Historical Perspective: A Journey Through Evolution of Classification Schemes
Guillermo A. Herrera
Louisiana State University Health Sciences Center
Classifications are created to clarify and standardize information. In Pathology they are essential
to provide clinicians with meaningful data that they can use to manage their patients. If
classifications become too complicated or not clinically relevant, they lose their significance and run
the risk of being considered too cumbersome or inadequate for routine use. This usually leads to a new
classification. Gastrointestinal (GI) stromal tumors have been subjected to numerous classifications.
As additional data was obtained from the use of new diagnostic ancillary techniques, it usually resulted
in a new classification scheme that was intended to provide more clinically useful information,
standardize nomenclature, and be more reproducible than the previously established classification. Note
that throughout this presentation the term GI stromal tumor (GIST) is used in a broad generic sense to
refer to all non-epithelial (mesenchymal) GI neoplasms.
Mesenchymal tumors of the GI tract (so-called stromal tumors) have attracted the attention of
pathologists for several decades. Classification schemes have been based on cell type, histogenesis and
differentiation, the fundamental criteria taken into account in most pathology classification schemes.
Molecular biology considerations have not played a role until recently. New therapeutic interventions
(so-called targeted therapeutics) that have become available are based on targeting molecular markers
that may be present in at least some of these malignant gastrointestinal stromal tumors, prompting us to
reassess how we analyze and classify these most interesting neoplasms.
The first comprehensive attempts to classify stromal tumors of the GI tract should be credited to
Dudley et al (1942) and Rabinovitch et al (1949) but both of these dealt with benign neoplasms. Probably
one of the early attempts to address the classification of malignant mesenchymal tumors of the GI tract
based on cell type / histogenesis was by France and Brines (1950) who published a seminal manuscript
titled: "Mesenchymal tumors of the stomach". Martin et al reported in 1960 six bizarre intramural
tumors in the stomach that he referred to as "myoid", suggesting smooth muscle differentiation. Arthur
Purdy Stout followed this publication with one of his own which he titled "Bizarre smooth muscle
neoplasms of the stomach" in 1962. In the introductory part of the manuscript he states: "The recent
excellent paper by Martin et al. dealing with 6 cases of bizarre intramural myoid tumors of the stomach
finally persuaded me that it is time to present these tumors to the English speaking public and to try to
determine whether they are benign or malignant tumors". Stout's paper, which compiled 69 such tumors in
the stomach, is probably the first attempt to carefully classify and analyze gastrointestinal stromal
tumors in terms of biologic behavior. Only two of the 69 neoplasms proved to behave in a malignant
fashion. Regarding these two tumors he stated: "These did not differ from most of then others except by
the fact that it was possible to find an elevated rate of mitotic division in some part or each of them".
In an effort to acknowledge the difficulty of predicting clinical behavior from morphologic evaluation,
he proposed to refer to these tumors with a name that carried no definite implications of benignancy or
malignancy. The term he coined for these tumors was leiomyoblastoma.
These mesenchymal neoplasms have been referred to using a variety of names. In 1983 Mazur and Clark
evaluated 28 such tumors from the stomach with emphasis on histogenesis. Only 12 of them had tissue
available for EM. He observed that two S-100 negative tumors clearly showed evidence of smooth muscle
differentiation and one S-100 positive neoplasm revealed Schwann cell differentiation. The other nine
neoplasms had neither smooth muscle nor schwannian features and they used the term stromal tumor to refer
to them. They suggested that some of these tumors might be of myenteric nerve origin. The findings
clearly demonstrated that many stromal GI tumors did not show overt smooth muscle or schwannian
In 1984, Herrera et al. reported a malignant small bowel neoplasm, which by
immunohistochemistry and electron microscopy had features that recapitulated myenteric plexus and termed
this tumor a plexosarcoma. This paper was followed by a number of other publications reporting similar
neoplasms. Walker and Dvorak coined the term Gastrointestinal Autonomic Nerve Tumor (GANT) to refer to
these neoplasms. By immunohistochemistry these neoplasms show evidence of neuroendocrine
differentiation. They generally express neuron specific enolase (NSE) and may also be positive for
synaptophysin and chromogranin while they exhibit no markers of smooth muscle or schwannian
differentiation. The ultrastructural appearance of these tumors is indeed quite characteristic. With
the addition of this new type of neoplasm it appeared that GI stromal tumors were then subdivided into
those with: smooth muscle, neural and myenteric plexus differentiation. This still left a group of
GISTs that ultrastructurally were composed of rather primitive cells with focal and subtle smooth muscle
The classification schemes not only attempted to provide a more accurate determination of type of
differentiation present in these GISTs but also aimed at better defining the biologic potential of these
neoplasms. The question that was always behind the scenes was: Should GISTs be assessed differently
according to type or site or both when biologic potential is to be determined? For example, the
observation that very small GANTs without necrosis and with virtually no atypical cellular features or
mitotic activity could metastasize widely and behave very aggressively suggested that using traditional
criteria to evaluate biologic potential of GANTs may not be appropriate.
