Mesenchymal Tumors of the Gastrointestinal Tract

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Chapter 30

Mesenchymal Tumors of the Gastrointestinal Tract

Erinn Downs-Kelly

Brian P. Rubin

John R. Goldblum

Introduction

Although epithelial neoplasms predominate in the tubal gut, a variety of mesenchymal neoplasms may originate from or secondarily involve the gastrointestinal (GI) tract. Given the rarity of these lesions and the fact that many have overlapping histologic features, their accurate classification can be challenging, especially in the setting of limited endoscopic biopsy material. That said, knowledge of a few key details can help narrow an often wide differential diagnosis. For example, mesenchymal neoplasms have favored anatomic locations within the tubal gut as well as characteristic sites of involvement or origin from the various components of the gastrointestinal tract (mucosa, submucosa, muscularis, or serosa), as described in Table 30.1. An important consideration when faced with an apparent spindle cell lesion involving the tubal gut is to exclude the possibility of a sarcomatoid or spindle cell carcinoma. In this instance, a panel of cytokeratin stains can usually correctly identify the lesion as a carcinoma. It is also important to remember that gastrointestinal stromal tumors (GISTs) account for as many as 90% of clinically significant mesenchymal neoplasms within the GI tract; for that reason, GISTs will receive major emphasis within this chapter.

Table 30.1

Favored Anatomic Locations and Involvement by Mesenchymal Neoplasms of the Gastrointestinal Tract

Neoplasm	Most Common Anatomic Location	Most Common Layer Involved within the Gastrointestinal Tract
Gastrointestinal stromal tumor (GIST)	Stomach (60%), jejunum and ileum (30%)	Muscularis propria and submucosa
Schwannoma	Stomach	Muscularis propria and submucosa
Gangliocytic paraganglioma	Duodenum	Submucosa
Polypoid ganglioneuroma	Colon	Mucosa
Mucosal perineurioma	Colon	Mucosa
Mucosal Schwann cell hamartoma	Colon	Mucosa
Granular cell tumor	Esophagus	Submucosa
Leiomyoma	Colon and rectum Esophagus	Muscularis mucosae Muscularis propria
Lipoma	Colon	Submucosa
Glomus tumor	Stomach	Muscularis propria
Inflammatory myofibroblastic tumor	Intraabdominal	Mesentery and omentum
Plexiform fibromyxoma	Stomach	Muscularis propria
Perivascular epithelioid cell tumor (PEComa)	Colon and rectum	Variable; mucosa and submucosa or entire thickness of bowel wall
Clear cell sarcoma–like tumor	Small bowel	Entire thickness of the bowel wall

Gastrointestinal Stromal Tumors (GISTs)

Although GISTs were once believed to represent smooth muscle neoplasms,¹^–³ it has now been established through ultrastructural and immunophenotypic studies that they arise from either the interstitial cells of Cajal (ICC) or the precursors of those cells.⁴^–¹⁰ ICCs are present throughout the wall of the GI tract. They function to coordinate peristalsis by generating and propagating electrical slow waves of depolarization.⁷^–⁹^,¹¹^,¹² Although the location and density of ICC vary, in most portions of the GI tract, the largest density occurs around the circumference of the myenteric plexus with extension between the inner and outer layers of the muscularis propria¹³ (Fig. 30.1).

FIGURE 30.1 KIT immunostain highlights the normal distribution of interstitial cells of Cajal in the myenteric plexus and adjacent muscularis propria.

