Pankreatische neuroendokrine Tumoren

Neuroendocrine tumors represent benign or malignant neoplasias which are either characterized by their secretion of biologically active biogenic amines or neuroendocrine peptides, respectively, or which lack any such secretion. The disease classification takes the site of origin into account as well as the nature of the secreted product, be it a biogenic amine or neuroendocrine peptide. Each disease category can be subdivided into a symptomatic state of hypersecretion or a clinically silent group of non-functional tumors. The majority of neuroendocrine tumors which hypersecrete a neuropeptide originate within the pancreas. They can thus be referred to as pancreatic neuroendocrine tumors. Diagnosis is either based on the specific hypersecretion syndrome or on the location of the tumor. Direct evidence for the existence of a neuroendocrine tumor is provided biochemically by direct measurement of the hypersecreted tumor product, by determining the effect of the hypersecreted product on the gastrointestinal tract, or by high-resolution imaging. Total surgical resection represents the only curative therapeutic option . However, control of the syndrome needs to be separated from control of the malignancy, and the risk of surgery has to be carefully adapted to the severity of the disease.     

Tumoren und Transplantation

The risk of developing tumors after transplantation is increased compared to the normal population and the prognosis of patients with a malignant disease after transplantation is often limited; therefore, avoidance of malignancies after transplantation is essential. This leads to important implications for the management of transplantation related to the development of post-transplant malignancies. Malignancies can reoccur from a previously diagnosed and treated malignancy, be transmitted by the donor or develop de novo post-transplantation. Ultimately, in the setting of transplantation the risk for development of a malignant disease needs to be balanced against the benefits of transplantation and should be assessed on an individual basis for the specific donor-recipient constellation. The patient needs to be informed about the potential risks for the development of malignancies (e.g. recurrence, transmission or de novo) when being placed on the list for transplantation. This review summarizes the data for the incidence of malignant diseases after transplantation and provides the basis for informed consent and the management of patients with regard to the development of malignant diseases after transplantation.     

Molecular alterations associated with bladder cancer initiation and progression

Bladder cancer is the fifth most commonly diagnosed non-cutaneous solid malignancy, and the second most commonly diagnosed genitourinary malignancy amongst people living in the United States, where it is estimated that more than 61,000 new cases of bladder cancer will be diagnosed in the year 2008. Approximately 90% of malignant tumors arising in the urinary bladder are of epithelial origin, the majority being transitional cell carcinomas. Early stage bladder tumors have been classified into two groups with distinct behavior and unique molecular profiles: low grade tumors (always papillary and usually superficial), and high-grade tumors (either papillary or non-papillary, and often invasive). Clinically, superficial bladder tumors (stages Ta and Tis) account for 75% to 85% of neoplasms, while the remaining 15% to 25% are invasive (T1, T2-T4) or metastatic lesions at the time of initial presentation. Studies from the author's group and others have revealed that distinct genotypic and phenotypic patterns are associated with early versus late stages of bladder cancer. Most importantly, early superficial diseases appear to segregate into two main pathways. Superficial papillary bladder tumors are characterized by gain-of-function mutations, mainly affecting classical oncogenes such as RAS and FGFR3. Deletions of chromosome 9, mainly allelic losses on the long arm (9q) are also frequent events in these tumors. Such genetic alterations are observed in most if not all superficial papillary non-invasive tumors (Ta), but only in a small subset of invasive bladder neoplasms. Flat carcinoma in situ (Tis) and invasive tumors are characterized by loss-of-function mutations, affecting the prototype tumor suppressor genes, including p53, RB and PTEN. These alterations are absent or very rare in the Ta tumors analyzed, but have been frequently identified in invasive bladder carcinomas. Based on these data, a novel model for bladder tumor progression has been proposed in which two separate genetic pathways characterize the evolution of superficial bladder neoplasms. Numerous individual molecular markers have been identified in the tissue specimens that correlate to some extent with tumor stage, and possibly with prognosis in bladder cancer. However, these molecular prognosticators do not play a role in the clinical routine management of patients with bladder tumors, mainly due to lack of large prospective validation studies. Thus, the need for development of specific tissue and serum tumor markers for prognostic stratification remains. The advent of high-throughput microarrays technologies allows comprehensive discovery of targets relevant in bladder cancer progression, which could be translated into new approaches for drug and biomarker development. Further investigation is warranted to define novel biomarkers specific for bladder cancer patients based on the molecular alterations of tumor progression, and multiplexed strategies for clinical management.     

Tumors of the thymus.

