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CT, MR, and CEUS imaging features of recurrent GIST of the pre-sacral space: A case report

We present the case of a 50-year-old woman affected by a rectal gastrointestinal stromal tumor (GIST), with a recurrence in pre-sacral and pre-coccygeal space after surgery and Imatinib therapy. GISTs are the most common mesenchymal tumors of the gastrointestinal tract and rectal GISTs are rare (only 2% of cases); magnetic resonance and computed tomography are the main imaging techniques for diagnosis and follow-up, while ultrasound and contrast-enhanced ultrasound may be useful to perform a percutaneous biopsy, as in the case presented: the imaging features of the lesion in all these imaging methods are displayed.


Introduction
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract and the organ most frequently involved is the stomach (60%-70%): these lesions arise from the interstitial cells of Cajal, which work as an intestinal pacemaker cell [1] .
Computed tomography (CT) and magnetic resonance (MR) of the abdomen and pelvis play a pivotal role in the diagnosis and follow-up. Moreover, imaging is fundamental for the biop- tic sampling, which represents a vital step for the diagnostic and therapeutic management [ 2 ,3 ]. The histologic diagnosis of GIST is performed with immunohistochemistry and electron microscopy, which are able to recognize the presence of straining for tyrosine kinase receptor KIT (CD 117), confirming the presence of the interstitial cells of Cajal [4] . Because of the strong association between GISTs and KIT or PDGFRA mutations, there is the possibility to treat these malignancies with biologic targeted therapy, for example, with imatinib mesylate (IM) [5] . In the 1970s IM therapy was discovered, a selective inhibitor of transmembrane receptor KIT protein tyrosine kinases which inhibits the proliferation of GIST tumor cells that are stimulated by the activation of this receptor [5] .
Of all the GISTs, rectal localizations are extremely rare, reported in literature in only 2% of cases, and resection appears curative, with extensive surgery not necessarily required due to the chance of downstaging with IM therapy [6] . However, whereas the appropriate surgical technique is still debated, the importance of a precise imaging follow-up is well established to early diagnose an eventual recurrence and to properly administer the adjuvant therapy [7] .
Thus, we present a multi-recurrent rectal GIST located in the pre-sacral/pre-coccygeal space, with an extensive description of CT, MR, ultrasound (US) and contrast-enhanced US (CEUS) imaging features of the recurrent lesion.

Case presentation
We describe the case of a 50-year-old woman with a multirecurrent rectal GIST. In 2000, during a routine gynecological check-up a perineal mass was found. A schwannoma was firstly suspected, but the biopsy established the presence of a rectal GIST, located between the rectum and the vagina, which was surgically removed with a laparoscopic anterior rectal resection (RARL). In 2001, she had a local recurrence and started immunotherapy with Imatinib, with subsequent progressive volume reduction of the mass. New Imatinib administration for local recurrence 2020 MR showing expansive solid mass in pre-coccygeal region 2021 Re-biopsy of the mass In 2003, the patient underwent a new surgery to remove the local recurrence, complicated by a recto-vaginal fistula. The fistula was surgically treated in 2005, and thereafter started a regular follow-up, without evidence of recurrences for 3 years, until 2008, when due to the evidence of a new local recurrence, she was administered a new cycle of IM.
After several years, a new follow-up MR exam performed at the end of 2020 ( Table 1 ) showed the presence of a new richly vascularized solid mass located in the pre-coccigeal region expanding in the fat tissue of the ischio-rectal fossae with confluent grape-shaped nodules ( Fig. 1 ). The recurrence was treated with IM and a new MR exam performed 6 months later showed the progression of the disease, with volumetric increase of the lesion (mean diameter of 4.5 cm vs 3.9 cm) ( Fig. 2 ).
On March 2022 the Patient was referred to our Interventional Radiology department to perform a reassessment  CEUS-guided biopsy, with subsequent molecular studies, in order to evaluate the possibility to start a new targeted biological therapy and to properly differentiate the presence of a different mesenchymal tumor. The pathological examination confirmed GIST histology, with positivity for CD117, DOG1 and CD34 and negativity for SMA and desmin. Molecular exams showed PD-L1 negative, PDGFRA negative and positive mutation of exon 11 of c-kit.

