Classification et aspects anatomopathologiques des tumeurs endocrines digestives

Gastrointestinal and pancreatic endocrine tumors GIPET are rare and represent only 2 % of malignant tumors. Beyond their common features, endocrine tumors are characterized by a marked diversity, which results from the large functional, structural and embryological heterogeneity of normal endocrine cells. Despite the rational basis for predicting prognosis provided by the WHO classification, there is no reliable means of predicting the clinical course of patients with gastrointestinal and pancreatic endocrine tumors. The current criteria used for the definition of the tumor grade remain unsatisfactory. According to the WHO classification system, pathologists vary significantly in their reporting of endocrine tumors. Recently, the European Neuroendocrine Tumour Society (ENETS) has proposed a TNM (tumor–node–metastasis) classification for gastrointestinal and pancreatic endocrine tumors. The use of this classification is considered simple and valuable. It is hoped that the combination of WHO classification, with anatomical staging systems TNM, and possibly incorporating molecular features of gastrointestinal and pancreatic endocrine tumors will provide clinicians with effective means of classification and prognostication of patients with these tumors.     

Médecine nucléaire et imagerie multimodalités des tumeurs endocrines

Endocrine digestive tumors have various clinical presentations (familial history, hindgut, midgut or foregut origin, histological type, functionality, and evolution). Depending on their radio-isotopic and uptake characteristics, various SPECT and PET radiopharmaceuticals, especially with CT-hybrid acquisition, are accurate to precise localisation and extension. They may also help to define new prognostic factors, to complement the WHO, Grade and TNM ENETS classifications. Their place in the follow-up have yet to be evaluated.     

Contemporary methods of diagnosis and treatment of neuroendocrine gastrointestinal tumors

Neuroendocrine tumors of digestive tract (GEP NET) occur rather rarely, causing many problems with both diagnosis and treatment. Thanks to the extreme devotion of specialists, a great leap has been made in the field development. Clinicians and scientists gathered in The European Neuroendocrine Tumour Society publish current proposals for diagnosis solutions, together with the most up-to-date methods of treatment, which we have attempted to present in this general overview. It describes general methods of treating patients with GEP NET, as well as discusses ways of dealing with cases of tumours type foregut, midgut and hindgut.     

Diagnostic and therapeutic guidelines for gastrointestinal neuroendocrine tumors (recommended by the Polish Network of Neuroendocrine Tumors)

We have recently observed an increased interest in gastro-entero-pancreatic neuroendocrine tumors (GEP NET). They are rare cancer types and therefore collaborative effort of specialists in various disciplines of medicine is necessary to work out the diagnostic and therapeutic guidelines. In this publication we present general guidelines of the Polish Network of Neuroendocrine Tumors for the management of patients with GEP NET, developed at the Round Table Conference which took place in Kliczków near Wroc?aw in November 2007. In the subsequent parts of this publication, we present the rules of diagnostic and therapeutic management of: - endocrine tumors of the stomach and duodenum (including gastrinoma); - pancreatic endocrine tumors; - neuroendocrine tumors of the small intestine and the appendix; - neuroendocrine tumors of the colon. We hope that the proposed guidelines by Polish and foreign experts representing various disciplines of medicine, including endocrinology, gastroenterology, surgery, oncology, nuclear medicine and pathomorphology, will become a useful tool in the diagnostics and treatment of these patients.     

Advances in molecular classification of renal neoplasms

Kidney neoplasms are classified by light microscopy using the World Health Organization (WHO) system. The WHO system defines histopathologic tumor subtypes with distinct clinical behavior and underlying genetic mutations. In adults, the common malignant subtypes are variants of renal cell carcinoma (RCC). Histopathologic classification is critical for clinical management of RCC, but is becoming more complex with recognition of novel tumor subtypes, development of procedures yielding small diagnostic biopsies, and emergence of molecular therapies directed at tumor gene activity. Therefore, classification systems based on gene expression are likely to become essential for diagnosis, prognosis and treatment of kidney tumors. Recent DNA microarray studies have shown that clinically relevant renal tumor subtypes are characterized by distinct gene expression profiles, which are useful for discovery of novel diagnostic and prognostic biomarkers. In this review, we summarize the WHO classification system for renal tumors, general applications of microarray technology in cancer research, and specific microarray studies that have advanced knowledge of renal tumor diagnosis, prognosis, therapy and pathobiology.     

