Mesenchymal tumors of the digestive system
2026-10-04 Paola Dal Cin, PhD , David Papke, MD Affiliation1.Brigham and Women's Hospital , Harvard Medical School, Boston , MA (USA)
2.Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
Keywords
digestive mesenchymal tumors, GI tract, stomachClassification
Definition
Most mesenchymal tumor types can arise throughout digestive system, at least on rare occasions. They show histopathological features and genetic markers no different from their soft tissue counterparts. Accurate diagnosis can be challenging, but the combination of morphologic, immunophenotypic and molecular findings represents the best strategy to allow accurate classification. Mesenchymal tumors that rarely occur in the gastrointestinal (GI) tract will not be covered specifically in this section; see the WHO 2020 Soft Tissue and Bone Tumors for details. Here, we will focus on histological or molecular features that are unique to, or have a predilection for, the digestive system. 1-4
Benign mesenchymal neoplasms show a higher incidence in the gastrointestinal tract than sarcomas and are often incidentally identified on endoscopy or colonoscopy. The most common, clinically significant, mesenchymal tumor type of the digestive system is gastrointestinal stromal tumor (GIST), a tumor type of interstitial cells of Cajal that harbors tyrosine kinase mutations that are associated with distinct mechanisms of response and resistance to targeted therapies. 5
Smooth muscle tumors within the GI tract are predominantly found in the esophagus and colorectum, surpassing the incidence of GISTs in these locations. 6
The stomach is a preferential site of involvement for some mesenchymal tumor types. Glomus tumors, plexiform fibromyxoma, and inflammatory fibroid polyps exhibit a predilection for the gastric antrum, while schwannomas and synovial sarcomas typically affect the gastric body. Liposarcomas and granular cell tumors are typically found in the esophagus.
Most vascular anomalies occur sporadically; however, several can be inherited, predisposing patients to developing multifocal vascular lesions. There are many genetic alterations associated with sporadic vascular anomalies. 7
| Mesenchymal tumors of the digestive system | Genetic events |
|---|---|
| Gastrointestinal stromal tumor | |
| Gastrointestinal stromal tumor | The genetic classification "gastrointestinal stromal tumor" (GIST) started in 1998 with the finding of KIT gain-of-function mutations as oncogenic driver events,8 and since that time various new molecular subtypes have been detected.5 KIT mutations, most commonly in exon 11, and less commonly in exons 9, 13 and 17, are present in most GISTs (80-85%). About 10% of gastric GISTs harbor PDGFRA mutations in exons 18, 12 and 14, which are usually mutually exclusive with KIT mutations.9 |
| About 2% of GISTs, usually in the small intestine, harbor bi-allelic NF1 inactivation. Rare driving alterations include BRAF V600E mutation, EGFR mutations, gene fusions in FGFR1, NTRK, and ALK, and KRAS mutations.1,5 KIT-mutant GISTs have a broader anatomical distribution, while BRAF V600E-mutant GISTs, GISTs with FGFR1 rearrangement and EGFR-mutant GIST tend to occur in the stomach. GISTs with NTRK3 and ALK fusions have been reported mainly in the intestine. | |
| The identification of oncogenic mutations in KIT and PDGFRA as drivers of the majority of GISTs (~%90) led to the regulatory approval of first-line imatinib, a tyrosine kinases inhibitor (TKI) that revolutionized outcomes. However, tumors eventually progress on imatinib due to acquired KIT secondary mutations in up to 90% of GIST patients.10 Subsequently, novel TKIs were developed and continue to be developed as post-first line therapeutic agents.11 | |
| SDH-deficient gastrointestinal stromal tumor | About 5-10% of gastric GISTs are instead driven by succinate dehydrogenase (SDH) deficiency, with inactivation of SDHA, SDHB, SDHC, or SDHD, and unlike other GISTs, SDH-deficient GISTs are commonly multifocal.12 They occur almost exclusively in the stomach, accounting for nearly all pediatric cases, and they follow a different clinical course than other GIST types, such that they should not be risk-stratified.13 SDH-deficient GISTs tend to develop in children and young patients and can be sporadic or associated with Carney-Stratakis syndrome (CSS) and Carney triad (CT). 14,15 |
