Neuroendocrine Tumor Grade Research Articles

Assessment of Microvascular Density in the Neuroendocrine Tumors of the Pancreas: a Correlation with Multidetector Computed Tomography (MDCT) Features and Tumor Grade

Introduction/ Background The biologic course of pancreatic neuroendocrine tumors (NET) can be accurately predicted on the basis of pathology parameters which, unfortunately, cannot be fully assessed until the entire tumor has been resected. When obvious landmarks of malignancy (metastases, vascular invasion) are lacking, tumour size is the only reliable preoperative parameter used to differentiate between presumably benign and malignant pancreatic NETs. It is generally accepted that pancreatic NETs exceeding 2 cm in their diameter may have borderline pathology or even malignancy. Anyway, up to 10% of tumors with diameter less than 2 cm are although malignant. That is why there is need in studies focusing on additional imaging characteristics, such as contrast-enhanced MDCT, useful for the aggressiveness assessment. Aims To determine whether it is possible to predict pancreatic NET Grade and microvascular density (MVD) according to contrast-enhanced MDCT findings. Methods A retrospective study was conducted and 70 patients with pancreatic NETs were retrieved from the institutional archives. Twenty eight of them had met the including criteria (a - patients underwent surgery in our Institution and b - patients underwent preoperative dynamic abdominal CT within 30 days prior surgery) and comprised the study population. Thus, research included 15 patients with functioning and non-functioning pancreatic NETs Grade 1 and 13 of patients with Grade 2 (according to the WHO classification of 2010). Radiology All preoperative CT examinations were performed by a 256-slice CT scanner. Dynamic CT images, including non-enhanced, arterial, portal venous and delay phase images, were obtained for all patients. For contrast-enhanced CT, 90–120 mL of high concentration contrast mediaiomeprol 400 (Iomeron 400; Bracco Imaging SpA, Milan, Italy). CT images were reconstructed with a section thickness of 1-2 mm. Pathology For identification of vessels, regardless lymphatic or venous, immunohistochemistry with CD34 (clone QBEnd/10, CellMarque) was performed on formalin-fixed paraffin-embedded (FFPE) tumor blocks. Image analysis Density of vessels was defined on 3 fields at x 200 (~ 1,8 mm2). The choice of fields of vision was carried out among sites with visually greatest density of vessels (“hot spots”). Determined total number of the pixels belonging to vessels by the Color Threshold tool (ImageJ) and divided this number into total of pixels in the image. Results The median of density of vessels at patients with NET Grade 1 made 8% ± 2% whereas in group of patients with NET Grade 2 this indicator made 5 ± 4%. The difference was statistically significant (p <0,05). Mean arterial enhancement ratio was 1.66(0.42) in Grade 1 and 1.04(0.39) in Grade 2 pancreatic NET (p<0.01); and correlated with intratumoral MVD (r=0.61, p<0.005) and tumor grade (p<0.01). Vascular invasion, metastases and pancreatic duct dilatation were observed in two cases, both in G2 tumors. Arterial enhancement ratio <1.1, size≥20 mm, ill-defined borders and tumor non-homogeneity showed 83%, 74%, 70% and 56% accuracy in diagnosing G2 tumor respectively, while the accuracy of two of these criteria used in combination was 91%. Contrast-enhanced MDCT-features of pancreatic NET correlate with MVD and can predict tumor grade during preoperative staging.

Efficacy of endoscopic ultrasonography-guided fine needle aspiration for pancreatic neuroendocrine tumor grading

Efficacy of endoscopic ultrasonography-guided fine needle aspiration for pancreatic neuroendocrine tumor grading