研究报告: 第五版《世界卫生组织中枢神经系统肿瘤分类指南》下成人胶质瘤诊断及预后

目的 脑胶质瘤是最常见的恶性原发性中枢神经系统肿瘤,近年来分子病理的快速发展对胶质瘤诊断及分级带来了重要影响,在2021年发布的《世界卫生组织中枢神经系统肿瘤分类指南》（第五版）引入了更多分子指标对肿瘤的诊断和分级进行指导。本研究旨在临床队列中比较最新版指南和上一版指南对肿瘤诊断及预后评估的影响,以期为临床实践活动中新版指南的应用提供数据参考和依据。方法 回顾性纳入了癌症基因组图谱数据库512例胶质瘤样本,分别依据2016版和2021版《世界卫生组织中枢神经系统肿瘤分类指南》进行诊断、通过Kaplan-Meier进行生存曲线绘制和中位总生存期计算和生存差异分析。结果 对512例样本分别完成了上一版指南和最新版指南的诊断及分级。在新版指南下分别有53和72例异柠檬酸脱氢酶（IDH）突变型和IDH野生型的胶质瘤诊断级别升级为了4级,且这些诊断级别升高的胶质瘤的预后更差。结论 最新版指南较上一版指南可对胶质瘤进行更为精准地分类及分级,在有条件的情况下应尽快依据最新版指南开展诊断及分级。     

Somatostatin receptors in human cancer: incidence, characteristics, functional correlates and clinical implications.

Somatostatin receptors (SS-R) have been identified in membrane homogenates or tissue sections from several hundred tumors. SS-R were found in most neuroendocrine tumors, i.e. GH and TSH producing pituitary tumors, endocrine gastroenteropancreatic (GEP) tumors, paragangliomas, pheochromocytomas, medullary thyroid carcinomas (MTC) and small cell lung carcinomas. SS-R were also expressed in a majority of malignant lymphomas, in several brain tumors (all meningiomas, most astrocytomas) and in breast tumors. The majority of tumors expressing SS-R are rather differentiated (i.e. astrocytomas vs glioblastomas), but exceptions exist (high grade malignant lymphomas). An inverse relationship exists between SS-R and receptors for epidermal growth factor (EGF-R) incidence in lung tumors, glial tumors and most breast tumors, whereas meningiomas express simultaneously both receptors. A minority of tumors (ovarian tumors, MTC, insulinomas) express a subtype of SS-R, characterized by low affinity for the octapeptide SS analog octreotide. The function mediated by SS-R in human tumors may differ according to the tumor type. SS-R in pituitary and GEP tumor mediate hormone secretion inhibition with, in addition, possibly some antiproliferative effects. In meningiomas, however, activation of SS-R inhibits forskolin-stimulated adenylate cyclase activity, and weakly stimulates proliferation. Whereas SS-R seem to mediate antiproliferative effects in animal models and cell lines of lymphomas, breast and lung tumors, such an effect has not yet been convincingly documented in human primary tumors. The clinical implications of the presence of SS-R in tumors are manyfold: (1) as a predictive marker for efficient therapy with octreotide in pituitary and GEP tumors; (2) as a diagnostic marker: for pathobiochemical classification of tumors, using in vitro detection methods; for clinical evaluation using in vivo scanning techniques; (3) as a prognostic marker; and (4) as a potential radiotherapeutic target.     