| Loss of expression of SDHB (termed SDH deficiency) occurs in all SDH-deficient GISTs regardless of which SDH subunit is inactivated and is generally required for diagnosis.16 Loss of expression of SDHA by immunohistochemistry is assocated only with SDHA mutation.17 | |
| Adipose tissue and (myo)fibroblastic tumors | |
| Inflammatory myofibroblastic tumor (IMT) | IMTs rarely occur in the gastrointestinal tract, where they have a predilection for the stomach, and ALK rearrangement can be confirmed when present using FISH analysis, immunohistochemistry or sequecing.18-20 Epithelioid inflammatory myofibroblastic sarcoma is a specific variant of IMT with ALK::RANBP2 or RANBP1::ALK fusions in most cases, and it also can occur in the stomach.21,22 There have been rare case reports of gastrointestinal IMT with ROS1 fusions.23,24 |
| Desmoid fibromatosis | CTNNB1 mutations are detected in approximately 85% of sporadic DFs, while APC mutations are present in Gardner syndrome-associated cases. There are mixed reports of whether CTNNB1 S45F mutations might be associated with higher local recurrence risk than other CTNNB1 mutations.25 |
| Lipoma | GI tract lipomas are not uncommon, usually asymptomatic and often incidentally detected on endoscopy. In rare instances, they can lead to life-threatening complications, with the large intestine having been the most commonly affected site.26 In general, simple chromosomal aberrations are observed in lipomas, with 12q14-15/ HMGA2 rearrangement being the most common one. So far, a single case of spindle cell lipoma of the small intestine with 13q14} deletion have been reported.27 |
| Liposarcoma | Well-differentiated liposarcoma has a predilection for the oesophagus among gastrointestinal tract sites. Tumors previously diagnosed as giant fibrovascular polyp generally represent oesophageal well-differentiated liposarcoma. Most cases arise in the proximal oesophagus near the cricopharyngeus muscle, just distal to the larynx. MDM2 amplification was demonstrated by FISH analysis.4,28 Outside of the esophagus, liposarcoma only rarely presents in the gastrointestinal tract, where it is generally an extinsic mass that invades through the wall into the mucosa. Detection of MDM2 and/or CDK4 amplification serves to distinguish well-differentiated/ dedifferentiated liposarcoma from benign adipose tumours.29,30 |
| Inflammatory fibroid polyp | Inflammatory fibroid polyp (IFP) is a benign neoplasm that can occur in any part of the gastrointestinal tract but has a striking predilection for the gastric antrum and the ileum.31 IFP harbors PDGFRA somatic mutations that are the same as those in GIST, in exons 12, 14 and 18.32,33 However, IFP is different from GIST because it is uniformly benign and does not show interstitial cell of Cajal differentiation. There is a localization-specific pattern: exon 12 mutations predominate in the small intestine, while exon 18 mutations occur more frequently in the stomach.34 |
| Germline PDGFRA mutations have been described in the “Devon syndrome," where patients develop multiple IFPs and multiple PDGFRA-mutant GISTs.35 | |
| Plexiform fibromyxoma | Plexiform fibromyxoma is a benign mesenchymal tumor type arises almost exclusively in the gastric antrum and pylorus, with rare occurence in the duodenum.36 GLI1 overexpression was detected, resulting from either t(11;12)(q11;q13) /MALAT1::GLI1 fusion or GLI1 amplification. 37 A subset of lesions demonstrated loss of the PTCH1 tumor suppressor.38 |
| Calcifying fibrous tumor | Calcifying fibrous tumor (CFT) commonly occurs in the serosa of abdominal organs, including gastrointestinal tract organs, and more rarely it can occur in the other layers of the gastrointestinal tract wall such as the muscularis propria or even mucosa.39,40 |
| Smooth muscle and skeletal muscle tumors | |
| Smooth muscle tumors | Smooth muscle tumors within the GI tract are predominantly found in the esophagus and colorectum, surpassing the incidence of GISTs in these locations.6 Leiomyomas, leiomyosarcomas, and EBV-associated smooth muscle tumors predominantly occur, respectively, in the oesophagus and colorectum, in the right side colon or the small intestine, and in the liver. |
| Diffuse leiomyomatosis occurirng mostly of the esophagus, is associated wit Alport syndrome, charcateized by deletions of the 5'-end of both the COL4A5 and the COL4A6.41 Li–Fraumeni syndrome, hereditary retinoblastoma syndrome, and radiation exposure may be predisposition factors for leiomyosarcoma. 42 T-lymphocyte immunosuppression with concomitant EBV infection is a risk factor for EBV-associated smoth muscle tumors. 43 | |
