Interstitial cells of Cajal as precursors of gastrointestinal stromal tumors

Interstitial cells of Cajal (ICC) are implicated in the regulation of gut p eristalsis and are immunostained by antibodies against Kit (CD117), a tyros ine kinase receptor. Most gastrointestinal mesenchymal tumors (GIMTs) are o f uncertain histogenesis, although many are CD34-positive. CD34 was found t o colocalize with vimentin (Vim) and the Kit-positive networks of cells wit hin and around neural plexi, indicating that ICC can be Vim- and CD34-posit ive. ICCs appear to be the only Kit+CD34+Vim+ cell in the gut. Formalin-fix ed, paraffin-embedded tissues from 43 GIMTs were immunostained for Kit, CD3 4, Vim, PGP 9.5 (PGP, a neural marker), muscle-specific actin (MSA), and ot her markers including desmin (Des). Eight tumors were myoid (MSA+Des+Vim-Ki t-CD34-), and one was a schwannoma (PGP+S100+Vim+Kit-CD34-), but 34 tumors were of uncertain histogenesis (gastrointestinal stromal tumors, GIST), exh ibiting neither a complete myoid nor a schwannian immunophenotype. All 34 w ere Vim+, and 33/34 were either Kit (n = 30) or CD34 (n = 23) immunoreactiv e. Of these 34 GIST, 24 were negative for all myoid and neural markers, 6 w ere PGP+S100-, and 4 were MSA+Des-. The Kit+CD34+Vim+ immunophenotype of GI ST suggests that they originate from, or have differentiated into, ICC-like cells; the term ICC tumor (ICCT) is suggested. Kit is a more sensitive mar ker than CD34 for ICCT, but both are required in tumor identification. All clinically malignant GISTs were pathologically malignant (size, mitoses) bu t also showed loss of either CD34 or Kit. "Blind" examination of electron m icrographs in 10 tumors showed them to be heterogeneous. Some had features seen in normal ICC, but cells could not be positively identified as being a dult ICC. GIMT may therefore be classifiable into those with pure myoid, sc hwannian (or neural) differentiation, but the majority are of ICC origin or show ICC differentiation immunophenotypically (ICCT).