Grading of lung cancer

In comparison with other tumor entities there is no common generally accepted grading system for lung cancer with clearly defined criteria and clinical relevance. In the recent fourth edition of the World Health Organization (WHO) classification from 2015 of tumors of the lungs, pleura, thymus and heart, there is no generally applicable grading for pulmonary adenocarcinomas, squamous cell carcinomas or rarer forms of carcinoma. Since the new IASLC/ATS/ERS classification of adenocarcinomas published in 2011, 5 different subtypes with significantly different prognosis are proposed. This results in an architectural (histologic) grading, which is usually applied to resection specimens. For squamous cell carcinoma the number of different histological subtypes in the new WHO classification was reduced compared to earlier versions but without a common grading system. In recent publications nesting and budding were proposed as the main (histologic) criteria for a grading of squamous cell carcinomas. The grading of neuroendocrine tumors (NET) of the lungs in comparison with NET in other organs is presented in a separate article in this issue. Certain rare tumor types are high grade per definition: small cell, large cell and pleomorphic carcinomas, carcinosarcomas and pulmonary blastomas. In the future it is to be expected that these developments will be further refined, e. g. by adding further subtypes for adenocarcinomas and cytologic and/or nuclear criteria for adenocarcinoma and/or squamous cell carcinomas.

The role of EUS-FNA in the diagnosis and grading of pancreatic neuroendocrine tumors

Pancreatic neuroendocrine tumors (PNETs) exhibit various tumor behaviors and symptoms that are difficult for physicians to stage and predict prognosis. We assess prognostic factors combined with staging classifications to optimal the models and try to improve follow-up strategy to monitor liver metastases after surgery.Patients with PNETs treated at Sun Yat-sen Memorial Hospital between 2000 and 2015 were recruited. Patients were regrouped on the basis of functional status and mitotic rates. Nomograms to predict the prognostic values of classifications (AJCC, ENETS, and WHO) were constructed; the accuracy of the nomograms were quantified by the C-index and calibration plots.We identified 78 PNETs patients with pathological reports. Correlations with OS in univariate analysis included nonfunctional status (P = 0.002), CgA>200 ng/ml (P < 0.001), Ki-67 (3–20%, P = 0.014; >20%, P < 0.001), and mitotic rate (3–20/10HPF, P = 0.011; >20/10HPF, P < 0.001). By multivariate analysis, nonfunctional status and mitotic rate maintained significance (P = 0.039; 3–20/10HPF, P = 0.015; >20/10HPF, P = 0.007). Evaluating the new proposed system, the difference in OS between low- and high-groups was statistically significant (P = 0.001). The C-index of the regrouped nomograms were higher than that of premise ones (AJCC cohort, 0.605 v 0.576, P < 0.01; ENETS cohort, 0.73 v 0.691, P < 0.01; WHO cohort, 0.678 v 0.603, P < 0.01).An prognostic model based on mitotic rates and functional status correlates strongly with survival. PNETs should return visits every 2 months for the first half years, and every 3 months as followed until 2 years after surgery.

Effectiveness and side-effects of peptide receptor radionuclide therapy for neuroendocrine neoplasms in Germany: A multi-institutional registry study with prospective follow-up

BackgroundMonocentric and retrospective studies indicate effectiveness of peptide receptor radionuclide therapy targeting somatostatin receptors of neuroendocrine neoplasms. We assessed overall and progression-free survival and adverse events of peptide receptor radionuclide therapy by a multi-institutional, board certified registry with prospective follow-up in five centres in Germany. MethodsA total of 450 patients were included and followed for a mean of 24.4 months. Most patients had progressive low- or intermediate grade neuroendocrine neoplasms and 73% were pretreated with at least one therapy. Primary neuroendocrine neoplasms were mainly derived of pancreas (38%), small bowel (30%), unknown primary (19%) or bronchial system (4%). Patients were treated with Lutetium-177 in 54%, with Yttrium-90 in 17% and with both radionuclides in 29%. Overall and progression-free survival was determined with Kaplan–Meier curves and uni-variate log rank test Cox models. FindingsMedian overall survival of all patients was 59 (95% confidence interval [CI] 49–68.9) months. Overall survival was significantly inferior in the patients treated with Yttrium-90 solely (hazard ratio, 3.22; 95% CI, 1.83–5.64) compared to any peptide receptor radionuclide therapy with Lutetium-177. Grade II (hazard ratio, 2.06; 95% CI, 0.79–5.32) and grade III (hazard ratio, 4.22; 95% CI, 1.41–12.06) neuroendocrine neoplasms had significantly worse overall survival than grade I neuroendocrine neoplasms. Patients with small neuroendocrine neoplasms of small bowel had significantly increased survival (hazard ratio, 0.39; 95% CI, 0.18–0.87) compared to neuroendocrine neoplasms of other locations. Median progression-free survival was 41 (35.9–46.1) months and significantly inferior in patients treated with Yttrium solely (hazard ratio, 2.7; 95% CI, 1.71–4.55). Complete remission was observed in 5.6% of patients, 22.4% had a partial remission, 47.3% were stable and 4% were progressive as best response. Adverse events of bone marrow and kidney function higher than grade III occurred in 0.2–1.5% of patients. InterpretationThese results indicate that peptide receptor radionuclide therapy is a highly effective therapy for patients with low to intermediate grade neuroendocrine neoplasms with minor adverse events.

