Clinical and molecuar studies of papillary thyroid carcinoma : with an emphasis on prognostic factors

Abstract

Thyroid cancer accounts for approximately 1% of all cancers reported. In Sweden 45/100, 000 inhabitants annually present with thyroid carcinoma. There are four different variants of thyroid carcinoma: papillary thyroid carcinoma (PTC), follicular thyroid carcinoma, medullary thyroid carcinoma and anaplastic thyroid carcinoma. PTC comprises 60-80% of thyroid cancers. The PTC prognosis is usually excellent with a long-term survival rate exceeding 90%. However, some patients develop distant metastases or die from the disease, and these are classified as having aggressive PTC. With the aim to predict the prognosis at the time for surgery, several prognostic factors have been established. Still, the natural course of the disease cannot always be predicted from the initial clinical presentation. Hence, there is a need for additional markers for the identification of patients who are at risk of developing aggressive PTC.

To evaluate associations between clinical and histopathological features and the patients' outcome, 220 patients who underwent surgery for PTC at the Karolinska University Hospital, Solna between 1980 -1999 were reviewed retrospectively. Of these, 19 patients (9%) developed aggressive PTC. Due to invasive tumor growth radical surgery could not be performed in 58% of these patients as compared to in 2% of the patients with non-aggressive PTC. Non-radical surgery proved the most powerful predictor for development of aggressive PTC. The reported excellent prognosis for patients < 45 years of age could not be confirmed; three of the patients who eventually died from PTC were below the age of 45 (Paper I).

The antibody MlIB-1 detects the Ki-67 antigen in proliferating cells. To investigate if assessment of the percentage of MIB-1 positive cells (MIB-1 index) can add prognostic information in PTC, MIB-1 immunoreactivity was analyzed in 30 PTCs. Thirteen patients were classified as having aggressive PTC, and tumors from these patients had a significantly higher MIB-1 index (median 5.4%) as compared to those from patients with non-aggressive PTC (median 1.1%). MIB-1 index >= 1.85% was found to be an independently significant risk factor for aggressive PTC (Paper II).

The RET proto-oncogene encodes a receptor tyrosine kinase normally not expressed in thyroid follicular cells. RET can be activated through rearrangements, generating the fusion oncogene RET/PTC. Today several variants have been described, but their association to clinical outcome is debated. To search for expression of RET or the oncogenes RET/PTC1 -4, 61 PTCs were analyzed using RT-PCR. RET-TK expression was detected in 48%. This proved to be due to a RET/PTC rearrangement in three cases only, and expression of wild-type RET in 12 cases. The remaining 14 tumors expressed RET-TK only, indicating presence of yet unidentified rearrangements. Expression of wild-type RET was detected significantly more often in aggressive PTCs and in poorly differentiated PTCs (Paper III).

In an attempt to identify chromosomal regions harboring potential oncogenes and tumor suppressor genes involved in PTC initiation and progression, 25 PTCs were screened for chromosomal imbalances using comparative genomic hybridization (CGH). Gain of 9q was the most common change, detected in close to 30% of the tumors. The total number of alterations was higher in tumors from patients with aggressive PTC. Gain of 1q and loss of 9q were exclusively seen in tumors from patients with aggressive disease, suggesting the location of genes important for PTC progression in these regions (Paper IV).

In summary, complete removal of all tumor cells appears to be most important and postoperative I131 treatment probably cannot compensate for an incomplete tumor resection. MIB-1 index is a valuable prognostic marker, which can add prognostic information to established prognostic parameters. RET/PTC1-4 oncogenes are rare in Swedish tumors, suggesting other mechanisms involved in PTC development. Still, expression of RET-TK may be of prognostic importance, and may point towards new treatment modalities. Although PTC is generally a genetically stable tumor, aggressive PTC tumors exhibit signs of chromosomal instability. At least three chromosomal regions have been defined as potential locations for tumor suppressor genes or oncogenes involved in PTC. Gain of 9q may be an early event, while loss of 1q and 9q may be involved in progression toward aggressive variants of PTC.