Relationship between diagnostic imaging features and prognostic outcomes in gastrointestinal stromal tumors (GIST).

Gastrointestinal stromal tumors (GISTs), the most frequent mesenchymal neoplasms of the gastrointestinal tract, are a relatively recently described entity. GISTs can occur across any age but are more common in patients older than 50 years. GISTs most commonly are in the stomach (60-70%), followed by the small intestine (20%-30%); they also rarely occur in the abdominal cavity, such as in the mesentery, the omentum and the retroperitoneum. Contrast-enhanced multi-detector computed tomography (MDCT) is the most largely used imaging modality for the localization, characterization and staging of GISTs. All patterns of enhancement on contrast-enhanced MDCT can be seen with GISTs, including hypoenhancing, isoenhancing, and hyperenhancing neoplasms. A lot of prognostication systems have been proposed for the risk stratification of GISTs. This review outlines the relationship between different diagnostic imaging features and prognostic outcomes in GISTs.

Introduction

Gastrointestinal stromal tumors (GISTs) are the most frequent mesenchymal tumors of the gastrointestinal tract, they are thought to arise from the interstitial cells of Cajal, which are intestinal pacemaker cells that allow peristalsis and segmentation of the smooth muscle (1-3).

Rubin et al. in their study said that GISTs have no predilection for either sex, and although they occur over a wide age distribution, in fact about 75% are diagnosed in patients older than 50 years (4). These tumors can arise everywhere in the gastrointestinal tract, but their most common locations are the stomach (60-70%) and the small bowel (20-30%) (5-7). About 5% of GISTs are in the colon and rectum, another 5% in the esophagus (4, 8-11). A small part of these tumors also develops within the mesentery, omentum, retroperitoneum, and pelvis (E-GIST) (12, 13).

Usually patients have non-specific symptoms including early satiety, bloating, gastrointestinal bleeding, fatigue from anemia, or obstruction (14). Bleeding can take the form of slow, intraluminal gastrointestinal bleeding or massive intraperitoneal bleeding following the rupture and can be seen regardless of the enhancement pattern (15). Aggressive GISTs have a defined pattern of metastasis to the liver or throughout the abdomen (usually as multiple serosal-based nodules), or both (5). Contrasting GISTs in elderly patients, lymphatic metastases represent a common route of initial spread in young patients (< or = 40 years) (16). Extra-abdominal diffusion is mainly to the lungs and bone but isn’t usual (17). Gold et al.showed that a lot of patients have localized disease (79.4%), but approximately 11.4% have regional-distant metastatic disease at the time of presentation; recurrences have been reported up to 30 years after initial diagnosis and resection (18).

GISTs have the classic tendency of exophytic growth, especially since they arise from the outer muscular layer. There is frequently some growth towards the lumen however, as up to 50% of GISTs will exhibit mucosal ulceration on the luminal surface. Among other macroscopic characteristics, there can be focal areas of hemorrhage, necrosis, calcifications, intralesional cavitation or cystic degeneration (19).

Histologically, GISTs can be classified into three main subtypes: spindle cell type (most common, 70%), epithelioid type (20%), and mixed (10%). The cellularity is also highly variable, passing from hypocellular to highly cellular with high mitotic rates (20, 21).

Kindblom et al. in their study described that GISTs can have many histological patterns and can be positive for c-KIT (95%), CD34 (60-70%), ACAT2 (smooth muscle actin; 30-40%), S100 (5%), DES (desmin; 1-2%), and keratin (1-2%) (22-25).

Zao et al.showed how C-KIT is the most specific and sensitive marker in differentiating GISTs from other entities (20). Mol et al.described how C-KIT positive tumors benefit from system therapy with imatinib mesylate, defined as a target therapy (26-28). However, a subset of the 5% of tumors that are c-KIT-negative might benefit from c-KIT-targeted therapy (29).

The wide range of clinical presentations along with non-specific symptoms can pose a challenge in differential diagnosis of GISTs. To date contrast-enhanced multi-detector computed tomography (MDCT) is the most largely used imaging modality for the localization, characterization and staging of GISTs (30).

In fact radiologists have a leading role in timely and accurate diagnosis for the frequent tumor’s variability in relation to location, pattern of enhancement, and other imaging features such as necrosis or cavitation.

Prediction of prognosis of primary tumors has been studied intensively. In their study Fletcher et al. proposed tumor size and mitotic activity as the two main factors for the risk stratification system (23).

We considered the correlation between AFIP criteria and MDCT features of GISTs; evaluating mitotic count and tumor size, this system incorporated tumor location as an additional variable and stratified prognosis of GISTs into 5 classes (none, very low, low, moderate, high) (31).

In this review of recent literature, we evaluated how some CT features such as location, size, margins, contrast enhancement are closely related to the malignancy risk and therefore to the outcome.

