Stromal Tumors

Synonyms: Gastrointestinal Stromal Tumors (GIST), Gastrointestinal Autonomic Nerve Tumors

GIST showing characteristic cytoplasmic vacuoles indenting the nuclear poles.

Definition

Nonepithelial spindled and epithelioid tumor, most often showing smooth muscle and/or neural differentiation, with varied benign and malignant behavior.

Clinical Features

Majority of primary nonepithelial neoplasms of stomach1
Occasionally associated with:
- Recklinghausen's disease2,3
- Carney triad:4–7
  - characteristically multiple and epithelioid
- a familial syndrome characterized by:
  - different from Carney triad 8
- familial small intestinal neuronal dysplasia:9
  - multiple GISTs with neural-like features (GANTs)
  - germline mutation of CD117 gene10,11
Exceptionally coincidental with anatomically separate epithelial tumors of stomach 12
Usually adult:13,14
- if child often clinically malignant 15–17
Most common symptoms:
- melena 18
- hematemesis if central ulceration
Location
- most clinically apparent in:
  - pars media (40%)
  - antrum (25%)19
- 20% near pylorus, but obstruction rare

Metastases

Most common sites:
- liver
- peritoneum
- lungs20,21 (Fig. 1
  Fig. 1: Gross appearance of liver metastasis from GIST.
  )
Can develop 30 years after removal of primary
Lymph node metastases extremely rare

Pathogenesis

May be neoplastic manifestation of phenotypical and functional potentialities of normal stromal cells
Attempts to subdivide along histogenetic lines are ill conceived22–26

Gross Pathology

≈60% submucosal and grow toward lumen to make a smooth projection (Fig. 2
Fig. 2: Gross appearance of GIST. This example is polypoid and has a large central scar. (Courtesy of Dr RA Cooke, Brisbane, Australia; from Cooke RA, Stewart B: Colour Atlas of Anatomical Pathology. Edinburgh, Churchill Livingstone, 2004)
)
- may be central ulceration (Fig. 3
  Fig. 3: Gross appearance of GIST. This example shows a deep, large ulceration, a common complication of this entity. (Courtesy of Dr RA Cooke, Brisbane, Australia; from Cooke RA, Stewart B: Colour Atlas of Anatomical Pathology. Edinburgh, Churchill Livingstone, 2004)
  ):
  - more common if clinically malignant
≈30% subserosal
10% intramural
Well circumscribed
Cut section:
- smooth, lobulated, or whorled-silk appearance
- may be hourglass defect at cardia or pylorus if encircles stomach
May be prominent fibrohyaline areas
- may calcify27

Histopathology

Wide range of differentiation along several lines

Differentiation Toward Smooth Muscle Cells
Smooth muscle features at hematoxylin–eosin level:
usually clearly identifiable if:
small
multiple minute subserosal neoplasms found incidentally28
difficult to identify for many:
clinically apparent tumors
hypercellular small tumors29
Smooth muscle differentiation suggested by:
spindle tumor cells with acidophilic fibrillary cytoplasm
cytoplasmic vacuoles at both ends of nucleus (Fig. 4
Fig. 4: GIST showing characteristic cytoplasmic vacuoles indenting the nuclear poles.
)
epithelioid appearance:
many exceptions
defined by presence of round to polygonal cells with:
central nucleus
usually abundant:
acidophilic cytoplasm (Fig. 5
Fig. 5: Microscopic appearance of GIST. In this case the cells are epithelioid, pleomorphic and with deeply acidophilic cytoplasm. This tumor had features of smooth muscle differentiation at the immunohistochemical level.
), or30–33
clear cytoplasm (Fig. 6
Fig. 6: Microscopic appearance of GIST. The tumor cells have a round epithelioid appearance, clear cytoplasm, and well-defined cell membranes. This corresponds to the pattern that has been traditionally designated as leiomyoblastoma.
):
thought to be artifact of fixation34,35
Differentiation Toward Neural Elements
Generally composed of spindle (but sometimes epithelioid) cells growing in:
fascicles
palisades
whorls
Amorphous eosinophilic extracellular collections of abnormal collagen (skenoid [skeinoid] fibers) (Fig. 7
Fig. 7: Skenoid fibers highlighted by the PAS stain.
):
immunoreactive for type VI
generally associated with neural differentiation:
also seen in tumors with smooth muscle-type or dual differentiation36–39
Features Not Helpful In Determining Line Of Differentiation
Degree of cellularity
Large cells with bizarre hyperchromatic nuclei
Marked diffuse vascularity
Nuclear palisading (Fig. 8
Fig. 8: GIST showing prominent palisading. This feature is not necessarily indicative of neural differentiation.
)
Conventional special stains such as:
Masson's trichrome
Mallory's phosphotungstic acid–hematoxylin
Additional Morphologic Variations
Some related to subtypes, some independent
Prominent myxoid matrix (Fig. 9
Fig. 9: GIST with abundant myxoid matrix separating the individual tumor cells.
)40
Signet ring cell features:
variation of cytoplasmic clearing41,42
Granular cell changes 43
Oncocytic cytoplasmic features:
in GANT-type tumors (see Diagnosis)44
Aneurone cell features:
seen ultrastructurally45
Crystalloid formation:
associated with schwannian differentiation46
Heavy inflammatory infiltrate47
Tumor giant cells (Fig. 10
Fig. 10: GIST containing numerous multinucleated tumor giant cells.
)
Osteoclast-like giant cells48