Thymic neoplasms are a common cause of an anterior mediastinal mass and may be benign or malignant. Thymic cysts are congenital or acquired and may be associated with a thymic malignancy. True thymic hyperplasia and thymic lymphoid hyperplasia may enlarge the thymus and simulate a neoplasm. Thymoma and thymic carcinoma are epithelial malignancies with distinct clinicopathologic features. Thymic carcinoid is a rare aggressive neuroendocrine malignancy associated with multiple endocrine neoplasia 1. Thymolipoma is a benign neoplasm. Hodgkin and non-Hodgkin lymphoma may primarily or secondarily involve the thymus. Primary mediastinal germ cell tumors may arise primarily within the thymus and include mature teratoma, seminoma, and non-seminomatous malignant germ cell tumors.     

Second primary neoplasms in patients with lung and gastroenteropancreatic neuroendocrine neoplasms: Data from a retrospective multi-centric study

BackgroundPatients with sporadic neuroendocrine neoplasms may exhibit a higher risk of a second primary tumor than the general population.AimThis study aimed to analyze the occurrence of second primary malignancies.MethodsA retrospective cohort of 2757 patients with sporadic lung and gastro-entero-pancreatic neuroendocrine neoplasms, managed at eight Italian tertiary referral Centers, was included.ResultsBetween 2000 and 2019, a second primary malignancy was observed in 271 (9.8%) neuroendocrine neoplasms patients with 32 developing a third tumor. There were 135 (49.8%) females and the median age was 64 years. The most frequent locations of the second tumors were breast (18.8%), prostate (12.5%), colon (9.6%), blood tumors (8.5%), and lung (7.7%). The second primary tumor was synchronous in 19.2% of cases, metachronous in 43.2%, and previous in 37.6%. As concerned the neuroendocrine neoplasms, the 5- and 10-year survival rates were 87.8% and 74.4%, respectively. PFS for patients with a second primary malignancy was shorter than for patients without a second primary malignancy. Death was mainly related to neuroendocrine neoplasms.ConclusionIn NEN patients the prevalence of second primary malignancies was not negligible, suggesting a possible neoplastic susceptibility. Overall survival was not affected by the occurrence of a second primary malignancy.     

Malignant pericardial diseases: diagnosis and treatment

Pericardial involvement in malignant disease is fairly common. Usually the various clinical presentations--effusion, tamponade, constriction--occur in patients with known malignancy. Primary malignancy of the pericardium is rare, whereas secondary tumor involvement of the pericardium is more frequently observed. The common secondary solid tumors involving the pericardium are from lung and breast carcinomas; of the nonhematologic malignancies, lymphomas and leukemias are most frequent. A high index of suspicion in patients with malignancy, along with a history, physical examination, x-ray films, ECG, and echocardiography, will often make the diagnosis in a hemodynamically compromised patient. Occasionally, cardiac catheterization and pericardial biopsy are necessary to differentiate malignant pericardial disease from radiation pericarditis and restrictive heart disease. Therapy is dependent on the underlying condition and includes pericardiectomy, chemotherapy to obliterate the pericardial space, and external beam radiotherapy. These therapies are all palliative, but provide months of hemodynamic relief. The underlying prognosis of malignant pericardial disease remains grave.     

Protein kinase Cδ inactivation inhibits cellular proliferation and decreases survival in human neuroendocrine tumors

The concept of targeting cancer therapeutics toward specific mutations or abnormalities in tumor cells, which are not found in normal tissues, has the potential advantages of high selectivity for the tumor and correspondingly low secondary toxicities. Many human malignancies display activating mutations in the Ras family of signal-transducing genes or over-activity of p21(Ras)-signaling pathways. Carcinoid and other neuroendocrine tumors have been similarly demonstrated to have activation of Ras signaling directly by mutations in Ras, indirectly by loss of Ras-regulatory proteins, or via constitutive activation of upstream or downstream effector pathways of Ras, such as growth factor receptors or PI(3)-kinase and Raf/mitogen-activated protein kinases. We previously reported that aberrant activation of Ras signaling sensitizes cells to apoptosis when the activity of the PKCδ isozyme is suppressed and that PKCδ suppression is not toxic to cells with normal levels of p21(Ras) signaling. We demonstrate here that inhibition of PKCδ by a number of independent means, including genetic mechanisms (shRNA) or small-molecule inhibitors, is able to efficiently and selectively repress the growth of human neuroendocrine cell lines derived from bronchopulmonary, foregut, or hindgut tumors. PKCδ inhibition in these tumors also efficiently induced apoptosis. Exposure to small-molecule inhibitors of PKCδ over a period of 24 h is sufficient to significantly suppress cell growth and clonogenic capacity of these tumor cell lines. Neuroendocrine tumors are typically refractory to conventional therapeutic approaches. This Ras-targeted therapeutic approach, mediated through PKCδ suppression, which selectively takes advantage of the very oncogenic mutations that contribute to the malignancy of the tumor, may hold potential as a novel therapeutic modality.     

