Interstitial Cells of Cajal as Precursors of Gastrointestinal Stromal Tumors

Abstract

Interstitial cells of Cajal (ICC) are implicated in the regulation of gut peristalsis and are immunostained by antibodies against Kit (CD117), a tyrosine kinase receptor. Most gastrointestinal mesenchymal tumors (GIMTs) are of uncertain histogenesis, although many are CD34-positive. CD34 was found to colocalize with vimentin (Vim) and the Kit-positive networks of cells within and around neural plexi, indicating that ICC can be Vim- and CD34-positive. ICCs appear to be the only Kit+CD34+Vim+ cell in the gut. Formalin-fixed, paraffin-embedded tissues from 43 GIMTs were immunostained for Kit, CD34, Vim, PGP 9.5 (PGP, a neural marker), muscle-specific actin (MSA), and other markers including desmin (Des). Eight tumors were myoid (MSA+Des+Vim-Kit-CD34-), and one was a schwannoma (PGP+S100+Vim+Kit-CD34-), but 34 tumors were of uncertain histogenesis (gastrointestinal stromal tumors, GIST), exhibiting neither a complete myoid nor a schwannian immunophenotype. All 34 were Vim+, and 33/34 were either Kit (n = 30) or CD34 (n = 23) immunoreactive. Of these 34 GIST, 24 were negative for all myoid and neural markers, 6 were PGP+S100-, and 4 were MSA+Des-. The Kit+CD34+Vim+ immunophenotype of GIST suggests that they originate from, or have differentiated into, ICC-like cells; the term ICC tumor (ICCT) is suggested. Kit is a more sensitive marker than CD34 for ICCT, but both are required in tumor identification. All clinically malignant GISTs were pathologically malignant (size, mitoses) but also showed loss of either CD34 or Kit. "Blind" examination of electron micrographs in 10 tumors showed them to be heterogeneous. Some had features seen in normal ICC, but cells could not be positively identified as being adult ICC. GIMT may therefore be classifiable into those with pure myoid, schwannian (or neural) differentiation, but the majority are of ICC origin or show ICC differentiation immunophenotypically (ICCT).

Immunohistochemical Spectrum of GISTs at Different Sites and Their Differential Diagnosis with a Reference to CD117 (KIT)

“…A unique feature for these tumors is the presence of activating mutations in the exon 11 of some c-kit genes, especially in the malignant tumors. Such mutations in the c-kit gene are a possible pathogenesis or explanation for the autonomous, unrestricted growth of malignant GISTs (2)(3)(4)(5)(6)(7)(8)(9)(10)(11).…”

Leiomyosarcomas and Most Malignant Fibrous Histiocytomas Share Very Similar Comparative Genomic Hybridization Imbalances: An Analysis of a Series of 27 Leiomyosarcomas

“…These profiles are suggestive of GIST (Breiner et al, 2000;Derré et al, 2000;El-Rifai et al, 1996. Moreover, a number of GIST can express muscular markers Sircar et al, 1999). Three other tumors (LMS 40, LMS 21, and LMS 47) were characterized by simple CGH profiles associated with multiple small amplifications (such as bands 12q14 -15).…”

Novel type of interstitial cell (Cajal-like) in human fallopian tube

“…One may expect a partial overlap of the two cell types, as some enteric ICC [102] and some Cajal-like cells [46,90,103] are positive for CD34 and, to a certain extent, look similar. However, it seems reasonable to assume important differences between the two cell types, as their proportions in the whole cell population are significantly dissimilar [101].…”