Gastrointestinal Stromal Tumor

Slide 1 · Gastrointestinal Stromal Tumor

Cell of origin • molecular drivers • morphology • clinicopathologic interpretation

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Identify the cell of origin and major molecular classes of GIST.

Distinguish gross and microscopic patterns and apply KIT/DOG1 staining.

Integrate size, mitotic activity, and site when discussing prognosis.

Connect genotype with targeted treatment and acquired resistance.

Slide 3 · GIST is a mesenchymal neoplasm of the gut

Mesenchymal tumor — not an epithelial carcinoma

Most common mesenchymal tumor of the abdomen.

Biologically distinct from epithelial gastric cancers.

Origin is linked to interstitial cells of Cajal.

Slide 4 · Gastric tumor families should not be conflated

Gastric tumor group

Examples

Diagnostic emphasis

Epithelial

Adenocarcinoma

Gland-forming epithelial neoplasm

Neuroendocrine

Neuroendocrine tumor

Neuroendocrine differentiation

Mesenchymal

GIST, leiomyoma, schwannoma

Morphology with lineage markers

The parent chapter distinguishes these tumor groups; Examples are not a complete classification.

Slide 5 · More than half of GISTs occur in the stomach

>½

Occur in the stomach

Site

Is a prognostic variable

The stomach is the predominant site. GIST also occurs at other gastrointestinal locations. Anatomic site matters when interpreting biological behavior.

Slide 6 · GIST is uncommon in population terms

11–20

New cases per million people annually

Annual incidence: 11–20 per million people. “Most common mesenchymal abdominal tumor” does not mean common among all neoplasms.

Slide 7 · GIST is mainly diagnosed in older adults

~60

Peak age (years)

<10%

Diagnosed before 40 years

Peak age at diagnosis: About 60 years. Fewer than 10% occur before the age of 40. Pediatric GIST is distinctly uncommon.

Slide 8 · Interstitial cells of Cajal provide the lineage context

Interstitial cells of Cajal

GIST lineage

Characteristic molecular / marker profile

Schematic lineage link; Not a literal progression sequence.

Slide 9 · “Stromal” reflects a historical naming problem

Historical interpretation

“Stromal” as nonspecific origin

Overlapping mesenchymal appearances

Current interpretation

Cajal-cell lineage recognized

Molecular and immunophenotypic correlation

Slide 10 · Other gastric mesenchymal tumors form key differentials

Smooth muscle tumors: Leiomyoma and leiomyosarcoma.

Nerve sheath tumor: Schwannoma.

Glomus-body resembling tumor: Glomus tumor.

These other mesenchymal neoplasms are uncommon in the gut.

Slide 11 · Microscopic GIST-like proliferations can be silent

Clinically silent microscopic foci are common.

They may represent precursors to overt GIST.

These small proliferations generally show low mitotic rates.

Slide 12 · Precursor foci seldom progress

Precursor-like focus ≠ inevitable clinically significant GIST

Textbook characterizes the risk of neoplastic transformation as extremely low.

Presence of a microscopic focus does not imply inevitable tumor progression.

Events allowing progression to overt GIST remain poorly defined.

Slide 13 · Chromosome losses accompany some progression

Microscopic proliferation

Poorly defined progression events

Overt GIST

Loss/deletion of chromosomes 9, 14, or 22 may accompany progression; Causation is not fully established.

Slide 14 · Some GISTs occur in inherited or syndromic settings

Rare germline KIT or PDGFRA mutations may yield multiple GISTs.

SDH-associated hereditary disease links GIST with paraganglioma.

Neurofibromatosis type 1 has increased GIST incidence.

Pediatric GIST may occur as part of the Carney triad.

Slide 15 · Carney triad defines a distinct association

GIST

Gastrointestinal stromal tumor

Paraganglioma

A second tumor type in the triad

Pulmonary chondroma

Third characteristic tumor

Slide 16 · Carney triad: Clinical demographic clues

The syndrome is of unknown cause in the supplied Robbins description.

It is usually reported in females.

A subset of uncommon pediatric GISTs is associated with the triad.

Slide 17 · Neurofibromatosis type 1 is a GIST-associated condition

Individuals with NF1 show an increased incidence of GIST.

Association with NF1 is distinct from the named Carney syndromes.

Do not infer a specific mutation pattern from the provided passage.

Slide 18 · The dominant GIST drivers are receptor kinases

~75%

KIT gain-of-function

~8%

PDGFRA activating mutation

Approximately 75% carry activating KIT mutations. Another 8% carry activating PDGFRA mutations. Both proteins are receptor tyrosine kinases.

Slide 19 · Mutant KIT is constitutively active

Activating KIT mutation

Constitutively active KIT

Downstream signaling

Simplified signaling relationship from the source; Individual effectors not specified.

