53 yo male, complaining of acute abdominal pain, with no other symptoms. Physical examination normal. CTScan reveals the presence of a mass, embedded in the wall of the small bowell in the pelvic area. Endoscopies were negative. Surgical excision of the tumor with wide margins is performed.

The specimen opened shows a large mass lobulated, firm, extending in the mesentery, mesuring 7 cm. A close up on the mucosae adherent to the tumor reveals a rounded ulcer on top of the lesion distorting the mucosal features.

The section along the ulcer demonstrates a yellowish mass adherent to the muscularis, extending in the mesenteric fat with pushing margins, and centered by large areas of necrosis and hemorrhage.

Low power views on the mucosal and serosal limits of the tumor.

Medium power views show variation in cellularity, with areas of hyaline changes.

Fascicular pattern of a spindle cell proliferation, moderately cellular, with slight atypia.

Mitotic figures count around 4 to 5 per 10 HPF in some areas.

The tumor cells express strong positivity to smooth muscle actin, and are negative to Desmin, S100.

DIAGNOSIS:

Size, location, mitotic count, and necrosis of this stromal tumor, are in favor of a malignant or at least of indeterminate malignant potential.

STROMAL TUMORS

Gastrointestinal stromal tumors (GISTs) constitute the largest category of primary nonepithelial neoplasms of the stomach and small bowel. They arise from cells located in the walls of the organ and show a remarkable variability in their differentiation pathways. This has resulted in a considerable degree of confusion in their interpretation, which if anything it has exacerbated recently. For many years, they were all regarded as being basically of smooth muscle nature and designated as leiomyomas and leiomyosarcomas when composed of spindle cells and as benign or malignant leiomyoblastomas (or epithelioid leiomyomas and leiomyosarcomas, respectively) when composed of epithelioid cells. The many immunohistochemical and ultrastructural studies that have been carried out by numerous authors in recent times have shown a much more complex picture. Acknowledging the fact that additional work needs to be done to fully understand these neoplasms, it would seem that they can be divided into four major categories on the basis of their phenotypical features:

I-Tumors showing differentiation towards smooth muscle cells, as evidenced immunohistochemically by the expression of smooth muscle actin and desmin and ultrastructurally by the presence of pinocytotic vesicles, subplasmalemmal dense patches, and cytoplasmic microfilaments; with focal densities. These tumors constitute by far the largest category. Theoretically, they could arise from the muscularis propria, muscularis mucosae, or vessel-related smooth muscle cells.

2-Tumors showing apparent differentiation toward neural elements, mainly determined by the presence on ultrastructural examination of neuron-like features such as long cytoplasmic processes resembling axons joined by primitive cell junctions, scattered microtubules consistentwith neurotubules, and dense-core neurosecretory type granules. These features have been likened to those of neural cells in the autonomic myenteric plexus and the tumors consequently designated as gastrointestinal autonomic nerve tumors (GANs), myenteric plexus tumors, or plexosarcomas. Curiously, immunohistochernical support for this interpretation has been meager, in the sense that neural/neuroendocrine markers such as neurofilaments, chromogranin, and synaptophysin have been generally absent and that the only markers in this category showing consistently positive results have been the less reliable neuron-specific enolase and/or S-100 protein. These tumors, which by definition lack markers of smooth muscle differentiation, constitute the second largest group. What relation they may have with the exceptional reported cases of gastric schwannoma is not clear. Suffice it to say that as a group GANs show ultrastructural features consistent with neuronal rather than schwannian derivation.

3-Tumors showing dual differentiation toward smooth muscle and neural elements, defined as per the criteria previously listed. These are the less common members of this family.

4-Tumors lacking differentiation toward either cell type, even after exhaustive immunohistochernical and ultrastructural probing. Some authors use the term GIST in a more restricted sense only for this particular group, which is almost as unusual as the third. Interestingly, a high percentage of tumors in this "uncommitted" category show immunoreactivity for CD34.