| The molecular pathogenesis and heterogeneity of LMS are still poorly understood, with several molecular subtypes, that may respond differentially to those targeted therapies,leading to better individualization of treatment.44 Frequent recurrent DNA copy-number alterations are reported including losses involving tumor suppressors ATRX, PTEN, RB1 and TP53.45,46 The presence of multiple tumor suppressor losses is associated with worse outcomes.45 | |
| Rhabdomyosarcoma | Embryonial rhabdomyosarcoma (ERMS) is most frequent subtype that occurs in the gastrointestinal tract, while other RMS types essentially never affect the gastrointestinal system. ERMS is generally characterized by multiple gains in chromosomes 2, 8, 11, 12, 13, and/or 20 and loss of 11p15.5, without any fusions. ERMS can harbor somatic driver mutations in the RAS pathway and loss of function mutations in BCOR.47 Botryoid-type ERMS is frequently associated with DICER1 and TP53 mutations.48 ERMS is associated with several syndromes such as Costello syndrome (HRAS mutations), neurofibromatosis type 1 (NF1 mutations), Noonan syndrome, and DICER1 syndrome.49 |
| Vascular and perivascular tumors | |
| Benign vascular anomalies and vascular tumors | Benign vascular lesions include hemagiomas and vascualr malformation. They can occur as single or multiple lesions, and they most commonly occur in the colon and oesophagus.50 Multiple lesions may arise in the setting of syndromes: Maffucci syndrome, Klippel–Trénaunay syndrome, blue rubber bleb naevus syndrome, and hereditary haemorrhagic telangiectasia.51 |
| The RAS/MAPK/ERK pathway and/or the PI3K/AKT/mTOR pathway are involved and many causal mutations have been identified, including: 1) TEK (TIE2) or PIK3CA mutations in sporadic venus malformations; 2) mainly MAP2K1 mutations and less frequently mutations in KRAS, HRAS, or BRAF in artetiovenous malformations; 3) GNAQ, GNA11 and PIK3CA mutations in hepatic congenital hemangiomas ;4) GNAQ, GNA11 and GNA14 mutations in anastomosing hemangiomas and hepatic small vessel neoplasms; 5) GJA4 mutations in hepatic cavernous ha\emangiomas.7 | |
| Epithelioid hemangioendothelioma | Epithelioid hemangioendothelioma (EHE) commonly occurs in the liver, where it can be mistaken for angiosarcoma and metastatic carcinoma due to expression of keratins.3 The t(1;3)(p36.3;q25) translocation resulting in CAMTA1::WWTR1 fusion accounts for the vast majority of cases. Immunohistochemistry against the C-terminus of CAMTA1 is highly sensitive and specific for the fusion.52 YAP1::TFE3 fusion hemangioendothelioma shows different clinicopathologic characteristics from conventional EHE and is now considered a separate tumor type.53 YAP1::TFE3 fusion EHE is exceedingly rare in the liver.54 |
| Kaposi sarcoma | The GI tract is commonly involved by Kaposi sarcoma, sometimes even in the absence of cutaneous involvement, and lesions can be histologically subtle.55 Immunohistochemistry is a sensitive and specific test for HHV8, the viral driver of Kaposi sarcoma. |
| Angiosarcoma | Primary angiosarcomas can (rarely) arise at any site of the GI tract, but are most commonly seen in the liver. Hepatic angiosarcoma frequently presents with concurrent splenic involvement, such that it can be difficult to determine whether the primary site is in the liver or spleen. About 20% of hepatic angiosarcomas show loss of ATRX expression, correlated with lengthening of telomere.56 |
| Glomus tumor | Glomus tumor rarely involves the GI tract, where it has a predilection for the stomach.57 Synaptophysin expression is seen in 70% of gastric glomus tumors, presenting a pitfall for misdiagnosis of a well-differentiated neuroendocrine tumor. CARMN::NOTCH2 fusions predominate in glomus tumors of the stomach.58-60 While both benign and malignant glomus tumors harbor CARMN::NOTCH2 fusions, only malignant tumors show concomitant complex copy number alterations, including recurrent loss of 9p21.3 - including CDKN2A, CDKN2B and MTAP loci - as well as ATRX inactivation.60 Occurrence of multiple familial glomus tumors is due to inactivating mutations in the glomulin gene GLMN. |
