Séance du mercredi 14 mai 2003

SEANCE COMMUNE AVEC LA SOCIETE MEDICALE DES HOPITAUX DE PARIS : TUMEURS NEURO-ENDOCRINES
15h00-17h00 - Les Cordeliers
Modérateurs : AndrE WARNET et Jean-Louis PEIX

Résumé
Les tumeurs neuro-endocrines sont un groupe de tumeurs composées
de cellules ayant un phénotype commun caractérisé par l'expression
de marqueurs protéiques généraux, au premier rang desquels
les chromogranines, et éventuellement par des produits de
sécrétion spécifiques, ce qui ne préjuge pas d'une origine embryologique
commune. Des tumeurs neuro-endocrines peuvent être rencontrées
dans la plupart des localisations, mais elles siègent majoritairement
dans le tube digestif et dans le pancréas. Elles sont classées
en tumeurs de haut grade et tumeurs de bas grade d'après la
classification des tumeurs neuro-endocrines pulmonaires. La plupart
des tumeurs neuro-endocrines digestives et pancréatiques étant
de bas grade, une classification spécifique tenant compte de la
taille, du degré d'invasion, de la sécrétion prédominante et du taux
de prolifération a été proposée récemment par l'OMS. La plupart
des tumeurs neuro-endocrines sont sporadiques; quelques unes surviennent
dans le contexte d'une néoplasie endocrinienne multiple de
type 1.

Abstract
Neuroendocrine tumours are defined by a common phenotype,
which is not supported by a common embryologic origin. This common
phenotype is characterized by the expression of general neuroendocrine
markers and sometimes by cell specific hormonal products.
Neuroendocrine tumours are ubiquitous, but the major localizations
are the digestive tract and the pancreas. According to the
WHO classification of lung tumours, they are divided in low grade
and high grade tumours. Since most digestive and pancreatic tumours
are low grade tumours, a specific classification of neuroendocrine
tumours was recently proposed by the WHO. Size, degree
of invasion, major secretion and proliferation rate are the main criteria
of this classification. Most neuroendocrine tumours are sporadic.
A few cases occur in the context of a multiple endocrine neoplasia
type 1.

Résumé
Le regroupement des tumeurs neuroendocrines au sein d’une même
entité de recherche se justifie non seulement par l’existence d’une
définition et de propriétés communes à l’ensemble de ces tumeurs,
mais également par leur rareté. Cette revue fait le point des avancées
récentes en matière de classification, détaille la place prise par
la Chromogranine A dans le bilan biologique de ces tumeurs, de la
scintigraphie des récepteurs de la somatostatine dans le bilan d’imagerie.
Elle rappelle la complexité de la prise en charge des patients
porteurs de tumeurs endocrines associées à un syndrome de prédisposition.
Enfin, elle souligne les avancées en matière de définition
des facteurs pronostiques et notamment la place croissante que
prennent les marqueurs de prolifération et d’invasion vasculaire
dans cette classification. Enfin, l’individualisation progressive du
phénotype histologique, clinique, biologique et morphologique des
patients, répondeurs aux différentes thérapeutiques disponibles, est
rappelée.

Abstract
Endocrine tumors (ET) are defined by positive immunostaining for
chromogranine A, synaptophysin and less specific markers such as
neuron-specific enolase and N-CAM. This definition includes various
tumors scattered within the body and which share common
characteristics : hormone secretion, association as part of inherited
syndrome, common prognostic parameters and therapeutic management.
Several points challenge the clinical management of these
tumors : confusion regarding previous definition (apudoma, carcinoid…),
their rarity, insufficient knowledge regarding prognostic
parameters of relapse and survival and poor chemosensitivity. ETs
stem from two main embryological tissues : the neuroectoderm
(medullary thyroid carcinoma and pheochromocytoma mainly) and
the endoderm (also called gastro-enteropancreatic (GEP) tumors).
In the latter group, ETs are subdivided into three subgroups with
various behavior regarding biological activity, association as part of
inherited syndrome frequency, prognosis : foregut-derived (head
and neck, thymus, bronchus, pancreas mainly), midgut-derived
(ileum), hindgut-derived (rectum) ET.
Classification aims at recognizing tumors with common clinical
presentation, prognostic or therapeutic behavior. Initial clinical management of these tumors has two main goals, to look for associated
hormone secretions and inherited syndromes, both being dependent
on the primary. The great majority of ETs secrete at least
one hormone with or without clinical consequences. Morbidity induced
hormone secretion (metanephrine, serotonine, insulin, gastrin)
should be early recognized and treated. Also, hormone secretion
may constitute helpful biological markers which high specificity
but various sensitivity. The recommended biological work-up
has been standardized according to the primary (Baudin et al, Ann
Oncol 2001). Of note, secretions in foregut -derived ETs, in contrast
with midgut-derived ETs are characterized by their biological diversity.
Screening for association as part of inherited syndrome is restricted
to neuroectoderm and well-differentiated endoderm-derived
ET. Familial and personal patient history, ET primary and tumor
presentation (multifocality, natural history) are major points to look
for a genetic screening. Main consequences of such a diagnosis are :
early diagnosis of associated tumors, and familial screening with a
various impact on cure rate depending on each syndrome. Main
inherited syndromes to be screened for are : multiple endocrine
neoplasia type 1 and 2, Von-Hippel-Lindau disease, type 1 neurofibromatosis,
mitochondrial complex type II disease. Genes responsible
for these syndromes are known and genotype-phenotype correlations
have been described for some.
ET prognosis mainly depends on pathological differentiation and
tumor stage. Primary impact on prognosis is still questioned, as well
as ET association as part of an inherited syndrome. Hormone secretion
is no more a major prognostic parameter. The best prognostic
approach has been brought by studying lung ETs. Travis demonstrated
that 4 subgroups of lung ETs can be distinguished according
to 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 carcinoma
by mitosis ranging between 2 to 10 / HPF and or punctiforme
necrosis, large cell (poorly differentiated ) endocrine carcinoma by
a high rate of mitosis above 10 / HPF , large necrosis area and lost
of the endocrinoid pathological pattern. For intestinal ETs, the
WHO 2000 classification defines benign or uncertain well differentiated
endocrine tumors depending on size, depth invasion and angioinvasiveness.
For pancreatic ETs, the Ki67 positive percentage
of cells and the mitotic count is taken into account instead of depth
invasion. Patients with locoregional extension or distant metastases
are classified as well differentiated endocrine carcinoma. Poorly
differentiated endocrine carcinoma may be encountered mainly in
pancreatic, 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 ET
patients treatment remains palliative and should therefore take into
account the natural history of the disease. Poorly differentiated ET
and pancreatic ET are chemosensitive but complete responses are
rare. In no or slowly progressive ET, a wait-and-see policy and/or
locoregional therapeutic approaches should be considered. Protocols
should include patients with morphologically progressive ET.