gastrointestinal stromal tumor: recent advances in pathology and genetics

Review Article

Gastrointestinal stromal tumor: Recent advances in pathologyand genetics

Hidetaka Yamamoto and Yoshinao Oda

Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University and Division ofPathology, Kyushu University Hospital, Fukuoka, Japan

The discovery of KIT gene mutation in gastrointestinalstromal tumor (GIST) has provided a paradigm shift in theclassification, diagnosis and molecular-targeted therapy ofgastrointestinal mesenchymal tumors. There is growing evi-dence of phenotype-genotype (KIT, platelet-derived growthfactor receptor-alpha, succinate dehydrogenase or otherdriver gene mutation) and genotype-therapeutic (sensitivityto imatinib) correlations in GIST. Risk stratification basedon mitotic counts, tumor size and rupture is useful for theprognostication and management of patients with GIST.Blood vessel invasion is a strong indicator of liver metas-tasis in GIST. In addition, novel biomarkers such as cell-cycle regulators, microRNAs and their targets have beendiscovered by using high throughput molecular analyses. Incontrast, leiomyosarcoma of the gastrointestinal tract hasbecome a very rare entity in the ‘KIT’ era, and its molecularpathogenetic mechanism is unclear. Recent studies haverevealed a wide spectrum of cytological atypia, mitoticcounts and biological behavior of gastrointestinal smoothmuscle tumors, suggesting the necessity of establishingthe criteria for malignancy. Collectively, both classical his-topathological procedures and modern molecular investiga-tions are indispensable for the evolution of diagnosis andtreatment of GIST and mimics.

Key words: gastrointestinal stromal tumor, KIT, leiomyosar-coma, PDGFRA, succinate dehydrogenase

Before the discovery of the oncogenic role of KIT gene muta-tion in gastrointestinal stromal tumors (GISTs) by Hirota et al.in 1998,1 most GISTs were lumped into the category ofsmooth muscle tumors or neurogenic tumors. In the ‘KIT’ era,

GIST has become the most common mesenchymal tumor ofthe gastrointestinal (GI) tract.2 According to a recent concept,GIST is considered a spindle or epithelioid cell neoplasmwhich expresses KIT protein and has KIT or platelet-derivedgrowth factor receptor-alpha (PDGFRA) gene mutation.2,3

The normal counterpart of GIST is believed to be the inter-stitial cell of Cajal (ICC), which is the pacemaker cell locatedat the Auerbach’s plexus of the GI tract.

Soon after the discovery of KIT gene mutation, a reportdescribed the first case of advanced GIST successfullytreated with imatinib, a tyrosine kinase inhibitor (TKI).4 Sincethen, effective imatinib therapy for unresectable or metastaticGISTs has been confirmed by several clinical studies.5 GISTshave served as an excellent model for the molecular-basedclassification, diagnosis and therapy of malignant tumors,because KIT is not only a diagnostic marker but also anoncogenic driver and therapeutic target.

Clinicopathological and histopathological features

The clinicopathological, phenotypic and genotypic features ofvariants of GIST are summarized in Table 1.

Most patients with GISTs are middle-aged to elderly adults,and pediatric cases under 20 years old are very rare. Mor-phologically, GIST is roughly classified as spindle cell type,epithelioid cell type or mixed type (Fig. 1). Miettinen andLasota have described the further cytological subtypes ofgastric GIST as follows: sclerosing spindle cell, palisading-vacuolated spindle cell, hypercellular spindle cell, sarcoma-tous spindle cell, sclerosing epithelioid cell, dyscohesiveepithelioid cell, hypercellular epithelioid cell and sarcomatousepithelioid cell.2 Among these subtypes, the sarcomatousspindle cell and sarcomatous epithelioid cell subtypes arecharacterized by plump and hyperchromatic nuclei, and areusually mitotically active with aggressive behavior. Mostintestinal GISTs are of spindle cell type, and occasionally

Correspondence: Hidetaka Yamamoto, MD, PhD, Department ofAnatomic Pathology, Graduate School of Medical Sciences, KyushuUniversity, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.Email: [email protected]

Received 7 August 2014. Accepted for publication 7 October2014.© 2014 Japanese Society of Pathology and Wiley Publishing AsiaPty Ltd