| Lymphatic anomalies | They include common lymphatic malformation (CLM) or generalized lesion (complex lymphatic anomaly (CLA) formerly referred to as lymphangioma/lymphangiomatosis). CLMs can arise throughout the GI tract, most commonly in the small intestine.61 PIK3CA mutations are detected in the majority of CMLs, while CLAs mainly harbor recurrent NRAS somatic mutations in children and young adultss with kaposiform lymphangiomatosis.62,63 Many mutations affecting the PI3K/AKT signaling cascade as well as the MAPK pathway occur in Gorham–Stout disease,64 and ARAF or EPHB4 variants occur in central conducting lymphatic anomaly.65,66 |
| Neural tumors | |
| Schwannoma (including microcystic/reticular schwannoma) | In contrast to schwannomas of soft tissue that harbor recurrent NF2 inactivation, schwannomas of the gastrointestinal tract instead harbor recurrent SOX10 in-frame insertions.67 Gastrointestinal tract schwannomas also show morphologic differences compared to conventional schwannoma, including a lack of Antoni A/B zonation and prominent peripheral lymphocytic inflammation. Microcystic/reticular schwannoma is a rare variant of schwannoma with a predilection for viscera, especially the gastrointestinal tract; it lacks NF2 alterations.67,68 NONO::TFE3 fusion has been identified in microcystic/reticular schwannoma in the skin, but not in the gastrointestinal tract.69 |
| Schwann cell hamartoma | Schwann cell hamartoma is a benign peripheral nerve sheath tumor type with a predilection for the distal intestine; so far, the genetics remain uncertain.70 |
| Granular cell tumor | Granular cell tumors (GCTs) are predominantly benign neoplasms, which have a predilection in the gastrointestinal tract for the distal oesophagus, followed by the colorectum, anus, stomach, appendix and small bowel.71 They overexpress TFE3 but lack TFE3 rearrangements.72 Loss-of-function mutations of ATP6AP1 and ATP6AP2, mapping respectively to Xq28 and Xp11.4, are the driving alterations in most GCTs.73 |
| Malignant granular cell tumors have the same underlying ATP6AP1 mutations as their benign counterparts, but also additional mutations in tumour suppressors or oncogenes.74 | |
| Perineurioma | Most gastrointestinal perineuriomas are "mucosal perineuriomas" and occur in the large intestine.75 Similar-appearing perineurial-type proliferations are commonly associated with neoplastic glands in serrated polyps, but they lack the mutations of the associated epithelial neoplasm and are thought to be reactive in nature.76 |
| Ganglioneuroma and ganglioneuromatosis | Ganglioneuromas arise in three main clinical settings: (1) solitary polypoid ganglioneuroma, which has no known syndromic associations; (2) multiple polypoid ganglioneuromas, also known as ganglioneuromatous polyposis and is associated with PTEN hamartoma (Cowden) syndrome; and (3) diffuse ganglioneuromatosis, which occurs in patients with multiple endocrine neoplasia type 2B (MEN2B) or (less commonly) neurofibromatosis type 1, and usually shows diffuse mural involvement.77-79 |
| Polypoid ganglioneuromas present as small mucosal polyps, and are usually detected incidentally during endoscopy. The clinical presentation of diffuse ganglioneuromatosis is quite variable, including acute intestinal obstruction, megacolon, and intestinal motility disorders; or it may be detected incidentally. Approximately 40% of individuals with MEN2B have diffuse ganglioneuromatosis of the GI tract. Most patients with multiple endocrine neoplasia type 2B (MEN2B) manifest gastrointestinal symptoms starting in infancy or early childhood.80 | |
| Mesenchymal tumors of uncertain cell of origin /differentiation | |
| PEComa | Perivascular epithelioid cell tumours (PEComas) are tumors that show dual melanocytic and smooth muscle differentiation. Most PEComas of the gastrointestinal tract occur in the liver, and the most common luminal gastrointestinal tract site is the intestine.81 PEComas are driven by TSC2/TSC1 inactivation, leading to mTOR pathway activation, or else by fusions involving TFE3 or MITF, both of which are downstream targets of the mTOR pathyway.82 In the liver, TSC2 mutations predominate, while PEComas of the luminal gastrointestinal tract sometimes instead harbor TFE3 rearrangement.83 While most PEComas are benign, malignant PEComas can also occur in the gastrointestinal tract; malignant examples generally show nuclear atypia, mitotic activity, and larger tumor size, and they tend to harbor second-hit mutations in TP53, ATRX, and RB1, as well as complex copy number alterations.84-88 |
