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Clinicopathologic assessment of postradiation sarcomas: KIT as a potential treatment target
Rudy Komdeur1, Harald J Hoekstra, Willemina M Molenaar
1Departments of Surgical Oncology, University Hospital Groningen, 9713 GZ Groningen, the Netherlands.
Purpose:
Postradiation sarcoma, a sarcoma developing in a previously irradiated field, is a rare tumor. Surgery appears to be the only curative treatment option. In general the prognosis is poor, and new treatments options are needed. One study reported the expression of KIT receptor tyrosine kinase in two postradiation angiosarcomas. Success of inhibition of KIT in malignant gastrointestinal stromal tumors with imatinib mesylate seems mutation-dependent, with a favorable response in the presence of exon 11 mutations.
Experimental Design:
We performed a clinical, immunohistochemical, and genetic assessment of postradiation sarcomas, including angiosarcomas. Archival tumor tissue was available from 16 patients diagnosed with a postradiation sarcoma between 1978 and 2001. Data on the first and secondary tumor, treatment, and follow-up was documented. KIT expression was assessed by immunohistochemistry. For comparison, 23 spontaneous soft tissue sarcomas of similar histological types were analyzed. Exon 11 of the c-kit gene was analyzed by direct DNA sequencing.
Results:
Fifteen patients received initial irradiation for malignant disease and 1 patient for a benign condition. The median delivered dose was 50 Gy. The median latency period between irradiation and diagnosis of postradiation sarcomas was 222 months. Histological types included: angiosarcoma, fibrosarcoma, malignant fibrous histiocytoma, osteosarcoma, rhabdomyosarcoma, and unspecified sarcoma. In concordance with the literature, patients had a poor outcome. Only 3 of 16 patients were disease-free 43, 60, and 161 months after being diagnosed of postradiation sarcoma, all 3 having favorable tumor and treatment characteristics. Fourteen of 16 tumor samples were KIT-positive (88%). In 8 cases >80% of tumor cells stained positively. Five of 23 (22%) spontaneous soft tissue sarcomas of comparable histological types, including 2 angiosarcomas, were KIT-positive. Molecular genetic analysis of exon 11 of the c-kit gene was attainable for 13 of the 16 postradiation sarcomas. No mutations were found.
Conclusions:
Postradiation sarcomas are aggressive malignancies, seldom amenable to curative treatment. A majority of the analyzed tumors showed extensive expression of the KIT protein, but no mutations in exon 11 of the c-kit gene were found. Still, without the availability of effective therapies, treatment with the KIT inhibitor imatinib mesylate might be considered for patients with postradiation sarcomas.
Insights
Postradiation sarcomas show high KIT protein expression but lack exon 11 mutations. Treatment with imatinib mesylate may be considered for these aggressive tumors despite poor prognosis.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Postradiation sarcoma is a rare and aggressive malignancy with a poor prognosis.
- Current treatment options are limited, necessitating the exploration of novel therapeutic strategies.
- KIT receptor tyrosine kinase expression has been observed in some postradiation sarcomas.
Purpose of the Study:
- To assess KIT expression and c-kit gene mutations in postradiation sarcomas.
- To compare KIT expression in postradiation sarcomas with spontaneous soft tissue sarcomas.
- To evaluate the potential of KIT-targeted therapy for postradiation sarcomas.
Main Methods:
- Clinical, immunohistochemical, and genetic analysis of 16 postradiation sarcomas.
- Assessment of KIT protein expression using immunohistochemistry.
- Direct DNA sequencing of exon 11 of the c-kit gene.
- Comparison with 23 spontaneous soft tissue sarcomas.
Main Results:
- 88% of postradiation sarcomas (14/16) exhibited KIT protein expression, with 8 cases showing >80% positivity.
- Only 22% (5/23) of spontaneous soft tissue sarcomas were KIT-positive.
- No mutations in exon 11 of the c-kit gene were detected in 13 analyzed postradiation sarcomas.
- Most patients (13/16) had a poor outcome, with only 3 disease-free survivors.
Conclusions:
- Postradiation sarcomas frequently overexpress KIT protein but do not harbor c-kit exon 11 mutations.
- The high KIT expression suggests potential therapeutic targeting, despite the absence of common mutations.
- Imatinib mesylate, a KIT inhibitor, warrants consideration as a treatment option for postradiation sarcomas, given the lack of effective therapies.