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Endocrine tumors

  1. Gastroepato
  2. Oncology
  3. Endocrine tumors
  4. Palliation of esophagogastric neoplasm
  5. Cancer of the esophagus
  6. Vomiting
  7. Oral cancer
  8. Dysplasia of the oral cavity
  9. Cancer of the esophagus
  10. Gastric cancer, causes and signs
notes by dr Claudio Italiano  

The stomach is a non-infrequent site of endocrine tumors (about 30% of endocrine G-I [gastrointestinal] tumors occur in the stomach). The endoscopic investigation made the diagnosis of these tumors and their preneoplastic conditions more frequent. The vast majority of endocrine stomach tumors originate in the osseous mucosa and derive from ECL; the neoplasms producing gastrin, somatostatin or serotonin are very rare. Although most gastrin cells reside in the antrum, gastrin-cell tumors are exceptional in the stomach, but are more common at the pancreatic and duodenal levels. Among the well-differentiated endocrine tumors the majority (> 75%) are associated with chronic atrophic osseous mucosa gastritis (so-called autoimmune atrophic gastritis) and have benign biological behavior (ECL type I carcinoids): the pathogenetic mechanism through which such neoplasms arise is linked to atrophy of parietal cells which involves achlorhydria, resulting in constant hypergastrinemia; in turn, gastrin exerts a trophic action on ECL cells that become hyperplastic, in this context dysplastic or neoplastic alterations (well-differentiated endocrine tumors or carcinoids) can also develop. A similar pathogenic mechanism (prolonged hypergastrinemia) underlies the type II ECL carcinoids that arise in patients with MEN 1 and with Zollinger-Ellison syndrome. Endocrine tumors not associated with hypergastrinemia are much rarer: carcinoids with ECL type III or sporadic cells and poorly differentiated endocrine carcinomas.

ECL cell carcinoids type I and II

These are gastrin-dependent neoplasms affecting the osseous mucosa in the form of multiple nodules, usually less than 5 mm; they arise in a context of ECL cell hyperplasia. The structure is typical of tumors of the widespread endocrine system: cords, trabeculae, microtubules consisting of well-differentiated, argentophile and histamine-containing cells. Biological behavior is usually benign, slow growth, limited mucosal and / or submucosal invasion. Only rare cases with dimensions> 1 cm, high mitotic index or vascular invasion may show more aggressive behavior.

Carcinids with ECL type III cells (sporadic) and poorly differentiated endocrine carcinomas

They do not associate with conditions involving hypergastrinemia and show malignant behavior (high-grade in poorly differentiated forms). Compared to previous cancers, these neoplasms produce discrete masses, unique and substantially not different from the common carcinomas of the stomach. The cytological atypia is evident. As a rule they are discovered for "mass" symptoms such as stenosis, bleeding, etc. while it is very rare that they are accompanied by endocrine symptoms (atypical carcinoid syndrome). The prognosis of poorly differentiated endocrine carcinomas is not different from that of non-endocrine gastric carcinomas and the course is characterized by relapses and distant metastases. Carcinoid syndrome is a paraneoplastic syndrome caused by the unregulated secretion of hormones (such as serotonin, histamine, callicrein) from neoplastic cells. The tumors that can cause this syndrome are neuroendocrine, in particular those originating from the ileum. You can have hot flushes, abdominal cramps and diarrhea. After several years, a right heart valvulopathy can develop. The syndrome is due to vasoactive substances (including serotonin, bradykinin, histamine, prostaglandins, polypeptide hormones) secreted by the tumor, which is typically a metastatic intestinal carcinoid. The diagnosis is made on the basis of the clinic and demonstrates an increased urinary excretion of 5-hydroxyindolacetic acid.

Physiopathology

Serotonin, acting on smooth muscles, causes diarrhea, colic and malabsorption. Histamine and bradykinin, due to vasodilatory effects, are responsible for flushing. The role of prostaglandins and other polypeptide hormones, sometimes produced by paracrine cells, has not yet been clarified; sometimes, in the presence of carcinoids, high levels of chorionic gonadotropin and pancreatic polypeptide are found. Some patients develop right endocardial fibrosis, which results in pulmonary stenosis and tricuspid insufficiency. Left cardiac lesions, which have been described in bronchial carcinoids, are rare because serotonin is degraded in passing through the lungs.