Special Stains and Immunohistochemistry

In addition to differentiation markers related to lines of differentiation (see Diagnosis)49:
- occasional reactivity for:
  - keratin
  - tau (a microtubule-associated protein)50

Diagnosis

Members of larger family:
- gastrointestinal stromal tumors (GISTs)51
  - involving:
    - small bowel
    - other portions of digestive tract
    - omentum
    - mesentery
    - retroperitoneum

Four Major Categories

Roughly divided into four categories on phenotypic features

1. Differentiation Toward Smooth Muscle Cells

Much the largest category
Immunohistochemically express:
- smooth muscle actin
- desmin
- calponin
- caldesmon
- myosin
Ultrastructurally:
- pinocytotic vesicles
- subplasmalemmal dense patches
- cytoplasmic microfilaments with focal densities52–63 (Fig. 11
  Fig. 11: Electron micrograph of GIST showing smooth muscle differentiation. Portions of neoplastic smooth muscle cells containing numerous actin microfilaments with interspersed fusiform densities are seen. Electron-dense membrane attachment plaques (arrow) are prominent. (×21,300; courtesy of Dr Robert A. Erlandson, Memorial Sloan-Kettering Cancer Center)
  )
Theoretically could arise from:
- muscularis propria,
- muscularis mucosae
- vessel-related smooth muscle cells

2. Differentiation Toward Neural Elements

Second largest category
Mainly determined by presence ultrastructurally of neural-like features:
- e.g.:
  - long cytoplasmic processes resembling axons joined by primitive cell junctions
  - scattered microtubules consistent with neurotubules
  - dense-core neurosecretory-type granules (Fig. 12
    Fig. 12: Electron micrograph of GIST showing neural differentiation. Dense core neurosecretory granules (arrow) and complex cell processes are seen joined by rudimentary cell junctions (right center). (×73,200; courtesy of Dr Robert A. Erlandson, Memorial Sloan-Kettering Cancer Center)
    )
- similar to those of neural cells in autonomic myenteric plexus:
  - therefore designated:
    - gastrointestinal autonomic nerve tumors (GANTs)
    - myenteric plexus tumors, or
    - plexosarcomas64–69
Little immunohistochemical support:
- only less specific neural/neuroendocrine markers are consistently positive, i.e.:
  - S-100 protein 53,70,71
By definition lack markers of smooth muscle differentiation
Relationship with exceptional gastric schwannoma not clear:72,73
- histochemical features, such as S-100 protein and GFAP,24 suggest central or peripheral schwannian/glial line

3. Dual Differentiation Toward Smooth Muscle And Neural Elements

Less common
Defined by criteria listed for categories 1 and 2

4. Lacking Differentiation Toward Either Cell Type

Almost as uncommon as group 3 tumors
GIST used in a restricted sense only for this group by some
High percentage immunoreactive for CD3474–76

Role of CD117

Some make CD117 positivity (Fig. 13
Fig. 13: Strong CD117 immunoreactivity in a GIST.(CD117)
) absolute requirement for definition of GIST, but:
- rare tumors do not stain for CD11777
- some CD117+ tumors are outside morphologic range of GIST
- most convincing pattern of CD117 positivity features both membrane and cytoplasmic components:
  - mesenchymal tumors other than GIST that may stain for CD117 (such as fibromatosis) tend to show only cytoplasmic staining
- CD117 immunoreactivity does not necessarily indicate presence of a gene mutation (see Genetics)
- a CD117 mutation can exist in absence of immunohistochemically detectable marker