KIT (CD117) has been identified as a receptor tyrosine kinase that plays a role in the development and maintenance of ICCs⁶^,¹⁴: the binding of KIT ligand leads to phosphorylation of signal transduction proteins that modulate cell proliferation and inhibit apoptosis.¹⁵^,¹⁶ Mice that are deficient in Kit or in stem cell factor (the normal ligand for Kit) do not have ICCs and show evidence of intestinal dysmotility.¹⁷ Activating mutations in KIT or in platelet-derived growth factor receptor-α (PDGFRA) have been identified in as many as 80% and 10% of GISTs, respectively, and these mutually exclusive gain-of-function mutations play a fundamental role in GIST development by leading to constitutive activation.¹⁸^–²³

Clinical Features

Approximately 4500 to 6000 GISTs are diagnosed annually in the United States.¹⁸^,¹⁹ GISTs can arise at almost any age, including childhood, but are most common in middle-aged and elderly patients, with approximately 75% diagnosed in patients older than 50 years.²⁰^–²² They may arise anywhere in the GI tract but are most common in the stomach (60%), followed by the jejunum and ileum (30%), the duodenum (5%), and the colorectum (<5%).²³^,²⁴ Very few cases have been described in the esophagus²⁵ or appendix.²⁶^,²⁷ GISTs may also occur as primary tumors outside the GI tract, in the retroperitoneum or abdomen (e.g., omentum or mesentery); such tumors are referred to as extraintestinal GISTs.²⁸^,²⁹

The presenting manifestations of GIST depend on the site of involvement in the GI tract, the size of the tumor, and the portion of the gut wall in which the tumor is located. A significant number of tumors are asymptomatic and are found incidentally at surgery performed for other reasons.³⁰^,³¹ The most common symptoms are GI bleeding with subsequent anemia, abdominal pain, nausea, vomiting, and weight loss.³² Signs and symptoms may lead to endoscopy and biopsy. In some cases, a histologic diagnosis of GIST can be made if a deep endocscopic biopsy is obtained or if the neoplasm infiltrates the overlying mucosa. Radiographic imaging studies, including use of barium contrast, computed tomography, and endoscopic ultrasound, are commonly used for evaluation and diagnosis of these neoplasms.³³^,³⁴ In addition, GISTs can be diagnosed by fine-needle aspiration cytology.³⁵

The behavior of GISTs ranges from benign to malignant. In adults, GIST behavior can be predicted by anatomic site, tumor size, and mitotic activity.¹⁸^,²⁰^,²³^,³⁶^,³⁷ Metastases usually develop within 2 years of diagnosis, and the expected pattern of metastatic spread is to the liver and serosa within the abdominal cavity.²⁰ Rare cases of metastatic disease outside the abdominal cavity have been seen, most commonly in the lungs, bone, soft tissue, and, very rarely in advanced cases, intracranial sites.²⁰^,³⁸^,³⁹ Historically, nodal metastases in GISTs have been extremely uncommon (<1% of cases). However, more recent studies show that succinate dehydrogenase (SDH)-deficient GISTs (described later) have a propensity for nodal metastases.⁴⁰^–⁴²

Pathologic Features

Gross and Microscopic Features

Most GISTs are uninodular and centered on the bowel wall; however, multifocal nodules have been described, especially in the pediatric population and in GIST syndromes. The tumor may ulcerate the overlying mucosa or grow exophytically and protrude toward the serosal aspect. Some GISTs are predominantly extramural and may be attached to the serosa of the tubal gut by only a thin stalk of tissue. On cut section, lesions may show areas of hemorrhage, necrosis, or cystic change—features that are not indicative of malignancy in GISTs (Fig. 30.2). The histomorphology varies greatly and includes pure spindle cell, pure epithelioid cell, and mixed spindle and epithelioid cell types.¹⁸ Epithelioid and mixed cell type GISTs are most commonly encountered in the stomach.⁴³^,⁴⁴

FIGURE 30.2 Gross appearance of a gastrointestinal stromal tumor in the stomach. The cut surface is granular and shows foci of hemorrhage. This gross appearance is quite distinct from that of typical smooth muscle tumors, which have a cut surface that is firm and uniform.