A case of rectal carcinoid, 7 mm in diameter, with skip metastasis to the lateral lymph node.

The present case study presented a 59-year-old man with a 7 mm submucosal tumor in the lower rectum and swelling in a 7 mm lateral lymph node (the obturator lymph node). No swelling of the lymph nodes within the mesorectum was observed. The patient underwent laparoscopic intersphincteric resection with left side lateral lymphadenectomy. At the pathological examination, the patient was diagnosed with a rectal neuroendocrine tumor (Grade 1; carcinoid), which had invaded the perirectal tissues and exhibited lateral lymph node metastasis; however, mesorectal lymph node metastasis was not observed, therefore, the definitive diagnosis was rectal carcinoid with skip metastasis to the lateral lymph node. No sign of recurrence was observed at the 3 year follow-up. The treatment algorithm of rectal carcinoid was decided by the risk of lymph node metastasis. The present study confirmed skip metastasis to the lateral lymph node from the rectal carcinoid, which is typically very slow growing and has a low grade malignant potential.

Clinicopathological analysis in patients with neuroendocrine tumors that metastasized to the brain.

BackgroundA neuroendocrine tumor (NET) can develop anywhere in the body, but is mainly found in the pancreas, gastrointestinal tract, and lungs. This report is a retrospective study of the clinicopathological features of NET patients with brain metastasis whose tissue diagnosis was made at our hospital.MethodsPatients with brain metastasis evidenced by clinical records and images were accumulated among 302 patients in whom tissue diagnosis of NETs was made at our hospital between 2008 and 2013. In the patients, the primary lesion, pathological classification, pattern of metastasis, details of treatment, and outcomes were analyzed.ResultsBrain metastasis was observed in 31 patients (10.3 %). The primary lesion was in the lungs in 26 patients (83.9 %), and the mammary glands, esophagus, and uterus in 1 patient each. Primary lesions were unknown in 2 patients, including 1 patient in whom NETs were detected in the lymph nodes alone. Pathological classification of the primary lesion was NET Grade 2 (Ki-67: 3 to 20 %) in 3 patients and neuroendocrine carcinoma (NEC, Ki-67: ≥21 %) in 26 patients. The median period from onset of the primary lesion up to diagnosis of brain metastasis was 12.8 months, and the brain lesion preceded brain metastasis in 6 patients. Ten patients had a single metastasis whereas 21 patients had multiple metastases, but no characteristics were observed in their images. Brain metastasis was extirpated in 10 patients. Stereotactic radiotherapy alone was administered in 6 patients, and brain metastasis was favorably controlled in most of the patients with coadministration of cranial irradiation as appropriate. The median survival period from diagnosis of brain metastasis was 8.1 months, and the major cause of death was aggravation of the primary lesion or metastatic lesions in other organs.ConclusionMost of NET patients with brain metastasis showed the primary lesion of NEC in the lungs, and they had multiple metastases to the liver, lymph nodes, bones, and so forth at the time of diagnosis of brain metastasis. The guidelines for accurate diagnosis and treatment of NETs should be immediately established based on further analyses of NET patients with brain metastasis.

