—  SPECIALTY CONFERENCE  —

SURGICAL PATHOLOGY

Case 2 - Gastrointestinal Stromal Tumor (Sarcoma)

Christopher Fletcher
Brigham and Women's Hospital, Harvard Medical School
Boston, Massachusetts

Case History
A 37 year old woman presented in 1997 with acute abdominal pain. At laparotomy a 6 cm hemorrhagic mass was found in the wall of the jejunum; the mass had "ruptured". Following excision, the patient did well for 2.5 years and then developed progressive abdominal fullness. CT scan revealed 3 large intra-abdominal masses (ranging in size up to 40 cm) along with innumerable peritoneal nodules. A debulking procedure was performed.

Slides  (Click to enlarge)


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Typical sheet-like proliferation of palely eosinophilic spindle cells. Note the syncytial quality of the cytoplasm and relatively uniform nuclei. Mitoses focally numbered up to 4 per 10 HPF. Immunostaining for c-kit (CD117) shows very strong and diffuse cytoplasmic positivity.

Diagnosis: Gastrointestinal Stromal Tumor (Sarcoma)

Neoplasms arising from the stromal (or mural) components of the gut can be divided broadly in two categories. Some tumors are not unique to the gastrointestinal wall and appear similar to their counterparts elsewhere - e.g. schwannomas, usual leiomyomas and (rare) leiomyosarcomas. The other category comprises spindle cell and epithelioid neoplasms histologically resembling smooth muscle tumors but either lacking (or presenting only limited) immunohistochemical and ultrastructural features of myogenic or neural differentiation and for which prediction of behavior has proved to be problematic. This latter group, which represent the substantial majority, are known as GI stromal tumors.

Stromal tumors of the gastrointestinal tract (GIST) occur over a wide age range but affect predominantly middle aged and older individuals, with a slight female predominance. The biologic behavior of GISTs is difficult to determine accurately from published data, given the different diagnostic criteria used, and the tendency for late metastases in some cases, with spread sometimes occurring after 20 to 30 years. The overall 5 and 10-year survivals of malignant GISTs, have been estimated at between 25 and 50%,1 although in one series, only 10% of patients remained free of disease after a median follow-up of 68 months.2 Most such patients succumb to disseminated intra-abdominal disease, although extra-abdominal spread may also occur.

GISTs were originally thought to arise from mural smooth muscle of the GI tract 3,4,5 Subsequently, morphologic differences were noted between these "leiomyomas" and "leiomyosarcomas" of the gastrointestinal tract and their counterparts in other sites: most gastrointestinal lesions appeared more cellular and the tumor cells often had more ovoid or elongated nuclei and less brightly eosinophilic, rather fibrillary cytoplasm. It also rapidly became clear that GISTs, unlike their apparent counterparts in other sites, could metastasize despite the absence of usual histologic features of malignancy (in particular, in the absence of significant mitotic activity) and that their behavior was much harder to predict.3,4,6 In the 1970s/early 1980s most ultrastructural studies failed to identify myofilaments with focal densities in the majority of GISTs. In addition, several authors identified Schwannian or neuroaxonal characteristics in some cases and, in 1984, a distinctive subset showing autonomic neural differentiation was first described.7 These were initially known as plexosarcoma, later as gastrointestinal autonomic nerve tumor (GANT)8 and are now being subsumed once more into the general GIST category (see below). In the 1980s and early 1990s numerous series of GIST were analysed immunohistochemically with inconsistent results. Although a large proportion (between 30% to 80%) of GISTs have been shown to express muscle markers, the most specific of those, desmin, has usually stained only a minority of tumors. Variable proportions of tumors with a neural phenotype have been identified (from none to approximately 40%) and, interestingly, divergent differentiation (coexpression of muscular and neural markers) was identified in up to 20% of cases.9 In the early 1990s, CD34 was shown to stain up to 80% of GISTs, with or without markers of other specific differentiation.10 Several authors tried (with little success) to correlate the immunophenotype of GISTs with tumor location, the histologic appearance and, more importantly, with prognosis.

The difficulty in classifying GISTs into benign and malignant categories has long been recognized. In a series of 87 GISTs, Kempson and Ranchod identified the mitotic count as the most useful indicator of malignancy. However, while the presence of 5 or more mitoses per 10 HPF was closely correlated with aggressive behavior, 40% of "leiomyosarcomas" had fewer mitotic figures.4 In order to refine the separation of benign and malignant GISTs, numerous studies subsequently analyzed the correlation between malignancy and various clinical and pathological parameters, often with variable results.11,12,13 The mitotic count has been most widely accepted as the best histologic prognostic indicator4,18 and it has been shown that a high mitotic count is associated with a shorter disease-free interval and shortened overall survival. Various cutoff levels, separating benign, borderline and malignant categories have been proposed. However, because of the overlap between clinically benign and malignant GISTs, and in view of the occurrence of metastasis in histologically bland, mitotically inactive tumors, none of these has proven reliable in the management of individual patients.

Tumor size has also been shown to be strongly correlated with metastasis.1,6 In Appelman's series of 127 cases, only one tumor < 6 cm metastasized.6 These results have been confirmed by most studies and, again, various cutoff levels have been proposed, usually being set at around 5 and 6 cm. Unfortunately, as for the mitotic count, some exceptions have been encountered, and, tumors as small as 2 cm have been reported to metastasize14 and I have personally encountered a number of such cases.

