Poorly Differentiated Endocrine Carcinomas Research Articles

Pancreatic neuroendocrine tumors: an analysis of 88 patients

Objective To analyze the clinicopathological characteristics,diagnosis,treatment outcomes and prognosis of patients with pancreatic neuroendocrine tumors (PanNETs).Methods The clinicopathological characteristcs and prognostic factors of 88 patients who were diagnosed with pancreatic neuroendocrine tumors by postoperative pathology were analyzed retrospectively.The data included age,sex,symptoms,tumor size,pathological grades,TNM staging,treatment and follow up.Results There were 28 males and 60 females.The ratio of male to female was 1 ∶ 2.1,with a mean age of 42 (range 8～75) years.Of the 88 PanNETs,74(84.1％) were nonfunctional tumors.Using the WHO 2000 pathological classification system,there were 35 well differentiated endocrine tumors (WDET),29 well differentiated endocrine carcinomas (WDEC),and 24 poorly differentiated endocrine carcinomas (PDEC).Using the 7th AJCC TNM staging system,23(26.1％),46(52.3％),13(14.8％) and 6 patients (6.8％) were diagnosed to have stage Ⅰ,Ⅱ,Ⅲ and Ⅳ,respectively.The overall 5-year survival rate was 72.0 ％.Univariable analysis revealed tumor size,histopathological grades,TNM staging and radical surgery were associated with prognosis.Multivariate analysis showed histopathological grades,TNM staging and radical surgery were independent risk factors of survival.Conclusions PanNETs are rare pancreatic neoplasms with high heterogeneity and low malignant potential.PanNETs have various clinical manifestations and the preoperative misdiagnosis rate is high.A definitive diagnosis depends on pathological examination.The new TNM and pathological classification systems have good predictive abilities on survival.The majority of patients who received radical surgery or surgical comprehensive therapy have good prognosis. Key words: Pancreatic neoplasms; Diagnosis; Therapy; Prognosis

1164P - Somatostatin Receptor (SSTR) Expression and Proliferative Index (KI 67) in 100 Patients (PTS) with Gastroenteropancreatic Neuroendocrine Tumors (Gep-Nets). Clinical-Pathological Correlation

ABSTRACT Introduction The expression of somatostatin receptors, mainly subtype 2 and 5 is a characteristic of well-differentiated GEP-NET. Its expression has prognostic and predictive implications for the use of somatostatin analogs. The Ki 67 is a nuclear antigen associated with cell proliferation, present during the cycle phases (G1, S, G2 and M). Objectives To describe the expression of SSTR, and Ki-67 in patients with GEP-NET. To evaluate in this population the correlation between the expression pattern of the 5 SSTR subtypes, Ki-67 and survival. Material and methods We performed the analysis on 100 pts. diagnosed with a GEP -NET, included in the database of Argentum Group. In all cases, was centralized pathology review to confirm the diagnosis. The survival analysis was performed by the Kaplan-Meier method. Log-rank was used to test the comparative analysis of the variables of interest in the study. Results We analyzed 100 pts: 73 pts. Well-Differentiated Endocrine Carcinoma (WDEC), 17 pts Had Well-differentiated neuroendocrine tumors (WDET) and 10 pts. Poorly differentiated endocrine carcinoma (PDEC). Age (median) 54 a. (r 18-84). Primary Location: small intestine 40, pancreas 26 pts. Appendix 9 pts., Stomach 8, rectum 6, unknown 6, colon 4, and esophagus 1 pte. Metastatic disease 76 pts., Localized disease in 24 pts. The expression of SSTR was: Subtype 2 (positive 80 pts.) and subtype 5 (positive 46 pts.). Ki 67 was less than or equal to 2% in 36 pts., between 3 and 15%, 49 pts. and more than 15% in 12 pts. 26/100 pts. had functioning tumors. The analysis included 55 pts. with SSTR 2 / 5 pos. Ki 67 less than or equal to 2% (Group 1), 38 pts. with SSTR 2 / 5 pos and Ki 67 more than 2% (Group 2), 5 pts. with SSTR 2 / 5 neg. Ki 67 less than or equal to 2% (Group 3) and 2 pts. with SSTR 2 / 5 neg and Ki 67 more than 2% (Group 4). Univariate analysis showed significant differences for the expression of SSTR 2 (p. 009), and Ki 67 (p. 001). Survival was higher in Group 1 versus Group 2, median OS was 97 months vs 49 months, and 36 to 23 months, in groups 3 and 4 respectively (p. 0001). Conclusions In this population of pts with GEP-NET we could identify a subgroup of better prognosis associated with expression of SSTR 2 / 5 and Ki 67 less than or equal to 2%. The assessment of SSTR 2 and 5 in tissue, and proliferative index are useful tools for evaluating prognosis in this setting. Disclosure All authors have declared no conflicts of interest.

