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Histology of neuroendocrine tumors

Endocrine tumors appear in all parts of the gastrointestinal tract. In the last edition of the WHO classification of tumors, this group was designated neuroendocrine tumors of the GI tract. The diagnosis is based on immunhistochemical positivity for one or several of the following markers: chromogranin, synaptophysin, neuron specific enolase (NSE) or CD56 (N-CAM).

Esophagus

Endocrine tumors rarely appear in the esophagus. These comprise only 0,1% of esophagus cancers. There are two types of endocrine tumors in the oesophagus:

  • Well differentiated endocrine carcinoma appears in the lower third of the oesophagus. Histologically, they grow as solid tumor cell islands in the deeper part of the esophagus wall.
  • Small cell carcinoma is almost identical to small cell carcinoma of the lung. The tumor consists of closely lying cells with sparse cytoplasm and hyperchromatic nuclei. This tumor appears in lower half of the oesophagus and can be difficult to separate from small cell carcinoma of the lung growing through the esophagus wall.

Gastric

Endocrine tumors of the gastric sac are not uncommon. Most tumors in the gastric sac are small and related to other clinical manifestations such as pernicious anemia or hypergastrinemia. They can be divided into the following groups:

Photomicrograph demonstrating the gastric mucosa with ECL hyperplasia. Click to enlarge. Immunhistochemical chromogranin staining of the tumor in the left image with positive brownish granula. Click to enlarge.

1. Well differentiated endocrine neoplasms

  • Enterochrommafin Cell Like – ECL endocrine neoplasms
  • Enterochrommafin Cell – EC, serotonin-produsing endocrine neoplasms
  • Gastrin-produsing G-cell endocrine neoplasms

2. Poorly differentiated endocrine carcinoma

  • Small cell carcinoma
  • Large cell endocrine carcinoma

3. Tumor-like lesions

  • Hyperplasias
  • Dysplasias

The most common endocrine neoplasia in the gastric mucosa is ECL neoplasia. They comprise 9 out of 10 endocrine neoplasms in the GI tract. In ECL neoplasms, three types are recognized depending on relation to autoimmue gastritis/pernicious anemia (type I), hypergastrinemia (type II) or abscence from autoimmune gastritis or hypergastrinemia, or sporadic ECL neoplasia.  The typical  type I and II tumors are relatively small tumors (< 15 mm) and they are localized within mucosa or submucosa. They show trebelcular tumor cell groups with monotonous cells and are positive for chromogranin. The sporadic (type III) tumors are generally larger than type I/II and demonstrate a more aggressive growth pattern with deeper invasion in the wall and more polymorphic cells and more frequent mitotic figures. They also often demonstrate vascular invasion.

Serotonin-producing endocrine neoplasms (EC cells) are mostly associated with the terminology carcinoid. EC neoplasms are frequent in the small intestine, but are rare in the gastric mucosa.

Gastrin-producing tumors are usually found incidently during endoscopy or gastrectomy. They are generally small growing in the mucosa or submuca and are immunhistochemically positive for gastrin.

Small cell carcinoma is similar to corresponding tumors in the lung and esphagus.

Large cell endocrine carcinoma consists of large cells often with rosette formations and pallisading features. Both small cell and large cell carcinomas are rarely observed in the gastric wall.

Tumor-like lesions (hyperplasia/dysplasia) are generally seen in autoimmune gastritis/hypergastrinemia with ”simple”, linear and micronodular ECL-hyperplasia. When nodules exceed 0.5 mm they are designated as endocrine neoplasms.

Small intestine

Endocrine tumors in the small intestine are divided according to localization: those within duodenum and proximal part of jejunum and those in the distal part of jejunum and ileum.

Endocrine tumors of the duodenum and proximal part of jejunum comprise 23% of all gastrointestinal endocrine tumors where > 90% are in the duodenum. The most common among these tumors are the gastrinomas (62%), somatostatin cell tumors (21%), and gangliocystic paraganglioma (9%).  Most tumors are less than 2 cm in diameter, although some can reach 5 cm. The microscopic appearance is similar to other well-differentiated endocrine neoplasias with trabecular, tubulo-glandular and nodular growth patterns. General neuroendocrine markers and specific hormone markers (gastrin, somatostatin) confirm the diagnosis. Gangliocytic paraganglioma is a rare tumor with mixed microscopic appearance consisting of three different cell types: spindle, epithelial, and ganglion cells. EC-cell serotonin-producing tumors (classic ”mid-gut” carcinoid) are rare in the duodenum and proximal part of the jejunum.

