THE VALUE OF MEASUREMENT OF RAS ONCOGENES AND NUCLEAR-DNA ANALYSIS IN THE DIAGNOSIS OF HURTHLE CELL TUMORS OF THE THYROID

Hurthle cell tumors (HCT) remain difficult to treat because some which appear non-malignant on light microscopy later metastasize. In order to improve diagnostic accuracy, the value of ras mutations and nuclear DNA analysis was determined in 65 patients with HCT. Rapid nuclear DNA cytometry (MicroTICAS system) was performed. Mutations of H-ras, K-ras, and N-ras genes were analyzed by oligonucleotide probe hybridizations to polymerase chain reaction (PCR) amplified DNA. HCT were classified by light microscopy as benign (n = 22), intermediate (n = 30), and malignant (n = 13). After a mean follow-up of 7 years, 1 (4.5%) of 22 benign tumors and 4 (13%) of 30 intermediate tumors had metastasized, leading to tumor death in 3 of these 5 patients. Six of the 13 cancers diagnosed by light microscopy also resulted in tumor-related deaths. Aneuploidy was found in 83% of all Hurthle cell cancers, including 3 (60%) of the 5 cancers not diagnosed microscopically. However, 49% of non-malignant HCT also demonstrated aneuploidy. A nuclear area of less than 55 square microns was found in 83% of all Hurthle cell cancers and in 100% of those cancers not diagnosed by light microscopy. However, 47% of non-malignant HCT also demonstrated a "small" nuclear area. Aneuploidy correctly identified 8 of 9 cancers that resulted in tumor death and each of 3 other tumors that developed metastases. However, 1 patient with a diploid tumor died of metastatic cancer. A nuclear area of less than 55 square microns identified each cancer that resulted in a tumor death. Ras mutations were found in 9 (14%) of 65 Hurthle cell tumors. Only N-ras mutations were found, and 8 of 9 were N-ras, codon 61. Twenty-two percent of Hurthle cell cancers and 11% of non-malignant HCT exhibited ras mutations (p = N.S.) Ras mutations were found in 2 (40%) of 5 cancers which were not recognized microscopically. Of 4 cancers which exhibited ras mutations, 2 (50%) resulted in tumor death. Of 14 cancers that were ras negative, 7 (50%) resulted in death from tumor. We conclude that nuclear DNA cytometric studies are not useful in separating bening from malignant Hurthle cell neoplasms. However, aneuploidy and a nuclear area less than 55 square microns clearly demonstrate those cancers that are likely to act in an aggressive manner and result in tumor death. It should be noted, however, that one patient with a diploid cancer died of metastatic Hurthle cell cancer. Finally, the presence of ras mutations has limited usefulness as a prognostic factor.