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 differentiation.

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 features.

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 GISTs.

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