Other investigations

Radiography:
- highly characteristic appearance due to:
  - smooth outline
  - central niche

Differential Diagnosis

Select up to 2 differential diagnoses to compare with Stromal Tumors

Depending on location and microscopic features:
- solitary fibrous tumor:
  - shares CD34 positivity with GIST
  - negative for CD11778
- fibromatosis:
  - particularly likely to be misdiagnosed as GIST because can:
    - extensively involve gastrointestinal wall
    - exhibit CD117 immunoreactivity:
      - tends to be exclusively cytoplasmic and not on cell membrane79
    - develops postoperatively in patients treated for GIST
    - nuclear positivity for β-catenin in fibromatosis helpful80
- inflammatory fibroid tumor
- glomus tumor
- schwannoma:
  - differences in DNA patterns81
- leiomyoma/leiomyosarcoma:
  - differences in DNA patterns81
- malignant lymphoma
- carcinoma

Genetics

Overwhelming majority of GISTs accompanied by:
- somatic mutation:
  - of CD117 (c-kit):
    - a tyrosine kinase receptor normally expressed by:
      - interstitial cells of Cajal
      - mast cells
      - germ cells82–85
    - independent of:
      - anatomic site 86
      - size
      - line of differentiation
      - cytologic features:
        claimed to be more common in spindle than epithelioid cell tumors87
  - primarily exon 11
  - rarely exons 9 and 13
  - occasionally other sites88,89
    - results in ligand-independent activation of receptor 90

Management

Excision with good margin of normal tissue:
- primary treatment
- operation type and extent depend more on tumor size and location than subtyping
- may involve partial, subtotal, or total gastrectomy
- simple enucleation discouraged
Wide resection of lymph node areas not indicated due to extreme rarity of lymph node metastases
Imatinib mesylate:91,92
- tyrosine kinase inhibitor
- sensitive response depends on presence and type of CD117 mutation
- spectacular results
- initial total regression sometimes followed by recurrence with acquired resistance to drug through additional mutation
- GIST-type morphology better predictor of response (because usually a CD117 mutation) than immunoreactivity for CD117 (may not be associated with mutation)

Prognosis

Prognostic factors:93–96

Some combine tumor size and mitotic activity to produce risk categories 100–102 (Table 1

Table 1. Risk categories for GISTs based on tumor size and mitotic activity

	Risk	Size (cm)*	Mitotic count (per 50 HPF)†
* Size represents the single largest dimension. May vary somewhat before and after fixation and between observers. General but poorly defined sense that perhaps size threshold for aggressive behavior should be 1–2 cm less in small bowel than elsewhere. † Ideally mitotic count should be standardized according to surface area examined (based on size of HPFs), but no agreed definitions. Despite inevitable subjectivity in recognition of mitoses and variability in the area of HPFs, such mitotic counts still prove useful.
	Very low	<2	<5
	Low	2–5	<5
	Intermediate	<5	6–10
		5–10	<5
	High	>5	>5
		>10	Any
		Any	>10

)

Good correlation between:
- PCNA (Ki-67 [MIB-1]) index and prognosis 103,104
No good evidence that measuring proliferative activity improves accuracy over mitotic count.
For gastric tumors composed of epithelioid cells features predicting aggressive behavior are:
- paucity of reticulin fibers 105
Seems to be relationship between clinical malignancy and pattern of differentiation:101
- not clear how independent this is from criteria of tumor size and mitoses
Tumors that tend to be aggressive fashion are those exhibiting:
- neural-type differentiation:
  - GANs, though not those containing numerous skenoid fibers
- dual smooth muscle and neural differentiation
- neither smooth muscle nor neural differentiation:
  - i.e. positive only for vimentin106
Poor outcome also been associated with loss of CD44 expression107
Claimed that DNA ploidy can provide prognostic information108–114
Also seems to be a relationship between prognosis and:
- apoptosis:
  - as measured with TUNEL technique and bcl-2 staining 115
- loss of heterozygosity at 1p36116
- a high level of ‘secondary’ cytogenetic aberrations117
- telomerase activity118
- c-myc expression119
CD117 mutation;
- no relationship with malignancy120,121
- important predictor of medical response

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Last updated: 9 Jan 2006