Discussion
As above-mentioned, imaging plays a pivotal role in the diagnosis and follow-up of primitive GISTs.
US is not routinely performed for GISTs; however, in our case, we decided to use CEUS as an aid to perform the biopsy. In a recent work, Wronski et al. showed that GIST has 3 main patterns of presentation on US [8] : -a homogeneously solid mass with low aggressiveness (most common); -a heterogeneous solid mass, with central necrosis and hemorrhage, usually associated with higher mitosis rate and higher aggressiveness; -a heterogeneously solid mass with irregular patchy hypoechoic or anechoic areas, also due to necrosis, associated to greater aggressiveness.
The case presented, as seen in the Fig. 3 , corresponds to the second pattern described; performing a CEUS-guided biopsy ensure to avoid the necrotic portion of the lesion, with higher accuracy of the histologic sampling.
Typical GISTs CT imaging features consist in the presence of a large, hyper vascular, enhancing mass, often with heterogeneous enhancement due to necrotic and hemorrhagic areas, sometimes directly invading surrounding structures [3] . The unenhanced CT scan performed in 2001 ( Fig. 4 ) showed a heterogeneous mass located in pre-sacral and pre-coccygeal space, with polylobate contours and small calcifications.
Besides, MR is an excellent exam to better characterize the GIST mass composition: it may help to distinguish the presence of hemorrhagic areas, necrosis, or cystic degeneration. Classically, the solid components of the tumor are typically hypointense on T1w, hypo/iso-intense on T2w, and show enhancement after contrast administration [2] . The presence of intra-tumoral cystic areas and solid components with restricted diffusion are predictors of high malignant potential [7] . As seen in the Figs. 1 and 2 , the mass was multi-loculated with cystic, necrotic, and solid components, demonstrating the typical features of a locally aggressive malignant tumor, as confirmed by the patient's history.
Local recurrence tends to have similar imaging features to the primitive tumor, usually presenting as an area of thickening with contrast enhancement, adjacent to the bed of the previous surgical excision.
The behavior of GISTs is mostly driven by mutations in the KIT or PDGFRA genes: Yu et al. [9] observed that KIT mutations have an impact on the recurrence rate after surgery and chemotherapy resistance in GISTs, in particular they demonstrated that exons 13, 17, 9, and in particular exon 11 are associated with a higher recurrence rate and chemotherapy resistance. Our patient had an exon 11 mutation, thus  explaining the resistance to chemotherapy and the high recurrence rate.
As in the case presented, most of primary rectal GISTs are typically managed with surgical resection as the first therapeutic option. In 2008 Hamada et al. [10] reported a case series of recurrent rectal GIST in Japan (33 patients) and concluded that the administration of IM before surgery not only allows a greater chance of complete excision of the tumor with negative margins, but it also reduces post-operative recurrences. Some of the cases reported were also GISTs with multiple cases of recurrence (recurrence rate up to 3), similar to our case.
Even though being still limited, the available data suggest that only 10%-20% of patients with rectal GISTS are completely cured with resection, and moreover, that recurrence represent a potential risk for up to 15 years, as in the case we presented, highlighting the importance of prolonged follow-up.
Lee et al. [11] reported the case of a 54-year-old woman with a GIST located to the rectovaginal septum: the authors considered that in this localization, it is quite difficult to discern the organ of origin between the rectum, the rectovaginal septum or the vagina. Several cases of EGIST are reported in literature, with different location, such as the retroperitoneal space [12] , but also the prostate [13] and the pancreas [14] . The recurrence site in our case was the pre-sacral and pre-coccygeal space: EGISTs typically do not arise from the GI tract; however, they histologically and immuno-histochemically resemble their GI counterparts.
Hence, it is difficult to properly classify these tumors as GISTs or extra-GISTs (EGISTs) and further studies are necessary to evaluate imaging, molecular and eventual prognosis differences between GISTs and EGISTs [11] .
To our knowledge, this is one of the first cases of pre-sacral and pre-coccygeal location of GIST recurrence with extensive imaging features in different modalities described.

Conclusion
Rectal GISTs are very rare: a case of multi-recurrent rectal GIST on pre-sacral and pre-coccygeal location is reported, with CT, MR and CEUS imaging features described. More studies are needed to understand the differences between GIST and EGIST about histology, prognosis, treatment, and imaging features.

Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Consent for publication
Consent for publication was obtained for every individual person's data included in the study.

Patient consent
Informed consent was obtained from all individual participants included in the study.