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digestive carcinoid tumor

Thursday 1 February 2007

Tumor classification

Digestive carcinoid tumors have traditionally been classified based on embryologic site of origin, morphologic pattern, and silver affinity.

This classification system, originally proposed by Williams and Sandler in 1963, subdivided carcinoids into tumors of the foregut (respiratory tract, thymus, stomach), the midgut (small intestine, appendix, proximal colon), and the hindgut (distal colon, rectum, genitourinary tract).

Microscopically, foregut carcinoid tumors characteristically exhibit a trabecular pattern, whereas midgut tumors typically appear as sheets of monotonous polygonal cells.

Likewise, the early divisions of carcinoid tumors were based on the staining characteristics when stained with silver.

Cells of foregut and rectal tumors accumulate cytoplasmic silver deposits only after being treated with a reducing agent, bestowing the term argyrophil cells.

Conversely, the cytoplasm of midgut tumors contains granules that stain black with ammoniacal silver nitrate, which is known as a positive argentaffin reaction.

Unfortunately, the clinical behavior of carcinoids within each embryologic division has been shown to vary considerably.

For instance, both chronic atrophic gastritis type A (CAG-A)-associated carcinoid tumors and carcinoid tumors associated with multiple endocrine neoplasia type 1 (MEN-1) found within the stomach exhibit an indolent disease course and are rarely associated with carcinoid syndrome, whereas sporadic gastric carcinoid tumors are often aggressive, displaying a high incidence of metastases and atypical carcinoid syndrome features.

As such, many authors have chosen to subdivide carcinoid tumors not only on the site of origin but also on variations in the histologic characteristics of these tumors.

Based upon this classification, carcinoid tumors may be characterized as typical or atypical.

Typical carcinoids are well differentiated, exhibiting a distinct recognized histologic pattern (insular, trabecular, glandular, mixed, or undifferentiated) of carcinoid morphology.

Conversely, atypical carcinoids may exhibit increased nuclear atypia, focal necrosis, or high mitotic indices.

More recently, the World Health Organization (WHO), in an effort to clarify the classification of carcinoid tumors and to standardize a system that would enable clinicians to compare patients and predict outcomes accurately, proposed a new classification of gastroenteropancreatic NETs.

Based on their malignant potential, the tumors are divided into five main categories:
- (1) well-differentiated endocrine tumor (proliferation index [PI] @<@2%),
- (2) well-differentiated endocrine carcinoma (PI >2% but @<@15%),
- (3) poorly differentiated endocrine carcinoma (PI >15%)
- (4) mixed exocrine–endocrine tumors
- (5) tumor-like lesions.

Proliferation indexs are typically based on monoclonal antibody (MIB-1) binding to the Ki-67 antigen, an important marker for cellular proliferation and mitotic activity.

The Ki-67 protein is detected in nuclear fractions of proliferating cells in the G1, S, G2, and M phases of the cell cycle; however, quiescent cells in G0 do not express the antigen.

Interestingly, several recent retrospective studies have identified the Ki-67 labeling index as an important independent predictor of carcinoid tumor biological behavior and patient survival.

Several single-institution experiences with carcinoid tumors have demonstrated a correlation between low Ki-67 values and longer survival.

Likewise, mean Ki-67 values were found to be significantly less in benign than in malignant tumors, and poorly differentiated tumors were characterized by very high Ki-67 indices that all exceeded 14%.

Based on these studies that suggest a role for Ki-67 as a prognostic factor, some authors have concluded that the Ki-67 labeling index may be used to establish indications for chemotherapy and clinically follow postoperative patients.

Though no prospective trials exist, Vilar et al. have postulated that tumors with high Ki-67 may respond better to chemotherapy.

Certainly, the role of Ki-67 labeling will continue to expand therapeutic and palliative strategies.

See also

- digestive tumors
- carcinoid tumors

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