Pathology International 2014 doi:10.1111/pin.12230

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associated with skenoid fibers. The epithelioid cell pattern israre in small intestinal GIST, but, if present, is linked withmalignancy.2

KIT, also called c-kit or CD117, is positive in the vastmajority (95%) of GISTs by immunohistochemical staining(IHC), whereas a minor subset (5%) show low or negativeexpression of KIT.2 DOG1, also known as ANO1, is con-stantly positive in GISTs irrespective of the KIT expressionlevel, supporting the diagnosis of GIST (Fig. 1).6 Interestingly,most KIT-negative GISTs occur in the stomach, and haveepithelioid cell morphology, DOG1 expression and PDGFRAgene mutation with usually less aggressive biologicalbehavior.6–8 It is notable that more than half of PDGFRA-mutant GISTs are positive for KIT by IHC.

The stomach is the most common site of GISTs, followedby the small intestine. Colorectal and esophageal primarytumors are less frequent. GIST typically presents as a sub-mucosal tumor of the GI wall, occasionally accompanied bymucosal ulcer and rupture of tumor. GIST rarely occursoutside the GI wall, such as in the omentum, mesentery,retroperitoneum or pelvic cavity; such GISTs are calledextragastrointestinal stromal tumor (EGIST).9 The histo-pathological and genetic features of EGIST are essentiallythe same as those of conventional GIST of the GI tract.Furthermore, KIT-negative EGIST is rarely encountered. Wefound that KIT-negative EGIST preferentially occurred in theomentum and had epithelioid cell morphology and PDGFRAgene mutation, similar to gastric KIT-negative GIST.10 Theorigin of EGIST is controversial. It is possible that someGISTs extend outward, losing their primary connection totheir GI tract origin and eventually becoming attached toadjacent soft tissue.11 In addition, multiple peritoneal meta-static GISTs from the GI tract are sometimes misdiagnosedas primary ‘EGIST’. However, rare cases of GIST actuallyoccur at sites far from the GI tract, such as the omentum andmesentery, or even the liver and thoracic cavity.12,13 Thepresence of ICC-like cells in the omentum and viscera otherthan GI tract has been proposed as a potential origin ofEGISTs, but this hypothesis should be further investigated.14

Driver mutation and phenotype-genotype correlation

KIT and PDGFRA are receptor tyrosine kinases (RTKs), andthe gain-of-function mutation of the KIT or PDGFRA geneplays a central role in the pathogenesis of GIST via theactivation of KIT downstream signals such as the RAS-RAF-MAPK and PI3K-AKT-mTOR pathways (Fig. 2).7,8 The muta-tions occur either in the extracellular (KIT exons 8 and 9),juxtamembrane (KIT exon 11, PDGFRA exon 12) or tyrosinekinase (KIT exons 13 and 17, PDGFRA exons 14 and 18)domain (Table 2). The mutation in KIT exon 11 is the mostfrequent (60–70%) in GIST, followed by mutations in KITTa

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2 H. Yamamoto and Y. Oda

© 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd

exon 9 (5–10%) and PDGFRA exons 12 (2%) and 18 (8%).7,8

Mutations in KIT exons 8, 13 and 17 and PDGFRA exon 14are very rare (∼1%).7,8 Approximately 10–15% of GISTs arenegative for mutations in both the KIT and PDGFRA genes,and about half of ‘wild-type’ GISTs have inactivating muta-tions in the genes coding subunits of the succinate dehydro-genase (SDH) complex (see below).15–18 A subset ofremaining ‘wild-type’ GISTs have mutations in BRAF(V600E), HRAS, NRAS or PIK3CA (∼1% each).8 Thesemutations presumably cause the constitutive activation of KITdownstream signal pathways.