| Mesenchymal hamartoma of the liver | Mesenchymal hamartoma and undifferentiated embryonal sarcoma of the liver are related tumor types that both harbor chromosome 19q13 structural alterations, affecting the largest human noncoding microRNA cluster C19MC.3 Mesenchymal hamartoma lacks TP53 alterations. |
| Calcifying nested stromal-epithelial tumor(CNSET) of the liver | CNSET is a rare, primary hepatic tumor that occurs in children and young adults. It harbors CTNNB1 alterations in all sequenced cases, and co-occurrent TERT promoter mutations appear to be common.89-91 There is a single reported case with a driving WT1 mutation.92 |
| Synovial sarcoma | Synovial sarcoma rarely involves the GI tract, where it shows a predilection for the stomach.93 It harbors gene fusions between SS18 and SSX1, SSX2, and SSX4 genes, 95% of which are now detectable using an SS18-SSX fusion-specific antibody that is 100% specific.94 SS18 fusions with alternate breakpoints are not detected by the antibody, and for these cases karyotype, FISH or RT-PCR can be used to confirm the diagnosis.95 |
| Malignant gastrointestinal neuroectodermal tumor (GNET) | GNET is an aggressive malignant neoplasm, with poor prognosis, most commonly arising in the ileum. EWSR1::ATF1 fusions predominate, as in clear cell sarcoma, while a minority of cases harbor EWSR1::CREB1 fusion. 96,97 In contrast to clear cell sarcoma, GNET lacks expression of HMB-45.98 |
| Embryonal sarcoma of the liver | Undifferentiated embryonal sarcoma of the liver is a liver-specific sarcoma type that is related to mesenchymal hamartoma, with which it is sometimes associated. It tends to occur in children. It harbors recurrent chromosomal aberrations on chr19q13, affecting the largest human microRNA cluster C19MC. Concurrent TP53 mutations and complex copy number alterations are present in essentially all cases.99 The most common C19MC alteration is t(11;19)(q13.1;q13), which leads to MALAT1::C19MC fusion.100 Germline pathogenic variants of TP53 and CHEK2 have been reported.101 |
| GLI1-altered neoplasms (including gastroblastoma) | Gastroblastoma is a very rare, biphasic neoplasm that occurs in the stomach in children and adults.1,102 Recurrent MALAT1::GLI1 fusions have been reported, and GLI1 immunohistochemistry can support the diagnosis.103,104 Other partner genes have been identified, including ACTB and, less commonly, PTCH1, AARS1, MRTFA, and DDIT3.105 PTCH1::GLI2 fusion has also been described.106,107 Two GLI1 tumors that were entirely epithelial (i.e. not biphasic) were also described.105 |
| NUT-rearranged sarcoma | NUT-rearranged sarcomas have been also reported in GI tract, mainly in women, and have poor prognosis. Tumors harbor rearrangements NUT family genes NUTM1 or, less commonly, NUTM2A, NUTM2B, and NUTM2G.108-110 These NUT genes form fusions with MAX family partners MXD1, MXD4, MXI1, and MGA, although tumors with MGA::NUTM1 fusions seem clinicopathologically distinct from the others and do not occur in the colon.109 Tumors with MXD1, MXD4, and MXI1 fusions have a predilection for abdominal organs, especially the colon.108 NUTM1 immunohistochemistry is positive in most cases, although it is negative in the rare tumors that harbor NUTM2 gene fusions.109,111 |
| Undifferentiated sarcoma (US) | Undifferentiated sarcoma (US) is a malignant neoplasm without any identifiable cellular differentiation and any definable molecular signature. It most commonly occurs in the extremities of middle-aged and elderly adults, and it is only rarely seen in visceral sites. Most often, cases reporting US occurring in the GI tract represent metastasis from soft tissue tumours of a defined tumour type. No substantial molecular data specific to primary US of the GI tract have been reported. Undifferentiated pleomorphic sarcoma (UPS) of soft tissue so far demonstrated substantial copy-number heterogeneity and frequent deletions/disruptive rearrangements involving tumor suppressors like CDKN2A and CDKN2B in 9p, PTEN in 10q, RB1 in 13q, and TP53 in 17p. They tend to show a low tumour mutation burden,112,113 although about 2-3% show microsatellite instability.114 |
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Citation
Paola Dal Cin, PhD ; David Papke, MD
Mesenchymal tumors of the digestive system
Atlas Genet Cytogenet Oncol Haematol. 2026-10-04
Online version: http://atlasgeneticsoncology.org/solid-tumor/209388
