Background Tumor grade is an important predictor of survival in gastroenteropancreatic (GEP) neuroendocrine tumors (NETs), as determined by Ki-67 expression and mitotic rate. NETs generally grow indolently, but some cells may acquire traits facilitating metastasis. It is unclear how frequently metastases differ in grade from their primary tumors, and whether increasing grade in metastases affects prognosis. Methods Ki-67 immunohistochemistry was performed on resected GEPNET specimens and cases with results for both primary tumors and concurrent metastases were identified. Grade was determined using a modified WHO classification (Ki-67:G1= 0–2%; G2 >2–20%; G3 >20%). Results Ki-67 was performed on both the primary tumor and metastases in 103 patients. Tumor grade was higher in metastases from 25 (24%) patients, 24 increased from G1 to G2, and 1 from G2 to G3; 68 (66%) patients had no change in grade (42 G1 and 26 G2) and 10 (10%) decreased from G2 to G1. No clinicopathologic factors were predictive of higher grade in metastases. The 5-year PFS was 55 % for patients with stable grade vs. 8% with increased grade, while 5-year OS was 92% and 54%, respectively. The 5-year OS of patients who had stable grade with G1 and G2 primaries was 92% and 64%, respectively. Conclusions Nearly one-third of patients had metastases with a different grade than their primary, and when grade increased, both PFS and OS significantly decreased. Determining the grade in both the primary tumor and a metastasis is important for estimating prognosis and to help inform decisions regarding additional therapies.

Objectives Many patients with small bowel neuroendocrine tumors (SBNETs) have multifocal tumors (MFTs), but the frequency of MFTs has varied widely across SBNET studies. It is also unclear whether patients with MFTs have more advanced disease or worse clinical course than those with unifocal SBNETs (UFTs). We set out to determine the frequency of multifocal and unifocal SBNETs, compare clinicopathologic factors, somatostatin receptor (SSTR2) expression, and survival. Methods Clinicopathologic variables from 179 patients with surgically managed SBNETs were collected. Statistical comparisons were made using Welch’s t-test, Wilcoxon test and Fisher’s exact test. Survival was assessed using the Kaplan-Meier method. SSTR2 expression was analyzed by qPC, and Ki-67 expression by immunohistochemistry. Results MFTs were found in 45% of patients with SBNETs. Clinicopathologic factors such as grade, TNM stage, presence of distant metastases, mean SSTR2 expression, success of imaging modalities, preoperative and postoperative hormone levels were not significantly different between multifocal and unifocal groups. Progression-free and overall survival were also not significantly affected by multifocality. Conclusions Clinicopathologic features and survival of patients with MFTs and UFTs are remarkably similar. Although the etiology of MFTs is unclear, patients with MFTs do not have a more aggressive clinical course than patients with unifocal SBNETs.

CDKN1B , a cyclin-dependent kinase inhibitor associated with G1 arrest, was recently proposed as an important tumor suppressor gene in small bowel neuroendocrine tumors (SBNETs). The rate of frameshift mutations in SBNET primaries are reportedly 7.4%, and hemizygous deletions are 6.7%. We set out to confirm the role of CDKN1B mutations and copy number variants (CNVs) in primary SBNETs, and whether these are also found in pancreatic neuroendocrine tumors (PNETs). Genomic DNA was isolated from 90 primary SBNETs and 67 PNETs. Coding exons of CDKN1B were amplified by PCR and sequenced. CNV analysis was performed by quantitative PCR, p27 expression was evaluated using immunohistochemistry. In SBNETS, three frameshifts, one missense mutation, and three CNVs were observed. The total rate of CDKN1B alterations was 7.0% (6 of 86; 95% confidence interval (CI) 3.2–4.4%). The frameshift rate was 3.5% (95% CI 1.1–9.8%). One SBNET patient had a hemizygous deletion of CDKN1B, and two patients had duplications (3.4%; 95% CI −0.41–7.2%). One PNET patient had a duplication, and two patients had hemizygous deletions (4.8%; 95% CI −0.44–10%). Alterations of cell-cycle control due to alterations in CDKN1B may be one mechanism by which SBNETs develop, which could have implications for new treatment modalities.

Interleukin-1 alpha (IL-1α) is a pleiotropic cytokine involved in inflammation and immune response and is upregulated in many solid tumors including head and neck squamous cell carcinomas. Although IL-1α expression is generally associated with poor prognosis, the implications of the subcellular localization of IL-1α expression in patient outcomes are poorly understood. This study is aimed at investigating the prognostic value of nuclear and cytoplasmic immunohistochemical IL-1α expression in oral squamous cell carcinomas (OSCCs). Tissue microarrays containing 146 OSCCs were analyzed for IL-1α and epidermal growth factor receptor (EGFR) expression by immunohistochemistry. IL-1α and EGFR expression scores were correlated with clinicopathological parameters and survival outcomes. IL-1α expression was observed in the nuclear and/or cytoplasmic compartments in 98% of evaluable tumors and 78% of tumors expressed IL-1α in both compartments. There were no differences observed in overall survival or progression-free survival between high, moderate, or negative IL-1α nuclear/cytoplasmic expression scores. When IL-1α nuclear/cytoplasmic expression scores were stratified by positive or negative EGFR expression, tumors with a combined EGFR-positive and high nuclear IL-1α expression profile were significantly more likely to possess perineural invasion and were significantly associated with a high risk of tumor recurrence and worse progression-free survival compared to all other EGFR and combined IL-1α/EGFR expression profiles. Altogether, nuclear IL-1α expression may enhance the prognostic value of EGFR in OSCC and warrants further study as a prognostic biomarker for recurrence.

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