Photomicrograph demonstrating a lymph node metastasis from an endocrine carcinoma of the cecum. Click to enlarge. Immunhistochemical staining for Synaptophysin in primary tumor (same patient as left image). Click to enlarge. Immunhistochemical staining for Ki-67 in primary tumor (same patient as left image). Click to enlarge.

Endocrine tumors in the distal part of jejunum comprise about 30% of all endocrine GI neoplasms. They are mainly classical ”mid-gut” carcinoid (EC-cell endocrine neoplasms) . They are often multiple, and more than half of them exceed 2 cm in diameter when diagnosed and grow in submucosa or deep in the mucosa. In some instances these tumors infiltrate muscularis propria or serosa. Extensive infiltration in the mesenterium which is often dependend on lymphatic spreading stimulates fibroblastic activity with desmoplasia. This can cause intestinal obstruction. EC-cell endocrine neoplasms are more aggressive than other well-differentiated endocrine carcinomas. They metastasize mainly to regional lymph nodes or to the liver. Patients are usually cured  when complete local resection has been performed, tumors are less than 1 cm, tumors are localized within mucosa/submucosa, no vascular invasion has been documented and Ki-67 score is less than 2%.

Appendix veriform

Endocrine tumors in the appendix vermiform comprise 50–75% of all tumors in this localization. The most common type of well-differentiated endocrine neoplasms in appendix is EC-cell neoplasias with similar appearance as in the ileum. They are generally less than 1 cm in diameter and are seen in the tip of the appendix. The majority of tumors are found incidentally during appendectomy. These tumor are less aggressive compared similar tumors in the ileum. This may be partly due to smaller size.

Photomicrograph demonstrating tumor cells with goblet appearance infiltrating the appendix wall. Click to enlarge. Immunhistochemical staining for Synaptophysin (same tumor as left image) confirms the diagnosis of goblet cell carcinoid. Click to enlarge. Immunhistochemical staining for Ki-67 (same tumor as left image). Only scattered positive nuclei. Click to enlarge.

Apart from  EC-cell endocrine neoplasias, there are variants of mucus-producing endocrine neoplasias and tubular endocrine neoplasias. The first group is represented by the goblet cell carcinoid that is characterized by groups of cells growing in the submucosa centrical around the lumen without forming a distinct tumor. The cell groups contain cells comparable to mature goblet cells in the intestinal mucosa. In these cell groups, immunohistochemical staining for neuroendocrine marker shows positivity. Earlier it was believed that goblet cell carcinoid were less aggressive, although today they are considered to be represented by a spectrum of well-differentiated to poorly differentiated signet ring carcinomas.

Tubular carcinoid is a rare entity and grows in tubular structure in the submucosa almost like an adenocarcinoma. Immunhistochemical neuroendiocrine markers and limited involvement of mucosa generally confirm the diagnosis.

Non-angioinvasive endocrine neoplasias in the appendix vermiform (except for goblet cell carcinoid) less than 2 cm in diameter, not infiltrating mesoappendix or resection borders may be cured by appendectomy.

Colon and rectum

Well-differentiated endocrine tumors appear mostly in the rectum (about 50%) followed by the cecum (20%).  EC-cell neoplasia appear more frequently in colon and less frequently in rectum. They are similar to those in well-differentiated endocrine carcinomas with varying malignancy potential depending on size, depth of infiltration and mitiotic count/Ki-67% activity. About 40% demonstrate local spread. L-cell, glucagon-like peptide and PP/PYY-producing tumors often demonstrate a typical trabecular growth pattern and are usually seen in the rectum. When they are smaller than 2 cm in diameter and do not infiltrate muscularis propria they have a benign clinical course. Four of five endocrine tumors in the rectum demonstrate positivity for PSA. Poorly differentiated endocrine neoplasms (small cell carcinoma and large cell endocrine carinoma) rarely appear in colon or rectum.

Anal canal

Endocrine tumors are very rare in the anal canal. Most of them are L-cell type.

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