Acknowledgment
The author would like to acknowledge the contributions of Dr. Brian Rubin to the preceding version of this chapter.
Gastrointestinal Stromal Tumor
Gastrointestinal stromal tumors (GISTs) arise from (or show differentiation toward) the interstitial cells of Cajal (ICCs) or ICC precursor cells, and thus share morphologic, immunohistochemical, and molecular features. The ICCs are pacemaker cells that function to set up a peristaltic wave that coordinates the movement of food through the digestive system; these cells are located in the myenteric plexus along the entire length of the tubal gut, and as such GIST may arise at any location along the gastrointestinal (GI) tract ( Fig. 18.1 ). The identification of activating KIT gene mutations in most GISTs made them a paradigm for targeted therapy of oncogenic proteins and oncogene addiction in solid tumors. , Indeed many developments in GIST diagnostics in the last few decades have accompanied genetic findings of therapeutic importance.
Interstitial cells of Cajal within myenteric plexus of the small bowel (KIT immunohistochemical stain).
Epidemiology and Clinical Features
Although once considered rare and thought to represent smooth muscle tumors, GISTs are now known to be the most common human sarcoma. , While population-based studies estimate the annual incidence at 10 cases per million, this is for clinically significant GISTs greater than 2 cm in size that require surgical evaluation and potentially systemic therapy. However, autopsy studies have identified “microGISTs” (tumors measuring less than 1 cm in diameter, also known as GIST tumorlets ) in up to 22.5% of all patients. The vast majority of microGISTs do not progress to clinically important lesions that require medical attention.
GISTs arise over a wide age range, from children to elderly persons, with a peak median age of 64 years at diagnosis. They occur with an approximately equal sex predilection (47.3% female; 52.7% male), except in children where there is a clear female predominance (see pediatric GIST later). No environmental or toxic/metabolic etiologic factors contributing to the development of GIST have been identified. However, while the vast majority of GISTs occur as sporadic tumors with somatic mutations, GISTs also rarely arise in the setting of various tumor syndromes (see later). The most common anatomic sites of involvement along the GI tract are the stomach (60%) and small intestine (jejunum and ileum, 30%). Tumors less often arise in the duodenum (5%) and colorectum (<5%), and rarely involve the esophagus, appendix, and gallbladder. Tumors may involve any layer of the GI tract, but are typically intramural, and may extend luminally to involve submucosa and mucosa, or may involve subserosa or be entirely serosal.
A very small number of GISTs have no apparent connection to the GI tract. These GISTs, known as extragastrointestinal GISTs ( EGISTs ), involve the omentum, mesentery, retroperitoneum, and perineum. The occasional finding of an omental or mesenteric GIST with a thin stalk attached to the stomach suggests that a subset of EGISTs arise on the serosal aspect of the stomach but eventually lose their connection to it. This is supported by molecular findings showing that EGISTs in the omentum share molecular characteristics with gastric GISTs.
Presenting symptoms depend on the anatomic location of the tumor, and may include pain, symptoms of upper or lower GI bleeding, anemia, abdominal fullness, or a palpable mass. GISTs can also be asymptomatic and discovered incidentally on imaging for other reasons.
GISTs have a characteristic pattern of metastasis. Unlike epithelial neoplasms of the gut, with one specific exception, succinate dehydrogenase (SDH)–deficient GISTs (see later), they do not metastasize to lymph nodes. More typical is hepatic metastasis or dissemination throughout the peritoneal cavity resulting in numerous metastatic nodules. It is unusual for GIST to metastasize outside the abdomen, but dermal/subcutaneous, bone, brain, and lung metastases rarely occur.
Gross Features
GISTs range in size from 1 mm to very large tumors, occasionally measuring greater than 20 cm, with a median size of clinically significant GISTs of 6 cm in the stomach, 4.5 cm in the duodenum, and 7 cm in the jejunum/ileum. Because GISTs arise from ICCs or ICC precursors, they are centered on the wall/muscularis propria of the gut ( Figs. 18.2 and 18.3 ). This has important clinical ramifications because endoscopic biopsies are often not deep enough to obtain tumoral tissue for diagnosis. The use of endoscopic ultrasound and fine-needle aspiration overcomes this limitation by directing the biopsy needle directly into the tumor. GISTs are typically well circumscribed and frequently ulcerate the overlying mucosa. The cut surface is tan and fleshy. Cystic degeneration and hemorrhage are common, but true tumor necrosis is uncommon. GISTs usually grow as a single tumor; the presence of multiple tumor nodules suggests either the presence of metastasis or the less common scenario of true multifocal disease due to a germline mutation or inherited disorder that predisposes to GIST. In these latter cases, tumors are usually located along the GI tract within the wall, i.e., the typical location of a primary tumor, whereas metastatic disease typically involves mesenteric fat or peritoneal serosal surfaces.
Gastric GIST with typical fleshy appearance and central degeneration.
Aggressive GIST infiltrating through wall of the small bowel.
Microscopic Features
GISTs are centered on the muscularis propria and are usually circumscribed and tend to respect the muscularis mucosae ( Fig. 18.4 ). When GISTs invade across the muscularis mucosae to involve the overlying mucosa, the lesional cells infiltrate among the epithelium. It is important to distinguish true invasion from simple erosion of the overlying mucosa, because true invasion is associated with a worse prognosis and is almost always associated with aggressive clinical behavior.
Typical spindle cell GIST with smooth, noninfiltrative interface with muscularis mucosae.