Neue Medikamente in der Onkologie

Background

Drug development in oncology has seen major innovations in recent years. Based on the molecular changes found in malignant tumors, new drugs are being developed which specifically target these altered signaling pathways.

Results

In addition to the already broadly used inhibitors of growth factor and angiogenic signaling pathways, new and innovative target structures have been identified. Cancer stem cells which are thought to be the reason for drug resistance and tumor recurrence are now being targeted. c-MET signaling has emerged as an important new signaling module which can be influenced pharmacologically. Inhibitors of immune checkpoints like antibodies which target the CTLA4 molecule are leading to impressive results in clinical trials. Drugs which influence the epigentic changes found in tumor cells are tested specifically for their ability to overcome drug resistance. Finally, treatment with oncolytic viruses has made a comeback in certain tumor entities.

Conclusion

Oncological treatments will see a significant addition of new drugs and treatment options in the next few years which will hopefully improve the survival of patients with tumors.     

Identification of potential gene markers and insights into the pathophysiology of pheochromocytoma malignancy

CONTEXT: Pheochromocytomas are catecholamine-producing tumors that are generally benign but that can also present as or develop into malignancy. Occurrence of malignant pheochromocytomas can only be asserted by imaging of metastatic lesions. OBJECTIVES: We conducted a gene expression profiling of benign and malignant tumors to identify a gene signature that would allow us to discriminate benign from malignant pheochromocytomas and to gain a better understanding of tumorigenic pathways associated with malignancy. DESIGN: A total of 36 patients with pheochromocytoma was studied retrospectively. There were 18 (nine benign and nine malignant) tumors used for gene expression profiling on pangenomic oligonucleotide microarrays. RESULTS: We identified and validated a set of predictor genes that could accurately distinguish the two tumor subtypes through unsupervised clustering. Most of the differentially expressed genes were down-regulated in malignant tumors, and several of these genes encoded neuroendocrine factors involved in prominent characteristics of chromaffin cell biology. In particular, the expression of two key processing enzymes of trophic peptides, peptidylglycine alpha-amidating monooxygenase and glutaminyl-peptide cyclotransferase, was reduced in malignant pheochromocytomas. CONCLUSION: The gene expression profiling of benign and malignant pheochromocytomas clearly identified a set of genes that could be used as a prognostic multi-marker and revealed that the expression of several genes encoding neuroendocrine proteins was reduced in malignant compared with benign tumors.     

BRAF and endocrine tumors: mutations are frequent in papillary thyroid carcinomas, rare in endocrine tumors of the gastrointestinal tract and not detected in other endocrine tumors

The tumorigenesis of sporadic endocrine tumors is still not fully understood. Activating point mutations of the serine/threonine kinase gene BRAF located on 7q34 are found in a wide range of malignancies, with the highest frequency (66%) occurring in malignant melanomas. Melanomas are tumors of neural-crest-derived cells as are medullary thyroid carcinomas, pheochromocytomas and paragangliomas. BRAF has not been examined in endocrine tumors of the diffuse neuroendocrine system or of neural-crest-derived cells. We examined 130 endocrine tumors of the pancreas, parathyroid gland, adrenal medulla, paraganglia, lung and gastrointestinal tract as well as follicular and c-cell-derived thyroid tumors. We found a high rate of V559E mutations in papillary thyroid carcinomas (47%), one V599E mutation in a well-differentiated gastric endocrine carcinoma (malignant carcinoid), but no activating BRAF mutations in all other endocrine tumors examined. These results point towards different pathways in tumorigenesis of endocrine tumors of various localizations and only rare involvement of the MAP kinase (MAPK) pathway in a subset of malignant neuroendocrine tumors.     

Metastatic neuroendocrine tumor of unknown primary presenting as acute pancreatitis

Neuroendocrine tumors of unknown primary site are rare. Among all the tumors of unknown primary, neuroendocrine tumors account for less than 5% of such cases. They are identified by immunohistochemical staining which is strongly positive for chromogranin, synaptophysin, or electron microscopy identification of neurosecretory granules. We present a case of metastatic poorly differentiated neuroendocrine tumor with no identifiable primary, presenting as acute pancreatitis, hypercalcemia, and disseminated bony metastasis. Such presentation has been rarely reported before. Although the nature of these tumors remains undefined, the diagnosis of poorly differentiated neuroendocrine carcinoma identifies a potentially treatable subgroup.     

