Gastrointestinal stromal tumours (GIST, smooth muscle tumour of uncertain malignant potential, STUMP, gastrointestinal autonomic nerve tumour, GANT, gastrointestinal pacemaker cell tumour, GIPACT)

This is a heterogeneous group of tumours, previously thought to be tumours of smooth muscle differentiation (leiomyo(sarco)mas). About 95% of stromal tumours of the stomach are classifiable as GISTs²¹. They are now thought to arise from the interstitial cells of Cajal, which act as pacemakers for peristalsis. Gain-of function mutations of c-kit are thought to be important in the pathogenesis of GIST, most commonly mutations in the juxtamembrane domain encoded by exon 11¹⁰. Germline mutations of c-kit occur in familial GISTs. A subset of GISTs, negative for CD117 by immunohistochemistry, lack a KIT mutation; PDGFRA mutations may provide an alternative oncogenic mechanism in these cases²⁰.

Epidemiology

GIST is the most common mesenchymal tumour of the gastrointestinal tract, with an incidence of 4 per million of the population per annum. The median age is 63 years: less than 3% of cases occur in those under 21 years of age and only 10% are under 40 years²¹. There is no sexual predominance. They may be multiple in Carney's triad (GIST / phaeochromocytoma / paraganglioma / pulmonary chondroma syndrome) and, rarely, in neurofibromatosis^6,21,24,25.

They are found throughout the gastrointestinal tract, most often in the stomach:

• stomach; 70% of tumours⁶ Location in the fundus, cardia or at the gastro-oesophageal junction is associated with a higher risk of progressive disease²¹.

• small intestine; 20-30% of tumours⁶: cases associated with neurofibromatosis I occur most often in the small intestines.

• oesophagus, colon and rectum (where true smooth muscle tumours are more common)⁶

• Four cases have been reported in the appendix¹¹.

• Similar tumours are occasionally found in extra-gastrointestinal sites such as the omentum, peritoneum and retroperitoneum⁶

Clinical presentation

The most common presentation is with GI bleeding, followed by pain and less commonly a large mass or an incidental finding at surgery, rarely obstruction or an acute abdomen due to tumour rupture²¹.

Macroscopic appearances

Gross features vary widely, variously being described as well demarcated, nodular, lobulated or bosselated²¹. Small tumours may form a plaque. Larger tumours may form polyps projecting into the lumen, often ulcerated, a spherical mass or a pedunculated mass within the peritoneal cavity. Cystic change is common. Colour varies from grey-white through yellow to tan-brown with haemorrhagic foci.

• Size varies from 1 to >20 cm diameter

• well circumscribed, unencapsulated or with a pseudocapsule

• submucosal, intramuscular or subserosal.

• may be solid or partly cystic

Histopathology

Various patterns have been described:

• spindle cell; 60-70%:

  • sclerotic spindle cell; 110/1242²¹; these tumours are of low cellularity with abundant collagen and commonly calcify. Mitotic count is low.

  • palisading and vacuolated spindle cell; 266/1242²¹; there are plump uniform spindle cells showing nuclear palisading and perinuclear vacuolation. Mitotic count less than 10/50HPF.

  • hypercellular spindle cell; 139/1242²¹; densely packed uniform spindle cells with nuclear palisading, perinuclear vacuolation and limited nuclear atypia. Mitotic count greater than 15/50HPF.

  • sarcomatous spindle cell; 240/1242²¹; diffuse atypia, often a myxoid stroma. Mitotic count greater than 20/50HPF.

• epithelioid; 30-40%. Cytoplasm varies from clear to amphiphilic to oncocytic

  • sclerosing epithelioid; 270/1242²¹; cohesive syncytial epithelioid cells in a diffuse collagenous matrix. Mitotic count is low.

  • dyscohesive epithelioid; 108/1242²¹; large dyscohesive polygonal cells in a scanty matrix. Mitotic count is low.