GISTs can have predominantly spindle cell (70%) or epithelioid (20%) cytomorphology, or a mix of both (10%), , and range from hypocellular to densely cellular lesions. GISTs of all types are usually monotonous in appearance with minimal cytologic pleomorphism. Significant de novo pleomorphism, when present, appears to have no clinical significance. GISTs with spindle cell features generally have a uniform monotonous appearance and show a fascicular growth pattern ( Figs. 18.5–18.9 ). The tumor cells have elongated nuclei with fine chromatin, inconspicuous nucleoli, and a moderate amount of pale eosinophilic and fibrillary cytoplasm which may appear syncytial. Epithelioid GISTs have a sheet-like or nested growth pattern. The tumor cells are round or polygonal with abundant eosinophilic or clear cytoplasm and often distinct cell borders, which may be glomus-like. Nuclei are round, usually with vesicular chromatin and variably prominent nucleoli.
Hypocellular spindle cell GIST.
Moderately cellular spindle cell GIST.
Hypercellular spindle cell GIST.
Epithelioid GIST with nested growth pattern.
Epithelioid GIST with sheet-like growth pattern.
The stroma of GIST varies from hyalinized to occasionally myxoid; cases with a predominantly myxoid stroma may be difficult to recognize as GIST. Prominent admixed lymphocytes may be present. Coarse calcifications and stromal hyalinization are typical of small, clinically insignificant microGISTs ( Fig. 18.10 ). Mitotic activity is variable, but most cases have low mitotic rates; the mitotic rate is used for risk stratification purposes (see below). Atypical mitotic figures are rare but may be a feature of high-grade or dedifferentiated GIST. Lymphovascular invasion is very uncommon except in SDH-deficient GISTs, approximately 50% of which metastasize to lymph nodes.
Hyalinized microGIST with coarse calcifications.
GISTs are well vascularized, and in occasional examples the blood vessels can be hyalinized, mimicking schwannoma ( Fig. 18.11 ) or thick-walled and “staghorn” in configuration, mimicking solitary fibrous tumor. Gastric GISTs can have striking nuclear palisading, also mimicking schwannoma ( Fig. 18.12 ). Ironically, gastric schwannomas are uniformly cellular and do not usually exhibit obvious nuclear palisading. Gastric GISTs can also have prominent cytoplasmic vacuolization ( Fig. 18.13 ). Another interesting histologic feature frequently encountered in GIST of the small intestine is so-called skeinoid fibers, prominent deposits of dense eosinophilic collagen that are periodic acid–Schiff (PAS) positive ( Fig. 18.14 ).
Spindle cell GIST with prominent hyalinized blood vessels mimicking a schwannoma.
Gastric spindle cell GIST with nuclear palisading mimicking a schwannoma.
Gastric GIST with prominent cytoplasmic vacuolization.
Skeinoid fibers in jejunal GIST.
Dedifferentiated GIST.
Dedifferentiated GIST is very rare and may arise de novo or after prolonged anti-KIT tyrosine kinase inhibitor therapy. These tumors are characterized by the presence of morphologically typical GIST juxtaposed with high-grade sarcoma that would otherwise be unrecognizable as GIST and shows no specific line of differentiation. These lesions are very rare, but the high-grade sarcomatous component loses KIT and/or DOG1 immunoreactivity, may show patchy expression of desmin and keratins, shows greater cytologic atypia and pleomorphism, is more mitotically active with atypical mitotic figures, and is clinically more aggressive than conventional GIST and generally resistant to tyrosine kinase inhibitors ( Figs. 18.15 and 18.16 ).
Dedifferentiated GIST (conventional component on left with abrupt transition to dedifferentiated component on right ).
Conventional spindle cell component ( A ) and dedifferentiated component with rhabdoid morphology ( B ) of dedifferentiated GIST. KIT immunohistochemical stain ( C ) shows abrupt loss of staining in dedifferentiated component ( upper right ).
Immunohistochemical Features
GISTs are diffusely and strongly positive for KIT (CD117, c-kit) in approximately 95% of cases. , Immunoreactivity can be cytoplasmic ( Fig. 18.17 ), membranous ( Fig. 18.18 ), dotlike perinuclear ( Fig. 18.19 ), or a combination of all these patterns, and is usually diffuse in distribution. There is no known clinical significance to the different staining patterns. Because other GI neoplasms, such as leiomyoma and schwannoma, can mimic GIST, it is important to confirm the histologic impression of GIST by confirmation with KIT immunohistochemistry (IHC). Diffuse expression of KIT is overall uncommon in other tumor types, with the exception of melanoma, which therefore should be kept in mind, especially in the evaluation of small biopsy samples. Approximately 5% of GISTs are negative for KIT on IHC. Most of these GISTs are PDGFRA mutant GISTs ( Table 18.1 ; see later section) and will express DOG1.
Cytoplasmic KIT immunoreactivity.
Membranous KIT immunoreactivity.
Dotlike KIT immunoreactivity.
Table 18.1
Immunohistochemistry According to GIST Genotype
| Immunohistochemistry | Genotype | |||||
|---|---|---|---|---|---|---|
| KIT Mutation | PDGFRA Mutation | BRAF Mutation | NF1 Mutation | SDHB , SDHC , or SDHD Mutation | SDHA Mutation | |
| KIT | + | − (weak) | + | + | + | + |
| DOG1 | + | + | + | + | + | + |
| SDHB | Retained | Retained | Retained | Retained | Lost | Lost |
| SDHA | Retained | Retained | Retained | Retained | Retained | Lost |
| BRAF V600E | – | – | + | – | – | – |
GIST , Gastrointestinal stromal tumor.