Mammalian target of rapamycin expression in poorly differentiated endocrine carcinoma: clinical and therapeutic future challenges

While the mammalian target of rapamycin (mTOR) signaling pathway is a promising target for well-differentiated endocrine carcinoma therapy with the mTOR inhibitor everolimus (RAD001), poorly differentiated endocrine carcinomas (PDECs) are usually excluded from clinical trials due to their aggressiveness. So far, mTOR activity in PDECs has only been tested in cell lines. This study reviewed 36 mono-institutional PDECs to determine mTOR expression. Slides of normal kidney as positive control were used to optimize mTOR staining. To ensure antibody specificity, consecutive sections were incubated in the absence of primary antibody. Immunoreactivity was evaluated on a semi-quantitative scale scoring the extent and intensity of staining. The product of these two scores was used to obtain a total immunostaining score. The main primary site of disease was the pancreas, and 83% of patients had stage IV disease. In 80% of samples, mTOR expression was maintained at similar levels, with no relationship to tumor origin or proliferation rate determined by MIB-1. This study seems to demonstrate that mTOR is expressed in human PDECs regardless of tumor site. Its role in relation to the activity of everolimus in this subset of patients needs to be confirmed.

Clinical effect of temozolomide‐based chemotherapy in poorly differentiated endocrine carcinoma after progression on first‐line chemotherapy

Patients with metastatic poorly differentiated endocrine carcinoma (PDEC) usually have a short survival. The chemotherapy combination of cisplatin and etoposide is frequently used as first-line palliative chemotherapy. There are, however, no published studies concerning second-line treatment of the disease. Temozolomide has shown clinical effect in well-differentiated endocrine carcinomas. This study was performed to evaluate the effect of temozolomide in PDEC patients who had progressed on first-line treatment. Twenty-five patients with PDEC (mainly gastrointestinal) were treated with temozolomide alone or in combination with capecitabine. A subset of patient also received bevacizumab. MGMT methylation was analyzed in tissue specimens. Data were collected retrospectively. One patient had a complete response, and 7 patients had partial response (33% response rate). Median duration of response was 19 months. Another 9 (38%) patients had a stable disease, after progression at inclusion, with a median duration of 18 months. Median progression-free survival for all patients was 6 months, and median overall survival was 22 months. Only 1 patient had a MGMT methylation. Treatment with temozolomide alone or in combination with capecitabine and bevacizumab resulted in objective response or stabilization in 71% of PDEC patients who failed on first-line chemotherapy. These results indicated that temozolomide may be used as second-line treatment in PDEC.

Response to temozolomide and bevacizumab in a patient with poorly differentiated neuroendocrine carcinoma

Poorly differentiated endocrine carcinomas (PDEC) are usually treated with cisplatin-based chemotherapy regimens. We here present a case with a dramatic response (both radiologically and biochemically) to the combination of temozolomide and bevacizumab, after failure of cisplatin and etoposide, with continued tumor shrinkage at 5 months. Temozolomide combined with bevacizumab might be a good treatment option in PDEC, perhaps even in a first-line setting. Prospective studies to answer this are warranted.

