What is the clinical significance of the Cd117 (Cluster of Differentiation 117) marker in diagnosis and treatment?

CD117 (c-kit) Marker: Clinical Significance in Diagnosis and Treatment

CD117 is the cornerstone diagnostic marker for gastrointestinal stromal tumors (GISTs), with approximately 95% of GISTs showing positive immunohistochemical staining, making it both highly sensitive and specific for distinguishing GISTs from other mesenchymal tumors of the gastrointestinal tract. 1

Diagnostic Applications

Primary Role in GIST Diagnosis

• CD117 expression with diffuse cytoplasmic staining pattern confirms GIST diagnosis when combined with compatible morphological features (spindle cell, epithelioid, or mixed cell types) 1
• The marker shows intense staining in 75% of cases, with immunohistochemical positivity independent of KIT and PDGFRA mutational status 1
• CD117 is more specific than CD34 for GIST diagnosis, as CD34 is expressed in various fibroblastic and endothelial tumors, whereas CD117 reliably separates GISTs from true leiomyomas and schwannomas 2

Complementary Markers When CD117 is Negative

• Between 4-5% of GISTs with typical morphological features are CD117-negative, requiring additional diagnostic workup 1
• For CD117-negative cases, DOG1 (discovered on GIST-1) immunostaining is highly recommended, as it is expressed in over 35% of CD117-negative GISTs 1
• When both CD117 and DOG1 are negative, mandatory mutational analysis for KIT and PDGFRA genes should be performed at reference centers 1

Differential Diagnosis Utility

Distinguishing GISTs from Other Tumors

• CD117 effectively differentiates GISTs from smooth muscle tumors (leiomyoma/leiomyosarcoma), schwannomas, and inflammatory myofibroblastic tumors, which are consistently CD117-negative 1, 2
• True leiomyomas (desmin and actin-positive) and schwannomas in both gastrointestinal and peripheral locations are consistently negative for CD117 2
• Solitary fibrous tumors and Kaposi's sarcomas, though typically CD34-positive, are consistently CD117-negative, providing clear diagnostic separation 2

Important Caveats

• CD117 is not entirely specific to GISTs; it can be expressed in mastocytoses, seminomas, adenoid cystic carcinomas, thymic carcinomas, and melanomas 3
• Approximately 9 of 25 metastatic melanomas and 7 of 15 clear cell sarcomas may show CD117 positivity 2
• However, these non-GIST tumors typically lack KIT gene mutations, making mutational analysis critical for therapeutic decision-making 3

Therapeutic Implications

Predictive Value for Targeted Therapy

• CD117 expression alone is insufficient to predict imatinib response; the presence of activating KIT mutations (found in 80-85% of GISTs) is required for sensitivity to tyrosine kinase inhibitors 4, 3
• Imatinib is FDA-approved for Kit (CD117) positive unresectable and/or metastatic GISTs, as well as adjuvant treatment following resection of Kit-positive GISTs 4
• Mutational analysis should be performed on all moderate or high-risk GISTs, specimens prior to neoadjuvant/adjuvant therapy, and all unresectable/metastatic cases to guide treatment selection 1

Mutation-Specific Treatment Considerations

• KIT exon 11 mutations (most common) respond to standard-dose imatinib (400mg) 1
• KIT exon 9 mutations may benefit from high-dose imatinib (800mg) 1
• PDGFRA p.D842V mutations are imatinib-resistant but may respond to avapritinib 1

Technical Considerations for Pathologists

Specimen Handling

• Samples should be fixed in 4% buffered formalin; Bouin fixative must be avoided as it prevents molecular analysis 1
• Immunohistochemistry should be performed without antigen retrieval, as this may result in false-positive CD117 staining 1
• Fresh snap-frozen tissue collection is encouraged for subsequent molecular assessments 1

Reporting Requirements

• The pathology report must include CD117 status along with tumor location, size, mitotic count (expressed as number of mitoses per 5 mm² total area), and margin status 1
• Mitotic count should replace the conventional 50 high-power field measurement to standardize reporting 1

Clinical Algorithm for CD117-Negative Cases

When encountering a suspected GIST with negative CD117 staining:

1. Perform DOG1 immunostaining immediately 1
2. If DOG1 is also negative, order KIT and PDGFRA mutational analysis 1
3. Refer complex cases to a reference sarcoma center with expertise in GIST diagnosis 1
4. Consider SDHB immunohistochemistry for KIT/PDGFRA wild-type GISTs, particularly in young patients with gastric location 1
5. Be aware that dedifferentiation can occur de novo or after chronic imatinib exposure, representing a diagnostic pitfall 1

Beyond GISTs: Other Clinical Contexts

• CD117 expression has been identified in approximately 75% of glial tumors, with higher expression in high-grade tumors like glioblastoma, though clinical utility for treatment selection remains investigational 5
• The marker is expressed in normal hematopoietic stem cells, mast cells, melanocytes, and interstitial cells of Cajal 3