July 2017 Case Cedars-Sinai Skip to content Close Select your preferred language English عربى 简体中文 繁體中文 فارسي עִברִית 日本語 한국어 Русский Español Tagalog English English عربى 简体中文 繁體中文 فارسي עִברִית 日本語 한국어 Русский Español Tagalog Translation is unavailable for Internet Explorer Cedars-Sinai Home 1-800-CEDARS-1 1-800-CEDARS-1 Close Find a Doctor Locations Programs & Services Health Library Patient & Visitors Community My CS-Link Education clear Go Close Academics Academics Faculty Development Community Engagement Calendar Research Research Areas Research Labs Departments & Institutes Find Clinical Trials Research Cores Research Administration Basic Science Research Clinical & Translational Research Center (CTRC) Technology & Innovations News & Breakthroughs Education Graduate Medical Education Continuing Medical Education Graduate School of Biomedical Sciences Professional Training Programs Medical Students Campus Life Office of the Dean Simulation Center Medical Library Program in the History of Medicine About Us All Education Programs Departments & Institutes Faculty Directory Anatomic and Clinical Pathology Residency Back to Anatomic and Clinical Pathology Residency Application Information Explore the Residency Training Curriculum Autopsy Pathology Rotation Bone and Soft Tissue Head and Neck Pathology Rotation Breast Pathology Rotation Cardiovascular Pathology Rotation Clinical Chemistry Rotation Coagulation Rotation Cytopathology Rotation Dermatopathology Rotation Forensic Pathology Rotation Frozen Section Rotation Gastrointestinal and Liver Pathology Genitourinary Pathology Rotation Genomic Pathology Rotation Gynecologic Pathology Rotation Hematopathology Rotation Laboratory Management Rotation Microbiology Rotation Neuropathology Rotation Pulmonary and Mediastinal Pathology Rotation Renal Pathology Rotation Transfusion Medicine Rotation Surgical Pathology Pathology Physician Scientist Training Program Residents Graduates Case of the Month Archive Publications Leadership Frequently Asked Questions July 2017 Case Authors Rob Bookstein, MD (Fellow), Mark Ewalt, MD (Molecular Pathology Attending), Wonwoo Shon, DO (Surgical Pathology Attending) Overall Subject Solid tumor profiling by NGS Clinical History A 70 year old man with a history of multiple back surgeries for spinal stenosis was found to have a right lower quadrant mass during follow-up CT scan. The outside imaging is not available, but reportedly showed a 9 x 8 x 7 cm circumscribed mass with features of a proteinaceous cyst, unrelated to appendix with no invasion of contiguous small bowel or colon. A CT-guided needle biopsy showed necrotic spindle cell tumor, and the patient underwent laparotomy for excision of the mass. Immunohistochemical Studies Study Test Clone Result DOG-1 (K9) Positive (tumor cells) Pancytokeratin (AE1/AE3) Negative (tumor cells) Actin, smooth muscle (Alpha am-1) Negative (tumor cells) Desmin (DE-R-11) Negative (tumor cells) S100 Polyclonal Negative (tumor cells) CD117 [C-Kit] QL Positive (tumor cells) ETS Transcription Regulator (EPR3864) Negative (tumor cells) ALK-1 Protein (5A4) Negative (tumor cells) Molecular Studies KIT gene sequencing (Mayo Laboratories) - test not performed due to lack of viable tumor CS-Focus GIST Panel by NGS (Cedars-Sinai PLM) - following macrodissection of small viable tumor area Diagnosis Predominantly necrotic spindle cell neoplasm, consistent with subtotally necrotic gastrointestinal stromal tumor (GIST). 7.3 x 6.3 x 5.8 cm >5 mitoses per high power field Tumor present at specimen surface KIT V559A variant (allele fraction 14.8%) detected by CS-Focus GIST Panel Discussion GISTs apparently originating outside of the gastrointestinal tract are often referred to as EGISTs. These are histologically and immunophenotypically similar to their gastrointestinal tract counterparts, however the clinical course is more aggressive. This case has high recurrence risk features including location, necrosis, mitotic rate, and tumor at margin. Activating mutations of the c-KIT gene (KIT or CD117) are found in about 85% of GISTs (https://www.mycancergenome.org/content/disease/gist/kit/, Maki, R., V. Keedy. 