Neuroendocrine neoplasms of liver - A 5-year retrospective clinico-pathological study applying World Health Organization 2010 classification.

AIMTo study the clinicopathological characteristics of neuroendocrine neoplasms (NEN) on liver samples and apply World Health Organization (WHO) 2010 grading of gastroenteropancreatic (GEP) NEN.METHODSClinicopathological features of 79 cases of NEN of the liver diagnosed between January 2011 to December 2015 were analyzed. WHO 2010 classification of GEP NEN was applied and the tumors were graded as G1, G2 or G3. Two more categories, D1/2 (discordant 1/2) and D2/3 (discordant 2/3) were also applied. The D1/2 grade tumors had a mitotic count of G1 and Ki-67 index of G2. The D2/3 tumors had a mitotic count of G2 and Ki-67 index of G3. The follow up details which were available till the end of the study period (December 2015) were collected.RESULTSOf the 79 tumors, 16 each were G1 and G2, and 18 were G3 tumors. Of the remaining 29 tumors, 13 were assigned to D1/2 and 16 were D2/3 grade. Male preponderance was noted in all tumors except for G2 neoplasms, which showed a slight female predilection. The median age at presentation was 47 years (range 10-82 years). The most common presentation was abdominal pain (81%). Pancreas (49%) was the most common site of primary followed by gastrointestinal tract (24.4%) and lungs (18%). Radiologically, 87% of the patients had multiple liver lesions. Histopathologically, necrosis was seen in only D2/3 and G3 tumors. Microvascular invasion was seen in all grades. Metastasis occurred in all grades of primary NEN and the grades of the metastatic tumors and their corresponding primary tumors were similar in 67% of the cases. Of the 79 patients, 36 had at least one follow up visit with a median duration of follow up of 8.5 mo (range: 1-50 mo). This study did not show any impact of the grade of tumor on the short term clinical outcome of these patients.CONCLUSIONLiver biopsy is an important tool for clinicopathological characterization and grading of NEN, especially when the primary is not identified. Eighty-seven percent of the patients had multifocal liver lesions irrespective of the WHO grade, indicating a higher stage of disease at presentation. Follow up duration was inadequate to derive any meaningful conclusion on long term outcome in our study patients.

Small neuroendocrine tumor of the duodenal bulb: Endoscopic submucosal dissection, laparoscopic and endoscopic cooperative surgery or surgery?

AbstractNeuroendocrine neoplasms of the gastric tube are less common than adenocarcinomas. Topography includes stomach, small intestine, Vater ampulla, and gross intestine. They are graded as neuroendocrine tumors grade I and II (NETs GI and GII) and neuroendocrine carcinomas GIII based on Ki-67 index and mitotic count.[1] Endoscopic treatment for GI NETs ≤1 cm that does not extend beyond the submucosal layer and does not demonstrate lymph node metastasis is recommended. Tumors ≥2 cm, with lymph node metastasis, are indicated for surgical treatment. The treatment strategy for tumors between 10 and 20 mm in size remains controversial.[2] We present a rare case of a 60-year-old male patient with end-stage renal failure who underwent a screening pretransplantation endoscopic control. Colonoscopy had no pathological findings. Gastroscopy reveals an abnormal mucosa in the anterior upper part of the duodenal bulb that was described as a micronodular mucosa and a central nodule of 6 mm with erythematous mucosa. Histology of the micronodular mucosa reveals a heterotopic gastric mucosa and a small hyperplastic polyp. Biopsies from the nodule reveal a carcinoid tumor (NET GI). Immunohistochemistry: Positive chromogranin levels, low mitotic index (1/10 HPF), and Ki-67 index &lt;1% [Figure 2]. Gastrin levels were normal and chromogranin levels were abnormal (314 ng/ml, ULN &lt;120 ng/ml). Spiral tomography of the thorax and the abdomen were normal. Endoscopic submucosal dissection is indicated for small NETs (≤1 cm). Laparoscopic and endoscopic cooperative surgery is a novel method, but the experience is limited. Surgery is the best choice for large NETs (&gt;2 cm) and those of the duodenal bulb with histological extensions and the lack of assessing depth invasion.