Spindle cell GISTs are composed of uniform, elongated cells that are consistent in size and shape. The cells have nuclei with evenly dispersed chromatin, inconspicuous nucleoli, and moderate amounts of pale to eosinophilic fibrillary cytoplasm (Fig. 30.3). Particular to gastric GISTs is the frequent presence of perinuclear vacuoles (due to fixation artifact) that indent the nucleus at one pole (Fig. 30.4). The architecture is that of intersecting short fascicles (Fig. 30.5). The vasculature can range from inconspicuous to hemangiopericytoma-like, whereas the stromal component may be inconspicuous or may exhibit prominent myxoid change, hyalinization, or dystrophic calcification (Fig. 30.6). Prominent collagen fibrils, so-called “skeinoid” fibers, have been described in small bowel GISTs (Fig. 30.7).⁴⁵^,⁴⁶

FIGURE 30.3 A gastrointestinal stromal tumor, spindle cell type, is composed of overall uniform cells with modest amounts of pale to eosinophilic fibrillary cytoplasm.

FIGURE 30.4 High-magnification view of a gastric gastrointestinal stromal tumor, spindle cell type, shows the typical prominent perinuclear vacuoles, which are an artifact of fixation.

FIGURE 30.5 A gastric gastrointestinal stromal tumor, spindle cell type, is arranged in intersecting tight fascicles.

FIGURE 30.6 Gastrointestinal stromal tumor, spindle cell type, shows prominent myxoid stromal change.

FIGURE 30.7 Small bowel gastrointestinal stromal tumor, spindle cell type, shows numerous eosinophilic collagen globules, so-called “skeinoid” fibers.

Epithelioid GISTs are composed predominantly of cells with either abundant eosinophilic or clear cytoplasm, typically arranged in nests and sheets. The nuclei are round with vesicular chromatin and variable nucleoli (Fig. 30.8). Scattered multinucleated giant cells, binucleated cells, or cells with bizarre nuclei may be present (Fig. 30.9).⁴⁷ The stromal alterations may include hyalinization or myxoid change (Fig. 30.10). Confusion with other epithelioid malignancies can be problematic on endoscopic biopsies, especially when an epithelioid GIST involves the mucosa (Fig. 30.11).

FIGURE 30.8 Gastrointestinal stromal tumor, epithelioid type, is composed of cells with rounded nuclei and ample eosinophilic cytoplasm.

FIGURE 30.9 Gastrointestinal stromal tumor, epithelioid type, in which the cells are arranged in broad sheets with occasional multinucleated cells.

FIGURE 30.10 Gastrointestinal stromal tumor, epithelioid type, shows prominent myxoid stromal change.

FIGURE 30.11 Small bowel gastrointestinal stromal tumor, epithelioid type, involving the lamina propria.

Immunohistochemical Features

CD117 (KIT), the product of the KIT gene, is a sensitive marker of GISTs, irrespective of site; it is expressed in as many as 95% of GISTs.⁴⁸ The pattern of immunoreactivity is typically diffuse and pancytoplasmic (Fig. 30.12), although membranous staining and a perinuclear dotlike immunoreactivity have been described (Fig. 30.13). Approximately 5% of GISTs do not react with antibodies to KIT⁴⁹^,⁵⁰; often, these tumors belong to the subset of GISTs that contain a PDGFRA mutation.⁵¹ The KIT-negative tumors are often located within the stomach and have epithelioid morphology. CD34, a hematopoietic stem cell marker, is expressed in roughly 70% of GISTs.⁵²^,⁵³ Approximately 20% to 30% of GISTs are positive for smooth muscle actin, 5% express some positivity for S100 protein, and 1% to 2% are positive for desmin or keratin.⁵^,¹⁸^,⁴⁸

FIGURE 30.12 Pancytoplasmic KIT immunoreactivity is observed within a gastrointestinal stromal tumor, spindle cell type.

FIGURE 30.13 Perinuclear dotlike accentuation of KIT is present in this gastrointestinal stromal tumor.