Chromosome 3p alterations in pancreatic endocrine neoplasia

Pancreatic endocrine tumors (PET) are rare neoplasms classified as functioning (F-PET) or non-functioning (NF-PET) according to the presence of a clinical syndrome due to hormonal hypersecretion. PETs show variable degrees of clinical aggressiveness and loss of chromosome 3p has been suggested to be associated with an advanced stage of disease. We assessed chromosome 3p copy number in 113 primary PETs and 32 metastases by fluorescence in situ hybridization (FISH) using tissue microarrays. The series included 56 well-differentiated endocrine tumors (WDET), 62 well-differentiated endocrine carcinomas (WDEC), and 6 poorly differentiated endocrine carcinomas (PDEC). Chromosome 3p alterations were found in 23/113 (20%) primary tumors, with losses being predominant over gains (14% vs. 6%). Loss of 3p was found in 5/55 (9%) WDET, 11/52 (21%) WDEC, and never in PDEC. Gains of 3p were detected in 4/55 (7%) WDET, no WDEC, but notably in 3/6 (50%) PDEC (OR 23.6; P = 0.003). Metastases were more frequently monosomic for 3p compared to primary tumors (OR 3.6; P = 0.005). Monosomy was significantly associated with larger tumor size, more advanced tumor stage, and metastasis. No association was found with survival. Chromosome 3p copy number alterations are frequent events in advanced stage PET, with gains prevailing in PDEC while losses are more frequent in WDEC, supporting the view that a specific pattern of alterations are involved in these diverse disease subtypes.

Poorly differentiated endocrine carcinoma of the pancreas responded to gemcitabine: Case report

Poorly differentiated endocrine carcinoma (PDEC) of the pancreas is a rare and aggressive tumor. First-line treatment is commonly a combination of etoposide and cisplatin, but there is no consensus regarding further treatment recommendations. In this report, we describe a case of pancreatic PDEC treated with gemcitabine as third-line chemotherapy. A 62-year-old man with pancreatic PDEC was administered etoposide plus cisplatin as first-line treatment; he then received irinotecan for tumor relapse. However, because irinotecan induced ileus in this patient, we chose gemcitabine as third-line chemotherapy. After two cycles of gemcitabine (1000 mg/m(2) on days 1, 8 and 15 every 4 wk), a partial tumor response was noted by computed tomography (approximately 68% reduction in tumor size). Our patient survived for 15 mo after diagnosis. This is a rare case of unresectable pancreatic PDEC, which showed a partial response to gemcitabine after the failure of two other regimens. Gemcitabine could be an effective treatment option for pancreatic PDEC that is resistant to other treatments.

1323 mTOR expression in gastrointestinal (GI) tract poorly differentiated endocrine carcinoma (PDEC)

1323 mTOR expression in gastrointestinal (GI) tract poorly differentiated endocrine carcinoma (PDEC)

Efficacy and tolerance of chemotherapy with dacarbazine or temozolomide associated or not with 5-fluorouracil (5-FU) in endocrine carcinomas: A retrospective multicentric study from the Groupe des Tumeurs Endocrines (GTE)