Loss of PTEN expression in neuroendocrine pancreatic tumors

PTEN (phosphatase and tensin homologue deleted from chromosome 10) is a well established tumor suppressor gene, which was cloned to chromosome 10q23. PTEN plays an important role in controlling cell growth, apoptosis, cell adhesion, and cell migration. In various studies, a genetic change as well as loss of PTEN expression by different carcinomas has been described. To date, the role of PTEN as a differentiation marker for neuroendocrine tumors (NET) and for the loss of PTEN expression is still unknown. It is assumed that loss of PTEN expression is important for tumor progression of NETs. We hypothesize that PTEN might be used as a new prognostic marker. We report 38 patients with a NET of the pancreas. Tumor tissues were surgically resected, fixed in formalin, and embedded in paraffin. PTEN expression was evaluated by immunohistochemistry and was correlated with several clinical and pathological parameters of each individual tumor. After evaluation of our immunohistochemistry data using a modified Remmele Score, a widely accepted method for categorizing staining results for reports and statistical evaluation, staining results of PTEN expression were correlated with the clinical and pathological parameters of each individual tumor. Our data demonstrates a significant difference in survival with existence of lymph node or distant metastases. Negative patients show a significant better survival compared with positive patients. Furthermore, we show a significant difference between PTEN expression and WHO or TNM classification. Taken together, our data shows a positive correlation between WHO classification and the new TNM classification of NETs, and loss of PTEN expression as well as survival. These results strongly implicate that PTEN might be helpful as a new prognostic factor.     

Limitations of Chromogranin A in clinical practice

Context: Usefulness of circulating Chromogranin A (CgA) for the diagnosis of neuroendocrine tumors (NEN) is controversial. The aim of the present study was to assess the actual role of this marker as diagnostic tool. Methods: Serum blood samples were obtained from 42 subjects affected with NEN, 120 subjects affected with non-endocrine neoplasias (non-NEN) and 100 non-neoplastic subjects affected with benign nodular goitre (NNG). Determination of CgA was performed by means of immunoradiometric assay. Results: The CgA levels among NEN-patients were not significantly different from NNG and non-NEN subjects. The Receiver operating characteristic (ROC) curves analysis failed to identify a feasible cut-off value for the differential diagnosis between NEN and the other conditions. Conclusion: Serum CgA is not helpful for the first-line diagnosis of NEN.     

Genetic analysis to complement histopathological diagnosis of brain tumors

Gliomas, the most frequent tumors originating in the human nervous system, are divided into various subtypes. Currently, microscopic examination alone is insufficient for classification and grading so that genetic profiles are increasingly being emphasized in recognition of the emerging role of molecular diagnostic approaches to glioma classification. Glioblastomas (WHO grade IV) may develop de novo (primary glioblastomas) or through progression from lower-grade astrocytomas (secondary glioblastomas), while both glioblastomas show similar histological features. In contrast, they do constitute distinct disease entities that evolve through different genetic pathways, and are likely to differ in prognosis and response to therapy. Oligodendrogliomas (WHO grade II) account for 2.7% of brain tumors and 5-18% of all gliomas. Since this tumor is recognized as a particular subtype of glioma that shows remarkable responses to chemotherapy, a correct diagnosis is of prime importance. The difficulty is that histological differentiation of oligodendrogliomas from diffuse astrocytomas is highly subjective in cases without typical morphological features and there is a lack of reliable immunohistochemical markers. While histological distinction of low-grade gliomas from reactive astrocytes is also often difficult, reactive astrocytes usually lack genetic alterations. More biological and molecular approaches to glioma classification thus appear warranted to provide improved means to achieve correct diagnoses.     

Limitations of Chromogranin A in clinical practice

Context: Usefulness of circulating Chromogranin A (CgA) for the diagnosis of neuroendocrine tumors (NEN) is controversial. The aim of the present study was to assess the actual role of this marker as diagnostic tool. Methods: Serum blood samples were obtained from 42 subjects affected with NEN, 120 subjects affected with non-endocrine neoplasias (non-NEN) and 100 non-neoplastic subjects affected with benign nodular goitre (NNG). Determination of CgA was performed by means of immunoradiometric assay. Results: The CgA levels among NEN-patients were not significantly different from NNG and non-NEN subjects. The Receiver operating characteristic (ROC) curves analysis failed to identify a feasible cut-off value for the differential diagnosis between NEN and the other conditions. Conclusion: Serum CgA is not helpful for the first-line diagnosis of NEN.     