Slide 20 · Mutant PDGFRA activates a parallel kinase route

Activating PDGFRA mutation

Constitutively active PDGFRA

Shared pathways

Schematic; The source does not enumerate individual downstream effectors.

Slide 21 · KIT and PDGFRA driver mutations are mutually exclusive

Molecular driver A

KIT gain-of-function

Receptor kinase signaling

Dominant molecular class

Molecular driver B

PDGFRA activation

Overlapping downstream signaling

Smaller molecular class

Slide 22 · The shared pathway is more important than the receptor name

KIT activation or PDGFRA activation

Shared downstream signals

GIST growth

A conceptual map rather than a complete biochemical cascade.

Slide 23 · Germline kinase mutations can yield multifocal disease

Germline KIT or PDGFRA mutation

Diffuse hyperplasia of interstitial cells of Cajal

Multiple GISTs may develop

Slide 24 · Not all GISTs carry KIT or PDGFRA mutations

A remaining subset lacks mutations of these two receptors.

Some of those tumors instead harbor defects in succinate dehydrogenase genes.

Molecular heterogeneity has practical consequences for treatment response.

Slide 25 · SDH-related GIST involves a mitochondrial enzyme complex

SDHA

SDH subunit A

SDHB

SDH subunit B

SDHC / SDHD

SDH subunits C and D

Slide 26 · SDH defects connect metabolism to oncogenesis

SDH gene alteration

Loss of SDH function

Metabolic-pathway oncogenesis

That mechanistic understanding remains incomplete.

Slide 27 · Hereditary SDH-related GIST may follow a two-hit pattern

Inherited altered SDH gene copy

Tumor acquires mutation / loss of second copy

Functional SDH loss

Slide 28 · Carney–Stratakis syndrome links GIST and paraganglioma

The syndrome is associated with inherited SDH-complex mutations.

The key tumor association is GIST plus paraganglioma.

It should not be treated as synonymous with the Carney triad.

Slide 29 · Carney triad and Carney–Stratakis differ

Feature

Carney triad

Carney–Stratakis

Tumor association

GIST + paraganglioma + pulmonary chondroma

GIST + paraganglioma

Cause

Unknown

Hereditary SDH deficiency

Teaching distinction

Three-tumor syndrome

GIST–paraganglioma dyad

Slide 30 · Molecular drivers should be classified explicitly

Pathway class

Alteration

Key implication

KIT-driven

KIT gain-of-function

Common major GIST molecular group

PDGFRA-driven

PDGFRA activating mutation

Related tyrosine kinase mechanism

SDH-related

SDHA–D loss of function

Metabolic-pathway disease subset

This table deliberately excludes frequency estimates for molecular subsets not quantified.

Slide 31 · Gastric GIST usually forms a discrete mass

Mucosal ulcer

Circumscribed mass

Schematic gastric wall (not a specimen)

Typically solitary and well circumscribed.

Gross cut surface is often fleshy.

A distinct lesion may be encountered at resection.

Slide 32 · Large gastric GIST may remain circumscribed

Up to 30 cm

Described maximum primary gastric GIST diameter

Gross size can be striking despite a defined border. Primary gastric GISTs as large as 30 cm. The measurement alone does not replace mitotic activity and site in risk assessment.

Slide 33 · Mucosal ulceration is a crucial gross finding

Mucosal ulcer

Circumscribed mass

Schematic gastric wall (not a specimen)

Mucosa overlying the mass is frequently ulcerated.

An ulcer provides a plausible route for tumor-related blood loss.

The gross appearance can explain anemia at presentation.

Slide 34 · The cut surface may have a whorled pattern

Describe the resection

Solitary mass

Defined circumscription

Fleshy or whorled cut surface

Then classify the tumor

Spindle or epithelioid histology

KIT / DOG1 marker evaluation

Clinical and molecular correlation

Slide 35 · Spindle-cell GIST shows elongated cells in fascicles

Original schematic — not H&E

Thin, elongated neoplastic cells.

Organized into bundles or fascicles.

This is a histologic growth pattern, not a separate molecular diagnosis.

Slide 36 · Epithelioid GIST has plumper cells

Original schematic — not H&E

Tumor cells are epithelial-appearing and rounded or plump.

Well-defined spindle-cell fascicles are absent.

The morphology can resemble gastric adenocarcinoma.

Slide 37 · Spindle and epithelioid patterns may coexist

Original schematic — not H&E

Mixed-pattern GIST contains both cell appearances.

Sampling may demonstrate different patterns within one tumor.

Recognition of either component directs lineage confirmation.