DOG1 (discovered on GIST 1), also known as ANO1 (anoctamin-1), is a chloride channel protein strongly expressed in ICC and is very sensitive and specific for the diagnosis of GIST. DOG1 is strongly expressed in up to 99% of GISTs ( Fig. 18.20 ). Importantly, it is expressed in most KIT-negative GISTs and therefore is useful in confirming the diagnosis of GIST in this subgroup ( Fig. 18.21 ). To ensure that a diagnosis of GIST is not missed, it is recommended that both KIT and DOG1 IHC be used in all cases of suspected GIST. DOG1 has somewhat higher specificity than KIT, and shows only very limited expression in a small number of other mesenchymal neoplasms (leiomyosarcoma, uterine-type retroperitoneal leiomyoma, low-grade fibromyxoid sarcoma, synovial sarcoma, and PEComa). ,
DOG1 expression in spindle cell GIST.
KIT ( A ) and DOG1 ( B ) immunohistochemistry in KIT-negative GIST.
Expression of CD34 is present in approximately 70% of GISTs, but due to lower specificity this marker is far less useful for the diagnosis of GIST. GISTs show expression of caldesmon in 65% and smooth muscle actin (SMA) in up to 40% of cases, but staining is usually more limited in extent than that seen in most pure smooth muscle tumors. GISTs are occasionally positive for S-100 (5%, usually duodenal GISTs), desmin (5%), and keratins (2%), and staining for these markers is again usually only focal.
For gastric GISTs, especially those with epithelioid morphology or multinodular growth, additional immunohistochemistry for SDHB helps identify the distinct group of SDH-deficient GIST, as discussed in further detail below. Loss of expression of the SDHB protein is a defining feature of this group and is demonstrated by complete absence of staining in tumor cells in the presence of intact expression in non-neoplastic cells (e.g., endothelium, fibroblasts, smooth muscle cells). In contrast, SDHB expression is consistently intact in KIT- and PDGFRA-mutant GIST and NF1-associated GIST. For those tumors that show loss of SDHB expression, additional staining for SDHA can help identify those tumors with SDHA mutations that show a corresponding loss of protein expression.
Ultrastructural Findings
Electron microscopy (EM) analysis of GIST reveals an organelle-poor undifferentiated phenotype or neural features, such as synaptic-type structures, perhaps as a result of their origin as ICCs, which have neuron-like functions ( Figs. 18.22 and 18.23 ). Because of its characteristic histologic, immunohistochemical, and genetic features, EM no longer plays a role in the diagnosis of GIST.
Electron micrograph of GIST with neuronal and synapse-like structures containing dense-core neurosecretory granules and microtubules (×17,700).
Courtesy of Dr. Robert Erlandson.
Electron micrograph of GIST illustrating details of synapse-like structures. Note the neurosecretory granules and vesicles. A portion of a neurite is also present [×35,700]).
Courtesy of Dr. Robert Erlandson.
Molecular Genetics of GIST with Clinicopathologic Correlates
KIT-Mutant GIST.
Approximately 70%–80% of GISTs contain constitutively activating mutations in KIT , which encodes a receptor tyrosine kinase that is strongly expressed in ICCs and is critical for ICC development and maintenance ( Fig. 18.24 ). , , KIT mutations are found in the smallest, subcentimeter GISTs, suggesting that KIT mutation is the initiating tumorigenic event in most GISTs. , This has been confirmed in mouse models where oncogenic KIT activation is all that is necessary to drive GIST tumorigenesis. However, additional secondary changes are required to develop GISTs that are clinically aggressive.
Schematic representation of KIT and PDGFRA with mutational hot spots.
KIT mutations are scattered along hot spots, including KIT exons 9, 11, 13, and 17 ( Fig. 18.24 and Table 18.3 ). Approximately 67% of KIT mutations involve exon 11, 10% occur in exon 9, and 1% each in exons 13 and 17. Other KIT mutations are identified rarely in exons 8, 12, 14, and 18. Mutations can be missense mutations, insertions, duplications, or deletions. Most KIT mutations are heterozygous. However, hemizygous and homozygous KIT mutations occur infrequently and are associated with aggressive clinical behavior. Whereas most mutations are found throughout the length of the GI tract, KIT exon 9 mutant tumors arise predominantly in the small bowel. ,
Table 18.3
Genetics of Gastrointestinal Stromal Tumors (GISTs)
Modified from Corless CL, Barnett CM, and Heinrich MC. Gastrointestinal stromal tumours: origin and molecular oncology. Nat Rev Cancer . 2011;11:865–878.
