Mesenchymal tumors of the digestive system

2025-03-05   Paola Dal Cin, PhD , David Papke  

1.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
GIST, Soft tissue tumors, GI tract, stomach, pancreas, liver, TKIs

Classification

Definition

Virtually any soft tissue tumors can arise at almost any site of digestive system, on at least 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 and are instead in the WHO 2020 Soft Tissue and Bone Tumors. Here, we will focus on unique 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 than sarcomas and are often incidental findings 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 and distinct mechanisms of response and resistance to targeted therapies. 5

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. Kaposi sarcoma primarily involves the lamina propria, esophageal and colorectal leiomyomas typically arise from muscularis propria and muscularis mucosa respectively. 4 Giant fibrovascular polyp is now known to represent well-differentiated liposarcomas with MDM2 amplification. 4

Mesenchymal tumors more frequent in the digestive system Genetic marker(s)
Gastrointestinal stromal tumor (GIST)The genetic classification "gastrointestinal stromal tumor" (GIST) started in 1998 with the finding of KIT gain-of-function mutations as oncogenic driver events,6 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 mutations in PDGFRA exons 18, 12 and 14, which are usually mutually exclusive with KIT mutations. About 5-10% of gastric GISTs are instead driven by succinate dehydrogenase (SDH) deficiency, with inactivation of SDHA, SDHB, SDHC, or SDBHD . About 2% of GISTs, usually in the small intestine, harbor bi-allelic NF1 inactivation. Rare driving alterations include BRAF V600E mutations, EGFR mutations, gene fusions in FGFR1, NTRK, and ALK, and KRAS mutations. 1,5
Within the gastrointestinal tract some genetic subtypes have predilections for particular locations: NF1-inactivated GIST occurs almost exclusively in the small intestine, while PDGFRA -mutant and SARDH-deficient GISTs occur almost exclusively in the stomach. SARDH-deficient GIST accounts for nearly all pediatric cases, and it follows a different clinical course than other GIST types, such that it should not be risk-stratified.7 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 patients' outcomes. However, tumors eventually progress on imatinib due to acquired KIT secondary mutations in up to 90% of GIST patients.8 Subsequently, novel TKIs were developed and continue to be developed as second line therapeutic agents.9
Fibroblastic and myofibroblastic tumors
Inflammatory myofibroblastic tumor (IMT)IMTs rarely occur in the gastrointestinal(GI) tract , where they have a predilection for the stomach, and ALK rearrangement can be confirmed when present using FISH analysis, immunohistochemistry or sequecing .10-12 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.13,14 There has been a single report of a gastric IMT with TFG::ROS1 fusion.15
Desmoid fibromatosis (DF)CTNNB1 mutations are detected in approximately 85% of sporadic DFs, while APC mutations are present in Gardner syndrome-associated cases. It is unclear whether CTNNB1 S45F mutations might be associated with higher local recurrence risk.16
Solitary fibrous tumor (SFT)Solitary fibrous tumor has been reported in different parts of the GI tract, liver and panceas. These lesions are characterized by recurrent NAB2::STAT6 fusions, due to a cryptic paracentric inversion at the 12q13. STAT6 immunohistochemistry is the most specific and sensitive diagnostic marker.17
Inflammatory fibroid polyp (IFP)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.18 IFP harbors PDGFRA somatic mutations that are the same as those in GIST, in exons 12, 14 and 18.19,20 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.21
Germline PDGFRA mutations have been described in the so-called “Devon syndrome," where patients develop multiple IFPs and multiple PDGFRA-mutant GISTs.22
Plexiform fibromyxomaPlexiform fibromyxoma is a benign mesenchymal tumor type arises almost exclusively in the gastric antrum and pylorus, with rare occurence in the duodenum.23 GLI1 overexpression was detected, resulting from either t(11;12)(q11;q13)/MALAT1:GLI fusion or GLI1 amplification. 24 A subset of lesions demonstrated loss of the PTCH1 tumor suppressor.25
GLI1 immunohostochemistry may be a useful diagnostic adjunct for mesenchymal neoplasms with GLI1 alterations.26
Adipocytic tumors
Well-differentiated liposarcomasMany tumors previously diagnosed as giant fibrovascular polyp represent oesophageal well-differentiated liposarcomas. Most cases arise in the proximal oesophagus near the cricopharyngeus muscle, just distal to the larynx.27 MDM2 amplification was demonstrated by FISH analysis.4,28
Smooth muscle tumours
LeiomyomaLeiomyomas of GI tract are benign tumors, and they occur most commonly as benign polyps of the muscularis mucosae in the large intestine, or else as mural masses in the esophagus.29 They often have entrapped interstitial cell of Cajal that undergo hyperplasia, presenting a pitfall for misdiagnosis of GIST.30