  • hypercellular epithelioid; 78/1242²¹; back-to-back epithelioid cells, nuclear atypia, higher n/c ratio. Mitotic count almost always less than 10/50HPF.

  • sarcomatous epithelioid; 31/1242²¹; high n/c ratio, prominent nucleoli, mitotic rate greater than 20/50HPF.

• Less commonly, the cells may be clear, plasmacytoid, granular, oncocytic or rhabdoid.

• The architecture varies, including solid, fascicular, storiform, alveolar, haemangiopericytomatous and palisaded patterns, sometimes with cystic change.

• glycogen is often present in a perinuclear distribution

• extracellular collagen (skenoid fibres) may be seen in small intestinal tumours^6,17.

• there is a variable lymphocytic and plasmacytic infiltrate. Rarely, GIST may show an intense inflammatory infiltrate. This may be in the form of cytotoxic T-cells (positive for CD3, CD4, CD8, granzyme B, TIA-1 and perforin)^15,16.

Immunohistochemistry

The published literature is variable and confusing (Reference 3 is based on a review of the literature³):

CD117	221/2443, 13/138, 24/269, 145/145 (all gastric tumours)17, 631/693 (usually diffusely strong, but 63 were weakly positive and 16 showed staining of less than 10% of tumour cells: 51 epithelioid and 11 spindle cell tumours were negative: 43 of the 62 negative tumours were also negative for CD34)21
CD34	168/2243; a lower rate in colorectal than gastric tumours7, 9/138, 23/269, 141/145 (all gastric tumours)17, 644/788 (117 epithelioid and 27 spindle cell were negative)21
muscle-specific actin	variable: 11/642
SMA	20-40%12, higher in small intestinal than gastric tumours7, 3/138, 9/269, 30/145 (all gastric tumours)17, 150/81121
desmin	variable7, 4/642 (non-neoplastic smooth muscle cells may become incorporated6), 0/138, 7/145 (all gastric tumours)17, 40/788 (30 epithelioid and 10 spindle cell tumours were positive)21
h-caldesmon	10/138, 117/145 (all gastric tumours)17
Calponin	2/138
S-100	some focally positive7, 0/138, 5/145 (all gastric tumours)17, 7/793 (only 2 cases showed more than focal positivity)21
CD68	scattered positive cells2
PGP9.5	16/269
NSE	20/269
tau	20/269
bcl-2	20/269
VS38c	positive (1/1, plus unpublished data)15
collagen type IV	4/118
laminin	2/118
cytokeratin 18 (clone DC-10)	2/118
Cam 5.2	3/42 (perinuclear dot-like positivity)18
AE1/3	0/145 (all gastric tumours)17
EMA	0/145 (all gastric tumours)17
chromogranin	0/118
synaptophysin	0/118, 4/269
neurofilament	0/269
CD20	0/118
CD45 (LCA)	0/118
calretinin	1/3214
inhibin	0/3214
vimentin	95% positive7, 62/642, 13/138, 26/269, 145/145 (all were gastric tumours)17

CD117 in GISTs is usually seen in the majority of cells: positivity of less than 10% of cells is an indication for cautious interpretation. Scanty cells positive for CD117 in a spindle cell tumour are likely to be mast cells⁶. The staining pattern is usually diffuse cytoplasmic and granular with membrane accentuation. There may be focal perinuclear staining¹⁰.

Molecular genetics

KIT mutations are more common in spindle cell tumours and PDGFRA mutations are more common in epithelioid tumours. Point mutations tend to occur in tumours with benign behaviour²¹.

		epithelioid	spindle	mixed	progressive disease
	KIT exon11 deletion +/- point mutation	12/72	56/72	4/72	11/72
	KIT exon11 point mutation	4/36	30/36	2/36	0/36
	KIT exon11 internal tandem duplications	0/9	8/9	1/9	1/9
	PDGFRA exon 18	52/86	15/86	19/86	9/86
	PDGFRA exon 12	4/9	3/9	2/9	0/9

Ultrastructure

Features of neural differentiation correlate with immunohistochemistry. Skenoid fibres (extracellular amorphous eosinophilic interwoven modified collagen) are a further feature of neural differentiation. GANT is only reliably distinguished from GIST on ultrastructural grounds.