| Genetic Type | Relative Frequency | Anatomic Distribution | Germline Examples |
|---|---|---|---|
| KIT Mutation (Relative Frequency: 75%–80%) | |||
| Exon 8 | Rare | Small bowel | One kindred |
| Exon 9 insertion AY502-503 | 10% | Small bowel and colon | None |
| Exon 11 (deletions, single nucleotide substitutions and insertions) | 67% | All sites | Several kindreds |
| Exon 13 K642E | 1% | All sites | Two kindreds |
| Ex-on 17 D820Y, N822K, and Y823D | 1% | All sites | Five kindreds |
| PDGFRA Mutation (Relative Frequency: 5%–8%) | |||
| Exon 12 (e.g., V561D) | 1% | All sites | Two kindreds |
| Exon 14 N659K | <1% | Stomach | None |
| Exon 18 D842V | 5% | Stomach, mesentery, and omentum | None |
| Exon 18 (e.g., deletion of amino acids IMHD 842–846) | 1% | All sites | One kindred |
| KIT and PDGFRA Wild Type (Relative Frequency: 12%–15%) | |||
| BRAF V600E | 3% | Stomach and small bowel | None |
| SDHA, SDHB, SDHC, and SDHD mutations | 3% | Stomach and small bowel | Carney–Stratakis syndrome |
| Sporadic pediatric GISTs | ∼1% | Stomach | Not heritable |
| GISTs as part of Carney triad | ∼1% | Stomach | Not heritable |
| NF1 related | Rare | Small bowel | Numerous |
| ETV6-NTRK3 | Very rare | Too few | None |
| FGFR1 gene fusions | Very rare | Too few | None |
NF1 , Neurofibromatosis type 1; PDGFRA , platelet-derived growth factor receptor α; SDH , succinate dehydrogenase.
PDGFRA-Mutant GIST.
About 7%–15% of GISTs have mutations in PDGFRA (platelet-derived growth factor receptor α; Table 18.3 ). Both KIT and PDGFRA reside next to each other on chromosome 4q, suggesting that one of them was created through a gene duplication event from the other. KIT and PDGFRA mutations are mutually exclusive and mechanistically drive GIST tumorigenesis in the same way. PDGFRA has one more exon than KIT, so the numbering system is offset by one. PDGFRA mutations occur in exons 12 (<1%), 14 (<1%), and 18 (5%–10%) ( Fig. 18.24 and Table 18.3 ). Exons 12, 14, and 18 of PDGFRA are homologous to exons 11, 13, and 17 of KIT . Most PDGFRA mutant GISTs arise in the stomach or omentum and have a specific morphology that is readily recognizable. PDGFRA mutant GISTs have epithelioid cytomorphology with prominent cell membranes and frequent binucleation, are negative or weakly positive for KIT IHC (see Table 18.1 ), show more pleomorphism than usual in KIT mutant GIST, and often have focally myxoid stroma ( Figs. 18.25 and 18.26 ). Interestingly, whereas 15% of GISTs had PDGFRA mutations in a prospective study, only 2.1% of metastatic GISTs had PDGFRA mutations. This suggests that PDGFRA mutant GISTs exhibit less aggressive clinical behavior than KIT mutant GISTs in general.
PDGFRA mutant GIST with epithelioid morphology and focal stromal edema.
PDGFRA mutant GIST with epithelioid morphology, frequent binucleation, and prominent cell membranes.
Approximately 12%–15% of GISTs lack KIT or PDGFRA mutations and have been collectively referred to in the past as wild-type GISTs (see Table 18.3 ). Many of the molecular aberrations of these GISTs have now been characterized with cases having either germline or somatic mutations or dysfunction of the ubiquitous succinate dehydrogenase (SDH) complex.
Succinate Dehydrogenase–Deficient GIST
The term SDH-deficient GIST describes a clinicopathologically and molecularly distinct subset of GIST that accounts for approximately 3% of all GISTs, 7.5% of gastric GISTs, 42% of wild-type GISTs, and most pediatric GISTs. , SDH-deficient GISTs have dysfunctional SDH-complex activity, due to loss-of-function mutations in SDH subunits A, B, C, or D ( SDHA , SDHB , SDHC , and SDHD ), hypermethylation of promoters, and other yet to be discovered mechanisms (see Tables 18.1 and 18.3 and later section). SDH mutations are mutually exclusive with KIT , PDGFRA , NF1 , BRAF , and other driver mutations.
Tumors are characterized by a predilection for gastric location, specifically the antrum, are composed of epithelioid or mixed epithelioid and spindle cell morphology, have a distinctive multinodular or plexiform growth pattern, and are often present as multiple adjacent lesions. Tumor cells are diffusely and strongly positive for KIT, and all demonstrate loss of SDHB expression by IHC ( Figs. 18.27 and 18.28 ; see Table 18.1 ). Approximately 27% of SDH-deficient GISTs also lack SDHA expression by IHC, reflecting loss-of-function mutations specifically in the SDHA gene.
SDH-deficient GIST showing typical plexiform growth pattern with prominent fibrous bands.
SDH-deficient GIST with epithelioid morphology ( A ). Corresponding KIT ( B ) and SDHB ( C ) immunohistochemical stains.
Germline mutations have been identified in SDH-deficient GISTs in the genes for four of the five protein subunits that comprise the SDH complex: SDHA , SDHB , SDHC , and SDHD (see Table 18.3 ). Most SDH mutations are germline; sporadic SDH mutations are much less common. Based on the limited data available, the overall frequency of these mutations cannot be determined at this time. However, SDH mutations have not been identified in the majority of SDH-deficient GISTs, and dysfunction of the SDH complex (with loss of protein expression) is thought to arise from other changes such as hypermethylation. Interestingly, loss of SDHA expression by IHC accurately predicts the presence of inactivating mutations in SDHA (see Table 18.1 ). Therefore, SDHA IHC can be used as a surrogate for inactivating SDHA mutations.