Vasculitis associated with malignancy.

A large variety of vasculopathic syndromes are uncommonly associated with malignancies. Vasculitis is usually manifested by skin lesions and is generally associated with hematologic malignancies rather than solid tumors. Evidence of autoantibodies, immune complexes, and complement consumption is typically absent. Myelodysplastic syndromes can be confidently linked to vasculitis on the basis of recent literature. The temporal relationship of malignancy to vasculitis development is variable except that vasculitis generally follows the discovery of hairy cell leukemia and splenectomy. Vasculitis may occasionally be a complication of chemotherapy, radiation therapy, and bone marrow transplantation. Occasionally, malignant disorders may mimic vasculitic syndromes. The etiopathogenesis of vasculitis in patients with malignant disorders is unknown. The recent literature on vasculitis and malignancy addresses predominantly case reports and small patient cohorts and identifies clinical characteristics rather than pathogenic mechanisms.     

High frequency of SDHB germline mutations in patients with malignant catecholamine-producing paragangliomas: implications for genetic testing

CONTEXT: Adrenal and extraadrenal paragangliomas are tumors of chromaffin cells that are usually benign but that may also develop into malignant disease. Mutations of the gene for succinate dehydrogenase subunit B (SDHB) are associated with a high risk of malignancy, but establishing the precise contribution requires relatively large numbers of patients with well-defined malignancy. OBJECTIVE: We assessed the prevalence of SDHB mutations in a series of patients with malignant paraganglioma. DESIGN: SDHB mutation testing was carried out in 44 consecutive patients with malignant paraganglioma. Clinical characteristics of patients with malignant disease due to SDHB mutations were compared with those without mutations. RESULTS: Pathogenic SDHB mutations were found in 13 of the 44 patients (30%). Close to one third of patients had metastases originating from an adrenal primary tumor, compared with a little over two thirds from an extraadrenal tumor. Among the latter patients, the frequency of SDHB mutations was 48%. CONCLUSION: This study establishes that missense, nonsense, frameshift, and splice site mutations of the SDHB gene are associated with about half of all malignancies originating from extraadrenal paragangliomas. The high frequency of SDHB germline mutations among patients with malignant disease, particularly when originating from an extraadrenal paraganglioma, may justify a high priority for SDHB germline mutation testing in these patients.     

Lung and digestive neuroendocrine neoplasms. From WHO classification to biomarker screening: Which perspectives?

The recent classifications of lung and digestive neuroendocrine neoplasms (NENs) make a fundamental distinction between well- and poorly-differentiated neoplasms. Well-differentiated NENs are termed carcinoids in the lung and neuroendocrine tumors in the gastroenteropancreatic sphere; their risk of malignancy is highly variable; histological grading is used to stratify patients into prognostically significant groups. Poorly-differentiated NENs are termed neuroendocrine carcinoma in both the lung and the digestive sphere; they constantly are of high grade of malignancy; two types are recognized on the basis of tumor cell morphology, the small cell and the large cell types. Recent studies have largely uncovered the genetic landscape of several subsets of well-differentiated NENs (lung, pancreas, small intestine) and of poorly-differentiated NENs. Some molecular markers may help to the differential diagnosis between highly proliferative neuroendocrine tumors and neuroendocrine carcinomas, especially in the pancreas. In well-differentiated tumors, MGMT status is proposed as a predictive marker of the response to temozolomide, but remains to be validated. In poorly-differentiated neoplasms, large cell neuroendocrine carcinoma has been shown to be a heterogeneous category, with some cases presenting the same molecular signature than small cell carcinoma and others the same signature than adenocarcinomas of the same body site. Rb protein has been recently shown to be a potential marker of response to platinum salts in neuroendocrine carcinoma. Much remains to be done to translate the rapid progress in the molecular understanding of NENS into diagnostic, prognostic or predictive markers.     