Imaging features

Cross-sectional imaging techniques are largely used for a variety of conditions and diseases both for diagnostic and interventional purposes (32-49). Ultrasonography is a radiation-free and well-tolerated imaging examination (50-53), but has a limited role in gastrointestinal pathology (54-61). MR has an excellent soft tissue contrast (62-65), but contrast-enhanced MDCT is the preferred technique for the diagnosis, staging and follow-up (66-73). The aspect of GISTs on imaging is highly variable with regards to location, relation to stomach-bowel wall, size, margins, pattern of enhancement and other imaging features that modify homogeneity of the lesion at non contrast-enhanced MDCT (hemorrhage, necrosis, calcifications, intralesional cavitation and cystic degeneration) (74, 75).

At the time of diagnosis with imaging GISTs could have variable dimensions range, measuring less than 1 cm to very large lesions measuring upwards of 35 cm (median 5 cm) (15). The tumors generally present as single nodules but they can consist also of multiple nodules. They are usually solid but can have central cystic degeneration. Calcification is an unusual feature of GISTs; it may occur in a smudged pattern or be present extensively throughout the tumor (Fig. 1) (22-24). Sharp et al.in their cases showed that central areas of low attenuation coincide with hemorrhage, necrosis, or cyst formation (76). Scatarige et al.said that lesions with extensive hemorrhage or necrosis may form large cystic spaces or cavities which may communicate with the gastro-intestinal lumen (77).

Figure 1.

Axial (a) and coronal (b) contrast enhanced MDCT images in the portal venous phase show an intraluminal mass of gastric corpus (white arrows). This GIST presents heterogeneous contrast enhancement, irregular margins and size < 5 cm with centimetric intralesional calcification

Through evaluation with contrast-enhancement MDCT, these tumors may show smooth and regular margins or irregular and jagged borders (78, 79) (Fig. 2, Fig. 3).

Figure 2.

Axial (a) and coronal (b) contrast enhanced MDCT images in the arterial phase demonstrate a voluminous GIST on the anterior wall of gastric corpus (white arrows). The lesion shows heterogeneous contrast enhancement, regular margins and size > 5 ≤ 10 cm

Figure 3.

Axial (a), coronal (b) and sagittal (c) contrast enhanced MDCT images in the portal venous phase demonstrate an intraluminal mass of gastric corpus (white arrows). The lesion presents heterogeneous contrast enhancement, irregular margins and size < 5 cm.

All patterns of enhancement on contrast-enhanced MDCT can be seen with GISTs, including hypoenhancing, isoenhancing, and hyperenhancing neoplasms (Fig. 4).

Figure 4.

Axial (a,b), coronal (c) and sagittal (d) contrast enhanced MDCT images in the arterial (a) and the portal venous phase (b,c,d) show an exophytic mass of the duodenum (white arrows), strictly adjacent to the inferior vena cava. This GIST presents heterogeneous contrast enhancement, irregular margins, size > 5 ≤ 10 cm and a central area with necrosis and cavitation

A peripheral enhancement pattern is present in the majority (92%) of cases on contrast-enhanced MDCT images. Homogeneous enhancement is present in a small part (8%) of cases (80). Contrast-enhanced MDCT may also demonstrate evidence of adjacent organ invasion, ascites, omental and peritoneal diffusion of tumor, or liver metastases (81-83) (Fig. 5, Fig. 6).

Figure 5.

Axial (a) and coronal (c) contrast enhanced MDCT images in the arterial phase demonstrate an extraluminal mass of gastric fundus (white arrows). The lesion shows heterogeneous contrast enhancement, irregular margins and size > 10 cm. Axial (b) contrast-enhanced MDCT image in the arterial phase shows some over-centimetric serosal-based nodules located in mesenteric adipose tissue (white arrows)

Figure 6.

Axial (a) and coronal (b) contrast enhanced MDCT images in the arterial phase demonstrate a nodular mass of the jejunum (white circles). This GIST presents heterogeneous contrast enhancement, irregular margins and size < 5 cm. Just above, there is a diffuse reticular thickening of mesenteric adipose tissue (a, white arrow), suggestive for multiple serosal-based nodules. Furthermore coronal (b) contrast-enhanced MDCT image shows a hypovascular liver metastasis (white arrow)

Prognostic system

Numerous prognostic systems have been proposed for the assessment of disease progression risk of GISTs, defined as the appearance of metastasis or tumor-related death. The most widely used systems today are the AFIP, the NIH, Joensuu modified NIH, and the Memorial Sloan Kettering Cancer Center nomogram.

The AFIP criteria were developed by Miettinen et al. in 2006 and based on previous AFIP studies reporting on 1055 gastric, 156 duodenal, 906 jejunal/ileal and 144 colorectal GISTs with no statistical validation.

Nevertheless, it remains uncertain which system is the most accurate. More validation and comparison studies are required to determine the optimal prognostic system for GISTs (23, 30, 84).

Imaging vs Prognosis

In the assessment of risk stratification, the AFIP criteria allow to subdivide these neoplasms in relation to the site of origin, GISTs located in the stomach turn out to be the least aggressive, followed by the duodenum or rectum and jejunum or ileum, characterized by greater risk of progression (85, 86).