SDH-deficient GISTs also have a distinct clinical course. Unlike conventional GISTs, SDH-deficient GISTs have a propensity to metastasize to lymph nodes, which occurs in approximately 50% of cases. Even though they metastasize with high frequency, they have a relatively indolent behavior as patients can survive decades with metastatic disease. This has prompted the recommendation that standard criteria for risk stratification should not be used for SDH-deficient GISTs.
BRAF-Mutant GIST.
Somatic BRAF V600E mutations have been identified in wild-type GISTs and may be a primary oncogenic driver event. They are present in up to 3% of all GISTs and 13% of wild-type GIST. , BRAF mutations in GIST may arise de novo or after treatment with tyrosine kinase inhibitors, where they may be a mechanism of secondary resistance . BRAF mutant GISTs are KIT-positive and show immunohistochemical expression of BRAF V600E (see Table 18.1 ). BRAF mutant GISTs most often arise in the small intestine, show spindle cell morphology, and are histologically indistinguishable from KIT-mutant GIST. Although data are limited, there is a slight female predilection and tumors have a tendency for aggressive behavior, although BRAF mutations have been reported in microGISTs, which essentially have a benign clinical course. BRAF mutations are important to identify because they may respond to BRAF inhibitors.
Other Genomic Aberrations in GIST.
Recently, somatic ETV6-NTRK3 and FGFR1-HOOK3 and FGFR1-TACC1 fusions have also been identified in exceptional (<0.5%) apparent GIST cases. , Although rare and controversial with regards to nosology in GIST, it is important to identify TRK gene fusions because they may respond to TRK inhibitors.
Germline mutations in NF1 are found in the rare subset of GISTs that arise in the setting of neurofibromatosis type 1 (see later, GIST syndromes). ,
KIT , PDGFRA , BRAF , SDH , and other mutations are undoubtedly the initiating events in GIST tumorigenesis, but other genetic events—secondary mutations—collaborate with these primary mutations. Most of what is known about secondary mutations originally came from comparative genomic hybridization (CGH) and cytogenetic studies, which have implicated many gene regions in GIST tumorigenesis. Areas with frequent loss or gain of genetic information include deletions of 1p, 9p, 11p, 14q, and 22q and gains of 8p and 17q. Most of the specific genes either amplified (oncogenes) or deleted (tumor suppressor) in these gene regions have not been identified, but progress continues.
Deletions within 9p result in loss of the CDKN2A gene that encodes both p14(ARF) and p16(INK4A), two well-known tumor suppressors. The tumor suppressor on 14q was recently identified as MAX (MYC-associated factor X). Loss of MAX is thought to be an early event in GIST tumorigenesis that dysregulates the cell cycle, resulting in increased proliferation. Another recent finding is loss of the DMD gene on Xp21.1, which is thought to be a late genetic event that promotes metastasis by promoting invasion and migration. Schaefer et al. proposed a temporal model of genomic progression based on these findings. Acquired/secondary resistance mutations are discussed in the section below on Treatment of GIST, Therapeutics, and Resistance Mutations.
Gastrointestinal Stromal Tumor Syndromes and Pediatric GIST
The majority of GISTs are sporadic, without any known predisposing genetic or environmental factors. However, GIST also occurs in the setting of several syndromes, including familial GIST, neurofibromatosis type 1 (NF1), Carney triad, and Carney–Stratakis syndrome (see Table 18.3 ). NF1, Carney triad, and Carney–Stratakis syndrome GISTs are all examples of “wild-type” GISTs because they lack somatic KIT or PDGFRA mutations.
Familial GIST.
Familial GIST is characterized by germline KIT or PDGFRA mutations inherited in an autosomal dominant pattern. , , Any family member who inherits a germline mutant KIT or PDGFRA allele will develop GIST. Familial GIST tends to be multifocal and can be accompanied by ICC hyperplasia. To date, germline KIT mutations have been identified in exons 8, 11, 13, and 17. Although most familial GIST kindreds harbor germline KIT mutations, germline PDGFRA mutations have also been identified in PDGFRA exons 12 and 18. In addition to GIST, patients with germline KIT mutations may also have hyperpigmentation, urticaria pigmentosa, or dysphagia, depending on their genotype. Patients with germline exon 18 PDGFRA mutations have large hands, in addition to multifocal GIST. A single patient with a germline exon 12 PDGFRA mutation had multifocal gastric GISTs, multiple lipomas, and fibrous tumors of the intestine.
Neurofibromatosis Type 1.
Neurofibromatosis type 1 is the most common tumor syndrome in humans and is characterized by the development of a variety of tumors, including (but not limited to) neurofibromas, malignant peripheral nerve sheath tumors, brainstem gliomas, and GISTs. Patients with NF1 have loss-of-function mutations in the NF1 gene and a higher risk of developing GIST than the general population; however, only a small number of patients with NF1 develop GIST, estimated at 7% in one study. NF1-associated GISTs do not harbor KIT or PDGFRA mutations, suggesting that NF1 mutations are the initiating tumorigenic event in these GISTs. However, it is unclear why only a small subset of NF1 patients develop GIST. NF1-associated GISTs tend to arise in the small bowel, often multifocally, and are usually small and spindle cell type with low mitotic activity. They appear to be clinically more indolent than KIT or PDGFRA mutant GIST. Intestinal resection specimens from patients with NF1-associated GISTs frequently demonstrate ICC hyperplasia, similar to patients with familial GIST ( Fig. 18.29 ).
