Clinicopathologic assessment of postradiation sarcomas: KIT as a potential treatment target.
OBJECTIVE
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.


METHODS
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.
Komdeur
Rudy
R
Departments of Surgical Oncology, University Hospital Groningen, 9713 GZ Groningen, the Netherlands.
Hoekstra
Harald J
HJ
Molenaar
Willemina M
WM
Van Den Berg
Eva
E
Zwart
Nynke
N
Pras
Elisabeth
E
Plaza-Menacho
Iwan
I
Hofstra
Robert M W
RM
Van Der Graaf
Winette T A
WT
D000293:Adolescent; D000328:Adult; D000368:Aged; D004307:Dose-Response Relationship, Radiation; D005091:Exons; D005260:Female; D006394:Hemangiosarcoma / Q000201:enzymology; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009381:Neoplasms, Radiation-Induced / Q000175:diagnosis*; D011379:Prognosis; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D011878:Radiotherapy / Q000009:adverse effects; D012509:Sarcoma / Q000175:diagnosis* / Q000201:enzymology; D012983:Soft Tissue Neoplasms / Q000175:diagnosis* / Q000201:enzymology; D013997:Time Factors
D019009:Proto-Oncogene Proteins c-kit