Variants

Gastrointestinal autonomic nerve tumour (GANT) differs ultrastructurally but are often morphologically and immunohistochemically indistinguishable from GIST. Some cases show a distinctly rich vascular pattern⁷. Variable positivity for NSE, synaptophysin and S-100 has been reported⁷. It has been thought to be a more aggressive tumour, but the latest paper suggests it is merely a variant of GIST.

• Gastric epithelioid GISTS were formerly known as epithelioid leiomyoblastoma. They usually present in the fifth to seventh decade of life. The cells have eosinophilic cytoplasm and sharp borders. They may express myoid and/or neural markers.

• Small intestinal GISTs with skenoid fibres (which stain with PAS and blue with Masson's trichrome) tend to pursue a benign course.

• Tumours arising in the mesentery and omentum have a lower rate of CD34 positivity.

Differential diagnosis

leiomyoma/leiomyosarcoma	may be CD34+ but reliably CD117negative12. GIST is usually negative for desmin but may be positive for SMA
Schwannoma	may be CD34+ but reliably CD117-
retroperitoneal dedifferentiated liposarcoma
vascular tumours
fibromatosis
solitary fibrous tumour	CD34 positive, consistently CD117 negative12
Kaposi' sarcoma	CD34 positive, consistently CD117 negative12
inflammatory myofibroblastic tumour v inflammatory GIST
fibroid inflammatory polyp v inflammatory GIST
spindle cell carcinoid
granular cell tumour of oesophagus	CD34 and CD117 negative, S-100 positive19
spindle cell melanoma	S-100 positivity usually diffuse, may be CD117 positive (9/2512)
clear cell sarcoma	may be CD117 positive (7/1512)
malignant fibrous histiocytoma	may be CD117 positive (1/2012)
spindle cell carcinoma
haemangiopericytoma	CD 34 positive, may be CD117 positive (2/1012)
dermatofibrosarcoma protuberans	CD 34 positive, may be CD117 positive (1/712)
follicular dendritic cell sarcoma1 v inflammatory GIST	this tumour is rare and would be CD21+, CD35+, CD68+, CD34- & CD117-

Although CD117 does not have a sensitivity of 100% for GIST, unless a pathologist is experienced, a diagnosis of GIST should not be made in the absence of immunoreactivity for CD117⁶.

Treatment

There are results from Phase I and II trials that indicate that the tyrosine kinase inhibitor STI-571 (Gleevec^TM; Novartis, Basel, Switzerland, Imatinib mesylate) may be highly efficacious in the treatment of GISTs⁵. Responsiveness to STI-571 may be a function of the exon in which the KIT mutation is found.⁶ In GISTs that are refractory to imatinib, the presence of an exon 9 c-kit mutation is associated with a greater response to SU11248, a multi-targeted tyrosine kinase inhibitor²².

Prognosis

10% to 30% of GISTs show malignant behavior (gastrointestinal stromal sarcoma)⁷. Local recurrence usually precedes metastasis. When metastasis occurs, it is usually to liver, peritoneum or lungs, rarely to lymph nodes or ovaries. The literature relating to prognosis is conflicting:

	"Benign" / low risk	Borderline	Malignant
de Saint Aubain Somerhausen	spindle cell, no atypia & MI = 0-2/30 HPF	spindle cell, no atypia and MI = 3-4/30 HPF	spindle cell, no atypia and MI>4/30 HPF
		spindle cell, mild atypia and MI = 2-3/30 HPF	spindle cell, frank atypia and MI > 2/30 HPF
	epithelioid & MI=0/30HPF	epithelioid and MI = 1/30 HPF	epithelioid and MI > 1/30 HPF
Miettinnen	gastric and MI = 0-1/10 HPF	gastric and MI = 2-5/10 HPF	gastric and MI > 5/10 HPF
	gastric and size < 5 cm	gastric and size = 5-10 cm	gastric and size > 10 cm
Kindblom	bland cytology, no necrosis and on mucosal infiltration & MI = 0/10 HPF	some but not all of the features of malignancy	frank atypia, necrosis, mucosal infiltration, haemorrhage & MI >= 1/10 HPF
GIST Workshop6	<2 cm and no mitoses	many tumours fall into this category with uncertain malignant potential	> 5cm and >50 mitoses/50 HPF or small intestine, any size and >10 mitoses / 50 HPF

MI = mitotic index, HPF = high power field.

Seidal and Edvardsson derived a formula to predict behavior²:

Z=2.428. x value for Ki67 - 2.092 x value for CD34 - 0.944 x value for grade + 0.096 x size in cm-0.041x patient age - 2.377

where the Ki67 staining was scored as: 0; no positivity, 1; <1% of nuclei, 2; >1% & <10% nuclei, 3; >10% nuclei staining, CD34 scored as 0 or 1, grade 1; monomorphic, little cellular atypia, grade 2; more cellular, moderate cytological atypia, grade 3; highly cellular with severe atypia.

If Z<0.66, the course is likely to be benign, if Z> 0.66, a malignant course is likely.

Trupiano et al¹³ found that tumor size > 7 cm, high cellularity, mucosal invasion, high nuclear grade, mitotic count >= 5 mitoses / 50 HPF, mixed cell type, extensive myxoid change and absence of hyalinisation all predicted an aggressive clinical course, but without allowing a confident separation of benign from malignant. More importantly, they believe that they can recognise clinically benign tumours are having the following features:

• the benign spindle cell pattern consists of a proliferation of cytologically bland spindle cells with pale to eosinophilic fibrillary cytoplasm. The cells are uniform at both low and high magnification and the architectural pattern ranges from whorls to short intersecting fascicles. Many tumours show prominent perinuclear vacuoles. There is commonly nuclear palisading and extensive stromal hyalinisation.

• benign epithelioid tumours are composed almost exclusively of epithelioid cells with a perinuclear condensed rim of of eosinophilic cytoplasm, often with a peripheral zone of cytoplasmic clearing. Scattered bizarre or multinucleate cells are often seen, cell membranes are well-defined and the nuclei are round with small nucleoli. Cellularity is never judged to be high at low magnification. There is frequently stromal hyalinisation.

• benign mixed pattern combining the two above patterns.

All other appearances are classed as "not benign".

Hawagaza¹⁷ on multivariate analysis found age >60 years, male sex, high tumour grade and tumour size 5 to 10 cm (relative risk 4.0) or >10 cm (relative risk 10.8) to be predictive of a fatal outcome.

• > 10 cm or high grade: high risk

• 5 to 10 cm and low grade: intermediate risk

• <5 cm and low grade: low risk

GISTs on the greater curvature of the stomach, even if large, may be more likely to be benign⁶. Oesophageal tumours have the most favorable prognosis and those of the small intestine the worst⁶. Inadequate resection may account for the recurrence rate in the rectum⁶. Certain cytogenetic gains and amplifications may be associated with malignant behaviour⁶. Mutations of c-kit are associated with malignant behaviour¹⁰.

The largest long-term study²¹ identified differences between histological subtypes:

• spindle cell sarcomatous subtype: 84% with progressive disease

• epithelioid sarcomatous subtype: 64% with progressive disease

• hypercellular epithelioid cell subtype: 21% with progressive disease

• hypercellular spindle cell subtype: 14% with progressive disease

• epithelioid sclerosing subtype: 64% with progressive disease

• sclerosing and palisading spindle cell subtypes: 2% with progressive disease

Coagulative necrosis is associated with progressive disease (50% vs 9%)²¹ but liquefactive necrosis is not²¹.