Importantly, the driver mutations of oncogenes are mutu-ally exclusive. Moreover, the vast majority of GISTs, exceptfor a subset (not all) of PDGFRA-mutants, are positive for KITby IHC, irrespective of the genotypes. Interestingly, somegenotypes are closely correlated with clinicopathological fea-tures and biological behavior as well as the sensitivity to TKI(Table 2).19–21 For example, GISTs with the KIT exon 11 dele-tion, in particular deletion involving the codons 557 and 558,are more aggressive than those with the KIT exon 11 mis-sense mutation or 3′ internal tandem duplication.19 The KITexon 9 mutation characterized by duplication of codon A502-

a b

c dFigure 1 Representative histopathologi-cal features of gastrointestinal stromaltumor (GIST) of the stomach. (a) Spindlecell type GIST consists of fascicles ofuniform spindle cells with eosinophiliccytoplasm. (b) KIT is positive by immuno-histochemical stain. (c) Epithelioid celltype GIST consists of tumor cells withround to oval nuclei and eosinophilic cyto-plasm. Myxoid matrix is noted. (d) DOG1is diffusely positive. KIT is negative in thiscase (not shown).

Figure 2 gastrointestinal stromal tumor(GIST) cell signaling pathways. Typically,the gain-of-function mutation of the KIT orPDGFRA gene leads to the activation ofKIT/PDGFRA downstream signals suchas the RAS-RAF-MAPK and PI3K-AKT-mTOR pathways. As for KIT/PDGFRA-wild GIST, the mutation in NF1(neurofibromin), BRAF, HRAS, NRAS orPIK3CA may cause the constitutive acti-vation of KIT downstream signal path-ways. Dysfunction of SDH complex isanother possible pathogenetic mecha-nism of ‘wild-type’ GISTs. Either the genemutation in a member of the SDH complexor an as-yet-unknown mechanism maycause destabilization of the SDH complex,and lead to accumulation of succinate,resulting in the stabilization of HIF1-α toactivate the transcription of target onco-genes related with cell proliferation andangiogenesis.

Pathology and genetics of GIST 3


Y503 is present almost exclusively in the intestinal GISTs,and these tumors are usually aggressive.7 The PDGFRAmutation is preferentially present in the gastric or omentalGISTs, some of which are immunohistochemically KIT-negative or -weakly expressing tumors.7,10 Most PDGFRA-mutant GISTs have epithelioid cell morphology and indolentclinical course. The SDH-deficient GISTs have distinctiveclinicopathological features (see below).

SDH-deficient GISTs; Carney-triad, Carney-Stratakissyndrome, pediatric GIST and adult‘pediatric-type’ GIST

The SDH complex is located in the inner mitochondrial mem-brane and plays a role in the electron transport chain andTCA cycle (Krebs cycle) by changing succinate to fumarate.17

The SDH complex consists of four subunits: SDHA, SDHB,SDHC and SDHD. Either the gene mutation in a member ofthe SDH complex or an as-yet-unknown mechanism isthought to cause destabilization of the SDH complex.17 Dys-function of SDH enzyme leads to accumulation of the sub-strate succinate, resulting in the stabilization of HIF1-α toactivate the transcription of target oncogenes (Fig. 2).17

Germline mutations in SDHB, SDHC or SDHD are associ-ated with familial paraganglioma syndromes.17 Likewise,germline mutations in SDH genes are linked to Carney-Stratakis syndrome (CSS) which is an inherited predisposi-tion to multiple gastric GIST and paraganglioma.22,23

Carney-triad (CT) is characterized by multiple gastric GIST,paragangliomas and pulmonary chondroma with a femalepredominance and no heritability.22,24 CT-associated GISTs

lack significant mutations in SDH genes despite a deficiencyof SDHB immunoreactivity.22

Recent studies revealed that most pediatric GISTs havemutations in a subunit of the SDH complex, such as SDHA,SDHB, SDHC or SDHD.15,16,18 Pediatric GISTs usually occurin the second decade with a female predominance, and arecharacterized by gastric location, multinodular growthpattern, epithelioid or mixed cell morphology and KIT/PDGFRA-wild type (Fig. S1).25 In addition, adult GISTs whichare histopathologically, genetically and biologically similar topediatric GISTs, namely adult ‘pediatric-type’ GISTs, havebeen reported.26

These four subtypes of GISTs show loss of SDHB expres-sion by IHC, and thus, are collectively called ‘SDH-deficientGISTs’. These tumors have common features, includingmanifestation in children or young adulthood, gastric location,multiplicity, multinodular/plexiform growth, epithelioid cellmorphology, absence of KIT/PDGFRA mutations (Tables 1,2,Fig. S1).15,16,22,25,26 In addition, SDH-deficient GISTs fre-quently metastasize, often to the lymph node (up to 50%cases), but pursue a relatively indolent clinical course. Somepatients live many years even after developing liver or peri-toneal metastasis. As SDHB is normally ubiquitously presentin the cells, loss of SDHB in tumor cells reflects dysfunctionof the SDH complex. Here, we emphasize again that SDH-deficient GIST is positive for KIT by IHC. The prevalence ofSDHB-deficient GIST is estimated as about 5% of all GISTs.8