Gene expression profiling studies of GISTs have identified two additional immunostains that appear diagnostically useful. Discovered on GIST 1 (DOG1),⁵⁴ also known as anoctamin 1 (ANO1), encodes a calcium-regulated chloride channel protein.⁵⁵^,⁵⁶ The corresponding ANO1/DOG1 antibody appears to be immunoreactive with GISTs regardless of their KIT/PDGFRA mutational status⁵⁷^,⁵⁸ and has a sensitivity similar to that of KIT (approximately 95%). However, DOG1 positivity has also been identified in a small subset of mesenchymal tumors, including leiomyomas and synovial sarcomas.⁵⁹ Gene expression studies have shown protein kinase C-theta to be consistently overexpressed in GISTs,⁶⁰^,⁶¹ and the initial immunohistochemical studies have shown this protein to be sensitive and specific for the diagnosis of GIST.⁶²

Molecular Findings

KIT and PDGFRA encode homologous transmembrane glycoproteins⁶³^,⁶⁴ that contain an extracellular ligand-binding domain with five immunoglobulin-like loops that function in ligand binding and dimerization. The corresponding cytoplasmic domain is composed of a juxtamembrane domain and a tyrosine kinase domain; the juxtamembrane domain regulates KIT tyrosine kinase activity by inhibiting activity in the absence of KIT ligand.⁶⁵ As mentioned previously, mutually exclusive mutations in KIT or PDGFRA have been identified in GISTs (as many as 80% and 10%, respectively).¹⁸^–²² The identification of these mutations in small, incidentally identified GISTs confirms their role as drivers of early tumorigenesis.³⁰^,⁶⁶ Although most of these mutations are somatic, germline mutations have been identified in rare families (see GIST Syndromes and Succinate Dehydrogenase–Deficient GISTs).⁶⁷^–⁷²

Approximately 70% of the mutations involving KIT are identified at the juxtamembrane domain in exon 11, resulting in ligand-independent activation of tyrosine kinase activity and ultimately promoting proliferation and cell survival.⁶⁵^,⁷³^–⁷⁵ The mutations cluster at either the 3′ or the 5′ end of the exon, with the mutation type frequently determining the clinical course. For example, internal tandem duplication mutations have been identified at the 3′ end of exon 11, and these patients typically have gastric GISTs that follow an indolent course.⁷⁶ In comparison, an aggressive clinical course with a higher risk of recurrence and shorter survival time has been observed in GISTs harboring deletions involving exon 11.⁷⁷^–⁷⁹ The second most common KIT mutation site, seen in approximately 10% of GISTs, has been identified within exon 9 (distal extracellular domain). Patients whose GISTs harbor this mutation commonly have small bowel involvement and a more clinically aggressive neoplasm.⁷⁶ Mutations in exons 13 and 17 affect the tyrosine kinase domain of KIT and are seen in fewer than 5% of sporadic GISTS.⁸⁰^,⁸¹ The corresponding morphology is typically spindle cell with frequent involvement of the small bowel.⁸²

The subset of GISTs that harbor a mutation in PDGFRA most commonly have a missense mutation in exon 18.⁸³^,⁸⁴ GISTs containing this mutation almost always involve the stomach and have an epithelioid morphology.⁴⁴^,⁸³^,⁸⁵ Less commonly, PDGFRA exon 14 and exon 12 mutations are seen; exon 14 mutations are also associated with epithelioid morphology, location within the stomach, and a favorable clinical course.⁸³ In general, PDGFRA mutations are found within GISTs of the stomach and omentum, and these lesions typically have epithelioid morphology.⁴⁴^,⁸⁵^–⁸⁷ A primary BRAF V600E mutation has been identified in a small subset of GISTs that lack either KIT or PDGFRA mutations.⁸⁸^–⁹⁰

Differential Diagnosis

GISTs with a spindle cell morphology must be distinguished from other spindle cell proliferations of the GI tract, including smooth muscle neoplasms, nerve sheath tumors, inflammatory fibroid polyps, inflammatory myofibroblastic tumors (IMTs), and intraabdominal fibromatoses (desmoid tumors) (Table 30.2).