e15523 Background: Small studies have shown that therapy with dacarbazine and temozolomide give up to 34% tumoral response rates in endocrine carcinomas. The aim of this large retrospective multicentric study was to evaluate efficacy and tolerance of chemotherapy with dacarbazine or temozolomide associated or not with 5-FU in endocrine carcinomas. Methods: Patients were recruited in 6 French and 1 German centers. All patients with well (WDEC) or poorly-differentiated endocrine carcinoma (PDEC), whatever the primary, and who have been treated with dacarbazine or temozolomide associated or not with iv 5-FU or capecitabine, were included. Response rates were evaluated according to RECIST criteria by one of the investigator and toxicity according to National Cancer Institute Common criteria. Results: 86 patients were included : 36 women, median age 61.7 years (27.7 - 85.7), 67 WHO-PS 0–1. Primaries were : pancreas (n=34), digestive tract (n=23), thyroid (n=9), lung (n=6), other (n=6), unknown (n=8). 64 patients had WDEC and 11 PDEC (11 not determined). The number of previous systemic treatments (chemotherapy, chemoembolization, radionuclide therapy) was: 0 (n=16), 1 (n=25), 2 (n=25), 3 (n=14), 4 and more (n=6). Treatments received were : dacarbazine (n=3), temozolomide (n=19), dacarbazine + 5-FU (n=48), temozolomide + capecitabine (n=16). Evaluation was impossible in two patients. Tumoral response rates (partial and stabilization) were 61.2% in WDEC and 18.2% in PDEC. The best response rates in WDEC were : partial response (n=6; 9.7%), stabilization (n=32; 51.6%), progression (n=24; 38.7%) without significant differences between regimens and primary location. Response rates in WDEC were 88.9%, 71.4% and 64.7% in first, second and third line therapies, respectively. Median progression free survival in WDEC was 5.7 months (0.1–41.7). Grade 3–4 toxicities were hematologic (n=8), digestive (n=10), infection (n=3). Conclusions: Dacarbazine and temozolomide therapy showed high partial response and stabilization rates up to 3rd line therapy in well-differentiated endocrine carcinoma, with moderate toxicity. MGMT tumoral status is currently investigated. No significant financial relationships to disclose.

EUS-FNA Predicts 5-Year Survival in Pancreatic Endocrine Tumors (PETs)

Background: PETs differ in clinical behavior and prognosis. Determination of malignant potential by EUS-FNA can help management. Aim: To determine the performance of EUS-FNA for diagnosing and classifying the malignant potential of PETs based on WHO classification. Methods: Single-center retrospective study. A review of medical records from 01/1999 to 08/2008 was performed to identify patients who had been diagnosed with PETs and submitted to EUS-FNA. The diagnosis of PET was established by EUS-FNA and/or histopathologic evaluation obtained by surgical resection. Antibodies against synaptophysin, chromogranin A, p53, Ki-67 were used. The lesions were classified as recommended by the WHO. Results: In overall, 90% (77/86) of patients had the diagnosis obtained by EUS-FNA. The sensitivity did not vary with size, type, location, and presence of hormonal secretion. Of 86 patients, 30 (35%) were submitted to surgery. The kappa index between the classification obtained by EUS-FNA and by surgery was 0.38 (p=0.003). Major discrepancies were found in the group of endocrine tumor of uncertain behavior(UBWDET) obtained by EUS-FNA, since 72% turned out to be well-differentiated endocrine carcinoma(WDEC). Sixteen patients(27%) died during a mean follow-up of 34 ± 27 months. The 5-year survival rates were 100% for endocrine tumors, 68% for WDEC, and 30% for poorly-differentiated endocrine carcinomas(PDEC)(p=0,008). Conclusions: This largest single-center experience demonstrated the accuracy of EUS-FNA in diagnosing and determining the malignant behavior of PETs. EUS-FNA predicts 5-year survival. Notes: BBWET=well differentiated endocrine tumor of benign behaviour

Low Expression of ARHI Is Associated with Shorter Progression-Free Survival in Pancreatic Endocrine Tumors

Little is known about the molecular anomalies involved in the development and progression of malignancy of pancreatic endocrine tumors (PETs). A recently identified member of the Ras family, Ras homologue member I (ARHI), has been shown to be involved in breast, ovary, and thyroid carcinogenesis. Unlike other members, it acts as a tumor suppressor gene that inhibits cell growth. Here we analyzed the mRNA expression of ARHI in 52 primary PETs and 16 normal pancreata using quantitative reverse transcription-polymerase chain reaction. ARHI expression showed a statistically significant difference between either normal pancreas or well-differentiated endocrine tumors (WDET) and poorly differentiated endocrine carcinomas (PDECs) (P < .001 and P < .001, respectively). Moreover, ARHI expression among WDEC samples was more heterogeneous than in WDET, with several tumors showing level of expression analogous to that observed in PDECs. A significant correlation between lower ARHI expression and shorter survival (P = .020) was identified, and a low ARHI expression was associated to a shorter time to progression (P < .001), even considering the proliferation index Ki67 in the multivariate analysis. ARHI is involved in PET progression. Its mRNA expression seemed to be a prognostic factor for disease outcome and, in association with the proliferative index Ki67, a predictor for a rapid tumor relapse.