While these classifications were evolving, "lumpers" insisted that classifying GISTs was an academic
exercise with no clinical relevance. They proposed a generic approach for the classification of these
tumors regardless of differentiation and highlighted the fact that the issue that really mattered was how
to accurately predict biologic potential. Numerous papers were generated defining criteria to determine
benign, indeterminate and malignant tumors regardless of cell type/differentiation.
In 1997, Hirota et al were the first to report the presence of c-kit in GISTs. They
pointed out that this receptor was present in many of GISTs detected with a polyclonal c-kit antibody
(CD-117 antigen). Notable exceptions were tumors with smooth muscle and schwannian differentiation,
which according to the authors did not express CD-117. Kindblom et al in 1998 postulated that GISTs
arise from stem cells that differentiate into interstitial cells of Cajal from the myenteric plexus, the
pacemaker cells of the GI tract. Recently these cells have been characterized ultrastructurally as
primitive smooth muscle cells (Min et al, unpublished observations).
Until recently, the only effective treatment for GISTs was surgical resection and the chemotherapy
that was available for those tumors that recurred or metastasized was extremely poor (less than 5%
response to doxorubicin). Therefore, the attempts to more accurately classify these tumors was perhaps
only useful for addressing issues pertaining to prognosis since therapeutic options were very limited.
A new drug known with various names Gleevec, Glivec, ST-1571 and Imatinib mesylate which
inhibits the tyrosine kinase activity of c-kit or ABL (among other inhibitory effects on families of
tyrosine kinases) was anecdotally reported in 2001 to have had a dramatic effect on a malignant GIST.
This generated much interest to test this new drug in malignant GISTs. The latest report published
August 2002 dealing with the use of this drug in a trial (147 patients with recurrent or metastatic
GISTs) revealed a partial response in 53.7% of the cases, stable disease (no progression) in 27.9% after
therapy but no patients with complete response to treatment. It was also noted that early resistance was
identified in 13.6% of all patients treated. This data has created much hope in regards to the use of
this new therapy (inhibiting the c-kit signal transduction pathway) for aggressive and metastatic GISTs.
Significant molecular heterogenicity has been documented in the alterations that can be observed in
GISTs. Mutations in exons 9, 11 and 13 have been described. Mutations in exon 11 appear to occur
preferentially in malignant GISTs and have been reported to be absent in leiomyomas and leiomyosarcomas.
Could molecular evaluation segregate these GISTs into groups and identify which are most likely to
respond or be resistant to molecular targeting?
So a new era has began in regards to the pathologic assessment and treatment of GISTs. Scientific
advances inevitably lead to new questions. Since not all CD-117 positive GISTs respond equally to anti
c-kit therapy, can we segregate a group of responders? Is this going to result from better
characterization of differentiation, detection of certain molecular alterations or perhaps related to the
more traditional criteria of size and morphologic indexes? Should we regard all GI stromal tumors that
express CD-117 as GISTs and consider them all one group? Is there any value in separating those with
smooth muscle or schwannian differentiation because these are often (but not always) CD-117 negative?
Are some commercially available antibodies to CD-117 more reliable than others? What is the actual role
of molecular testing in the evaluation of GISTs? Should all GISTs be tested using molecular tools?
Should we equate tumors arising from interstitial cells of Cajal which appear to be morphologically
composed of primitive smooth muscle cells with those with myenteric plexus differentiation (GANTs) which
are indeed characterized as neuroendocrine using immunomorphologic parameters? Are we to use the same
criteria to evaluate behavior in all GISTs regardless of differentiation and molecular make up?
In summary, there are myriads of questions that remain to be answered in regards to the
characterization of GISTs and possible clinical implications. The speakers that follow my presentation
will provide the latest information available. They were chosen because of their expertise, interest,
and experience in the field. The advent of new therapies addressing molecular targets offers an added
dimension to the management of these patients. GISTs appear to be the tumor prototype linking molecular
characterization to targeted therapy of molecular markers displayed. The challenge is to identify those
patients who would benefit from receiving the new therapy, especially those with metastatic or recurrent
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