Mucosal infiltration in a "lymphoma-like" pattern correlated with sarcomatous tumours and a poor prognosis²¹.

However, the suggested guidelines for assessing the malignant potential are based on tumour size and mitotic activity²¹:

	Reference 21	Number of cases	Alive, no disease	Alive with disease	Dead of unrelated cause	Dead of disease	Postoperative death	Dead of unknown cause	Prognostic conclusion
	tumour < 2 cm & mitoses <= 5 / 50 HPF	76	34 (45%)	0	42 (55%)	0	0	32 (42%)	benign
	tumour 2-5 cm & mitoses <= 5 / 50 HPF	320	172 (54%)	1	134 (42%)	5 (2%)	8	120 (38%)	probably benign
	tumour 5-10 cm & mitoses <= 5 / 50 HPF	229	136 (59%)	3	80 (35%)	5 (2%)	5	50 (22%)
	tumour >10 cm & mitoses <= 5 / 50 HPF	140	74 (53%)	1	47 (34%)	16 (11%)	2	44 (31%)	low to moderate malignant potential
	subtotal mitoses <= 5 / 50 HPF	765	416 (54%)	5	303 (40%)	26 (3%)	15	246 (32%)
	tumour < 2 cm & mitoses > 5 / 50 HPF	6	3	0	3	0	0	2	uncertain or low malignant potential
	tumour 2-5 cm & mitoses > 5 / 50 HPF	99	57 (58%)	1	26 (26%)	15 (15%)	0	32 (32%)	low to moderate malignant potential
	tumour 5-10 cm & mitoses > 5 / 50 HPF	96	25 (26%)	2	18 (19%)	50 (52%)	1	49 (51%)	high malignant potential
	tumour >10 cm & mitoses > 5 / 50 HPF	108	10 (9%)	1	5 (5%)	88 (81%)	4	78 (72%)
	subtotal mitoses > 5 / 50 HPF	309	95 (31%)	4	52 (17%)	153 (50%)	5	161 (52%)
	total	1074	511 (48%)	9	355 (33%)	179 (17%)	20	407 (38%)

Patients with tumours containing an exon 11 c-kit mutation have a longer event-free survival than those whose tumour carry other mutations²³.

References

¹ K-C Chang et al. Follicular dendritic cell sarcoma of the colon mimicking stromal tumour. Histopathology 2001; 38:25-29.

² Seidal, T., Edvardsson, H. Expression of c-kit (CD117) and Ki67 provides information about the possible cell of origin and clinical course of gastrointestinal stromal tumours. Histopathology 1999;34:416-424.

³ JF Graadt van Roggen et al. The histopathological differential of diagnosis of gastrointestinal stromal tumours. J Clin Pathol 2001; 54: 96-102.

⁵ CDM Fletcher. KIT (CD117) immunostaining and treatment with STI-571. Advances in Anatomic Pathology 2001;8:304.

⁶ Berman, J., O'Leary, T. J. Gastrointestinal stromal tumor workshop. Human Pathol 2001; 32:578-582.

⁷ Al-Nafussi, A., Wong, N. A.Intra-abdominal spindle cell lesions: a review and practical aids to diagnosis. [review] Histopathology 2001;38:387-402.

⁸ Miettinen, M., Paal, E., Lasota, J., Sobin, L. H. Gastrointestinal glomus tumors: a clinicopathologic, immunohistochemical, and molecular genetic study of 32 cases. Am J Surg Pathol 2002;26:301-311

⁹ Chambonniere, M. L., Mosnier-Damet, M., Mosnier, J. F. Expression of microtubule-associated protein tau by gastrointestinal stromal tumors. Human Pathol 2001;32:1166-1173.