Clinical Significance of p16INK4Aand p53 Overexpression in Endocrine Tumors of the Gastrointestinal Tract

This study was designed to determine the expression of p16, p53, and CD117 in gastrointestinal tract endocrine tumors. Immunohistochemical studies of p16, p53, and CD117 were performed in 57 gastrointestinal tract endocrine tumors, including 22 poorly differentiated endocrine carcinomas (PDECs) and 35 well-differentiated endocrine tumors (WDETs). Overexpression of p16 and p53 was observed in 16 (73%) and 10 (45%) of the PDECs, respectively, whereas only 1 WDET showed overexpression of p53 and none showed overexpression of p16. A total of 18 (82%) of the PDECs showed overexpression of p16 or p53 proteins. This is closely associated with PDEC (P < .0001). By using overexpression of p16 or p53 as the criteria for PDEC, the sensitivity and specificity are 81.8% and 97.1%, respectively, with positive and negative predictive values of 94.7% and 89.5%, respectively. CD117 was not detected in any of the 57 gastrointestinal endocrine tumors by immunohistochemical analysis.

Clinical Significance of p16 INK4a and p53 Overexpression in Endocrine Tumors of the Gastrointestinal Tract

This study was designed to determine the expression of p16, p53, and CD117 in gastrointestinal tract endocrine tumors. Immunohistochemical studies of p16, p53, and CD117 were performed in 57 gastrointestinal tract endocrine tumors, including 22 poorly differentiated endocrine carcinomas (PDECs) and 35 well-differentiated endocrine tumors (WDETs). Overexpression of p16 and p53 was observed in 16 (73%) and 10 (45%) of the PDECs, respectively, whereas only 1 WDET showed overexpression of p53 and none showed overexpression of p16. A total of 18 (82%) of the PDECs showed overexpression of p16 or p53 proteins. This is closely associated with PDEC (P < .0001). By using overexpression of p16 or p53 as the criteria for PDEC, the sensitivity and specificity are 81.8% and 97.1%, respectively, with positive and negative predictive values of 94.7% and 89.5%, respectively. CD117 was not detected in any of the 57 gastrointestinal endocrine tumors by immunohistochemical analysis.

Xq25 and Xq26 identify the common minimal deletion region in malignant gastroenteropancreatic endocrine carcinomas

Loss of heterozygosity (LOH) for markers on X chromosome are associated with malignancy in endocrine tumors of the stomach and pancreas. The aim of this work is to investigate low-grade, well-differentiated endocrine carcinomas (WDEC) vs high-grade, poorly differentiated endocrine carcinomas (PDEC) of the gastroenteropancreatic (GEP) tract for common deletion regions on X chromosome. We performed a comparative allelotyping analysis with 24 highly polymorphic markers for the X chromosome in 12 WDECs and 5 PDECs. Overall, the LOH frequency in all informative loci investigated was 59% in primary and 61% in metastasis, with a significantly higher rate in PDECs than in WDECs (p<0.015 for primary and p<0.00005 for metastasis). In both WDECs and PDECs, the small Xq25 region as defined by DXS8059, DXS8098, and DXS8009 markers showed higher LOH rate as compared to the rest of the chromosome markers (p<0.04). In addition, LOH was very frequently elevated also in DXS294 and in DXS102 loci mapping the chromosomal region Xq26. In no instances differences were found between primary tumors and metastases. Methylation analysis revealed that Xq25 loss preferentially occurred on the inactive X chromosome, a feature in agreement with findings from other human cancers suggesting escape of tumor suppressor genes to X chromosome inactivation at this region. Overall, our data indicate that the two chromosomal regions, Xq25 and Xq26, may participate to the malignant progression of GEP endocrine carcinomas.