Slide 38 · Epithelioid GIST can mimic adenocarcinoma

Potential pitfall

Plump epithelial-appearing cells

Loose or absent fascicles

Carcinoma-like first impression

Diagnostic correction

Maintain GIST in the differential

Use morphology and immunohistochemistry

Avoid lineage assignment from shape alone

Slide 39 · Marked pleomorphism is not a defining feature

Nuclear pleomorphism is uncommon in GIST.

The diagnosis depends on an integrated morphological and immunophenotypic assessment.

Pleomorphism alone is not the textbook’s principal risk classifier.

Slide 40 · Metastatic GIST commonly remains intra-abdominal

Primary GIST

Peritoneal serosal nodules

Hepatic lesions

Outside abdomen: Uncommon

Slide 41 · Serosal nodules may represent intraperitoneal deposits

Primary gastric GIST

Peritoneal dissemination

Multiple serosal nodules

Slide 42 · The liver is an important metastatic site

Primary GIST

Peritoneal serosal nodules

Hepatic lesions

Outside abdomen: Uncommon

Slide 43 · KIT (CD117) is a major diagnostic IHC marker

KIT gene

Molecular sequence alteration

Gain-of-function mutation in many GISTs

Predictive relevance for kinase inhibitor use

KIT / CD117 protein

Immunohistochemical expression

Stains normal Cajal cells and many GISTs

Diagnostic role distinct from mutation assay

Slide 44 · Approximately 95% of gastric GISTs are KIT-positive

95%

Gastric GISTs show KIT IHC staining

KIT immunoreactivity in 95% of gastric GISTs. The percentage applies specifically to gastric tumors in the cited description. A negative stain does not logically exclude the diagnosis.

Slide 45 · Epithelioid GIST may be KIT-negative

The source states that epithelioid-type GISTs are usually KIT-negative.

An epithelioid pattern with negative KIT remains diagnostically possible.

A second lineage marker is particularly useful in this setting.

Slide 46 · DOG1 complements KIT in GIST diagnosis

95%

GISTs show DOG1 positivity

DOG1 means “discovered on GIST 1.” DOG1 positivity in 95% of GISTs. DOG1 includes the epithelioid-type tumors described as KIT-negative.

Slide 47 · Diagnostic staining and gene sequencing answer different questions

Assessment

What it demonstrates

Primary teaching role

H&E morphology

Spindle / epithelioid architecture

Suggests tumor lineage

KIT / DOG1 IHC

Protein expression in tissue

Supports GIST diagnosis

KIT / PDGFRA genotype

Mutational driver status

Informs targeted treatment

Slide 48 · An integrated GIST diagnosis has sequential steps

Recognize a mesenchymal gastric tumor pattern

Evaluate spindle / epithelioid morphology and KIT / DOG1 expression

Interpret molecular results when clinically relevant

Slide 49 · GIST is not synonymous with every gastric spindle-cell mass

Tumor type

Lineage cue from name

Why separation matters

GIST

Cajal-cell tumor

KIT / DOG1 and molecular phenotype

Leiomyoma / leiomyosarcoma

Smooth-muscle resemblance

Different mesenchymal entity

Schwannoma

Nerve-sheath resemblance

Different mesenchymal entity

Glomus tumor

Glomus-body resemblance

Different mesenchymal entity

Slide 50 · Clinical symptoms often reflect mass effect

Presenting complaints commonly reflect space-occupying effects.

Symptomatic manifestations depend on what the growing mass affects.

Some lesions remain asymptomatic and are discovered incidentally.

Slide 51 · Mucosal ulceration creates a bleeding pathway

Mucosal ulceration

Blood loss

Anemia / related symptoms

Schematic clinicopathologic chain; “approximately half” refers to the presenting anemia-related symptoms.

Slide 52 · Incidental discovery is common enough to remember

Symptomatic route

Mass effects

Mucosal ulceration

Blood loss / anemia

Incidental route

Radiologic examination

Endoscopy

Surgery for another reason

Slide 53 · Prognosis requires multiple pathologic variables

Tumor size

Mitotic index

Anatomic location

Combined prognosis / risk assessment

Slide 54 · Tumor size influences metastatic potential

<5 cm — gastric GIST

Recurrence / metastasis rare

Low risk is not identical to zero risk

Other variables remain important

>10 cm — mitotically active

Recurrence / metastasis common

Mitotic activity is part of the statement

Anatomic site must still be considered

Slide 55 · Mitotic index modifies risk independently of size

Mitotic activity is essential to risk interpretation

Avoid inventing a numeric cutoff where the supplied source gives none.

Slide 56 · Anatomic location changes GIST behavior

Stomach

More than half of GISTs arise here

Relatively less aggressive behavior

Gastric-specific small-size example

Small intestine

Another important site

Relatively more aggressive behavior

Cannot assume gastric risk is identical

Slide 57 · Many GISTs have intermediate or uncertain potential

Risk assessment is probabilistic—not a binary label

Not every lesion falls clearly into a low- or high-risk group.