One of the three main prognostic factors in Miettinen classification is tumor size: tumors smaller than 5 cm have a favorable prognosis, intermediate between 5 and 10 cm and unfavorable greater than 10 cm (31).

Another important aspect to stress is the significant associations of several MDCT features with the size of the tumor. Some MDCT features could be observed more frequently with increasing tumor size. In fact neoplasm size seems to be statistically significantly associated with the pattern of contrast enhancement, necrosis, the shape of margins and adjacent organ invasion (76).

Zhou et al. in their study demonstrated that the analysis of the distribution of all these parameters among the different classes of size showed that heterogeneous contrast enhancement, irregular margins, and the other previously mentioned features (hemorrhage, necrosis, intralesional cavitation, cystic degeneration) trend to grow up with the increase of the size of tumor, being mostly detected in tumors sized 5 to 10 and greater than 10 cm (87-90).

The presence of single or multiple nodules is not correlated with an increased risk of disease progression. The finding of intralesional calcifications seems to be an aspecific parameter and not related to the prognosis. On the other hand, hemorrhage, necrosis, intralesional cavitation and cystic degeneration are associated with an increased risk of malignancy and therefore of disease progression (91).

Moreover, a significant association has been observed between shape of lesion margins and mitotic index (closely related to the outcome): most of lesions with a number of mitoses less than or equal to 5/50 HPFs showed regular margins, suggesting that solid lesions with smooth and not crispy borders could be less aggressive than the ones with jagged borders (75, 80). The presence of irregular margins showed a linear correlation with the risk classes, as it was absent in the none, very low, and low classes, whereas it could be observed in the moderate class and in high class (75, 80). In fact the mean number of mitoses was higher among the lesions with irregular margins compared with the mean value of mitoses detected in neoplasms showing regular margins (80, 92-95).

Many studies demonstrate that the presence of heterogeneous pattern of contrast enhancement is mainly observed in GISTs belonging to the moderate and high classes of risk. On the other hand, tumors belonging to the none and very low risk classes appear in most cases as lesions with a homogenous pattern of contrast enhancement (94, 96-104) (Table 1).

Table 1.

Relationship between different diagnostic imaging features on MDCT and prognostic outcomes in GISTs

CT characteristics	Favorable prognosis	Intermediate prognosis	Unfavorable prognosis	Author, Year
Site	Stomach	Duodenum or rectum	Jejunum or ileum	Al-Thani et al., 2014
Size	<5 cm	>5 cm <10 cm	>10 cm	Miettenen et al., 2006
Single or multiple	Not related	Not related	Not related	Maldonado et al., 2018
Margins	Regular	/	Irregular	Iannicelli	et al., 2009
Enhancement	Homogenous	/	Heterogeneous	Levy et al., 2003

Even Levy et al. in their study notice that the degree of contrast enhancement, if high, was considered as a remarkable characteristic of tumor biological activity (74) (Table 2).

Table 2.

GISTs MDCT features that modify the homogeneity: hemorrhage, necrosis, calcifications, intralesional cavitation and cystic degeneration

Tumor characteristics	Characteristics	Prognosis	Author, Year
Hemorrhage	Area of hyper/iso/hypodensity	Unfavorable	Zhou et al., 2016
Necrosis	Area of hypodensity	Unfavorable	Lee et al., 2004
Calcifications	Focal or smudged hyperdensity	Not related	Maldonado et al., 2018
Intra-lesional cavitation	Intralesional hypodensity (air density)	Unfavorable	Kim et al., 2004
Cystic degeneration	Central area of hypodensity	Unfavorable	Maldonado et al., 2018

Discussion

To the best of our knowledge, only few studies had investigated the correlation of GISTs MDCT findings with pathology (74, 90-93). The study of Iannicelli et al. could be considered the first article where many features related to GISTs prognosis and behavior are compared with CT findings to assess whether any MDCT findings could be predictive or specific of the Miettinen classes of risk (80).

In this review we want to underline how unfavorable prognostic aspects are represented by the jejunal-ileal localization, tumor size greater than 10 cm, irregular margins, heterogeneous enhancement and other imaging features that modify homogeneity of lesion at non contrast-enhanced MDCT (hemorrhage, necrosis, intralesional cavitation and cystic degeneration) (87-91). Intermediate prognostic features are duodenal or rectal localization and lesion dimensions between 5 and 10 cm (31, 85). Favorable prognostic elements consist of gastric localization, tumor size below 5 cm, smooth margins, lesion with homogeneous density and homogeneous enhancement (74, 75, 91). The presence of single or multiple lesions and the intralesional calcifications (focal or smudged) do not seem to be correlated with the prognosis (91).

In conclusion MDCT imaging features are crucial in GISTs detection and contribute to the risk stratification evaluating localization and size of the tumor; moreover, MDCT morphological features could be correlated with pathological parameters like the mitotic rate which is the expression of the tumor biology. Therefore, MDCT parameters could give a first step orientation, before the pathological examination, of the biological behavior and the prognostic outcome of GISTs.