Interstitial cells of Cajal (ICC) hyperplasia arising from myenteric plexus in small bowel resection specimen from patient with multifocal NF1 GIST.
Carney Triad.
Carney triad is characterized by the presence of epithelioid gastric GIST, extraadrenal paraganglioma, and pulmonary chondroma. , It affects mainly females and is sporadic (see Table 18.3 ). GISTs in Carney triad are typically SDH-deficient, and show the corresponding clinical, histological, and immunohistochemical features of this subtype. However, GISTs associated with Carney triad usually lack SDHA, SDHB, SDHC, and SDHD mutations. Instead, Carney triad–associated GISTs are characterized by hypermethylation of the SDHC promoter, resulting in silencing of SDHC expression. , As described in SDH-deficient GISTs, Carney triad–associated GISTs have indolent clinical behavior, even in the presence of lymph node and liver metastasis.
Carney–Stratakis Syndrome.
Carney–Stratakis syndrome is characterized by the dyad of SDH-deficient (epithelioid and gastric) GISTs and paragangliomas. It is inherited in an autosomal dominant pattern and affects both males and females. Patients with Carney–Stratakis syndrome have germline mutations in SDHA , SDHB , or SDHD (see Table 18.3 ) and show the corresponding clinical, histological, and immunohistochemical features of this subtype.
Because most patients with SDH-deficient GISTs, except Carney triad–associated GIST patients, harbor germline mutations, it is important to offer genetic testing to all first-degree relatives. Furthermore, because of the association of paragangliomas/pheochromocytomas with SDH-deficient GISTs, patients should undergo screening and periodic surveillance as early detection may lead to a better prognosis.
Pediatric Gastrointestinal Stromal Tumor.
Pediatric gastrointestinal stromal tumor essentially refers to all GISTs in patients age 18 years or younger and may even affect neonates. GISTs in the pediatric population are rare, accounting for less than 1% of all GISTs, and they have many characteristics that distinguish them from adult GISTs. Most pediatric GISTs are now known to be SDH-deficient type and therefore affect female patients, are multifocal or multinodular gastric tumors with epithelioid morphology, have frequent lymph node metastases, and a much better prognosis than adult patients with GISTs. Pediatric SDH-deficient GISTs may arise due to germline SDH mutations or in the setting of Carney triad and Carney–Stratakis syndrome.
KIT and PDGFRA mutations are found in less than 15% of pediatric GISTs. Those pediatric patients with KIT or PDGFRA mutations are almost always male and have GISTs with clinical, morphologic, and molecular findings typically seen in adults.
Risk Stratification and Prognostication of GIST
As mentioned previously, SDH-deficient GISTs have distinct clinical behavior from GISTs with KIT , PDGFRA , or BRAF mutations, which preclude them from being risk-stratified. Although there is some evidence that NF1-associated GISTs may also be associated with more indolent behavior, the data are less clear, and at this point they should be risk-stratified as for conventional GISTs.
The most important risk determinants for conventional GISTs are anatomic location, size, and mitotic rate. Tumor rupture is also associated with a worse prognosis. Mucosal invasion has been associated with a poor prognosis but true mucosal invasion is rare and potentially subjective, so it is not currently incorporated into the major risk stratification schemes for GIST.
There is evidence that KIT mutation status is also of prognostic importance. KIT exon 9 mutations and KIT exon 11 codon 557–558 deletions have been linked to aggressive behavior. GISTs with PDGFRA exon 18 mutations have been associated with a better prognosis.
Several risk stratification schemes have been proposed. The first scheme established, the National Institutes of Health (NIH) Consensus Criteria, used mitotic rate and size to determine risk for recurrence ( Table 18.4 ). After it was established, its utility was confirmed in independent sets of GISTs with long-term follow-up. , Based on several large studies, the Armed Forces Institute of Pathology (AFIP) modified the NIH Consensus Criteria and added anatomic location ( Table 18.5 ), including the stomach, duodenum, jejunum/ileum, and rectum. Those GISTs that develop in other anatomic locations (e.g., EGISTs) are classified according to the criteria for the jejunum/ileum. Mitotic rate is subdivided into GISTs with 5 mitotic figures or less per 5 mm 2 and those with more than 5 figures/5 mm 2 . Size is also subdivided (≤2 cm; >2 cm and ≤5 cm; >5 cm and ≤10 cm; >10 cm). The AFIP criteria are recommended by the College of American Pathologists (CAP) and included in their CAP GIST checklist.
Table 18.4
NIH Consensus Criteria for GIST Risk Stratification
| Risk Category | Tumor Size in Largest Dimension | Mitotic Count (per 50 hpf) |
|---|---|---|
| Very low | <2 cm | <5 |
| Low | 2–5 cm | <5 |
| Intermediate | <5 cm | 6–10 |
| 5–10 cm | <5 | |
| High | >5 cm | >5 |
| >10 cm | Any mitotic rate | |
| Any size | >10 |
GIST , Gastrointestinal stromal tumor; hpf , high-power fields; NIH , National Institutes of Health.