Table 30.2

Comparison of GIST Immunophenotype with Other Spindle Cell Tumors of the Gastrointestinal Tract

Tumor	KIT	CD34	SMA	Desmin	S100
GIST	+ (95%)	+ (70%)	+ (30-40%)	Very rare	Very rare
Schwannoma	−	−	−	−	+
Fibromatosis	−	Very rare	+	Very rare	−
Smooth muscle neoplasms	−	+ (10-15%)	+	+	Very rare
Inflammatory myofibroblastic tumor	−	−	+	+	−

GIST, Gastrointestinal stromal tumor; SMA, smooth muscle actin; −, absent; +, present.

Modified from Fletcher CD, Berman JJ, Corless C, et al. Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum Pathol. 2002;33:459-465.

Although smooth muscle tumors of the GI tract are much less common than GISTs, location is important because leiomyomas are more common than GISTs in the colon, rectum, and esophagus. GI leiomyomas are composed of spindle cells with cigar-shaped nuclei and eosinophilic fibrillar cytoplasm arranged in fascicles. Leiomyosarcomas of the GI tract are exceptionally rare and have cytologic pleomorphism and atypical mitotic figures, both of which are uncommonly seen in GISTs. The cells are strongly and diffusely immunoreactive for actin (smooth muscle actin and muscle-specific actin) and are often immunoreactive for desmin, but there is no expression of KIT.³⁸^,⁴⁵

Nerve sheath tumors are also a consideration, including neurofibromas, schwannomas, and malignant peripheral nerve sheath tumors. GI schwannomas, the most common of these nerve sheath tumors, usually occur in the stomach. They are composed of bundles of spindle cells with focal atypia, often arranged in a microtrabecular growth pattern, and they are associated with a dense peripheral lymphoid infiltrate. They stain strongly for S100 protein and for glial fibrillary acidic protein (GFAP) and are negative for KIT. Malignant peripheral nerve sheath tumors have rarely been described as arising within the GI tract; they resemble their counterparts in the peripheral soft tissues. In contrast to GISTs, these lesions do not express KIT and are variably immunoreactive for S100 protein.

Less commonly, inflammatory fibroid polyps (see Chapter 20) enter the differential diagnosis. They have been described throughout the GI tract,⁹¹ but they have a propensity for the stomach and ileum, where they a form an intramural mass. These lesions are composed of randomly distributed, spindle- and stellate-shaped cells associated with numerous blood vessels and inflammatory cells, especially eosinophils, plasma cells, lymphocytes, and mast cells. Frequently, there is a concentric whorling of the spindle cells in an onion-skin pattern around blood vessels. KIT highlights the scattered mast cells, whereas the spindle cells are negative for KIT. The spindle cells and vessels are immunoreactive for CD34, posing potential confusion with GISTs.⁹² Additionally, inflammatory fibroid polyps have been found to harbor gain-of-function mutations in PDGFRA within the same genomic hot spots as those identified within GISTs that lack an activating KIT mutation.⁹³ Despite having similar activating mutations, inflammatory fibroid polyps behave in a benign fashion and are not thought to be related to GIST.

IMTs are most common in children and young adults and can arise as an intraabdominal mass involving the GI tract. The constituent cells have the light microscopic and immunohistochemical features of myofibroblasts, intermingled with inflammatory cells and collagen. The cells are KIT negative and frequently express anaplastic lymphoma kinase (ALK) caused by rearrangements of the ALK gene on 2p23.⁹⁴

Intraabdominal fibromatosis (desmoid tumor) is the most common primary tumor of the mesentery; it often originates from the gastrocolic ligament and omentum. Mesenteric fibromatosis is arranged in long, sweeping fascicles that have finger-like projections extending into the surrounding soft tissue. Scattered keloid-type collagen fibers may be present, as are dilated thin-walled vessels. The lesional spindled or stellate-shaped cells are cytologically bland and monotonous and are distributed evenly within a collagenous or myxoid stroma. By immunohistochemistry, the lesional cells are immunoreactive for vimentin, smooth muscle actin, and muscle-specific actin, and they frequently have β-catenin nuclear immunoreactivity.⁹⁵ These lesions are typically KIT negative, although one group has reported KIT immunoreactivity in these tumors.⁹⁶