LeiomyosarcomaLeiomyosarcoma is very rare in the GI tract, where it can occur at any site and most commonly involves the small intestine and colorectum. Risk stratification criteria have been proposed, but they have not yet been widely adopted in part because larger-scale validation studies are needed.31
Vascular and perivascular tumours
Epithelioid haemangioendothelioma (EHE)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) resulting in CAMTA1::WWTR1 fusion is the most commonly identified genetic abnormality. Immunohistochemistry against the C-terminus of CAMTA1 is highly sensitive and specific for the fusion.32 An alternate YAP1::TFE3 fusion has been detected in a small and distinct subset of cases, including liver.33 YAP1::TFE3 fusion EHE has different morphologic and clinical features, such that it possibly should be considered a different tumor type from CAMTA1-rearranged EHE.34
Kaposi sarcomaThe GI tract is commonly involved by Kaposi sarcoma, sometimes even in the absence of cutaneous involvement, and lesions can be histologically subtle.35 Immunohistochemistry is a sensitive and specific test for HHV8, the viral driver of Kaposi sarcoma.
AngiosarcomaPrimary 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.36
Glomus tumor(GT) Glomus tumor rarely involves the GI tract, where it has a predilection for the stomach.37 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.38-40 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 CDKN2A /CDKN2B and MTAP and ATRX inactivation.40 Occurrence of multiple familial glomus tumor is due to inactivating mutations in the glomulin gene GLMN OMIM:601749.
Neural tumors
Mucosal Schwann cell hamartomaMucosal Schwann cell hamartomas are benign neural proliferations that usually arise in the left colon, typically in adults, with slight female predominance. There is no association with with neurocristopathy syndromes.41
SchwannomaGastrointestinal schwannomas can occur throughout the GI tract, where they most commonly involved the stomach, and they have a female predilection. Most cases of GI schwannomas lack NF2 alterations, and they show morphologic differences from schwannomas at other sites, suggesting that they might represent a morphologically and genetically distinct group of peripheral nerve sheath tumours.42
Granular cell tumor (GCT)Granular cell tumors (GCTs) are predominantly benign neoplasms, mainly located is the distal oesophagus, followed by the colorectum, anus, stomach, appendix and small bowel.43 They overexpress TFE3 but lack TFE3 rearrangements.44 Loss-of-function mutations of ATP6AP1 and ATP6AP2, mapping respectively to Xq28 and Xp11.4, are the driving alterations in most GCTs.45
Malignant granular cell tumors have the same underlying ATP6AP1 mutations as their benign counterparts, but also additional mutations in tumour suppressors or oncogenes. 46
Tumors of uncertain differentiation
Synovial sarcomaSynovial sarcoma rarely involves the GI tract, where it shows a predilection for the stomach.47 It harbors gene fusions between SS18 and SSX1/SSX2 genes in 95% of cases, events now detectable using an SS18-SSX antibody that is essentially 100% specific for these fusion.48 SS18::SSX4 fusions are not detected by the antibody, and for these cases karyotype, FISH or RT-PCR can be used to confirm the diagnosis.49
Malignant gastrointestinal neuroectodermal tumour (GNET)/clear cell sarcoma-like tumor of the GI tractGNET mostly harbor EWSR1::ATF1 fusions similar to those of clear cell sarcoma, and a minority of cases contain an EWSR1::CREB1 fusion.50,51 In contrast to clear cell sarcoma, GNET lacks expression of HMB-45.
Gastroblastoma Gastroblastoma is a very rare, biphasic neoplasm that occurs in the stomach in children and adults.1,52 Recurrent MALAT1::GLI1 fusions have neen reported, and GLI1 immunohistochemistry can support the diagnosis.26,53 PTCH1::GLI2 fusion has also been described. 54,55 Two tumors that were entirely epithelial (i.e. not biphasic) were also described.56
PEComa, including angiomyolipomaPEComas of the digestive tract most commonly arise in the liver, and they can arise throughout the luminal GI tract, especially in the intestine.57 Most PEComas harbor TSC2 inactivation, and these PEComas can occur in the setting of tuberous sclerosis complex.58 Rarely, PEComas show TFE3 rearrangement, although this event appears to be very uncommon in the GI tract .59-61
Mesenchymal hamartoma of the liver (MHL)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.
Embryonal sarcoma of the liverEmbryonal 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.62 The most C19MC alterations is t(11;19)(q13.1;q13), which leads to MALAT1::C19MC fusion.63 Germline pathogenic variants of TP53 and CHEK2 have been reported.64
Calcifying nested stromal-epithelial tumor of the liver (CNSET)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.65-67

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Citation

Paola Dal Cin ; David Papke

Mesenchymal tumors of the digestive system

Atlas Genet Cytogenet Oncol Haematol. 2025-03-05

Online version: http://atlasgeneticsoncology.org/solid-tumor/209310