Table 18.5
AFIP Risk Criteria for GIST
Modified from Miettinen M, Lasota J. Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Pathol . 2006;23(2):70–83.
| Tumor Parameters | Risk of Progressive Disease a (%), Based on Site of Origin | ||||
|---|---|---|---|---|---|
| Mitotic Rate | Size | Gastric | Duodenum | Jejunum/Ileum | Rectum |
| ≤5 per 50 hpf | ≤2 cm | None (0%) | None (0%) | None (0%) | None (0%) |
| >2, ≤5 cm | Very low (1.9%) | Low (8.3%) | Low (4.3%) | Low (8.5%) | |
| >5, ≤10 cm | Low (3.6%) | (Insufficient data) | Moderate (24%) | (Insufficient data) | |
| >10 cm | Moderate (10%) | High (34%) | High (52%) | High (57%) | |
| >5 per 50 hpf | ≤2 cm | None b | (Insufficient data) | High b | High (54%) |
| >2, ≤5 cm | Moderate (16%) | High (50%) | High (73%) | High (52%) | |
| >5, ≤10 cm | High (55%) | (Insufficient data) | High (85%) | (Insufficient data) | |
| >10 cm | High (86%) | High (86%) | High (90%) | High (71%) | |
AFIP , Armed Forces Institute of Pathology; hpf , high-power fields.
Data based on long-term follow-up of 1055 gastric, 629 small intestinal, 144 duodenal, and 111 rectal GISTs; Miettinen M et al. Gastrointestinal stromal tumors of the stomach: a clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with long-term follow-up. Am J Surg Pathol . 2005;29(1):52–68; and Gastrointestinal stromal tumors of the jejunum and ileum: a clinicopathologic, immunohistochemical, and molecular genetic study of 906 cases before imatinib with long-term follow-up. Am J Surg Pathol . 2006;30(4):477–489.
Joensuu has proposed a simplification to the AFIP criteria that groups anatomic location into either gastric or nongastric sites to reflect that gastric tumors have a better prognosis ( Table 18.6 ). Furthermore, he subdivided mitotic rate into three categories (vs. two): 5 or less, 6–10, and more than 10 mitotic figures per 50 high-power fields (hpf). The inclusion of the 6–10 mitotic figure category applies only to gastric GISTs that are 5 cm or less in greatest dimension and is meant to capture this group as intermediate risk . Tumor rupture is added as an automatic criterion for determining a GIST as high risk . The Joensuu criteria were superior to other systems in identifying a single risk group (high risk) who were at risk for local recurrence/metastasis. This is critically important because the major use of risk stratification criteria, at this point, is for determining who should and should not receive adjuvant imatinib therapy after resection. The ability to identify definitively a single high-risk category is advantageous for this purpose.
Table 18.6
Joensuu Risk Criteria for GIST
| Risk Category | Tumor Size (cm) | Mitotic Index (per 50 hpf) | Primary Tumor Site |
|---|---|---|---|
| Very low risk | <2.0 | ≤5 | Any |
| Low risk | 2.1–5.0 | ≤5 | Any |
| Intermediate risk | 2.1–5.0 | >5 | Gastric |
| <5.0 | 6–10 | Any | |
| 5.1–10.0 | ≤5 | Gastric | |
| High risk | Any | Any | Tumor rupture |
| >10.0 | Any | Any | |
| Any | >10 | Any | |
| >5.0 | >5 | Any | |
| 2.1–5.0 | >5 | Nongastric | |
| 5.1–10.0 | ≤5 | Nongastric |
The NIH, AFIP, and Joensuu criteria suffer from having to break down size and mitotic rate into discrete variables. This is a problem when considering a GIST with 5 or 6 mitotic figures/50 hpf because 1 figure can make a large difference in behavior prediction, and possibly therapy. Systems that can evaluate size and mitotic rate as continuous variables will more accurately reflect the continuum of biologic behavior. By pooling population-based studies, Joensuu et al. developed novel “heat maps” and contour maps that evaluated size and mitotic rates as continuous variables. These systems were shown to be more accurate in estimating the risk of recurrence after surgery than conventional risk stratification systems.
For patients presenting with metastatic disease, the GIST should be classified as malignant ; formal risk stratification is unnecessary in such lesions. Risk stratification is only for localized primary GISTs that have not been treated. Neoadjuvant pretreatment also invalidates risk stratification.
Treatment of GIST, Therapeutics, and Resistance Mutations
Treatment of primary localized GIST is surgical. However, approximately 40% of GISTs will recur or metastasize after complete resection of the primary tumor. Treatment of recurrent/metastatic GIST is primarily based on targeting oncogenic KIT and PDGFRA mutant proteins. Imatinib mesylate (Gleevec, Novartis Pharmaceuticals) is a small-molecule tyrosine kinase inhibitor (TKI) that targets KIT and PDGFRA as well as other non-GIST relevant proteins, such as BCR-ABL kinase. Imatinib is US Food and Drug Administration (FDA) approved for first-line use in the treatment of recurrent/metastatic GIST. Before use of imatinib, recurrent/metastatic GIST patients had a response rate to conventional chemotherapy of less than 5% and a median survival of 18 months. Using imatinib, patients with unresectable GIST now have a median survival of 55 months.
Response to imatinib varies with KIT and PDGFRA mutation status. KIT exon 11 mutant GISTs have the best response to imatinib. Increasing the imatinib dose from 400 mg/day to 800 mg/day improves the response of KIT exon 9 mutant GISTs. The most common PDGFRA mutation that encodes PDGFRA D842V is unresponsive to imatinib. However, about one-third of PDGFRA mutant and some wild-type GISTs respond to imatinib. SDH-deficient GIST also does not respond to imatinib. The requirement to provide 800 mg/day of imatinib to KIT exon 9 mutant GISTs, the lack of efficacy in treating PDGFRA D842V mutant GISTs with imatinib, and the lack of imatinib response in SDH-deficient GIST argue for a personalized medicine approach by determining the KIT-PDGFRA mutation or SDHB expression status of each GIST (as appropriate based on clinicopathologic correlates) before administration of imatinib in any setting.
