts of CAP than CNP. In contrast, MANF expression in acini was lower in CAP than CNP and NPT. There was a positive correlation between fibrosis and MANF levels in the ducts.
To develop recommendations for systemic therapy for well-differentiated grade 1 (G1) to grade 3 (G3) metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs).
ASCO convened an Expert Panel ...to conduct a systematic review of relevant studies and develop recommendations for clinical practice.
Eight randomized controlled trials met the inclusion criteria for the systematic review.
Somatostatin analogs (SSAs) are recommended as first-line systemic therapy for most patients with G1-grade 2 (G2) metastatic well-differentiated GI-NETs. Observation is an option for patients with low-volume or slow-growing disease without symptoms. After progression on SSAs, peptide receptor radionuclide therapy (PRRT) is recommended as systematic therapy for patients with somatostatin receptor (SSTR)-positive tumors. Everolimus is an alternative second-line therapy, particularly in nonfunctioning NETs and patients with SSTR-negative tumors. SSAs are standard first-line therapy for SSTR-positive pancreatic (pan)NETs. Rarely, observation may be appropriate for asymptomatic patients until progression. Second-line systemic options for panNETs include PRRT (for SSTR-positive tumors), cytotoxic chemotherapy, everolimus, or sunitinib. For SSTR-negative tumors, first-line therapy options are chemotherapy, everolimus, or sunitinib. There are insufficient data to recommend particular sequencing of therapies. Patients with G1-G2 high-volume disease, relatively high Ki-67 index, and/or symptoms related to tumor growth may benefit from early cytotoxic chemotherapy. For G3 GEP-NETs, systemic options for G1-G2 may be considered, although cytotoxic chemotherapy is likely the most effective option for patients with tumor-related symptoms, and SSAs are relatively ineffective. Qualifying statements are provided to assist with treatment choice. Multidisciplinary team management is recommended, along with shared decision making with patients, incorporating their values and preferences, potential benefits and harms, and other characteristics and circumstances, such as comorbidities, performance status, geographic location, and access to care.Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines.
The American Joint Committee on Cancer (AJCC) staging system for all cancer sites, including gastroenteropancreatic neuroendocrine tumors (GEP‐NETs), is meant to be dynamic, requiring periodic ...updates to optimize AJCC staging definitions. This entails the collaboration of experts charged with evaluating new evidence that supports changes to each staging system. GEP‐NETs are the second most prevalent neoplasm of gastrointestinal origin after colorectal cancer. Since publication of the AJCC eighth edition, the World Health Organization has updated the classification and separates grade 3 GEP‐NETs from poorly differentiated neuroendocrine carcinoma. In addition, because of major advancements in diagnostic and therapeutic technologies for GEP‐NETs, AJCC version 9 advocates against the use of serum chromogranin A for the diagnosis and monitoring of GEP‐NETs. Furthermore, AJCC version 9 recognizes the increasing role of endoscopy and endoscopic resection in the diagnosis and management of NETs, particularly in the stomach, duodenum, and colorectum. Finally, T1NXM0 has been added to stage I in these disease sites as well as in the appendix.
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