Evaluation of the WHO 2010 Grading and AJCC/UICC Staging Systems in Prognostic Behavior of Intestinal Neuroendocrine Tumors

Background

The increasing incidence and heterogeneous behavior of intestinal neuroendocrine tumors (iNETs) pose a clinicopathological challenge. Our goal was to decribe the prognostic value of the new WHO 2010 grading and the AJCC/UICC TNM staging systems for iNETs. Moreover, outcomes of patients treated with somatostatin analogs were assessed.

Methods

We collected epidemiological and clinicopathological data from 93 patients with histologically proven iNETs including progression and survival outcomes. The WHO 2010 grading and the AJCC/UICC TNM staging systems were applied for all cases. RECIST criteria were used to define progression. Kaplan-Meier analyses for progression free survival (PFS) and overall survival (OS) were performed.

Results

Mean follow-up was 58.6 months (4–213 months). WHO 2010 grading yielded PFS and disease-specific OS of 125.0 and 165.8 months for grade 1 (G1), 100.0 and 144.2 months for G2 and 15.0 and 15.8 months for G3 tumors (p = 0.004 and p = 0.001). Using AJCC staging, patients with stage I and II tumors had no progression and no deaths. Stage III and IV patients demonstrated PFS of 138.4 and 84.7 months (p = 0.003) and disease-specific OS of 210.0 and 112.8 months (p = 0.017). AJCC staging also provided informative PFS (91.2 vs. 50.0 months, p = 0.004) and OS (112.3 vs. 80.0 months, p = 0.005) measures with somatostatin analog use in stage IV patients.

Conclusion

Our findings underscore the complementarity of WHO 2010 and AJCC classifications in providing better estimates of iNETS disease outcomes and extend the evidence for somatostatin analog benefit in patients with metastatic disease.     

Value of 111In-Pentetreotide scintigraphy and 18F-FDG PET for clinical prognosis of patients with neuroendocrine neoplasms

Despite the existence of biological markers of aggressiveness, the clinical course of gastro-entero-pancreatic (GEP) neuroendocrine neoplasms (NEN) remains difficult to predict. Discrepancies between imaging data generated with ¹¹¹In-pentetreotide scintigraphy and ¹⁸F-FDG-PET could reflect the degree of cellular de-differentiation. NEN patients with both types of studies were identified retrospectively from the SwissNET database, which is collecting information on Swiss NEN patients since 2008. Progression free survival (PFS) and overall survival (OS) were assessed depending on functional imaging results. Correlation between histological grading (according to the WHO 2010 classification) and functional imaging status was also assessed. We identified 31 patients with both imaging studies, either on the primary tumor site (21/31) or for metastases (21/31), with 12/31 on both sites. Mean follow-up was 36 months (95% CI 27–45). 21 patients had a metastatic disease at diagnosis and 11 died at follow-up. 7/31 (22%) were NET G1, 16/31 (52%) were NET G2 and 8/31 (26%) were NEC G3. Only ¹⁸F-FDG PET status almost reached statistical significance (P = 0.054) with histological grading. Progression free-survival was significantly poorer in the ¹⁸F-FDG positive group (n = 21), with a median time for progression of 8 months, compared to 51 months in the negative group (n = 10) with a HR of 3.2 (97.5% CI 1.1–9.5, P = 0.04). Overall survival tended to be worse with a positive PET and a negative ¹¹¹In-pentetreotide scintigraphy status with a HR 1.63 (97.5%CI 0.11–21, P = 0.08). ¹¹¹In-pentetreotide scintigraphy status was not found to be predictive of survival nor progression.ConclusionThese data demonstrate the poorer prognostic value of a positive ¹⁸F-FDG-PET imaging in this cohort of patients.     