Approximately 50% of GIST patients develop acquired resistance to imatinib within 2 years of therapy, and most will acquire imatinib resistance within 10 years. Therapeutic resistance in these cases is a result of second-site intraallelic KIT mutations within exons 13, 14, 17, or 18 that either inhibit binding to imatinib or render KIT insensitive to imatinib. Resistance can be localized, often occurring as a single tumor nodule that demonstrates growth in the background of other tumors that are under control, or as generalized resistance with numerous sites of progression.
Sunitinib Maleate
Sunitinib maleate (Sutent, Pfizer Pharmaceuticals) is another small-molecule TKI that is FDA approved for the treatment of those patients intolerant of or resistant to imatinib. Sunitinib targets vascular endothelial growth factor receptors (VEGFRs) 1–3, in addition to KIT and PDGFRA. In a placebo-controlled trial of patients resistant to or intolerant of imatinib, the median time to tumor progression was 27.3 weeks in the treatment arm versus 6.4 weeks in the placebo arm. The two most common KIT mutations that give rise to secondary resistance, V654A and T670I, are sensitive to sunitinib.
Regorafenib
Regorafenib (Stivarga, Bayer), a multikinase inhibitor that targets KIT, PDGFR, VEGFR1-3, TIE2, RET, fibroblast growth factor receptor 1, RAF, and p38 mitogen–activated protein kinase, showed efficacy in patients who failed both imatinib and sunitinib, with a median progression-free survival of 13.2 months. Regorafenib is now FDA approved as third-line therapy for the treatment of imatinib- and sunitinib-resistant GIST.
The success of treatment of recurrent/metastatic unresectable GIST with imatinib suggested that adjuvant therapy with imatinib might delay the time to recurrence/metastasis. Most patients with localized, resectable GIST are cured by surgery and will not benefit from adjuvant therapy. However, about 40% of GISTs will recur, and adjuvant therapy should be considered after resection in each patient with GIST. Adjuvant therapy has been examined in two large trials. Follow-up at 19.7 months of a large, randomized placebo-controlled trial that examined recurrence-free survival (RFS) after 1 year of adjuvant imatinib demonstrated a 1-year RFS of 98% in the imatinib arm versus 83% in the placebo arm. A subsequent trial comparing 1 year to 3 years of adjuvant imatinib demonstrated an 87% RFS in the 3-year treatment group versus 60% at 1 year. There was also a difference in overall survival: 92% versus 82% at 5 years of follow-up in the 3-year and 1-year treatment groups, respectively. With this strong argument for adjuvant therapy, imatinib received FDA approval for the adjuvant treatment of patients with GIST.
Ripretinib
Ripretinib (QINLOCK, Deciphera Pharmaceuticals) is considered fourth-line therapy for adult patients with advanced GIST who have received treatment with three or more kinase inhibitors, including imatinib. The INVICTUS trial showed improved median progression-free survival of 6.3 months versus 1.0 month with placebo, as well as improved median overall survival (statistical significance could not be evaluated due to the methodology). In addition, it has been shown that efficacy may be associated with specific resistance mutation types in the activation loop exons, such that KIT exon 11 plus 17/18 mutations may be the more sensitive to ripretinib than sunitinib.
There has been significant progress in the treatment of PDGFRA D842V mutant GISTs. Avapritinib (BLU-285, Blueprint Medicines), an oral receptor TKI, has shown great efficacy in the treatment of PDGFRA D842V mutant GIST and was approved by the FDA in 2020 as first-line therapy for patients with unresectable or metastatic GIST harboring PGFRA exon 18 mutations. Avapritinib is also active in inhibiting other KIT and PDGFRA mutants, so it may find greater utility in the treatment of GIST patients. Avapritinib has also shown marked activity in patients with systemic mastocytosis, which is characterized by KIT D816V activation loop mutations.
With rare exceptions, SDH-deficient GISTs do not respond to imatinib. There is some evidence for activity in SDH-deficient GIST with sunitinib and regorafenib. , However, the number of responses is small and the duration of response unclear. Further studies are required to determine the long-term efficacy of sunitinib and regorafenib in SDH-deficient GIST and to identify an optimized therapy for this GIST subtype.
Some evidence from case reports indicates that BRAF V600E mutant GISTs respond to BRAF inhibitors and may benefit from treatment with this class of drugs.
Histologic Assessment of Treated GIST
Neoadjuvant therapy is often used for locally advanced or large tumors to shrink and ultimately make them amenable to surgical resection. Pathologists may be asked to evaluate the therapeutic response. Morphologic changes in GIST treated with imatinib include hyalinization, hypocellularity, and occasionally myxoid stroma and necrosis ( Fig. 18.30 ). Within the hypocellular hyalinized areas, tumor cells are almost always present but may be difficult to identify by H&E alone and may be more readily identifiable with KIT or DOG1 immunostains. In addition, discrete foci of hypercellular viable tumor may be present, sometimes as separate nodules and sometimes within a larger hyalinized tumor (“nodule within a nodule” appearance). Mutational analysis has demonstrated the presence of secondary resistance mutations within these viable hypercellular foci, reflecting disease progression.
