Diagnosis
Immunohistochemistry
Positive staining for KIT is the key immunohistochemical feature of GIST.1 Approximately 95% of GISTs stain positive for CD117, an extracellular epitope of KIT. Membrane staining is frequently present and more readily observed in epithelioid GISTs (Table 1).1-3 CD34, the hematopoietic progenitor cell antigen expressed in endothelial cells, is found in approximately 70% to 80% of GISTs.1,2 Although CD34 is a relatively sensitive immunohistochemical marker for GIST, it is also expressed in a wide range of mesenchymal tumors, including endothelial cell tumors (eg, angiosarcoma and Kaposi’s sarcoma), and is thus not specific for GIST.4
Other immunohistochemical features of GIST appear less frequently: 30% to 40% of tumors are positive for smooth muscle actin, whereas desmin and keratin both occur rarely, in only 1% to 2% of GISTs.2
| Feature | Typical of GIST |
|---|---|
| Clinical presentation | Origin in the GI tract (>95%) Large GISTs often grow between the abdominal organs Frequent intra-abdominal implants and liver metastases Lung and lymph node metastases are absent |
| Histopathology/ immunohistochemistry |
Spindle-cell, epithelioid-cell, or mixed morphology Immunostaining for KIT (CD117) is positive (approximately 95%) Immunostaining for CD34 is positive (approximately 70%) Immunostaining for PKC? is positive (>70%) Immunostaining for desmin is negative (>95%) Immunostaining for S100 is negative (approximately 95%) |
| Gene mutation analysis | KIT mutation usually is detectable (approximately 75%-85%) PDGFRA mutation sometimes is detectable (approximately 5%) |
| Therapeutic features | Controlled with Glivec® therapy (CR/PR/SD, approximately 80%-90%) Responds rarely to conventional therapy (approximately 5%) |
CR, complete response; GI, gastrointestinal; GIST, gastrointestinal stromal tumor; PKC, protein kinase C theta; PR, partial response; SD, stable disease. Adapted with permission from Joensuu H. Ann Oncol. 2006;17(suppl 10):x280-x286.3
Absence of KIT stain
Although most GISTs stain positive for KIT, approximately 5% do not. Further analysis by a pathologist who is an expert GIST diagnostician may include KIT and PDGFRA mutational analyses.1 Approximately 35% of GISTs that stain negative for KIT may harbor PDGFRA mutations (Figure 1)5,6 In one series of 7 tumors that did not stain positive for KIT on immunohistochemistry, mutational analysis of KIT exons 9, 11, 13, and 17 and PDGFRA exons 12 and 18 found no KIT isoforms, but 3 tumors harbored
activating mutations in PDGFRA exon 18.7 Alternative activating mechanisms may be responsible for a small subset of tumors.8
More recently, protein kinase C theta (PKC?) has been identified as a diagnostic marker for GISTs without KIT expression and/or with PDGFRA mutations. Because it is strongly activated in most GISTs, PKC? also has potential as a novel therapeutic target.9-11
Figure 1
Immunohistochemistry for KIT in gastrointestinal stromal tumors (GISTs) harboring KIT versus PDGFRA mutations. Strong staining is observed in 3 samples of KIT-mutant GIST on a tissue microarray (A, C, and D), whereas a PDGFRα-mutant GIST sample (B) is negative (original magnification x100). (A) KIT exon 11 deletion. (B) PDGFRA exon 12 deletion. (C) KIT exon 11 deletion. (D) KIT exon 11 point mutation. Reprinted with permission from Corless CL et al. J Clin Oncol. 2004;22:3813-3825.6
GIST Molecular Analysis
For the minority of GIST cases that are not CD117 positive, the diagnosis should be referred to a pathologist who is experienced in diagnosing GIST. Of the 5% of histologically suspected GIST that are CD117 negative, molecular analysis for KIT and PDGFRA mutations should be considered.12 In mutational analysis of the KIT and PDGFRA genes, about 35% of GISTs that stain negative for KIT may harbour mutations in the PDGFRA gene.5
References:
1. Miettinen M, Lasota J. Gastrointestinal stromal tumors (GISTs): definition, occurrence, pathology, differential diagnosis and molecular genetics. Pol J Pathol. 2003;54:3-24.
2. Demetri G, Benjamin R, Blanke CD, et al. NCCN Task Force report: optimal management of patients with gastrointestinal stromal tumor (GIST)—expansion and update of NCCN Clinical Practice Guidelines. J Natl Compr Canc Netw. 2004;2(suppl 1):S1-S26.
3. Joensuu H. Gastrointestinal stromal tumor (GIST). Ann Oncol. 2006;17(suppl 10):x280-x286.
4. Sarlomo-Rikala M, Kovatich AJ, Barusevicius A, Miettinen M. CD117: a sensitive marker for gastrointestinal stromal tumors that is more specific than CD34. Mod Pathol. 1998;11:728-734.
5. Heinrich MC, Corless CL, Duensing A, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003;299:708-710.
6. Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointestinal stromal tumors. J Clin Oncol. 2004;22:3813-3825.
7. Debiec-Rychter M, Wasag B, Stul M, et al. Gastrointestinal stromal tumours (GISTs) negative for KIT (CD117 antigen) immunoreactivity. J Pathol. 2004;202:430-438.
8. Heinrich MC, Rubin BP, Longley BJ, Fletcher JA. Biology and genetic aspects of gastrointestinal stromal tumors: KIT activation and cytogenetic alterations. Hum Pathol. 2002;33:484-495.
9. Motegi A, Sakurai S, Nakayama H, et al. PKC theta, a novel immunohistochemical marker for gastrointestinal stromal tumors (GIST), especially useful for identifying KIT-negative tumors. Pathol Int. 2005;55:106-112.
10. Duensing A, Joseph NE, Medeiros F, et al. Protein kinase C theta (PKC theta) expression and constitutive activation in gastrointestinal stromal tumors (GISTs). Cancer Res. 2004;64:5127-5131.
11. Blay P, Astudillo A, Buesa JM, et al. Protein kinase C theta is highly expressed in gastrointestinal stromal tumors but not in other mesenchymal neoplasias. Clin Cancer Res. 2004;10:4089-4095.
12. Blay JY, Bonvalot S, Casali P, et al. Consensus meeting for the management of gastrointestinal stromal tumors. Report of the GIST Consensus Conference of 20-21 March 2004, under the auspices of European Society for Medical Oncology. Ann Oncol. 2005;16:566-578.