GISTs/Interstitial Cells of Cajal: How do they fit together?
Ultrastructural and Immunohistochemical Correlates
Manchester, United Kingdom
The classification of gastrointestinal stromal tumors (GISTs) has been a continually evolving process
reflecting our increasing understanding of the biological nature of these tumors. This 'biological
nature' is an end-product of such phenomena as gene expression, primary polypeptide synthesis,
post-translational biochemical change, cell organelle elaboration and the organization of tumor cells
into architectural patterns - all complicated by the varying external environment in which cells find
themselves. The object of this presentation is to discuss the biological nature of GISTs, with an
emphasis on post-genomic features, which, collectively, represent the cellular differentiation or
phenotype of the tumor.
2. Phenotype of Interstitial cells of Cajal as cell counterparts to GIST cells
As in other groups of tumors, differentiation or phenotype is important in GISTs because it
encapsulates criteria for practical histopathological diagnosis: it also provides an appreciation of
what GIST tumor cells are biologically, and this can be important in
understanding how they behave, especially in terms of how they might react to therapeutic agents.
One of the most important concepts of recent years has been that GISTs are showing the
differentiation of the Interstitial cell of Cajal (ICC)(Kindblom et al
1998). ICCs form a network
within the gut musculature with pacemaker activity, which controls the smooth-muscle cell
contractions of peristalsis. In the light of this concept, it is appropriate to define the features of
ICCs, because they form the basis for diagnosing GIST, and because there are misconceptions in the
literature on the nature of ICCs, which in turn impact on our appreciation of the nature of GISTs.
Human ICCs often appear as solitary cells with very elongated profiles; they are found in specific
locations in relation to smooth-muscle layers and more numerously around plexuses; they express the c-kit
proto-oncogene as tyrosine kinase receptor, KIT (the latter being identifiable by CD117 immunostaining);
and are vimentin-positive and desmin-negative (Faussone-Pellegrini et al 1989; Rumessen and Thuneberg
1991; Rumessen et al 1993a; Rumessen et al 1993b; Rumessen 1994; Faussone-Pellegrini and Thuneberg
1999). There appear to be CD34+ and CD34- subpopulations (Vanderwinden et al 1999;
Robinson et al 2000).
With regard to ultrastructure, in spite of subtle site-specific differences, ICCs have several
smooth-muscle cell features – in particular, caveolae, lamina, and myofilaments – which form the basis of
regarding ICCs as cells showing a primitive level of smooth-muscle differentiation, and in fact these
cells have been referred to as 'myoid' (Rumessen and Thuneberg 1991). There are, however, additional
features which are found in ICCs which are less typical of smooth-muscle cells, although found in them
(Eyden et al 1992; Faussone-Pellegrini and Cortesini 1985): abundant intermediate filaments; dense
bodies amid these intermediate filaments; and smooth endoplasmic reticulum. The dense bodies amid
abundant intermediate filaments (Rumessen and Thuneberg 1991) have also been seen in an unambiguous
leiomyosarcoma (Eyden and Banerjee 2002) and in a transplanted leiomyosarcoma (Sawada et al 1992), and
may represent a marker of a primitive level of smooth-muscle differentiation.
In summary, ICC ultrastructure suggests a primitive myoid cell characterized by a low expression of
typical smooth-muscle features, as well as certain other features consistent with but perhaps not
absolutely specific for or characteristic of smooth-muscle.
ICCs are not neuronal. Ramon y Cajal may have regarded the cells named after him as neuronal but the
detailed ultrastructural studies by the Faussone-Pellegrini and Rumessen/Thuneberg groups suggest a myoid
cell, an unusual myoid cell maybe, but not a neuronal cell, and in
particular a cell without neuroendocrine granules. This needs to be emphasised because it conflicts with
certain published views on the ICC – for example, " … ultrastructural features described as being
diagnostic of GANT [see below] are, in fact, characteristics of gastrointestinal pacemaker cells "
(Kindblom et al 1998); and that "[Interstitial cells of Cajal] … have immunophenotypic and
ultrastructural features of both smooth muscle and neuronal differentiation …" (Fletcher et al 2002).
3. Ultrastructure and immunophenotype of GIST
Is it possible to identify GI tumors which correlate phenotypically with ICCs and which can,
therefore, be designated as GIST? On the basis of our own recent study of 82 mesenchymal GI tumors
(Eyden et al 2002), GISTs can indeed be identified by ICC features, although the picture is complicated
by phenotypic overlap with gastrointestinal autonomic nerve tumor (GANT) and, as already suggested, true
smooth-muscle tumor. 36 tumors were identified as having varying expression of processes containing
abundant intermediate filaments, so-called solitary focal densities amid
these intermediate filaments, and smooth endoplasmic reticulum, as well as a varying but usually low
expression of more typical smooth-muscle features such as myofilaments, attachment plaques, caveolae and
lamina. Most were also KIT-positive, a lesser percentage were CD34 positive, but a significant
proportion showed smooth-muscle expression as indicated by
a-smooth-muscle actin, pan-actin (HHF35) and, less frequently, desmin.
4. Gastrointestinal autonomic nerve tumor (GANT) and its relationship to GIST
The foregoing ultrastructural definition of GIST also assumes the absence of neuroendocrine granules, cell structures which characterize GANTs.
GANTs, however, also have partial phenotypic overlap with GIST: most are KIT positive and some are CD34
positive; there is some smooth-muscle differentiation as determined immunophenotypically and
ultrastructurally; and they have processes containing intermediate filaments (less commonly
microtubules), smooth endoplasmic reticulum, while some have solitary focal densities amid intermediate
Despite a distinctive ultrastructure, GANT has been either equated with GIST (Schmid and Wegmann
2000) or regarded as a variant of GIST (Lee et al 2001). This is largely because of the KIT-positivity
of GANTs, although it has to be said that the GANTs from these studies have been diagnosed
ultrastructurally on the basis of granules which have been pointed out as looking more like lysosomes
than true neuroendocrine granules (Eyden 2001, 2002). That having been said, many of the
ultrastructurally confirmed GANTs containing bona fide neuroendocrine
granules in our own study (Eyden et al 2002) are indeed KIT-positive. So, we regard GIST and GANT as
having partial immunophenotypic and ultrastructural overlap, but we also maintain that these are
different from each other. It seems inconceivable that a cell with a primitive level of smooth-muscle
differentiation should not be biologically different from a neuronal cell: differences in behaviour
could be identifiable with appropriate further investigation.
The Interstitial cell of Cajal has the immunophenotype and ultrastructure of a relatively primitive
smooth-muscle cell but with certain unusual additional features: however, these cells are not neuronal
and they lack neuroendocrine granules. Mesenchymal tumors of the GI can be identified with the features
of ICCs and can therefore be designated as GISTs. Neuroendocrine granules allow the distinction from
GANT, which on this basis is a biologically different tumor. However, GANT and GIST exhibit partial
immunophenotypic and ultrastructural co-expression, suggesting a complex genetic and post-genomic control
over cellular features.
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I would like to thank my histopathologist colleagues, Dr Kathy Chorneyko
(Hamilton, Canada), Dr Lia P Menasce, Dr Jonathan H Shanks and Dr S Sankar Banerjee, for providing the
histopathological background to this presentation.