Esophagus

Other tumors

Gastrointestinal stromal tumor



Last author update: 3 November 2022
Last staff update: 3 November 2022

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PubMed Search: Gastrointestinal stromal tumor esophagus

Feriyl Bhaijee, M.D.
Israh Akhtar, M.D.
Page views in 2021: 1,808
Page views in 2022 to date: 1,757
Cite this page: Bhaijee F, Akhtar I. Gastrointestinal stromal tumor. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/esophagusGIST.html. Accessed December 7th, 2022.
Definition / general
Essential features
  • Rare in esophagus < 1% (0.7%); most common site is stomach (Mod Pathol 2022;35:554)
  • Most are due to mutations in proto-oncogene KIT (exon 11)
  • 3 histologic types: spindle, epithelioid and mixed
  • Diagnosis confirmed immunohistochemically using KIT and DOG1 antibodies
  • Prognosis: depends on tumor size, mitotic rate and site of origin
  • Treatment: surgical excision or imatinib
Terminology
  • Gastrointestinal stromal tumor (GIST)
  • Microscopic GIST: sporadic interstitial cell of Cajal hyperplasia, seedling GIST, minimal GIST
  • Historic terms:
    • Gastrointestinal smooth muscle tumor
    • Gastrointestinal autonomic nerve tumor
    • Leiomyoblastoma
    • Smooth muscle tumor of uncertain malignant potential
    • Gastrointestinal pacemaker cell tumor
ICD coding
  • ICD-10: C49.A1 - GIST, esophagus
Epidemiology
Sites
Pathophysiology
  • GISTs arise from interstitial cells of Cajal (ICC)
  • Driver event involves gain of function mutations in KIT and PDGFRA most frequently
  • Most of these tumors respond to the tyrosine kinase inhibitor, imatinib
  • Less frequently, a BRAF V600E mutant is involved as the driving force and these cases are less responsive to imatinib
  • Etv1, a major transcriptional regulator of ICC - intramuscular and ICC - myenteric, induces BRAF expression in a mouse model
  • Smooth muscle cells have recently been proposed as an alternative cell of origin for GIST, and these tumors are BRAF V600E driven and resistant to imatinib (J Pathol 2020;252:441)
Etiology
  • Mostly sporadic
  • 5% of GISTs arise in patients with:
    • Neurofibromatosis type I syndrome (NF1, multiple small intestinal tumors)
    • Carney triad (gastric epithelioid GISTs in young females) (Arch Pathol Lab Med 2006;130:1466)
  • Familial GIST syndrome: rare, autosomal dominant genetic disorder, characterized by germline KIT or PDGFRA mutations, early onset of multiple GIST tumors, skin pigmentation abnormalities (Cancer 2015;121:2960, Arch Pathol Lab Med 2006;130:1466)
Clinical features
Diagnosis
  • May be an incidental finding during imaging or endoscopic examination for other clinical symptoms
  • Endoscopy shows as a subepithelial lesion; both leiomyoma and GIST appear similar on CT and EUS (J Thorac Dis 2015;7:E648)
    • Biopsy with immunohistochemical stains / molecular required for confirmation
Radiology description
  • Barium studies: smooth intraluminal mass or large ulcerative mass extending intraluminally (see radiology image 1)
  • Endoscopic ultrasound determines size, shape and intratumoral characteristics of the lesion, its relationship to layers of the bowel wall and enables image guided core needle biopsy or fine needle aspiration (J Gastrointestin Liver Dis 2008;17:131) (see clinical image 1)
  • CT / MRI: useful for preoperative and metastatic evaluation
  • PET FDG avidity correlates with malignant potential of GIST
    • Also used to monitor response to chemotherapy (tyrosine kinase inhibitor therapy) and evaluate postoperative recurrence (see radiology image 3)
Radiology images

Images hosted on other servers:

