Classification and treatment of Endocrine Tumors (ET)

Endocrine tumors (ET) are defined by positive immunostaining forchromogranine A, synaptophysin and less specific markers such asneuron-specific enolase and N-CAM. This definition includes varioustumors scattered within the body and which share commoncharacteristics : hormone secretion, association as part of inheritedsyndrome, common prognostic parameters and therapeutic management.Several points challenge the clinical management of thesetumors : confusion regarding previous definition (apudoma, carcinoid…),their rarity, insufficient knowledge regarding prognosticparameters of relapse and survival and poor chemosensitivity. ETsstem from two main embryological tissues : the neuroectoderm(medullary thyroid carcinoma and pheochromocytoma mainly) andthe endoderm (also called gastro-enteropancreatic (GEP) tumors).In the latter group, ETs are subdivided into three subgroups withvarious behavior regarding biological activity, association as part ofinherited syndrome frequency, prognosis : foregut-derived (headand neck, thymus, bronchus, pancreas mainly), midgut-derived(ileum), hindgut-derived (rectum) ET.Classification aims at recognizing tumors with common clinicalpresentation, prognostic or therapeutic behavior. Initial clinical management of these tumors has two main goals, to look for associatedhormone secretions and inherited syndromes, both being dependenton the primary. The great majority of ETs secrete at leastone hormone with or without clinical consequences. Morbidity inducedhormone secretion (metanephrine, serotonine, insulin, gastrin)should be early recognized and treated. Also, hormone secretionmay constitute helpful biological markers which high specificitybut various sensitivity. The recommended biological work-uphas been standardized according to the primary (Baudin et al, AnnOncol 2001). Of note, secretions in foregut -derived ETs, in contrastwith midgut-derived ETs are characterized by their biological diversity.Screening for association as part of inherited syndrome is restrictedto neuroectoderm and well-differentiated endoderm-derivedET. Familial and personal patient history, ET primary and tumorpresentation (multifocality, natural history) are major points to lookfor a genetic screening. Main consequences of such a diagnosis are :early diagnosis of associated tumors, and familial screening with avarious impact on cure rate depending on each syndrome. Maininherited syndromes to be screened for are : multiple endocrineneoplasia type 1 and 2, Von-Hippel-Lindau disease, type 1 neurofibromatosis,mitochondrial complex type II disease. Genes responsiblefor these syndromes are known and genotype-phenotype correlationshave been described for some.ET prognosis mainly depends on pathological differentiation andtumor stage. Primary impact on prognosis is still questioned, as wellas ET association as part of an inherited syndrome. Hormone secretionis no more a major prognostic parameter. The best prognosticapproach has been brought by studying lung ETs. Travis demonstratedthat 4 subgroups of lung ETs can be distinguished accordingto their survival by taking into account the mitotic count and necrosis.Typical carcinoid is characterized by a low mitotic count (< 2 /10 HPF), atypical carcinoid or well differentiated endocrine carcinomaby mitosis ranging between 2 to 10 / HPF and or punctiformenecrosis, large cell (poorly differentiated ) endocrine carcinoma bya high rate of mitosis above 10 / HPF , large necrosis area and lostof the endocrinoid pathological pattern. For intestinal ETs, theWHO 2000 classification defines benign or uncertain well differentiatedendocrine tumors depending on size, depth invasion and angioinvasiveness.For pancreatic ETs, the Ki67 positive percentageof cells and the mitotic count is taken into account instead of depthinvasion. Patients with locoregional extension or distant metastasesare classified as well differentiated endocrine carcinoma. Poorlydifferentiated endocrine carcinoma may be encountered mainly inpancreatic, colon and rectum ET.Therapeutic management aims at reducing both hormone secretion(always first) and tumor burden. The only curative therapy is surgery in patients presenting with localized ET mainly, appendix,rectum, bronchus and insulinoma. In the majority of metastatic ETpatients treatment remains palliative and should therefore take intoaccount the natural history of the disease. Poorly differentiated ETand pancreatic ET are chemosensitive but complete responses arerare. In no or slowly progressive ET, a wait-and-see policy and/orlocoregional therapeutic approaches should be considered. Protocolsshould include patients with morphologically progressive ET.