GISTs with epithelioid features raise a broad differential diagnosis that includes melanoma, neuroendocrine tumors, and carcinoma; judicious use of immunohistochemical stains is warranted in this setting given the histologic overlap (Table 30.3). Because expression of KIT has been identified within a subset of melanomas,⁹⁷^–⁹⁹ excluding the possibility of melanoma by performing a panel of melanocytic markers including S100 protein, human melanoma black (HMB)-45, or melan-A is warranted. Rare examples of epithelioid GISTs show focal cytokeratin immunoreactivity, so the coexpression of CD34 and DOG1 with KIT (or without KIT in epithelioid GISTs containing PDGFRA mutations) is essential to avoid misdiagnosis of such cases as carcinoma.

Table 30.3

Comparison of GIST Immunophenotype with Other Epithelioid Tumors of the Gastrointestinal Tract

Tumor	KIT	CD34	Cytokeratin	S100	Neuroendocrine Markers
GIST	+ (95%)	+ (70%)	Very rare	Very rare	−
Melanoma	+ (up to 50%)	−	Very rare	+	−
Neuroendocrine tumor	−	−	+	Very rare	+

GIST, Gastrointestinal stromal tumor; −, absent; +, present.

Overall, nuclear pleomorphism is unusual in GISTs, and the finding of marked cytologic pleomorphism could suggest sarcoma, sarcomatoid carcinoma, or the very rare dedifferentiated GIST. This dedifferentiation is akin to dedifferentiation in other sarcomas, wherein a transition from a morphologically recognizable low-grade tumor to an anaplastic or pleomorphic morphology is appreciated (Fig. 30.14). In the setting of GIST with dedifferentiation, the morphology changes, and the immunophenotype undergoes a transition as well, with loss of KIT immunoreactivity within the anaplastic cells.¹⁰⁰ Dedifferentation has been described both as a de novo event and as occurring after treatment with the selective tryosine kinase inhibitor imatinib mesylate (ST1571 or Gleevec; Novartis Pharmaceuticals, East Hanover, N.J.).¹⁰⁰

FIGURE 30.14 Dedifferentiated GIST is highlighted by areas of marked cellular pleomorphism that lack immunoreactivity for KIT. In most cases, a recognizable “low-grade” area of conventional GIST is identified.

Prognosis and Treatment

Tyrosine kinase inhibitors have played a pivotal role in the management of GISTs, and the U.S. Food and Drug Administration (FDA) has approved two targeted therapies. Imatinib mesylate is a selective tryosine kinase inhibitor that targets KIT and PDGFRA. Sunitinib malate (SU11248 or Sutent; Pfizer, New York, N.Y.) targets several receptors including those for KIT, PDGFRA, and vascular endothelial growth factor.¹⁰¹^–¹⁰³ The original indication for imatinib was for the treatment of metastatic or unresectable GISTs, with patients showing clinical responses in as many as 80% of cases¹⁰⁴; current FDA-approved labeling includes use in the adjuvant setting after complete gross resection of GISTs.¹⁰⁵ Sunitinib is approved for patients who do not tolerate imatinib or who have tumor progression on imatinib therapy. Tumor genotype has been shown to correlate with response to these drugs. For example, tumors with an exon 11 KIT mutation have shown the best imatinib response rates, whereas tumors without a KIT mutation and those with a PDGFRA D842V mutation are less likely to have a favorable or a sustained response to imatinib.⁵¹^,¹⁰⁶ Other studies suggest that patients with an exon 9 KIT mutation benefit from a higher dose of this drug.¹⁰⁷^,¹⁰⁸ Approximately 50% of GIST patients being treated with imatinib will acquire a secondary mutation that confers tumor resistance to imatinib,¹⁰⁹^–¹¹² and in such cases, sunitinib is approved as a second-line therapy. The most common secondary KIT mutations that escape imatinib are KIT V654A and KIT T670I, both of which are sensitive to sunitinib. Regorafenib (Stivarga; Bayer HealthCare, Whippany, N.J.) has been approved by the FDA as third-line therapy for patients whose disease progresses on sunitinib.