Some GISTs are already clearly identifiable as of smooth muscle nature at the hematoxylin-eosin level, in that they look similar to their counterparts in the uterus, esophagus, rectum, and other sites. This is nearly always the case with the small and sometimes multiple subserosal neoplasms that are seen frequently as incidental findings at autopsy or in stomachs removed for other reasons. For many of the clinically apparent tumors, however, the prediction concerning which of these four categories they will belong to is notoriously difficult to make. Spindle tumor cells with acidophilic fibrillary cytoplasm and the presence of cytoplasmic vacuoles at both ends of the nucleus should suggest smooth muscle differentiation. An epithelioid appearance is also more likely to be associated with evidence of smooth muscle differentiation, but many exceptions occur. This particular morphology is defined by the presence of round to polygonal cells with central nucleus and a usually abundant acidophilic or clear cytoplasm; the latter is regarded as an artifact of fixation. A prominent myxoid matrix may be present in between the tumor cells. Tumors with features of neural differentiation are generally composed of spindle (but sometimes epithelioid) cells growing in the form of fascicles, palisades, and whorls. Deposition of amorphous eosinophilic extracellular collections of abnormal collagen referred to as skenoid fibers is generally associated with neural differentiation. Features such as degree of cellularity, presence of large cells with bizarre hyperchromatic nuclei, marked diffuse vascularity, and nuclear palisading are of no help in this regard. Conventional special stains such as Masson's trichrome or Mallory's phosphotungstic acid-hematoxylin are also uninformative as a rule. In the final analysis, the categorization of many of these tumors is largely dependent on the results provided by the special studies previously enumerated.

An issue of obvious practical importance is the determination of malignancy in these tumors. This shows a statistical association with the pattern of differentiation. All tumors in category 2 (GANs) are currently regarded as malignant, even if those containing numerous skenoidfibers (and referred to as myenteric tumors) seem to behave in a less aggressive fashion. It would seern that the rare tumors in categories 3 and 4 are also to be regarded as malignant or potentially malignant. Along those lines, all of the GISTs in one series that were positive only for vimentin, had a rather primitive phenotype were malignant. By contrast, those tumors belonging to the first and largest category (those with smooth. muscle features) are divided into benign, borderline, and malignant, independendy of whether they are composed of spindle or epithelioid cells. Features favoring malignancy are size larger than 5 cm, necrosis, hemorrhage, hypercellulafity, nuclear atypia, and mitotic activity. In tumors composed of epithelioid cells, additional features suggestive of malignancy are location in the proximal anterior wall (rather than the antropyloric region), small tumor cell size, alveolar arrangement, and paucity of reticulin fibers. Although the correlation between mitotic activity and behavior is not nearly as good as for uterine smooth muscle tumors, it remains one of the most powerful predictors.

By combining this parameter with size, Amin et al.divided their cases into three groups: (1) benign: mitotic count less than 5 X 50 HPF, tumor size 5 cm or less; (2) borderline, same mitotic number but tumor size larger dian 5 cm; (3) malignant: mitotic count greater than 5 X 50 HPF, any size tumor. None of their nineteen benign or sixteen borderline tumors recurred or metastasized, whereas seven of ten malignant tumors metastasized, and one recurred. These authors found a good correlation between mitotic count and PCNA index, and others have reported a similarly good correlation between PCNA index and prognosis.

Clinically, the most common symptoms associated with GISTs are abdominal pain and melena. The large majority of the cases occur in adults; however, they have also been reported in children, and most of these have been malignant. In terms of location, most clinically apparent GISTs are located in the pars media (40%) of the stomach, followed by the antrum (25%). Although 20% occur near the pylorus, obstruction is rare. About 60% are submucosal and grow toward the lumen, where they make a smooth projection. In time, a central ulceration may occur (more commonly with the malignant tumors),that may penetrate into the tumor mass and result in hernatemesis.The smooth outline of the tumor and the central niche result in a highly characteristic radiographic appearance. About 30% of the tumors are subserosal, and the other is intramural. Grossly, the better differentiated smooth muscle tumors have a very typical appearance. On section, they are well-circumscribed and have a smooth, lobulated, or whorled-silk appearance. An hourglass defect may occur at the cardia or pylorus if the tumor encircles the stomach. Prominent fibrohyaline arm may be present, and they may undergo calcification.

The treatement consists of excision of the tumor with a good margin of normal tissue. Depending on the site and size of the tumor, this may involve a subtotal gastrectomy. Sirnple enucleation of the tumor should be discouraged. Wide resection of lymph node areas is not indicated because of the extreme rarity of lymph node metastases. The type of extent of the operation are more dependent on the tumor size and location than its subclassification in the GIST group.