Numerous other clinical, macroscopic and histologic parameters have been assessed, most of which have been shown, at least in some univariate studies, to have some correlation with survival or the development of metastases. Although the presence of unequivocal necrosis is usually regarded as highly suspicious for malignancy, this has been reported in rare clinically benign cases. Ulceration of the overlying mucosa has also been considered as a worrisome feature by some authors.15,16 Significant differences in terms of outcome according to tumor site have only been observed in one study, in which the ten year survival reached 74% for gastric lesions, while it was only 17% for small bowel tumors.17

Because of this imperfect separation between benign and malignant GISTs using conventional pathologic criteria, ancillary techniques such as evaluation of ploidy and proliferation markers were introduced in the early 1990s. Most studies suggested that DNA ploidy correlates (by univariate analysis) with histologic grade and that aneuploidy is associated with decreased survival. However, most authors compared tumor ploidy with malignancy defined either clinically with limited follow-up or by histologic criteria. Most of these studies included aneuploid cases that did not show clinical evidence of malignancy and, more importantly, a few patients with diploid tumors (even of small size), developed disseminated disease. Because of this overlap, ploidy does not appear to be more discriminant than morphology when applied in individual cases. Similar problems have occurred with studies utilizing proliferation markers such as PCNA, MIB-1 and AgNORs.

Most recently, in light of the considerable interest focused on GISTs as a consequence of the introduction of effective therapy for relapsed lesions (see below), NIH convened a workshop in April 2001 with the goals of better defining diagnostic and prognostic criteria for GIST.18 This led to the development of concensus guidelines (shown in the table below),19 the key component of which is to think in terms of risk assessment, rather than to label any of these lesions as definitely benign. Experience gained from currently ongoing very large clinical trials of relapsed or metastatic GIST supports this approach.

Proposed Guidelines for Defining Risk of Aggressive Behavior in Gastrointestinal Stromal Tumors19
  Size Mitotic Count
Very low risk < 2 cm < 5 per 50 HPF
Low risk 2 - 5 cm < 5 per 50 HPF
Intermediate risk< 5 cm
5 - 10 cm 		6 - 10 per 50 HPF
< 5 per 50 HPF
High risk > 5 cm
> 10 cm
Any size		> 5 per 50 HPF
Any mitotic rate
> 10 per 50 HPF

Recent Developments
C-Kit is a proto-oncogene encoding a transmembrane tyrosine-kinase receptor, KIT or CD 117 which plays an important role in the development of melanocytes, germ cells, mast cells and the interstitial cells of Cajal (ICCs). The latter, which are located between the muscular layers of the gastric and intestinal wall in association with the myenteric plexus, are known to regulate autonomous peristaltic contraction and, ultrastructurally, show features of both incomplete myogenic and neural differentiation. These cells are characterized by dual immunopositivity for CD34 and CD 117. Recently, the hypothesis that GISTs might differentiate towards an ICC phenotype, has been supported by extensive immunohistochemical, ultrastructural and molecular studies20,21,22,23 and it has been demonstrated that immunoreactivity for CDl17 is seen in 85 to 100% of GISTs (whether spindle cell, epithelioid or mixed), while most other sarcomas or other neoplasms are negative. In addition, activating c-kit mutations were identified in 5 of 6 cases from the original series20 and our own personal experience with larger case numbers has been similar.24,25 The fact that c-Kit plays a central role in tumor development or progression has received additional support with identification of germline mutations in families with multiple GISTs.

CDl17-positive GISTs are also positive for CD34 in 60-70% of cases, and smooth muscle actin is positive in 15 to 30% of cases. Interestingly, all tumors showing immunohistochemical evidence of true smooth muscle differentiation i.e. desmin positivity and diffuse actin positivity fail to stain for CD 117, further justifying the separation of GISTs and conventional smooth muscle tumors. These findings have led to a unifying concept, regarding GISTs as a morphologically (and immunophenotypically) heterogeneous group of tumors characterized by CD 117 immunoreactivity and differentiating towards an ICC phenotype.19,23 GANTs in our experience, are usually immunoreactive for CD 117 but often negative for CD34 and, in truth, fall within the spectrum of GISTs, since they also show the same c-kit mutations.26

The recognition of GISTs as a cohesive but phenotypically heterogeneous group of tumors, defined by the expression of KIT (CDl17), and their more objective separation from other mesenchymal neoplasms will allow more reproducibility between studies and may help to refine our criteria for malignancy and/or prognostic factors. The expression of KIT also appears as a useful adjunct in the diagnosis of those GISTs arising in less usual sites, such as the mesentery, omentum or retroperitoneum,27 as well as in their separation from other intra-abdominal neoplasms. Remarkably, a novel small molecule, STI-571 (Gleevec), which blocks the receptor tyrosine kinase function of c-kit is already proving to be very effective in treatment of GISTs which, until now have been regarded as a chemo-insensitive group of tumors. These remarkable results in KIT-expressing GISTs (with appreciable responses in 60% or more of patients with uncontrolled local relapse or metastasis) make it especially important for pathologists to use consistent diagnostic criteria in conjunction with reproducible immunohistochemical stains.

References

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