Clinically, SDHB-deficient GISTs are resistant to imatinib.15,26

Interestingly, loss of SDHB is due to not only the mutation inthe SDHB gene itself but also mutations in other subunitsof the SDH complex.15,16,27 This phenomenon is explained bythe fact that mutation in a SDH subunit causes instability and

Table 2 Correlation between the genotypes and clinical features in gastrointestinal stromal tumors (GISTs)

Gene Domain Frequency (%) Site Biological behaviorImatinib

sensitivity

KIT 75Exon 8 EC ∼1 Small intestine Aggressive? +?Exon 9 EC 5–10 Intestine Aggressive +Exon 11 JM 60–70 Stomach, intestine Various (del557,558;

aggressive)++

Exon 13 TK 1 Small intestine Unknown −Exon 17 TK 1 Small intestine Unknown −

PDGFRA 10Exon 12 JM 2 Stomach Indolent +/−Exon 14 TK ∼1 Stomach Indolent +/−Exon 18 TK 8 Stomach Indolent − (D842V)

KIT, PDGFRA-wild 15SDH A,B,C,D 7 Stomach Indolent (frequent lymph

node metastasis)−

BRAF V600E 1 Small intestine Unknown −NF1 various ∼1 Small intestine Indolent −

Others

EC, extracellular; JM, juxtamembrane; TK, tyrosine kinase.



degradation of the SDH complex. However, in some cases ofSDHB-deficient GISTs including CT-associated GIST, no dis-tinctive mutations can be found in any SDH subunits, aphenomenon for which the molecular basis remainsunclear.22,28 Nevertheless, IHC for SDHB is helpful to identifyGISTs having unique clinicopathological features and toavoid ineffective therapy.

Multiple GIST syndromes

The GISTs in this category of disease present as multipletumors, but have different pathogenetic mechanisms andclinicopathological characteristics (Table 1). The features ofCT and CSS are described above.

Familial GIST is caused by germline mutation of the KIT orPDGFRA gene, and is inherited in an autosomal dominantmanner.29 These mutations are identical to those present insporadic GISTs. Most patients with this syndrome developmultiple GISTs in the small intestine, colon or stomach bymiddle age, but manifestation in childhood is rare, in contrastwith many other inherited tumor syndromes. Some of thesepatients have other manifestations linked with KIT activation,including uriticaria pigmentosa and hyperpigmentation.Histopathologically, familial GISTs are similar to sporadicGISTs. Broad band-like, hyperplastic lesions of ICC andmicroscopic-sized tumors—namely, ‘micro GIST’ or ‘GISTtumourlets’—can also be found within the muscularis propria(the identical location of ICC at the Auerbach’s plexus) of thesame gut. The presence of these precursor lesions stronglysupports the notion that ICC is the normal counterpart of GIST.

Neurofibromatosis type 1 (NF1) is characterized by cuta-neous multiple neurofibromas and Café-au-lait spot. Approxi-mately 7% of NF1 patients have GISTs.30 NF1-related GISTsoccur exclusively in the small intestine as multiple tumorswith spindle cell morphology.31,32 Hyperplasia of ICC is alsocommon in patients with NF1-related GIST, similar to familialGIST. Neither KIT nor PDGFRA gene mutations are presentin NF1-related GISTs. In our study, MAPKp44/42(ERK1/2)was activated (phosphorylated) in the majority of NF1-relatedGISTs, suggesting that loss-of-function of the NF1 geneproduct (neurofibromin) may cause constitutive activations ofRAS and the downstream RAF-MAPK signaling pathway totake the place of the KIT-activating mutation (Fig. 2).32