The Application of ImmunohistoChemical Markers for Diagnosis, Classification and Grading of Neuroendocrine Tumors

objectives: To study the sensitivity of Chromogranin A in the diagnosis of neuroendocrine tumors from various locations in the body and its association with clinicopathological parameters like site and grade of tumors . Methodology: This study is conducted in the Department of Pathology, Faculty of Medicine, University of Kufa from January - October 2013. A total of 50 patients with neuroendocrine tumors from different locations. their ages ranging between 22-80 years with a mean age of 48.3 years. Two step Envision TM flex method was employed for immunohistochemical detection of ki67 antigen (MIB -1) and Chromogranin A . Results: Main site for patients with neuroendocrine tumors included in this study is gastroenteropancreatic system and there is female predominance, from 50 patients 44 (88%) cases was positive for Chromoranin A expression , there was no significant differences in expression of the Chromogranin A with location and grade of tumors (P value &gt;0.05) Conclusion: Chromogranin A is highly sensitive marker in diagnosis of neuroendocrine tumors irrespective to tumors location and tumor grade . Recommendation: We advise to use Chromogranin A immunohistochemical marker as a main marker in diagnosis of neuroendocrie tumors in addition to that this marker can be used as target for new modality in tumor therapy .

Efficacy of endoscopic ultrasonography and endoscopic ultrasonography-guided fine-needle aspiration for the diagnosis and grading of pancreatic neuroendocrine tumors

Background and aim: Pancreatic neuroendocrine tumors (pNETs) are histologically categorized according to the WHO 2010 classification by their mitotic index or Ki-67 index as G1, G2, or G3. The present study examined the efficacy of endoscopic ultrasonography (EUS) and EUS-guided fine-needle aspiration (EUS-FNA) in the diagnosis and grading of pNET. Methods: We retrospectively reviewed 61 pNETs in 51 patients who underwent EUS between January 2007 and June 2014. All lesions were pathologically diagnosed by surgical resection or EUS-FNA. We evaluated the detection rates of EUS for pNET and sensitivity of EUS-FNA, and compared the Ki-67 index between EUS-FNA samples and surgical specimens. EUS findings were compared between G1 and G2/G3 tumors. Results: EUS showed significantly higher sensitivity (96.7%) for identifying pNET than CT (85.2%), MRI (70.2%), and ultrasonography (75.5%). The sensitivity of EUS-FNA for the diagnosis of pNET was 89.2%. The concordance rate of WHO classification between EUS-FNA and surgical specimens was 69.2% (9/13). The concordance rate was relatively high (87.5%, 5/6) in tumors <20 mm but lower (57.1%; 4/7) in tumors ≥20 mm. Regarding EUS findings, G2/G3 tumors were more likely to be large (>20 mm), heterogeneous, and have main pancreatic duct (MPD) obstruction than G1 tumors. Multivariate analysis showed large diameter and MPD obstruction were significantly associated with G2/G3 tumors. Conclusions: EUS and EUS-FNA are highly sensitive and accurate diagnostic methods for pNET. Characteristic EUS findings such as large tumor size and MPD obstruction are suggestive of G2/G3 tumors and would be helpful for grading pNETs.

High expression of the putative cancer stem cell marker, DCLK1, in rectal neuroendocrine tumors.