Classification and clinical aspects

 The neuroendocrine tumors of the small intestine are a heterogeneous group of neoplasms presenting different clinical-pathological aspects especially for the site of onset, duodenum and proximal fasting, against distal jejunum and ileum. In general, regardless of the site, neoplasms can be well differentiated (well-differentiated neuroendocrine tumors, in the past called carcinoids) or poorly differentiated and in this case are always malignant and high-grade (poorly differentiated neuroendocrine carcinomas). The nomenclature used by the various authors to name these neoplasms, not being uniform, has created some confusion. Recently the World Health Organization (WHO) has unified the various terminologies and proposed a precise classification system. In fact, these tumors can be classified, on the basis of the prevalent phenotype, also on the basis of the hyperfunctional clinical syndrome due to hormonal hypersecretion (for example: Zollinger-Ellison syndrome, carcinoid syndrome). For this reason the neoplasms are distinguished in functioning and not working. The functioning tumors are distinguished from the ending in "oma": gastrinoma, somatostatinoma, based on the characteristics of the clinical syndrome and the blood levels of specific hormones secreted. Exceptions are the tumors that work with enterochromaffin cells (EC), which are called carcinoids, because the syndrome associated with them is that of the carcinoid. The hyperfunctional syndrome that characterizes a neuroendocrine tumor has a predictive value that often results greater than the morphological typing of the neoplasia itself. For non-functioning neoplasms, ie not associated with clinical symptoms of hormonal hypersecretion, the prevalent cellular type present in the neoplasm is specified, which is identified by defining, with immunohistochemical techniques, the hormone produced: for example "secretory G-cell neuroendocrine noise" gastrin ". Patients with malfunctioning tumors do not show endocrine signs due to hormonal action, but may still have clinical pictures due to tumor mass (digestive haemorrhage, intestinal obstruction, perforation). The clinical aspects of functioning tumors vary according to the hormone produced. Gastrinomas cause Zollinger-Ellison syndrome characterized by hypergastrinemia, (gastric hypersecretion, peptic ulcers); these pictures are rarely caused by gastric endocrine tumors of type II ECL cells (see relevant paragraph). Carcinoid syndrome occurs only in patients with liver metastases and is characterized by the presence of flushing, diarrhea and, in advanced stages, heart failure for endocardial fibrosis and associated valvular fibrosis.

Tumors of the duodenum and proximal jejunum

Duodenal neuroendocrine tumors account for about 22% of all gastrointestinal endocrine neoplasms, while proximal jejunal tumors are rare (about 1% of all gastrointestinal endocrine neoplasms). The most frequent tumors are those in G cells, which produce gastrin (62%), followed by D cell noises, which produce somatostatin (21%) and gangliocytic paragangliomas. There is a slight predilection for the male sex being the average age of onset around about 60 years. Some tumors have preferential onset sites. Non-functioning gastrin-cell tumors (G-cells), which are generally benign and often incidental findings, are typically located in the mucosal-submucosal duodenal bulb. In contrast, functioning G-cell tumors (gastrinomas) affect all duodenal portions and also proximal fasting. Gastrinomas can be very small (only a few millimeters) and give metastases to the regional lymph nodes, despite their small size; they are also often multiple when they are associated with a MEN-1 syndrome. Somatostatin (D) cell tumors, gangliocytic paragangliomas, EC-cell carcinoids and poorly differentiated neuroendocrine carcinomas are mainly located in the second portion of the duodenum, especially in the ampullary region. D-cell tumors generally invade the muscular tunic and often give metastases to the regional lymph nodes. These tumors, unlike the pancreatic ones, do not induce a somatostatinoma syndrome, while they may appear in association with a von Recklinghausen disease (neurofibromatosis type I). Gangliocytic para-gangliomas, in spite of their deep localization in the duodenal wall, are generally benign. Cases with lymph node metastasis, only of the epithelial component, of these tumors are very rare. Poorly differentiated neuroendocrine carcinomas are large, very aggressive tumors that invade the wall deep and generally present metastasis at the time of diagnosis. Morphology. Macroscopically, tumors are usually small in size generally less than 2 cm in diameter. They appear as small gray nodules located in the mucosa and submucosa. Other neoplasms may have a polypoid appearance and may also be ulcerated on the surface. Poorly differentiated neuroendocrine carcinomas appear as often ulcerated, deep-infiltrating lesions. Gastrin tumors tend to be smaller than somatostatin and gangliocytic paragangliomas. Having the various neoplasms differences in the histological picture are here treated distinctly.