Esophageal barium meal

CT scan

PET avidity

Esophagography, endoscopy, CT and FDG PET

Prognostic factors
  • Nashville Risk Score is utilized in predicting progression free survival of patients with GIST (Histopathology 2022;80:874, Mod Pathol 2022;35:554)
  • Risk stratification based on tumor size, mitotic activity and site of origin per 50 high power fields (HPF or 5 mm²)
    • Low risk:
      • < 5 cm and < 5 mitoses/50 HPF or 5 mm²
    • Intermediate risk:
      • < 5 cm and 6 - 10/50 HPF
      • 5 - 10 cm and < 5 mitoses/50 HPF or 5 mm²
    • High risk:
      • > 5 cm and mitoses > 5/5 mm²
      • > 10 cm and any mitotic rate
      • Any size and > 10/50 HPF or 5 mm²
    • Presence of rupture at the time of surgery and male sex independent risk factor

Risk stratification of esophageal GISTs using the new Nashville risk score
Risk category Tumor size Mitotic rate/50 HPF or 5 mm²
Low < 5 cm < 5
Intermediate < 5 cm 6 - 10
Intermediate 5 - 10 cm < 5
High > 5 cm > 5
High > 10 cm Any mitotic rate
High Any size > 10
Case reports
Treatment
  • Surgical resection for localized GIST (3 - 5 cm) (Surg Case Rep 2022;8:109)
  • Neoadjuvant therapy, small molecule tyrosine kinase inhibitors: imatinib mesylate (STI571, Gleevec), sunitinib maleate may be given preoperatively to reduce the size of tumor
  • Imatinib is considered in patients with high mitotic rates or larger tumor sizes to obtain negative microscopic margins (R0 resection) and to reduce the risk of intraoperative complications, including tumor rupture (Histopathology 2017;71:805) (see radiology image 4)
Clinical images

Images hosted on other servers:

Endoscopy

Gross description
Gross images

Images hosted on other servers:

Solid tumor

Malignant tumor

Frozen section description
  • Spindle cell neoplasm; defer to permanent for definite categorization
Microscopic (histologic) description
  • Histologic heterogeneity: 3 morphologic types - spindle (70%), epithelioid (20%) and mixed (10%)
    • Spindle cell type: bland spindle cells with eosinophilic cytoplasm in short fascicles or syncytia, elongated nuclei with inconspicuous nucleoli, indistinct cell borders, paranuclear cytoplasmic vacuoles (more common in gastric), stromal lymphocytes and microcystic stromal degeneration (as in schwannoma), minimal collagen, delicate thin walled vessels, stromal hemorrhage
      • Subtypes: sclerosing, palisaded, vacuolated, diffuse hypercellular, can have sarcomatoid features with significant nuclear atypia and mitotic activity
    • Epithelioid type: round cells with vesicular chromatin, eosinophilic or clear cytoplasm in nests or sheets, more pleomorphism than spindle type
      • Subtypes: sclerosing, discohesive, hypercellular, sarcomatous with significant atypia and mitotic activity
    • Mixed type: combination of cells with both spindle and epithelioid type, may have abrupt transition between the 2 or complex comingling
  • SDH deficient: epithelioid or mixed with spindle cell component, multinodular, minimal nuclear pleomorphism, occasional atypical mitosis (gastric location strictly, not seen in esophagus)
  • Dedifferentiated: anaplastic morphology with unusual phenotype such as loss of KIT expression or aberrant expression of markers such as cytokeratin
  • Stromal skeinoid fibers (< 20%): hyaline or fibrillary brightly eosinophilic PAS+ structures, representing nodular tangles of collagen fibers; more common in small or large bowel GIST (Case Rep Gastroenterol 2014;8:257)
  • Rarely: cytologic atypia, myxoid stroma
  • Variable mitotic activity
  • Microscopic GIST: < 10 mm, spindle cells with hyalinized stroma and variable calcification (Pathology 2008;40:9, Histopathology 2017;70:211)
  • Treated GIST can microscopically have hyalinized areas or areas of necrosis
Microscopic (histologic) images