Doublecortin-like kinase 1 (DCLK1), a microtubule-associated protein, is known to regulate neuronal differentiation, migration and neurogenesis. Recent evidence suggests that the protein is a putative marker for intestinal and pancreatic stem cells, including their cancer stem cell counterparts. The present study conducted immunohistochemical analyses for DCLK1 and the stemness marker, NANOG, in human intestinal neuroendocrine tumors (NETs), as their expression had not been previously investigated in these tumors. Eighteen patients with endoscopically resected rectal NETs were enrolled in the study. The mean age of the patients was 51 years old. The mean diameter of the resected tumors was 5.2 mm, and a histological diagnosis of NET grade G1 was formed for all tumors. Immunohistochemical analysis was performed not only for DCLK1, but also for the known NET markers, synaptophysin, chromogranin A and cluster of differentiation (CD)56. The intensity and distribution of staining were scored on a scale of 0–3 and 0–2, respectively. The sum of the scores was calculated for each specimen. Co-expression of DCLK1 and NANOG was also examined. The mean scores for DCLK1 and synaptophysin were significantly higher than those for chromogranin A (P<0.0001) and CD56 (P<0.01). There were no significant differences in the scores between DCLK1 and synaptophysin or between chromogranin A and CD56. Notably, NANOG was expressed in high quantities in all the tumor tissues studied, showing clear co-expression with DCLK1. In conclusion, DCLK1 may be a novel marker for rectal NET, potentially indicating the presence of the stemness gene product, NANOG.

PROX1 is involved in progression of rectal neuroendocrine tumors, NETs.

PROX1 is a homeobox transcription factor involved in the development of the lens, liver and heart and found upregulated in colorectal cancers. We studied PROX1 expression by immunohistochemistry in rectal neuroendocrine tumors (NETs). Approximately 10 to 15 % of gastroenteropancreatic NETs occur in the rectum, and some may metastasize. Yet little is known about the molecular pathogenesis of rectal NETs or their metastasis propensity. The objectives were to find out whether PROX1 plays a role in progression of rectal NETs and whether it has value as prognostic marker. In grading of rectal NETs, we applied the WHO 2010 classification. We carried out immunohistochemical staining of PROX1 on 72 primary tumors and six metastases and evaluated nuclear positivity in each tumor. Correlation between PROX1 expression, metastasis and patient survival was then assessed. Annexin A1, a downstream target of PROX1, was immunohistochemically assessed in 18 tumors. PROX1 protein was detected in about half of the tumors, with stronger expression in metastasized cases. PROX1 expression correlated with tumor metastasis and patient prognosis. Annexin A1 was negative in most of the high-grade tumors correlating strongly with grade and metastatic potential. Our results indicate that immunohistochemical detection of PROX1 correlates with a more malignant phenotype in rectal NETs. High PROX1 expression was associated with increased metastatic potential and poor patient survival but not as strongly as grade by the WHO 2010 classification. PROX1 may be involved in progression of rectal NETs as a part of the Wnt pathway.

Pancreatic neuroendocrine tumors: Correlation between the contrast-enhanced computed tomography features and the pathological tumor grade

ObjectiveTo determine whether CT features can predict the pathological tumor grades of pancreatic neuroendocrine tumors (PanNETs) according to the recent WHO classification. Materials and methodsIn all, 28 patients with histologically confirmed PanNETs underwent preoperative contrast CT examinations. Thirteen tumors were classified as G1 and 15 as G2. Two radiologists independently evaluated the CT features (tumor delineation, peripancreatic vascular involvement, upstream pancreatic duct dilatation, N (regional lymph node metastasis) and M (distant metastasis) grades, tumor homogeneity, cystic or necrotic change, and tumor conspicuity). The tumor sizes and Hounsfield unit values of all PanNETs during each phase on CT were measured by one radiologist. We compared the CT features between pathological tumor grades using Fisher's exact test for nominal scales and Mann–Whitney U test for ordinal scales or continuous variables. Additionally, we evaluated the performances of the CT findings and their combinations to diagnose G2 tumors. ResultsG2 tumors showed significantly larger in tumor size than G1 tumors (p=0.029). All 4 tumors with hepatic metastases were G2. Non-hyperattenuation compared with pancreatic parenchyma during portal venous phase (PVP) was significantly associated with G2 (p=0.016). The accuracy for G2 diagnosis of tumor size (≥20mm), M grade (M1), and tumor conspicuity (non-hyperattenuation during PVP) were 71%, 61%, and 71%, respectively, while the accuracy of their combination was 82%. ConclusionContrast-enhanced CT features (tumor size, M grade, and tumor conspicuity during PVP) can predict the pathological tumor grades of PanNETs.

Prognostic Significance of Defining L-Cell Type on the Biologic Behavior of Rectal Neuroendocrine Tumors in Relation with Pathological Parameters.

