Date of Award

2009

Document type

Thesis

Degree Name

MD (Medical Doctor)

First Supervisor

Professor Michael Walsh

Second Supervisor

Professor D Bouchier-Hayes

Third Supervisor

Dr Claire Condron

Keywords

Thyroid Neoplasms

Abstract

This body of work was conducted over a four year period. Within this timeframe we have conducted a National Epidemiology project, established a National Head and Neck Cancer database and completed Oncology laboratory investigations.

Anaplastic thyroid cancer (ATC) is the most aggressive endocrine disease in nature. Within the thyroid gland a heterogeneous group of neoplasms may develop. These can range from well differentiated tumours with an excellent prognosis, to ATC tumours which present with distant dissemination of disease in 20-50% of cases, adjacent tissue invasion in 90% of cases, have a reported tumour volume doubling time of one week, and place the patient at a very real risk of death attributed to upper airway obstruction and suffocation. The mean survival is approximately 3-7 months however the most important prognostic factor appears to be disease burden at the time of diagnosis. The high percentage of dissemination highlights the need for effective systemic chemotherapy and prompted a 'Lancet' editorial in 2005 to quote 'There is a pressing need for novel chemotherapeutic strategies in the treatment of anaplastic thyroid cancer'.

Thyroid cancer has undergone a seismic epidemiology shift in the last 30 years. The incidence of thyroid cancer has risen 2.4 fold over this period. In an Irish context we began our project by estimating the impact ATC has had on this country. Following acquisition of consent from twenty eight Irish consultants (whom the patients are tracked to, according to The National Cancer Registry, NCR) we analyzed the registry data, andpatients' charts to examine the epidemiology of ATC in Ireland between 1994 and 2004. Clinically relevant data regarding gender distribution, age, diagnosis, treatment and survival was considered.

A total of 51 cases were confirmed in this period representing 6.3% of all Thyroid cancers for this period. Males present earlier with mean age 66 years old, females at 72 years old. Analysis revealed a gender predominance of females (64.7%). Average survival was 3.8 months. 49% of patients never smoked however, the remainder who did presented a decade earlier. We report no statistical impact of any treatment option upon survival.

Further work is necessary on the NCR data uptake to improve the quality of clinically relevant information amenable for audit analysis. We then established the IHNOD project, Irish Head and Neck Oncology Database to receive oncology details from all head and neck cases presenting in the Republic of Ireland. This Database marks a commitment to improved audit evaluation of our patients which we believe will impact on administrative, medical and surgical aspects of care. The National database has been launched since January 08.

Our epidemiology results confirmed ATC is a fatal malignancy and suggest a higher prevalence of this disease in Ireland than international statistics. The gender imbalance may direct clinical and laboratory research towards an endocrine treatment approach. Armed with this information we started our laboratory investigations by performing immunohistochemical analysis of the Estrogen Receptor - 1, EGF-R1 and Her2lneu expression in ATC. This was examined retrospectively using archival tissue from eight patients who attended St Vincent's Hospital Dublin over a five year period from 1995 - 2005.

The Her2/neu, ER-1, and EGF-R1 expression was immunohistochemically detected on sections from formalin-fixed, paraffin-embedded tissues using monoclonal antibody staining with Trilogy antigen retrieval and The Vector Elite Detection system to visualise the antibody-antigen complex. Our controls were ER positive human breast tissue, HER positive human breast tissue and human placenta for erb-1. With confirmation of low Estrogen receptor expression we explored the non estrogenic role of the most successful chemotherapeutic agent in oncology, Tamoxifen.

We analysed the anti-proliferative effects of Tamoxifen using colorimetric dimethylthiazol- diphenyltetrazolium bromide (MTT), pro-apoptotic effects were observed using flow cytometry. Tumour metastatic potential was investigated with a Matrigel invasion assay with tamoxifen and chemotactic agents VEGF and EGF. Anaplastic thyroid tumour cells are acutely sensitive to Tamoxifen. It induces apoptosis, decreases proliferation and the metastatic potential of ATC through blockade of a VEGF dependent mechanism. Tamoxifen now merits a phase I clinical trial as part of a multimodal chemotherapeuticagent treating ATC.

We then investigated the anti-neoplastic properties of 17-Allylamino-17- demethoxygeldanamycin (1 7-AAG) on CAL-62 and BHT- 101 Anaplastic thyroid cell lines. The anti-proliferative effects were observed using colorimetric dimethyl-thiazoldiphenyltetrazolium bromide (MTT), and proapoptotic effects observed using flow cytometry (annexin V). Tumour metastatic potential was investigated with a Matrigel invasion assay with 17-AAG and chemotactic agents Epidermal Growth Factor and Vascular Endothelial Growth Factor. We found 17 AAG to be a potent chemotherapeutic agent. It induces apoptosis, decreases proliferation and reduces the metastatic potential of the tumour cell through blockade of a Vascular Endothelial Growth Factor and Epidermal Growth Factor dependent, dual kinase mechanism. Heat shock protein 90 inhibitor 17 AAG is a promising new alternative treatment for ATC.

ATC remains a devastating disease for these unfortunate patients and their families. The National Institutes of Health lists seven treatment trials currently recruiting. Clinical trials are paramount is this rare devastating disease and success will have significant implications for the treatment of many other cancers. Multidisciplinary care and combination therapeutic strategies are required. Progress has been made understandingthe cellular processes governing the mechanism of post malignant de-differentiation and the metastatic process. This has brought a variety of novel therapies of sufficient merit to conduct further phase trials. We believe this thesis offers fresh insight into all aspects of this disease which we hope, in part, may offer new clinical investigators a variety of options for oncology study.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 License.

File Size

7,658 KB

Comments

A thesis submitted for the Award of Doctor of Medicine (MD) to the Royal College of Surgeons in Ireland, 2009.

Share

COinS