Gastrointestinal Stromal Tumors in the Rectum

Definition of GIST

GISTs are an uncommon group of mesenchymal tumors, arising from intestinal cells of Cajal or their precursors, the intestinal mesenchymal precursor cell. They are more common than true leiomyomas, leiomyosarcomas and schwannomas of the gastrointestinal tract, which are also mesenchymal tumors of smooth muscle cell origin. They are separated from them mostly by their positive expression of c-Kit or CD117.^[7] c-Kit is a proto-oncogenic receptor whose ligand is a stem cell factor.^[8] The true leiomyomas and schwannomas do not express CD 117, nor do they express CD34, a myeloid progenitor cell antigen, which is expressed by 70~80% of GIST.^[9,10] The expression of the muscle marker SMA by GIST is variable and occurs in 20~40% of the cases. Expression of desmin is uncommon whereas the majority of true leiomyomas express SMA and desmin.

Characteristic of rectal GISTs

No specific symptoms or specific serum tumor markers could be found in the early stages of rectal GISTs. It is difficult to distinguish GISTs from rectal cancer but digital palpation has been recommended as an easy and efficient method to diagnose rectal GISTs. Intact overlying mucosa covering the intramural GISTs in the rectum is commonly seen in colonoscopy and always leads to negative findings in biopsies.^[7] Both smooth muscle tumors and GISTs always display a spindle cell appearance, especially for the tumors of the rectum,^[1,9] and light microscopy is not helpful in differentiating smooth muscle tumors from GISTs.^[11] None of the 19 cases were diagnosed exactly through biopsy during colonscopy or rapid frozen tissue sections during operation. Deep-site biopsy or repeated biopsy, combined with immunohistochemical staining, was helpful for a definitive GIST diagnosis. It is difficult to get a proper pathologic diagnosis and difficult to decide whether to save the rectal sphincter prior to operating.

GISTs have a low incidence ^[4,12,13] with only sporadic reports concerning rectal GISTs published from 1990 to 2004. Previously most of the tumors were regarded as leiomyomas of the gastrointestinal tract and now would probably fall into the new GIST definition. Mi-ettinen et al,^[14] indicated that mesenchymal tumors of the muscularis mucosae of the rectum were benign leiomyomas and should be separated from GISTs.

Pathologic diagnosis

GISTs occur in the entire gastrointestinal (GI) tract but may also arise from the omentum, mesenteries and retroperitoneum. Originally thought to be of smooth muscle origin from the intestinal wall, they were referred to as leiomas or leiomyosarcomas. However, more recent studies have suggested that their true origin may be from intestinal pacemaker cells, having a neural and muscle appearance. These are also referred to as cells of Cajal.^[15] A highly spindle cell morphology was common in pathological examinations. Alternatively, these tumors may show epithelioid features, with active or quiescent mitotic activity. Additionally, most have tyrosine kinase receptors (KIT) and stain positive for CD117 or CD34 markers.^[16]

Criteria for distinguishing benign GISTs from malignant GISTs, or at least to identify those lesions which are more likely to metastasize, has been sought, analyzed, and disputed for many years. Many parameters have been proposed, but the morphologic features that have gained greatest acceptance as being predictive of outcome are mitotic rate and tumor size. ^[4,17,18] The problem that has persisted (and still remains unresolved) is that whereas these indices correlate with a relative risk of malignant behavior, the fact remains that lesions which are very small (even <2 cm) and lesions with very low mitotic rates (even <5 per 50 HPF) occasionally metastasize. In fact, an increasing number of centers are reluctant to use the term “benign" for any GIST, with the possible (but disputed) exception of very small lesions (usually <1 cm) found incidentally during abdominal surgery for other reasons.

With prolonged follow-up, it appears that almost any GIST patient presenting with clinical symptoms or signs leading to treatment has the potential to behave in a malignant fashion. Having said this, no more than 50% of primary localized GISTs relapse within the first 5 years of follow-up,^[4] but the situation at 10 years is much less clear ^[19] likely reflecting different populations under study. What is absolutely clear is that, to date, if these tumors recur locally within the peritoneal cavity or give rise to hepatic metastasis (the 2 most common forms of first relapse for GIST), then the prognosis is almost invariably poor, albeit sometimes over a prolonged time scale. Although some experts disagree and maintain that at least some benign lesions can be accurately identified on morphologic grounds alone, it seems most prudent to develop a scheme based on risk assessment, rather than try to define strict criteria to separate benign from malignant (which appears to be a practical impossibility at the current time).^[20,21] Thus, instead, one would indicate for a given GIST its risk (low, intermediate, or high) of pursuing an aggressive clinical course, recognizing that some subset of cases (hopefully <10%) will behave in an unpredicted or unexpected fashion and that no lesion can be definitively labeled as benign.

According to the standard definition of NIH, there were 5 cases of high risk (26.3%), 3 cases of intermediate risk (15.8%), 4 cases of low risk (21.1%) and 7 cases of very low risk (36.8%) of aggressive GIST behavior in our study. The frequency of benign versus malignant GISTs varies between sites. Benign GISTs outnumber malignant GISTs in the stomach, whereas malignant GISTs are more common in the intestines. ^[22] But there have been only sporadic reports about rectal GISTs. The ratio of low and very low risk cases in our study was consistent with the - reports of Michalopoulos et al.^[23] and Changchien et al.^[24] We speculate that rectal GIST has a low risk of aggressive behavior and is different from those found in the stomach and intestine.

Management and prognostic

Before the development of imatinib, surgical resection was the only treatment for tumors classified pathologically as GIST.^[25] The primary goal of surgery is complete resection of the lesions, because rupture at surgery is another poor prognostic factor.^[26,27] With a 1.5 cm safe resection margin, trans-anal resection was recommend for sub-mucosal GISTs (<3.0 cm) of the rectum and lymphadenectomy was not absolutely necessary^[28] Trans-anal or vaginal local resection was performed on 11 patients of low or very low risk of aggressive behavior and one of these patients had disease-free survival for 214 months. A second radical resection was needed if there was a post-operation diagnosis of high risk of aggressive behavior. Due to a high recurrence rate, highly aggressive risk cases were unsuitable for local resection. ^[29] Two cases of high risk and intermediate risk in our study had a local recurrence after trans-anal resection. A lowanterior resection should be applied for a tumor more than 4 cm and if located in the upper level of the rectum. Multivisceral resection could improve the prognosis for locally advanced (without diffuse metastasis) rectal GISTs. Palliative management such as colostomy was suitable when there is disseminated tumor or a tumor mass.

Most patients with a malignant stromal tumor have had either a local recurrence or metastasis to the liver. Locally recurrent tumors have not usually been amenable to complete resection because of peritoneal implantation,^[30] nor has chemotherapy been very effective.^[31] Solitary liver metastasis could be surgically resected,^[32] but multiple liver metastases are difficult to manage. Trans-catheter arterial embolization has been used, but the partial response rate was low. The five year survival rate of patients with GIST is 35~65%.^[4]

Of the 19 patients, 16 cases have survived more than one year and 6 cases have survived more than 5 years. All the patients have survived up to now. Chang chien^[24] indicated that radical resection was superior to wide local excision in the prevention of local recurrence, but not that of distant metastases The recent introduction of a new targeted therapy, STI-571 (imatinibmesylate,GIeevec)areceptortyrosinekinaseinhibitorofactivated KIT protein, for the first time provides an effective treatment for recurrent or metastatic GISTs. Lo et al^[33] reported that neoadjuvant therapy with imatinib decreased the tumor size ofrectal GISTs, permitting sphincter-sparingtrans-anal excision.