Robbins recognizes an intermediate group whose malignant potential cannot be predicted.

Communicate uncertainty rather than promising benign behavior.

Slide 58 · Pathology reporting must integrate three risk axes

Size

Mitotic activity

Tumor site

Combined prognosis / risk assessment

Slide 59 · Localized gastric GIST is primarily treated by resection

Localized gastric GIST

Complete surgical resection

Pathologic risk assessment

Slide 60 · Molecular phenotype becomes central in advanced disease

Unresectable, recurrent, or metastatic GIST requires particular attention to molecular status.

KIT- or PDGFRA-mutant GIST frequently responds to tyrosine kinase inhibition.

Tumors lacking these mutations are generally resistant description.

Slide 61 · Imatinib targets susceptible kinase-driven GIST

KIT / PDGFRA mutant tumor

Tyrosine kinase inhibitor

Possible tumor response

Slide 62 · Acquired imatinib resistance can involve new mutations

Susceptible mutant tumor receives imatinib

Secondary kinase mutation emerges

Clinical resistance may develop

Slide 63 · Other kinase inhibitors may overcome some resistance

Some resistant tumors respond to other tyrosine kinase inhibitors.

The source describes agents that bypass resistance-producing mutations.

Specific drug sequences and mutation-by-drug rules are not given in this excerpt.

Slide 64 · The management logic runs from site to genotype

GIST diagnosis + stage of disease

Localized: Resection / Advanced: Molecular phenotype

Treatment selection and reassessment

Simplified clinical framework derived; Not a complete guideline algorithm.

Slide 65 · Case 1: Small gastric spindle-cell tumor

Teaching vignette

An older adult undergoes resection of a 3-cm, well-circumscribed gastric mass. Microscopy shows elongated cells in fascicles. Mitotic activity is low.

Interpretation tasks

Most likely tumor family?

What risk variables matter?

Which stains support diagnosis?

Slide 66 · Case 1: Interpretation

Case interpretation

GIST is favored by the characteristic mesenchymal spindle pattern.

KIT / DOG1 help support the diagnosis.

The small gastric size is favorable; Full risk interpretation still includes mitotic index and site.

Slide 67 · Case 2: Large, mitotically active gastric tumor

Teaching vignette

A patient presents with anemia. A 12-cm gastric mass is ulcerated and mitotically active; Nodules are also found on the peritoneal surface.

Interpretation tasks

Why anemia?

What does serosal spread suggest?

How does risk compare?

Slide 68 · Case 2: Interpretation

Case interpretation

Ulceration provides the source-supported explanation for bleeding/anemia.

Serosal nodules indicate a metastatic distribution in this scenario.

Large size with mitotic activity is associated with frequent recurrence/metastasis.

Slide 69 · Case 3: GIST with paraganglioma in a young patient

Teaching vignette

A young person is diagnosed with GIST and a paraganglioma. A hereditary predisposition is being considered; No pulmonary chondroma has been reported.

Interpretation tasks

Which gene complex is relevant?

What syndrome is suggested?

How does Carney triad differ?

Slide 70 · Case 3: Interpretation

Case interpretation

Germline SDH-complex defects are linked to Carney–Stratakis syndrome.

Carney triad also includes pulmonary chondroma and is described as having unknown cause.

Tumor pairing alone does not establish a genetic diagnosis.

Slide 71 · Case 4: KIT-negative epithelioid lesion

Teaching vignette

A gastric mass is composed of plump epithelioid tumor cells without clear fascicles. KIT immunostaining is negative and DOG1 is positive.

Interpretation tasks

Is GIST excluded?

What is the morphologic mimic?

Which result is informative?

Slide 72 · Case 4: Interpretation

Case interpretation

Negative KIT does not exclude epithelioid GIST.

Adenocarcinoma is an important morphologic mimic.

DOG1 positivity supports GIST in this source-defined immunophenotypic setting.

Slide 73 · Integrated summary: Recognize, classify, stratify, act

Cajal-cell lineage, spindle/epithelioid morphology, and KIT/DOG1 establish the diagnostic framework.

KIT/PDGFRA activation and SDH defects define biologically important molecular groups.

Size, mitotic index, and location guide prognosis; Genotype guides advanced-disease therapy.

Slide 74 · References and figure provenance

Core text: Robbins, Cotran & Kumar, Pathologic Basis of Disease, 11th ed. (2026).

Topic reading: Gastrointestinal Stromal Tumor.

Cell illustrations in this lecture are conceptual schematics, not H&E microscopic specimens.