The most common site of metastases of malignant GISTs are the liver, peritoneum, and lungs. These metastases can develop as long as 30 years after the removal of the primary tumor. In one series, the overall 5-year survival rate for GISTs classified as gastric leiomyosarcoma was 56%; large turnor.size, invasion of adjacent organs, and high microscopic grade affected the prognosis adversely. The assignment of a microscopic grade largely depends on mitotic

count and is a powerful prognostic indicator. The presence of neural features along GAN lines is associated with a very aggressive behavior, but this goes pari passu with the high mitotic: activity that characterizes these tumors. Determination of DNA ploidy by flow cytometry can distinguish benign from malignant GISTs, but it provides information of prognostic value in the subgroup of malignant tumors.

SMALL BOWEL STROMAL TUMORS

Stromal. tumors may occur in any portion of the bowel, but those exhibiting smooth muscle differentiation (which are the majority) predominate distally. Thus a review of 421 cases reported as small bowel leiomyosarcoma. revealed that 10% were in the duodenum, 37% in the jejunum, and 53% in the ileum.

The large majority of GISTs of the small bowel are solitary, but cases presenting as multiple nodules in small and large bowel have been reported. Grossly, they are fairly well circumscribed, and their pattern of growth may be predominantly submucosal or subserosal. The former may develop a central ulcer niche similar to that more often seen in their gastric counterparts. Those growing toward the mesentery can reach huge dimensions. The symptoms depend on their growth pattern. They may be detected because of occult or massive bleeding, pain, obstruction, intussusception, or perforation . Those located in the pelvis often have clinical and radiographic features resembling ovarian neoplasms. Exceptional cases have been associated with evidence of HCG production.

As in the stomach, these tumors may show immunohistochemical/ultrastructural evidence of differentiation towards smooth muscle elements (the majority), neural elements (the second largest group), both, or neither. Those exhibiting features of neural differentiation have been the subject of a particularly close scrutiny in recent years. This includes the subset of tumors containing skenoid fibers, which allegedly are less aggressive than the others. A myenteric plexus origin has been proposed for them, even if the features of the tumor cells do not exactly match any of the well-characterized component of this structure. However, some interesting similarities with the interstitial cell of Cajal exist. The percentage of tumor of uncommitted type may be higher in the small bowel than in stomach, as suggested by the large number of cases showing immunoreactivity for CD34; this, however, may be associated with immunoreactivity for smooth muscle markers.

Also in analogy with the stomach, some relationship exists between these differentiation patterns and the clinicopathologic features. Thus multiple stromal nodules involving both small and large bowel are always obviously muscular in nature ("leiomyomatosis"). Those tumors occurring in the AIDS-affected population also have smooth muscle features and often exhibit a close microscopic relationship w ith vessel walls, suggesting an origin from them. The percentage of tumors with epithelioid morphology is smaller than in GISTs located in the stomach. The subdivision into benign, borderline, and malignant tumors is based on criteria similar to those used for their gastric counterparts. Any small bowel GIST should be regarded as malignant or at least of indeterminate malignant potential if any of these features is present: large size (over 5 cm), fresh tumor necrosis, extensive hemorrhage unrelated to surgery, extreme cellularity, marked atypia, or high mitotic activity (five or more mitoses per ten high-power fields). Of these, high mitotic activity is the single most important microscopic feature, both to place tumors in a malignant category and to further divide them into low and high grades. Among GISTs of the duodenum, those composed of large cells and having an organoid pattern are predictably benign, whereas highly cellular tumors with small cells and little or no organoid pattern are malignant. It should also be kept in mind that the percentage of malignant cases is higher in,GIST of small bowel than in those for the stomach.

Malignant GISTs of small bowel may invade adjacent structures such as the pancreas by direct extension. They also tend to invade the bloodstream and metastasize distantly. Staging, microscopic grading, and DNA ploidy have been shown to correlate with prognosis. Of twenty patients studied by Ranchod and Kempson, fifteen developed metastases (usually to the liver and peritoneum), and four others developed intra-abdominal tumor with prominent retroperitoneal spread; only one patient was found to be alive and free of disease at the time of the last follow-up.

(Ref. Ackerman's Surgical Pathology. 8ed.)