Tissue inhibitor of matrix metalloproteinase-2 in nasopharyngeal carcinoma

By regulating matrix metalloproteinase (MMP) activity and controlling the breakdown of extracellular matrix components, tissue inhibitors of metalloproteinases (TIMPs) play an important role in the process of tumor invasion and metastasis. The present study was designed to clarify the role of TIMP-2 in nasopharyngeal carcinoma (NPC) patients and to evaluate its importance relative to clinicopathologic parameters. It was carried out in 30 patients with NPC and 20 controls. Tissue biopsies were studied and graded pathologically, and Western blot analysis was performed to assess TIMP-2 protein expression. Clinically, in accordance with TNM classification (T: tumor size, N: lymph node involvement, M: distant metastasis), 8 cases were diagnosed as stage II, 12 as stage III, and 10 cases as stage IV; however, pathologic typing with use of the World Health Organization (WHO) classification revealed the presence of 9 specimens of squamous cell carcinoma (WHO type 1), 6 cases of nonkeratinizing carcinoma (WHO type 2), and 15 cases of undifferentiated carcinoma (WHO type 3). The difference in percentage of TIMP-2 positivity between NPC patients (76.6%) and normal controls (30%) was statistically highly significant (P < .01). In addition, there was a significant positive correlation between TIMP-2 protein positivity and either the clinical staging or the histopathologic typing (P < .01) using Chi-square test (x(2)), suggesting that TIMP-2 can be used as a marker of the severity of NPC.Accordingly, we can assume that TIMP-2 may play a role in regional lymph node and/or distant metastasis and in progression of squamous cell carcinoma. Further studies are needed to investigate the role of TIMP-2 as a marker for tumor progression and to evaluate its potential value in the follow-up of patients.     

Pancreatic endocrine tumors - management guidelines (recommended by the Polish Network of Neuroendocrine Tumors)

Pancreatic endocrine tumors (PETs) are rare neoplasms of this organ. The majority of PETs are tumors without hormonal activity. In this publication, we present the diagnostic and therapeutic guidelines for the management of these tumors proposed by the Polish Network of Neuroendocrine Tumors. These guidelines refer to biochemical and location diagnostics, including scintygraphy of somatostatin receptors, endoscopic ultrasonography and other anatomical and functional imaging methods. High importance is attached to correct histopathological diagnosis which determines further management of patients with PETs. Antitumor therapy requires multidirectional procedure, and therefore the rules of surgical treatment, biotherapy, chemotherapy and peptide receptor radionuclide therapy are discussed.     

Neuroendocrine tumors of the colon - management guidelines (recommended by The Polish Network of Neuroendocrine Tumors)

The neuroendocrine tumors (NET) of the colon are rare with a rising incidence due to an increased number of diagnostic examination including screening colonoscopy. According to distinct prognosis and treatment these tumors are classified as colonic or rectal NET. This paper provides the consensus guidelines for management of patients with these neoplasms recommended by the Polish Neuroendocrine Tumor Network Group. Furthermore the epidemiology and clinical presentation are described.     

An algorithm of radiation and endoscopic diagnosis of colonic tumors

By analyzing the results of examination and treatment in 87 patients, the authors show the potentialities of radiation and endoscopic studies in the diagnosis of malignant and benign tumors of the large bowel. The algorithm developed on the basis of the complex, multistage, goal-oriented use of radiation and endoscopic studies in terms of its specific features may timely and early detect malignant colonic tumors and preliminary rank them in accordance with the international TNM classification, to perform adequate treatment, and to monitor benign space-occupying lesions.     

Significance of plasma chromogranin A determination in neuroendocrine tumour (NET) diagnosis

The secretory nature of NETs implies the determination of the CgA concentration as a standard marker. The concentration of CgA in plasma correlates with the degree of histopathological differentiation, tumor stage, and is an essential prerequisite for therapy. A retrospective analysis of the results of the plasma CgA concentrations in relation to histopathological and clinical findings (type of NET according to the WHO classification, severity of disease based on the presence of metastases and clinical symptoms) as well as somatostatin receptor scintigraphy was performed in 41 patients with NET. The patients were treated in The Regional Oncology of Lublin from February 2005 to May 2008. Data from the literature and results of this study suggest the use of CgA in the diagnosis and prognosis of NET. Plasma CgA concentration analysed together with histopathological assessment of tumor and the clinical picture is a useful marker in the diagnosis of neuroendocrine tumours. High plasma CgA concentrations may indicate the presence of highly-differentiated NET (WDNEC), and also may indicate the presence of tumor metastasis. The highest CgA concentrations were observed in patients with neuroendocrine tumors associated with carcinoid symptoms and the presence of metastases to the liver.