Allelotypes and Fluorescence In situ Hybridization Profiles of Poorly Differentiated Endocrine Carcinomas of Different Sites

The aim of this work was to investigate the genotypic profiles of 36 poorly differentiated endocrine carcinoma (PDEC) of different sites to verify if their very similar phenotype may reflect similar pattern of genetic anomalies and if useful diagnostic or prognostic markers may be pointed out. All tumors were microallelotyped at 57 microsatellite on 11 autosomes and the allelotypes of a selected panel of tumors were validated by interphasic fluorescence in situ hybridization with centromeric probes for chromosomes 1, 3, 6, 11, 17, and 18 and a probe specific for p53. Regardless of the primary sites, PDECs exhibit very complex allelotypes (86%) and TP53 allelic imbalance (89%). Among these cases, fluorescence in situ hybridization analysis confirmed the presence of multiple aneusomies and a chromosome instability phenotype. Very low percentage of allelic imbalance (AI) and few aneuploidies were detected in only five PDECs for which an overall longer survival was observed. We found recurrent AI on 3p, 5, and 11q13 in lung PDECs, on 5q21, 8p, and 18q21 in colorectal PDECs and on 7 and 11q22 in gastric PDECs. Significantly better outcome was observed in patients with PDEC exhibiting 8q AIs and absence of AI at chromosome regions 6q25 and 6p. The concurrence of p53 inactivation and aneuploidies or chromosome instability are the main features of PDECs. However, the specific allelotypes observed in relation to primary site support the hypothesis that PDECs and exocrine carcinomas of all sites may share early pathogenetic mechanisms. Molecular markers of potential diagnostic and prognostic values for PDECs of different sites have been identified.

CDX2 as a marker of intestinal EC-cells and related well-differentiated endocrine tumors

Gastroenteropancreatic (GEP) endocrine tumors (ETs) are neoplasms showing different hormonal profiles and different clinical and prognostic features, which depend consistently on the site of origin. Histological features and general endocrine markers do not differentiate tumors in relation to their location, making it difficult to establish the site of origin of a GEP ET that has metastasized to the liver or lymph nodes. A site-specific marker would be particularly useful in the examination of small specimens where there is not sufficient material for an extensive study of the hormonal expression. CDX2 is a transcription factor that has been recently proposed as a marker of intestinal adenocarcinomas. Our aim was to evaluate the immunohistochemical expression of CDX2 in normal tissues and in 184 formalin-fixed and paraffin-embedded ETs to verify whether it could be used to identify intestinal ETs with a high degree of sensitivity and specificity. Of these cases, 154 were primary tumors (99 GEP and 55 non-GEP tumors), 101 were well-differentiated endocrine tumors, and 53 were poorly differentiated endocrine carcinomas (PDECs). Of the cases, 30 were metastases from differently located ETs. Nuclear CDX2 immunoreactivity was found in all EC-cells (serotonin-producing cells), in about 10% of G-cells (gastrin-producing cells), in about 30% of GIP-cells (gastric inhibitory peptide cells) and in a few motilin-positive cells of the normal intestinal mucosa, while other gastrointestinal endocrine cell types were CDX2 negative. All midgut EC-cell tumors, their metastases, and two of three pancreatic EC-cell ETs were diffusely and intensely CDX2 positive. The other GEP ETs, their metastases, as well as the non-GEP ETs, were all CDX2 negative, with the exception of four PDECs, five gastrinomas and one pheochromocytoma, which were only focally positive. We conclude that CDX2 may be considered a sensitive and specific marker of midgut EC-cells and EC-cell tumors, and its expression may be useful in the diagnosis of metastases from occult ETs.