Histopathological prognostic factors andrisk assessment

GISTs exhibit a wide range of biological behaviors frombenign to malignant. Malignant cases metastasize to the liverand/or peritoneum. However, it is difficult to draw a sharp linebetween benign and malignant lesions based on histological

findings alone. Based on the consensus approach developedat the National Institutes of Health (NIH) in 2001, Fletcheret al. have recommended the use of risk assessment topredict GIST behavior.3 This risk grade is defined by a com-bination of tumor size and mitotic counts. Subsequently,Miettinen and colleagues proposed a modified gradingsystem based on the follow-up data of very large numbers ofGISTs.2 More recently, risk stratification using tumor size,mitotic counts and rupture has been proposed by Joensuuet al., because tumor rupture is strongly correlated with therisk of peritoneal metastasis.33,34 Table 3 summarizes thethree grading systems. Representative histological findingsrelated with adverse outcome of GIST are shown in Figure 3.

Our previous study revealed that blood vessel invasion(BVI) is a strong indicator of liver metastasis in GIST.35 In thatstudy, when BVI was present in the primary localized GIST,approximately 80% of cases subsequently developed livermetastasis. It is not surprising that the presence of BVI isclosely related with hematogenous metastasis to the liver.Among high-risk GISTs, the rate of liver metastasis washigher in the BVI-positive cases than in the BVI-negativeones (83% vs 50%), suggesting that the former can be des-ignated as ‘very high-risk’ GISTs.35 Interestingly, a smallpopulation of low- or moderate-risk GISTs had BVI in theprimary tumor, and most of these BVI-positive tumors alsoeventually metastasized to the liver.35 Because the predictionof metastasis of low- to moderate/intermediate-risk GIST isdifficult by risk grade alone, the evaluation of BVI is a usefultool to predict the metastasis of GIST, irrespective of riskgrade.

In rare instances, GISTs have morphologically and/orimmunohistochemically heterogeneous components within asingle tumor. In such biphasic phenotypic GISTs, the cyto-logical appearance, immunohistochemical marker expres-sion (KIT, CD34, etc.) and/or mitotic counts are different inthe two components.36 However, each component has patho-logical features consistent with conventional GIST. At themolecular level, both components have the same mutation(KIT or PDGFRA), suggesting clonal evolution. For practicaldiagnosis, the more mitotically active component should bereferenced when assigning the risk grade.

In contrast, the concept of dedifferentiated GIST hasrecently been proposed.37 The dedifferentiated component isKIT-negative, and is morphologically similar to undifferenti-ated pleomorphic sarcoma, which has a cellular appearancequite different from that of conventional GIST (Fig. 3). Inother words, dedifferentiated GIST is a tumor with a highgrade sarcoma component lacking the features of conven-tional GIST in terms of both cytomorphology and phenotype.From a clinical viewpoint, dedifferentiated GIST is highlymalignant and lethal, and is resistant to imatinib.37 The detailsof the molecular mechanism of dedifferentiation have beenunclear to date.



TKI treatment-related genetics and histopathology

The KIT or PDGFRA genotype is very closely related with thesensitivity to imatinib, and influences the prognosis afterimatinib therapy (Table 2).7,20,21 In general, GISTs with KITexon 11 mutations are sensitive to imatinib. GISTs with KITexon 9 are less sensitive, but a higher dose of drug canincrease the therapeutic effect.38 GISTs with mutations at thetyrosine kinase domain (KIT exons 13 and 17 and PDGFRAexon 18, and particularly the D842V mutation) are resistant toimatinib, because imatinib is not able to bind to the tyrosinekinase domain of these mutant proteins.20,39 SDH-deficientGISTs are also imatinib-resistant.15

During the treatment with TKIs, the tumor may grow largeragain even if the therapy was initially effective. Secondaryimatinib-resistance is often associated with secondary KITmutation at the tyrosine kinase domain (exon 13 or 17).40

Once secondary resistance occurs, the prognosis of patientswith GIST is usually very poor. Overcoming the secondaryresistance to TKIs will thus be one of the most importantgoals of GIST research in the near feature.