PurposeIn 2010, the World Health Organization categorized L-cell type neuroendocrine tumors (NETs) as tumors of uncertain malignancy, while all others were classified as malignant. However, the diagnostic necessity of L-cell immunophenotyping is unclear, as are tumor stage and grade that may guide diagnosis and management. To clarify the predictive markers of rectal neuroendocrine neoplasms (NENs), 5- and 10-year overall survival (OS) was analyzed by pathological parameters including L-cell phenotype.Materials and MethodsA total of 2,385 rectal NENs were analyzed from our previous multicenter study and a subset of 170 rectal NENs was immunophenotyped.ResultsIn univariate survival analysis, tumor grade (p < 0.0001), extent (p < 0.0001), size (p < 0.0001), lymph node metastasis (p=0.0063), and L-cell phenotype (p < 0.0001) showed significant correlation with the prognosis of rectal NENs; however, none of these markers achieved independent significance in multivariate analysis. The 10-year OS of tumors of NET grade 1, < 10 mm, the mucosa/submucosa was 97.58%, 99.47%, and 99.03%, respectively. L-Cell marker, glucagon II (GLP-1&2), with a cut off score of > 10, is useful in defining L-Cell type. In this study, an L-cell immunophenotype was found in 83.5% of all rectal NENs and most, but not all L-cell type tumors were NET G1, small (< 10 mm) and confined to the mucosa/submucosa.ConclusionFrom these results, the biological behavior of rectal NENs does not appear to be determined by L-cell type alone but instead by a combination of pathological parameters.

Surgical resection improves the outcome of the patients with neuroendocrine tumor liver metastases: large data from Asia.

How to properly manage neuroendocrine liver metastasis (NELM) remains debatable, and only limited clinical data have been published from Asian population. The objective of this study is to identify possible prognostic factors affecting overall survival time and to provide a guideline for future clinical practice.A retrospective study was performed on 1286 patients who had neuroendocrine tumors in our specialized center, and data from 130 patients who had NELM were summarized. Demographic and clinicopathologic data, tumor grade, treatment method, and prognosis were statistically analyzed.Most of the NELMs originated from pancreas (65.4%). Important prognostic factors that included tumor location and size were identified with multivariate analysis. Patients with either primary tumor resection or liver metastasis resection showed a 5-year survival of 35.7% or 33.3%, respectively, whereas resection of both resulted in a 50% 5-year survival. More importantly, resection was performed on 7 patients with grade 3 (G3) tumors, and resulted in 1-year, 3-year, and 5-year survival of 100%, 42.8%, and 28.6%, respectively, whereas the other 9 G3 patients without resection died within 3 years. P = 0.49 comparing the resected group with nonresected group in G3 patients. Besides, the overall 5-year survival rates for resected and nonresected patients were 40.5% and 5.4%, respectively.Multiple prognostic factors influenced the overall outcome of NELM including patient age, tumor location, and size, etc. Aggressive surgical approaches could be considered for maximum survival time disregarding the pathological grade of the tumor. Study with larger sample size should be considered to reevaluate the recommendation of the WHO guidelines for G3 neuroendocrine tumors.

A case of primary renal carcinoid tumor.

Primary renal carcinoid tumors are extremely rare kidney lesions, with fewer than 100 reported cases previously. We describe a 75-year-old man with an incidentally detected cystic renal mass. Computed tomography showed a 3 cm tumor with a cystic component enhanced with contrast. No evidence of metastasis was detected. We treated the patient with radical nephrectomy. Pathological examinations revealed a cellular arrangement specific to carcinoid tumor and positive for chromogranin A, neural cell adhesion molecule, and somatostatin receptor type 2. The tumor cells had a mitotic count of 4 mitoses/10 high-power fields, and the level of the proliferation marker Ki-67 was 5%. The pathological diagnosis was renal neuroendocrine tumor grade 2. No local recurrence and no systemic metastasis were detected during the 18-month follow-up period. To our knowledge, this is the 6th case of renal neuroendocrine grade 2 tumor reported thus far.