G cell tumors

They consist of a proliferation of well-differentiated, monomorphic cells that assume gyriform or trabecular structures. Their characteristic is the intense positivity to the argentophilous reaction of Grimelius; they are also immune-reactive for general endocrine markers (synaptophysin and chromogranins) and for gastrin.

D cell tumors

These tumors have a predominantly tubulo-glandular architecture. In the glandular spaces there are frequent basophilic concentric laminated structures, called psammomatous bodies or psammomas. Psammomas are only rarely observed in pancreatic forms. The tumors do not show a significant positivity to the Grimelius method, but are intensely positive for somatostatin.

EC cell tumors

They are quite rare in the duodenum and consist of cells, arranged to form solid nests, positive for serotonin.
Gangliocytic paragangliomas. These tumors consist of three different components: 1) the positive spindle cells for the S-100 protein, which form small bundles; 2) epithelial cells with a solid or trabecular nidi architecture generally positive for somatostatin or pancreatic polypeptide and finally 3) sparse ganglion-like cells.

Tumors of distal jejunum and ileum

These tumors have an incidence of 0.28-0.89 per 100,000 and represent about 25% of all gastrointestinal neuroendocrine tumors. They have the same distribution in the two sexes being the peak of onset between the sixth and seventh decade of life. The majority of these tumors are represented by well-differentiated neoplasms (carcinoids) consisting of seconent EC cells of serotonin / substance P in addition to a series of growth factors (fibro-blastic growth factors, hepatocytes, transforming a and 3, and others).
> Morphology. In about 25-30% of the cases the tumors are multiple, usually small with a diameter of about 1-1.5 cm.
Macroscopically, they appear as yellow nodules affecting the mucosa and submucosa, although deep infiltration up to the serosa is frequent. Often there is an infiltration of the mesentery capable of stimulating a desmoplastic reaction that can cause angulations of the loops and lead to intestinal infarction. The causes of this marked desmoplastic reaction are not completely known. Recently it has been hypothesized that the numerous growth factors produced by neoplastic cells may play a role.
Microscopically, tumors show a characteristic architecture consisting of solid nests that are well demarcated, on the periphery, by a palisade of richly granulated and intensely immunoreactive cells for serotonin as well as for general neuroendocrine markers.

Treatment

Relief of symptoms
Some symptoms, including flushing, are relieved by octreotide (which inhibits the release of most hormones) without reduction of urinary 5-hydroxyindolacetic acid (5-HIAA) or gastrin. Numerous studies have shown good results with octreotide, a long-acting somatostatin analogue. Octreotide is the drug of choice for controlling diarrhea and flushing. The efficacy of tamoxifen is occasionally reported in the literature; leukocyte interferon (IFN-α) has temporarily improved the symptoms.
Flushes can also be treated with phenothiazines (eg, prochlorperazine 5-10 mg or chlorpromazine 25 to 50 mg PO every 6 h). Type 2 histamine agonists (H2) may also be used. Phentolamine (an α-blocker) at a dose of 5-15 mg EV prevented experimentally-induced hot flashes. Corticosteroids (eg, prednisone 5 mg PO every 6 h) may be useful in severe flushing caused by bronchial carcinoids.
Diarrhea can be controlled with codeine, 15 mg PO every 4-6 h, opium tincture 0.6 mL every 6 h, loperamide 4 mg PO as a dose
The other treatments are surgical and highly specialized to treat the basic tumor.

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