胃肠胰神经内分泌肿瘤的临床诊治

胃肠胰神经内分泌肿瘤是起源于神经内分泌组织的一组异质性肿瘤,近年来生长抑素类似物已经应用于神经内分泌肿瘤的临床治疗,新药物如血管靶向治疗及mTOR通路阻滞药物等也为神经内分泌肿瘤的治疗带来新的曙光。     

Clear cell hepatocellular carcinoma arising 25 years after the successful treatment of an infantile hepatoblastoma

Primary liver tumors in children are rare with hepatoblastoma (HB) being the most common malignancy. Clear cell carcinoma, a variant of hepatocellular carcinoma (HCC), is another rare tumor of the liver that tends to affect adults. We describe the diagnosis and management of the only known documented case of a primary clear cell HCC arising twenty-five years after the patient was successfully treated with chemotherapy and surgical resection for a malignant HB as an infant. While some evidence has shown a genetic link between HB and various types of HCC, other research has shown distinct chromosomal alterations and molecular mechanisms unique to both. Further knowledge of liver tumorigenesis will help elucidate the complicated genetic, molecular, and environmental factors involved in the development of these two rare hepatic malignancies.     

Endoscopic ultrasound-guided ethanol ablation therapy for tumors

Endoscopic ultrasonography (EUS) has evolved into a useful therapeutic tool for treating a broad range of tumors since being introduced into clinical practice as a diagnostic modality nearly three decades ago. In particular, EUS-guided fine-needle injection has proven a successful minimally invasive approach for treating benign lesions such as pancreatic cysts, relieving pancreatic pain through celiac plexus neurolysis, and controlling local tumor growth of unresectable malignancies by direct delivery of anti-tumor agents. One such ablative agent, ethanol, is capable of safely ablating solid or cystic lesions in hepatic tissues via percutaneous injection. Recent research and clinical interest has focused on the promise of EUS-guided ethanol ablation as a safe and effective method for treating pancreatic tumor patients with small lesions or who are poor operative candidates. Although it is not likely to replace radical resection of localized lesions or systemic treatment of metastatic tumors in all patients, EUS-guided ablation is an ideal method for patients who refuse or are not eligible for surgery. Moreover, this treatment modalitymay play an active role in the development of future pancreatic tumor treatments. This article reviews the most recent clinical applications of EUS-guided ethanol ablation in humans for treating pancreatic cystic tumors, pancreatic neuroendocrine tumors, and metastatic lesions.     

Animal models of adrenocortical tumorigenesis

Over the past decade, research on human adrenocortical neoplasia has been dominated by gene expression profiling of tumor specimens and by analysis of genetic disorders associated with a predisposition to these tumors. Although these studies have identified key genes and associated signaling pathways that are dysregulated in adrenocortical neoplasms, the molecular events accounting for the frequent occurrence of benign tumors and low rate of malignant transformation remain unknown. Moreover, the prognosis for patients with adrenocortical carcinoma remains poor, so new medical treatments are needed. Naturally occurring and genetically engineered animal models afford a means to investigate adrenocortical tumorigenesis and to develop novel therapeutics. This comparative review highlights adrenocortical tumor models useful for either mechanistic studies or preclinical testing. Three model species – mouse, ferret, and dog – are reviewed, and their relevance to adrenocortical tumors in humans is discussed.     

Diagnostic accuracy of endoscopic retrograde cholangiopancreatography in hepatic, biliary, and pancreatic malignancy.

This paper reports the radiographic findings in 84 cases of biopsy-proven pancreatic and biliary malignancies studied by endoscopic retrograde cholangiopancreatography. In the 73 successful studies a diagnosis of tumor could be made in 67 patients (92%). The study was successful in 40 of 43 patients with pancreatic carcinoma and the diagnosis could be made in 37 on the basis of stenosis or obstruction of the ducts. There were 33 successful studies in the 41 patients with miscellaneous tumors including primary bile duct, ampullary, gallbladder, metastatic carcinoma, lymphoma, and hepatoma. A diagnosis of tumor was made in 30 studies. As has been observed in carcinoma of other hollow structures, the hallmark of malignancy in the pancreatic and biliary tract is obstruction and stenosis. This study indicates that malignant disease of the pancreas and tract is accurately assessed by this endoscopic method.     

Novel membrane-based targets – Therapeutic potential in gynecological cancers

Recent advances have been made in the molecular profiling of gynecological tumors. These discoveries have led to the development of targeted therapies that have the potential to disrupt molecular pathways involved in the oncogenesis or tumor progression. In this review, we highlight areas of recent progress in the field of membrane receptor inhibitors in gynecological malignancies and describe the biological rationale underlying the inhibition of these receptors. We will introduce drug immuno-conjugates, and give an update on the biological rationale and the clinical studies involving agents directed against EGFR, HER3, IGFR, MET, FGFR, NOTCH, and TRAIL. We also discuss the challenge facing these new therapies.