2014. KIT in GIST. My Cancer Genome). KIT p.V559A (valine to alanine substitution at codon 559, encoded by c.1676T>C thymine to cytosine substitution at mRNA nucleotide position 1676) is a recurrent variant in malignant melanoma and GIST (COSM1255 and COSM12453, COSMIC database accessed June 2017). As with oncogenic "gain-of-function" variants of other receptor tyrosine kinases, mutations of GIST tend to cluster in certain protein domains where they perturb the receptor into a constitutively active state. For GIST, relevant domains are encoded by exons 9 (extracellular dimerization), 11 (juxtamembrane), 13 (kinase 1) and 17 (kinase 2). Some mutational diversity comprising missense (amino acid substitution) and short in-frame amino acid insertions or deletions is observed. Common recurrent variants are associated with more preclinical and clinical information than rare or novel variants; however, those in each domain/exon are usually observed to have common properties with respect to therapy prediction. In particular, exon 11 variants like V559A, which are most common in GIST relative to variants in other exons, confer a better response (by RR, PFS, OS) to first-line imatinib (Gleevec) therapy, but a worse response to sunitinib, than GISTs with other exonic variants. Also like other receptor tyrosine kinases, targeted anti-KIT therapies may induce secondary resistance mutations; in GIST, these occur primarily in exons 13, 14, 17, and 18. Resistance to imatinib may be managed by changing to other second or third generation tyrosine kinase inhibitors (TKIs) such as regorafinib, sorafenib, ponitinib, or nilotinib, optimally via clinical trials. The 15% of GISTs with wild-type KIT may instead have variants in PDGFRA, BRAF or SDH (succinate dehydrogenase), in decreasing order of frequency. Cases with mutations in BRAF or SDH will require other drug treatment strategies due to the lack of the correct molecular target for TKIs. In summary, the molecular finding of KIT V559A despite extensive necrosis is consistent with the IHC studies and the pathologic diagnosis of GIST, provides valuable prognostic and predictive information, and supports a therapeutic rationale for instituting adjuvant imatinib therapy for this patient, which is currently underway. References 1. Heinrich MC et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003 Dec 1;21(23):4342-9. 2. Debiec-Rychter M et al. Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumours entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer. 2004 Mar;40(5):689-95. 3. Heinrich MC et al. Correlation of kinase genotype and clinical outcome in the North American Intergroup Phase III Trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group. J Clin Oncol. 2008 Nov 20;26(33):5360-7. doi: 10.1200/JCO.2008.17.4284. Epub 2008 Oct 27. 4. Rutkowski P et al. The outcome and predictive factors of sunitinib therapy in advanced gastrointestinal stromal tumors (GIST) after imatinib failure - one institution study. BMC Cancer. 2012 Mar 22;12:107. doi: 10.1186/1471-2407-12-107. 5. Blanke CD et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol. 2008 Feb 1;26(4):626-32. doi: 10.1200/JCO.2007.13.4452. 6. Demetri GD et al. NCCN Task Force report: update on the management of patients with gastrointestinal stromal tumors. J Natl Compr Canc Netw. 2010 Apr;8 Suppl 2:S1-41; quiz S42-4. Have Questions or Need Help If you have questions or would like to learn more about the Anatomic and Clinical Pathology Residency Program at Cedars-Sinai, please call or send a message to Academic Program Coordinator, LeeTanya Marion-Murray. Department of Pathology and Laboratory Medicine 8700 Beverly Blvd., Room 8709 Los Angeles, CA 90048-1804 310-423-6941 send a message Please ensure Javascript is enabled for purposes of website accessibility