GISTs are risk stratified based on mitotic rate, size, and anatomic location; these features define the Miettinen criteria for risk stratification (Table 30.4),²³ which establish a risk of progressive disease, defined as either metastatic disease or tumor-related death. The criteria are based on large studies by the Armed Forces Institute of Pathology (AFIP) that evaluated how the clinicopathologic features of GISTs within different sites (gastric, small intestinal, duodenal, and rectal locations) affected prognosis in the pre-imatinib era.³⁸^,⁴³^,⁴⁵^,⁴⁶ To assign an accurate risk of progressive disease, a precise gross tumor measurement with a thorough mitotic count should be performed, evaluating a total area of 5 mm². For modern wide-field microscopes with wide-field eyepieces, the mitotic count correlating with the total area of 5 mm² is obtained from 20 high-power fields (HPFs).⁵

Table 30.4

Risk Stratification of Primary GIST by Mitotic Index, Size, and Anatomic Site

Tumor Parameters		Risk of Progressive Disease* (%)
Mitotic Index	Size	Gastric	Duodenum	Jejunum/Ileum	Rectum
≤5 per 5 mm²	≤2 cm	None (0%)	None (0%)	None (0%)	None (0%)
	>2 to ≤5 cm	Very low (1.9%)	Low (8.3%)	Low (4.3%)	Low (8.5%)
	>5 to ≤10 cm	Low (3.6%)	Insufficient data	Moderate (24%)	Insufficient data
	>10 cm	Moderate (10%)	High (34%)	High (52%)	High (57%)
>5 per 5 mm²	≤2 cm	None^†	Insufficient data	High^†	High (54%)
	>2 to ≤5 cm	Moderate (16%)	High (50%)	High (73%)	High (52%)
	>5 to ≤10 cm	High (55%)	Insufficient data	High (85%)	Insufficient data
	>10 cm	High (86%)	High (86%)	High (90%)	High (71%)

^* Based on long-term follow-up of 1055 gastric, 629 small intestinal, 144 duodenal, and 111 rectal GISTs. Progression is defined as metastasis or tumor-related death.

^† Denotes small numbers of cases.

GIST, Gastrointestinal stromal tumor; HPF, high-power field.

Data from references 23, 38, 43, 45, and 46.

Other factors that have been reported to be associated with poor outcome include tumor necrosis, mucosal invasion, and ulceration.⁴³^,¹¹³^,¹¹⁴ Tumor rupture, either spontaneous or at the time of surgery, increases the risk of recurrence with intraabdominal seeding.¹¹⁵^,¹¹⁶ Patients whose complete resection is complicated by tumor rupture have a significantly shortened survival time, compared with patients with complete resection without tumor rupture.¹¹⁶^–¹¹⁸

GIST Syndromes and Succinate Dehydrogenase–Deficient GISTs

Although most GISTs are sporadic, almost 5% are associated with a tumor syndrome, including familial GIST syndrome, neurofibromatosis type 1 (NF1), the Carney triad, and Carney-Stratakis syndrome.

Familial GISTs arise from germline mutations in exons 8, 11, and 13 of KIT and in exon 12 of PDGFRA, identical to the mutations identified in sporadic GISTs.⁶⁹^,⁷⁰^,¹¹⁹^–¹²⁴ GISTs will develop in almost all patients who harbor these germline mutations, typically within the stomach and small bowel. These lesions most commonly develop in middle-aged patients, but they have been documented in patients as young as 18 years. Other clinical manifestations of KIT activation, such as mastocytosis (urticaria pigmentosa) and hyperpigmented macules on the skin of the perineum, axilla, hands, and face, may also be found in these patients, as well as a background of diffuse ICC hyperplasia in the bowel wall.⁶⁹^,⁷² This latter finding raises the possibility of a hyperplasia to neoplasia sequence, with additional clonal genetic alterations needed to progress from ICC hyperplasia to GIST.¹²⁵