¹⁰ Gibson, P. C., Cooper, K. CD117 (KIT): a diverse protein with selective applications in surgical pathology. Adv Anat Pathol 2002;9:65-69.

¹¹ Miettinen, M., Sobin, L. H. Gastrointestinal stromal tumors in the appendix: a clinicopathologic and immunohistochemical study of four cases. Am J Surg Pathol 2001;25:1433-7.

¹² Sarlomo-Rikala, M., Kovatich, A. J., Barusevicius, A., Miettinen, M. CD117: a sensitive marker for gastrointestinal stromal tumors that is more specific than CD34. Mod Pathol 1998;11:728-34.

¹³ Trupiano, J.K., Stewart, R.E., Misick, C., Appelman, H.D. and Goldblum, J.R. Gastric stromal tumors: a clinicopathologic study of 77 cases with correlation of features with nonaggressive and aggressive clinical behaviors. Am J Surg Pathol 2002;26:705-14.

¹⁴ Shah, V.I., Freites, O.N., Maxwell, P. and McCluggage, W.G. Inhibin is more specific than calretinin as an immunohistochemical marker for differentiating sarcomatoid granulosa cell tumour of the ovary from other spindle cell neoplasms. J Clin Pathol 2003;56:221-4.

¹⁵ Suarez-Vilela, D. and F. M. Izquierdo-Garcia (2003). "Cytotoxic T-lymphocyte-rich, gastrointestinal stromal tumour." Histopathology 43(4): 398-400.

¹⁶ Shek, T. W., I. S. Luk, et al. (1996). "Inflammatory cell-rich gastrointestinal autonomic nerve tumor. An expansion of its histologic spectrum." Am J Surg Pathol 20(3): 325-31.

¹⁷ Hasegawa, T., Y. Matsuno, et al. (2002). "Gastrointestinal stromal tumor: consistent CD117 immunostaining for diagnosis, and prognostic classification based on tumor size and MIB-1 grade." Hum Pathol 33(6): 669-76.

¹⁸ Nga, M. E., A. S. Wong, et al. (2002). "Cytokeratin expression in gastrointestinal stromal tumours: a word of caution." Histopathology 40(5): 480-1.

¹⁹ Prematilleke, I. V., V. Sujendran, et al. (2004). "Granular cell tumour of the oesophagus mimicking a gastrointestinal stromal tumour on frozen section." Histopathology 44(5): 502-3.

²⁰ Heinrich, M. C., C. L. Corless, et al. (2003). "PDGFRA activating mutations in gastrointestinal stromal tumors." Science 299(5607): 708-10.

²¹ Miettinen, M., L. H. Sobin, et al. (2005). "Gastrointestinal Stromal Tumors of the Stomach: A Clinicopathologic, Immunohistochemical, and Molecular Genetic Study of 1765 Cases With Long-term Follow-up." Am J Surg Pathol 29(1): 52-68.

²² Maki RG, Fletcher CDM, Heinrich MC et al. Resutls from a continuation trial of SU11248 in patients with imatinib-resistant gastrointestinal stromal tumour. J Clin Oncol 2005;23(165):9011 (Abstract).

²³ Hahn HP, Fletcher CDM. The role of cytogenetics and molecular genetics in soft tissue tumour diagnosis - a realistic approach. Current Diagnsotic Pathology 2005;11:361-370.

²⁴ 1.Perry CG, Young WF, Jr., McWhinney SR, et al. Functioning Paraganglioma and Gastrointestinal Stromal Tumor of the Jejunum in Three Women: Syndrome or Coincidence. Am J Surg Pathol 2006; 30:42-49

²⁵ Miettinen M, Fetsch JF, Sobin LH, et al. Gastrointestinal Stromal Tumors in Patients With Neurofibromatosis 1: A Clinicopathologic and Molecular Genetic Study of 45 Cases. Am J Surg Pathol 2006; 30:90-96

This page last revised 14.1.2005.

©SMUHT/PW Bishop