Sometimes, GISTs are surgically resected after imatinibtherapy and serve as pathological specimens. Strict histo-pathological criteria for evaluation of the therapeutic effects ofTKI have not been established yet, and further study isneeded. As for radiological evaluation, not only decreasedtumor size but also decreased density on computed tomogra-phy indicates a response to TKI therapy, since the latterreflects tumor necrosis or myxoid degeneration.41 In parallelwith this phenomenon, the resected GISTs responding to TKItherapy often grossly show necrosis, cystic change, hemor-rhage and extensive myxoid and gelatinous degeneration atthe cut-surface (Fig. S2).21 Histologically, these tumors areextremely hypocellular with abundant myxoid matrix, hyalin-ization or necrosis. However, tumor necrosis alone is not areliable indicator of therapeutic response, because necrosiscan occur naturally in imatinib-naïve, high-grade GISTs. It isnotable that, even in a tumor with good response, there areusually microscopic foci of viable tumor cells positive for KIT; inother words, complete loss of tumor cells is rare. In such asituation, assessment of the risk of recurrence or metastasisafter surgical intervention is difficult. On the other hand,increased tumor size and density on computed tomographyindicate resistance to therapy.21,41 A new nodule within apre-existing nodule represents tumor progression. GISTsresistant to imatinib show, at least focally, hypercellular prolif-eration of viable tumor cells often with mitotic activity (Fig. S2).

Newly identified biomarkers other than drivergene mutations

MicroRNAs (miRNAs) are small, non-coding RNAs that areup- or down-regulated in several types of cancer, and play anTa

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important role in the tumorigenesis and progression. By usingmiRNA array, we found that miR-133b was down-regulatedand mRNA of fascin-1, a target of miR-133b, wasup-regulated in high-grade GISTs.42 Furthermore, fascin-1protein overexpression was significantly correlated withshorter disease-free survival time and several aggressivepathological factors, including blood vessel invasion andmucosal ulceration. Fascin-1 is known as an actin-bindingprotein, and functionally contributes to tumor invasion andmetastasis. In this context, our result is consistent with theidea that down-regulation of miR-133b and overexpression offascin-1 may play an important role in the progression ofGIST.

Pfetin, a potassium channel protein, is another potentialbiomarker revealed by using a proteomic approach. Mostcases of GIST are positive for pfetin, while reduced expres-sion of pfetin is a worse prognostic factor in GIST.43

Losses on the chromosome arms 1p, 9p, 14q and 22q arecommon events in GISTs.32,44 Several studies have reportedthat the loss of 9p and inactivation of the p16INK4a genelocated at 9p21 are each correlated with aggressive behaviorof GIST.45 The loss of 9p in GISTs was accompanied bydown-regulation of p16INK4a together with increased levelsof phosphorylated RB and E2F1, suggesting promotion of theG1/S phase of the cell cycle.45

The INI1 gene, located at 22q11.23, is a tumor suppressorgene that is frequently altered in malignant rhabdoid tumor.46

INI1 plays an important role in chromatin remodeling, andnegatively regulates the G1-S phase of the cell cycle viaup-regulation of p16INK4a transcription and down-regulation

of cyclin D1; alternatively, inactivation of INI1 leads to theacceleration of G1/S transition. In our previous study, areduction in the INI1 expression level was correlated with thepresence of loss of heterozygosity (LOH) at 22q11.23, andthis LOH was more frequently present in high-grade GISTsthan in low-grade ones.47 Thus, the hemiallelic loss of INI1due to 22q loss might play a role in the increased proliferativeactivity of GIST cells. Immunohistochemically, GISTswith LOH at the INI1 locus often show a focally reduced,mosaic expression pattern of INI1, which may reflect thehaploinsufficiency of INI1.47

Collectively, these results suggest that characteristic chro-mosomal abnormalities in GIST may be closely related withaltered cell-cycle regulation, leading to increased tumor cellproliferation and tumor progression. It has also been reportedthat overexpression of G2-M regulators such as cyclin A,cyclin B1 and cdc2 are correlated with higher mitotic activityand/or aggressive behavior of GIST.48