Contributed by Israh Akhtar, M.D.
Intramural mass

Intramural mass

Fascicles of spindle cells

Fascicles of spindle cells

Spindle cells Spindle cells

Spindle cells

Nuclear details

Nuclear details


Mast cells

Mast cells

KIT KIT

KIT

DOG1 DOG1

DOG1


CD34

CD34

Desmin Desmin

Desmin

Ki67

Ki67

Posttherapy

Posttherapy


Epithelioid GIST

Epithelioid GIST

Mitosis

Mitosis

Malignant GIST

High grade GIST

KIT

KIT

Cytology description
  • Endoscopic ultrasound guided fine needle aspiration may be primary diagnostic modality
    • Cellular smears, single cells and loosely cohesive fascicles of monomorphic spindle to epithelioid cells
    • Irregularly outlined clusters of cells
    • Prominent vascular pattern is commonly observed
    • Spindle / round / oval nuclei, vesicular chromatin, wispy cytoplasm with long extensions
    • Perinuclear or paranuclear vacuoles may be present
    • Nuclear palisading can occur
    • Stripped spindled to epithelioid nuclei
  • Cohesive fragments with admixed delicate, thin walled vessels
  • Features of malignant behavior of tumor predicted by cytologic atypia, cellular dyscohesion, nuclear pleomorphism, prominent nucleoli, increased mitotic activity, prominent necrosis
  • Reference: DeMay: The Art & Science of Cytopathology, 2nd Edition, 2012
Cytology images

Contributed by Israh Akhtar, M.D.
High cellularity

High cellularity

Spindle cells

Spindle cells

Fascicular pattern

Fascicular pattern

Spindle cells

Spindle cells

Epithelioid GIST

Epithelioid GIST


Epithelioid cells

Epithelioid cells

Cell block

Cell block

DOG1

DOG1

Malignant GIST Malignant GIST

High grade GIST

Positive stains
Negative stains
Electron microscopy description
  • Relative lack of differentiation (Endocr Relat Cancer 2007;14:853)
    • Incomplete smooth muscle or neuroaxonal differentiation
    • No bundles of actin filaments (seen in true smooth muscle tumors)
Electron microscopy images

Images hosted on other servers:

Cytoplasmic vesicles in high risk GIST

Molecular / cytogenetics description
  • Mutually exclusive activating mutations in the proto-oncogene KIT (75%) or platelet derived growth factor alpha (PDGFRA) receptor tyrosine kinase (10%)
    • In frame deletions, point mutations, duplications, insertions
    • Most common: KIT juxtamembrane domain (exon 11) mutations
      • Confers a better response to tyrosine kinase inhibitor therapy
  • References: Science 2003;299:708, Cancers (Basel) 2019;11:679, Semin Diagn Pathol 2006;23:91
Sample pathology report
Differential diagnosis
Board review style question #1

The image above demonstrates an esophageal mass in a 57 year old man. Of the following, which scenario is associated with best prognosis?

  1. 3 cm mass and mitosis < 3/5 mm²
  2. 4 cm mass and mitosis > 7/5 mm²
  3. 6 cm mass and mitosis < 4/5 mm²
  4. 6 cm mass and mitosis > 6/5 mm²
  5. 9 cm mass and mitosis < 2/5 mm²
Board review style answer #1
A. 3 cm mass and mitosis < 3/5 mm². Size more than 5 cm, mitosis greater than 5 per 5 mm² and site are associated with disease progression in esophageal GIST. Tumor size > 5 cm and mitotic rate > 5/5 mm² are independent risk factors for progression. Esophageal and colonic GIST are more aggressive than gastric GIST. Of the choices above, A is low risk, D is high risk and others have moderate risk of progression (Mod Pathol 2022;35:554).

Comment Here

Reference: Gastrointestinal stromal tumor
Board review style question #2
Succinate dehydrogenase deficient GIST is seen exclusively in which part of the gastrointestinal system?

  1. Colon
  2. Esophagus
  3. Ileum
  4. Stomach
Board review style answer #2
D. Stomach. Succinate dehydrogenase deficient GIST has a female preponderance and seen almost exclusively in stomach (predilection for distal stomach and antrum) (Am J Surg Pathol 2010;34:636).

Comment Here

Reference: Gastrointestinal stromal tumor
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