GISTs arising in patients with NF1 have been recognized for some time and may even be the most common GI tract tumor associated with NF1.²⁴ As estimated from a series of duodenal GISTs reported by the AFIP, patients with NF1 have an increased risk for GIST of as high as 180-fold compared with the general population.⁴⁵ Most NF1-associated tumors arise in the small bowel, often in a multifocal fashion.¹²⁶^,¹²⁷ Distinguishing patients with NF1 and multiple GISTs from patients with sporadic GIST and multiple metastatic nodules is of major clinical significance. Most NF1-associated GISTs are relatively small, are mitotically inactive, and follow an indolent course. Therefore, the index of suspicion for NF1 should be high when one encounters multiple small GISTs, particularly in the small bowel. Diffuse ICC hyperplasia is often seen in the myenteric plexus adjacent to these tumors. The pathogenesis of NF1-associated GISTs appears to be different from that of sporadic GISTs because several studies have shown a very low frequency of associated KIT or PDGFRA mutations in these tumors.¹²⁶^,¹²⁸^–¹³¹

The identification of GIST arising in the setting of a germline mutation in the SDH complex family¹³² has led to the recognition of a distinctive group of SDH-deficient GISTs that are found in the stomach and share histologic, immunohistochemical, and clinical similarities. These GISTs arise in the setting of Carney-Stratakis syndrome, Carney triad, pediatric GIST, or “pediatric-type” GISTs in adults.¹³³^–¹³⁵ They have a multinodular or plexiform growth with lobules of tumor separated by bands of smooth muscle, are hypercellular, and have epithelioid cytomorphology.¹³³^–¹³⁶ In contrast to conventional GISTs, which show granular cytoplasmic staining for succinate dehydrogenase subunit B (SDHB), GISTs arising in these settings show a loss of immunohistochemical staining for SDHB.¹³⁴ Clinically, these tumors metastasize to lymph nodes and are insensitive to imatinib mesylate; however, despite recurrences and distant metastases, they typically follow a more indolent clinical course.⁴⁰^,¹³³^,¹³⁶^,¹³⁷

Carney-Stratakis syndrome is characterized by paraganglioma and gastric GISTs.¹³⁶ It has been shown to result from a germline mutation in one of the SDH complex subunit genes and is inherited in an autosomal dominant manner.¹³²^,¹³⁸^,¹³⁹ GISTs arising in this setting lack KIT and PDGFRA mutations.¹³⁹

Carney triad, which includes epithelioid gastric GISTs, paraganglioma, and pulmonary chondroma, occurs exclusively in the stomach and usually arises in much younger patients with a striking female predilection (approximately 85%).¹³⁶^,¹⁴⁰ Although mutations in KIT and PDGFRA have not been identified so far in this subset of GISTs, they typically stain with KIT.⁴⁰^,¹⁴¹ Recent literature suggests that GISTs in the setting of Carney triad are quite different from sporadic GISTs.⁴⁰

GISTs may arise in children, albeit rarely, accounting for fewer than 1% of all GISTs.⁴¹ In the pediatric population, GISTs predominate in girls, are usually located in the stomach, and are frequently multifocal with epithelioid or mixed morphology.¹⁴² These lesions often metastasize to lymph nodes, and although they stain with KIT, they often lack mutations in KIT and PDGFRA; approximately 50% harbor mutations in SDH complex subunit genes.⁴¹^,⁴²^,¹⁴³ Approximately 3% of adults with GISTs have so-called “pediatric-type” GISTs, which are SDH-deficient; this subtype accounts for roughly 7% of gastric GISTs in adults. These tumors have histomorphology identical to that seen in pediatric patients and a similar clinical course, with nodal metastases, imatinib resistance, and an overall indolent course.¹⁴²^,¹⁴⁴

Tumors of Neural Origin