LEIOMYOSARCOMA

In the pre-GIST era, smooth muscle tumors of the GI tractwere separated into leiomyoma, leiomyoblastoma and leio-myosarcoma. The vast majority of leiomyoblastomas andleiomyosarcomas in the earlier literature now correspond toGIST, with the former being consistent with epithelioid GIST.According to the most recent classification, ‘true’ leiomyosar-coma (LMS) of the GI tract is very rare. The incidence ofprimary LMS of the GI tract was estimated at about 1/50 to

a b

c d

Figure 3 The pathological findingsrelated with aggressive behavior ofgastrointestinal stromal tumor (GIST).(a) Mitotic figures. The tumor cells haveplump spindle-shaped nuclei and prolifer-ate in hypercellular fascicular pattern,consistent with sarcomatous spindle celltype GIST. (b) Rupture of tumor. Theserosal aspect of tumor shows destructionaccompanied by hemorrhage. (c) Bloodvessel invasion. Tumor thrombus in thevein is highlighted by elastica-van Giesonstain (pointed by arrow). (d) Dedifferenti-ated GIST. The tumor is composed oflarge atypical cells with oval, polygonal orbizarre-shaped nuclei, accompanied byfrequent mitotic figures.



1/60 that of GIST.49 GI-LMSs preferentially occur in the smallintestine and large intestine, while gastric and esophagealtumors are very rare.49 Although most GI-LMSs have manymitoses (>20/50 HPFs) and significant nuclear atypia, asmall subset of them show low mitotic activity (1–6/50HPFs) and/or mild nuclear atypia. Even such ‘low-grade’LMSs of the GI tract have a risk of malignant behavior(local recurrence or metastasis) despite low mitotic activityor low-grade atypia.49 There is a similar problem in the caseof smooth muscle tumors in the subcutis or deep softtissue, which can recur and/or metastasize even whennuclear atypia is mild and mitoses are few (1–2/50 HPFs),indicating the difficulty in predicting the malignant potentialof smooth muscle tumors.50 Thus, pathologists should paymore attention to low-grade malignant smooth muscletumors rather than simply separating GI-smooth muscletumors into leiomyoma and LMS. On the basis of theseobservations, GI-smooth muscle tumors may be classifiedas leiomyoma, smooth muscle tumor of undeterminedmalignant potential (SMTUMP) or LMS, based on nuclearatypia, mitotic activity and coagulative necrosis (Table 4).49

LMS can be further subdivided into low-grade and high-grade tumors. However, further studies in a larger series ofpatients will be needed to establish reliable criteria for themalignancy of GI-smooth muscle tumors. Neither themolecular oncogenic mechanism nor an effective mode oftherapy has been fully elucidated in GI-LMS.

CONCLUSION

In summary, recent investigations on gastrointestinal mes-enchymal tumors have revealed clinicopathological, histo-pathological and underlying molecular genetic features,leading to the development of molecular abnormality-basedclassification, diagnosis and therapy. In addition to drivergene mutations, several molecular events related to chro-mosomes, cell-cycles, invasion and metastasis may play animportant role in the stepwise progression of GIST. Furthernovel insights into the biology of GISTs are expectedto establish better tailor-made therapy for patients withGISTs.

ACKNOWLEDGMENTS

We thank Yoko Zaitsu, M.D., Aya Fujita, M.D., PhD.,Masakazu Imamura, M.D., PhD., Norimoto Nakamura,M.D., PhD. and Ms Naomi Tateishi for their assistance withthese studies. Professors Masazumi Tsuneyoshi andTakashi Yao also provided expert advice. The Englishusage in this article was reviewed by KN International(http://www.kninter.com/).

Hidetaka Yamamoto has been announced as the winner ofThe Japanese Society of Pathology; Pathology ResearchAward in 2013.

Disclosure

The authors have no conflicts of interest to report in regard tothis review article.

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SUPPORTING INFORMATION

Additional Supporting Information may be found in the onlineversion of this article at the publisher’s web-site:

Figure S1 Histopathological features of pediatric GIST ofthe stomach. (a) Multinodular growth pattern of epithelioidcells is characteristic. (b) Tumor cells show loss of SDHBexpression, whereas non-neoplastic stromal cells andendothelial cells show granular cytoplasmic staining forSDHB.Figure S2 Histopathological features of GISTs resectedafter imatinib therapy. (a) A case of imatinib-responsive GISTshows an extremely hypocellular proliferation of spindle cellsembedded in abundant myxo-hyalinous materials. (b) A caseof imatinib-resistant GIST. Microcystic degeneration suggest-ing therapeutic effect is partially present (right upper),whereas hypercellular foci of viable tumor cells are residual,indicating resistance to imatinib (left).



gastrointestinal stromal tumor: recent advances in pathology and genetics

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