English

Neuroendocrine tumors (NETs) can arise in various organs of the body and share many common pathologic features. Although there are various classification systems, World Health Organization (WHO) proposed classification of NETs based on differentiation and grading for prognostic and therapeutic implications. Ki-67 index and Mitotic index are the most important criteria for grading of NETs. Many studies have been done concerning prognostic role of Ki-67 index in NETs specific to organ systems, but fewer data are available about patients with NETs of heterogenous origin. The aim of our study was to evaluate the prognostic significance of Ki-67 index and mitotic index in NETs. A total of 50 patients undergoing multidisciplinary management were analyzed prospectively over a period of 4 years, from 2010 to 2014. Among various locations, NETs most commonly involved gastrointestinal tract. The study population was classified into three grades. Grade I (13 patients), Grade II (10 patients) and Grade III (27 patients). There was a significant association between tumor grading and metastasis where tumor grading served the most important predictor of outcome.

Grading of Neuroendocrine Neoplasms: Mitoses and Ki-67 Are Both Essential

Background: The current WHO classification for neuroendocrine neoplasms (NEN) of the gastrointestinal tract requires Ki-67 and mitotic index for grading. However, both indexes might be conflicting as far as grade is concerned. In this study, we investigate which of the two indexes is most informative to predict survival. Methods: We assessed 362 patients with NEN of gastrointestinal (n = 148), pancreatic (n = 29), lung (n = 77), unknown primary site (n = 102) and of miscellaneous (n = 6) origin. Follow-up and proliferative indexes were recorded. Results: Survival was clearly correlated with both proliferative indexes (p < 0.001). One hundred and nineteen samples (34%) showed discordance in grading between the Ki-67 and the mitotic index, of which 74 (62%) were biopsies and 45 (38%) resection specimens (p = 0.001). In 86% of these cases, survival matched with the highest proliferative index, which was the Ki-67 index in 87% of these cases. Seventeen cases had a mitotic index of 2 (threshold grade 2) and a Ki-67 index of <3% (grade 1). For these cases, survival curve matched that of patients with concordant indexes of grade 1. Conclusion: Grading NEN using two proliferative markers results in discordance between these indexes in one third of cases, more often in biopsy material than in resection specimens. If results are discordant, survival is for the most part associated with the grade of the highest index, for the most part Ki-67. Thus, grading with two proliferative indexes is useful as it highlights cases where one of these indexes may be incongruent.

Assessing the short- and long-term outcomes after resection of benign insulinoma.

Insulinoma is a rare functional pancreatic neuroendocrine tumour (NET) believed to have an excellent long-term outcome, but few studies have solely focused on this issue after apparently curative resection. This study aimed to assess post-operative and long-term outcomes after resection of benign insulinomas. From 1998 to 2013, 36 consecutive patients with insulinomas underwent surgery. Three patients had multiple endocrine neoplasia type-1 (MEN-1). Demographics, operative findings, tumour grade (2010 World Health Organization (WHO) NET classification), post-operative pancreatic fistula (POPF) grade (International Study Group of Pancreatic Fistula (ISGPF)), complications and recurrence were analysed. Eighteen (50%) had enucleation while the rest underwent pancreatic resection. The majority (86.1%) of insulinomas belonged to WHO NET grade G1. POPF occurred in 58.3% of patients while clinical fistula (ISGPF grades B and C) occurred in 19.4%. One (2.8%) patient required reoperation. The occurrence of POPF was not related to type of resection or surgical approach. There was no perioperative mortality. After a mean follow-up of 83.6 months, two patients (5.7%) developed disease recurrence at 34.4 and 131.9 months after initial surgery. No patients developed distant metastasis. The 10- and 15-year disease-free rates were 95.6 and 85.4%, respectively. POPF occurred frequently and posed a significant morbidity after resection of insulinoma. However, it occurred independently of type of resection or surgical approach. Although the immediate cure rate after resection was high (100%), long-term disease recurrence in sporadic (non-MEN-1) cases was not insignificant. Regular long-term follow-up is recommended.