Assessment of Cardiac Myxoma Tumour Markers and Development of a Calretinin Grading System.

Indra A. J Nordstrand (2010). Assessment of Cardiac Myxoma Tumour Markers and Development of a Calretinin Grading System. MPhil Thesis, School of Medicine, The University of Queensland.

       
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Author Indra A. J Nordstrand
Thesis Title Assessment of Cardiac Myxoma Tumour Markers and Development of a Calretinin Grading System.
School, Centre or Institute School of Medicine
Institution The University of Queensland
Publication date 2010-02
Thesis type MPhil Thesis
Supervisor A/Prof. Philip J Walker
Mr. E Gregory Stafford
Dr. Belinda Clarke
Total pages 258
Total colour pages 54
Total black and white pages 204
Subjects 11 Medical and Health Sciences
Abstract/Summary Abstract _____________________________________________________________________ INTRODUCTION Cardiac myxomas represent the most common primary tumour of the heart with a propensity to produce significant morbidity and mortality related to their morphological features and clinical profiles (Terracciano et al 2000; Acebo et al 20011; Shapiro 2001; Keeling et al 2002; Val-Bernal et al 2003). Correct and early diagnosis impacts on outcome by ensuring referral to a tertiary cardiothoracic surgical centre for definitive management – that is, tumour excision (Pinede et al 2001). Embolism is an important subgroup of clinical profiles associated with this tumour. Despite the devastating nature of this presentation, diagnosis is often delayed with an absence of cardiac features pointing toward a cardiac source (Álvarez-Sabín et al 2001). Being able to direct investigation may influence outcome. Whilst the majority of embolic events are to the head, a proportion affects the peripheral circulation (eg. limbs). All material retrieved through embolectomy should be examined histologically for possible tumour embolisation (Hashimoto et al 1999; Shapiro 2001; Val-Bernal et al 2003). Immunohistochemistry (IHC) has transformed the practice of histopathology; informative in diagnosing surgical pathology (Muro-Cacho 1998; Werner et al 2000; Rüdiger et al 2002). Previous IHC analysis of cardiac myxomas has been of little use due to inconsistent results (Burke and Virmani 1996; Basso et al 1998; Chopra et al 1999; Pucci et al 2000; Terracciano et al 2000; Val-Bernal et al 2003). Calretinin (Cal) is a consistent marker identified for cardiac myxomas (Terracciano et al 2000; Acebo et al 20011) with a recognised need for extended validation (Acebo et al 20011). Immunohistochemistry with Cal could provide definitive diagnosis of cardiac myxoma in terms of primary disease and metastatic deposits. This research represents the largest experience investigating Cal IHC in the world. It will attempt to verify previous European studies (Terracciano et al 2000; Acebo et al 20011) and report if such a relation does exist. It also represents the first such examination to be performed outside of large European and American clinical centres. Unlike previous studies, this research also aims to establish a recommendation for routine IHC analysis with Cal of all retrieved embolectomy tissue and excised intracardiac tumour tissue. To assist introduction into the pathology community, a semi-structured grading system for Cal IHC will be developed. Surface thrombus on cardiac myxomas is a feature directly related to embolic clinical profile (Basso et al 1997; Robbin et al 1997; Fernandes et al 2001; Kamiya et al 2001). Currently, the use of antithrombotics in patients with cardiac myxoma is empiric but recommended in high-risk cases. However, routine use of antithrombotics has an identifiable bleeding risk. Therefore, it would be advantageous to target antithrombotic therapy to those who would best benefit while avoiding it in those at low-risk of thromboembolic complications. Thrombomodulin (TM) is an anticoagulant whose expression has been identified on cardiac myxoma surface cells and an active role in protection against thrombus formation has been suggested (Weiler-Guettler et al 1998; Acebo et al 20011; Ashkenas 2001; Isermann et al 2001). This research aims to investigate the thromboprotective role of TM expression in relation to macroscopic surface thrombus or thromboembolic sequelae in patients with cardiac myxoma. It will also be the second series in the world to examine the relation between TM and cardiac myxomas. The hypotheses of this Master of Philosophy research are: 1. That the clinical experience with cardiac myxoma (presentation, management and outcomes) at The Prince Charles Hospital will be comparable to worldwide experience. 2. That a semi-structured grading system for Calretinin IHC in the diagnosis of cardiac myxoma can be developed. 3. That Calretinin is a consistent tissue marker for cardiac myxoma and thus should be recommended for routine immunohistochemical staining to accurately diagnose or exclude this tumour. 4. That Thrombomodulin expression will vary in cardiac myxomas and that: (i) high expression of Thrombomodulin correlates with an absence of macroscopic surface thrombus and low rate of thromboembolic complications (ii) low expression of Thrombomodulin correlates with macroscopic surface thrombus and a higher rate of thromboembolic sequelae. 5. That antithrombotic agents should be prescribed in all patients with cardiac myxoma regardless of presenting features because of the morphological nature of the tumour but especially in those presenting with embolic clinical features of cardiac myxoma or familial disease. The aims of this Master of Philosophy degree are: 1. To retrospectively review the experience with cardiac myxomas at The Prince Charles Hospital assessing clinical presentation and management for comparison with worldwide experience. 2. To develop a semi-structured grading system for examining Calretinin immunohistochemical marking that demonstrates validity and reproducibility of results for introduction into the pathology community. 3. To examine the consistency of Calretinin as a tissue marker in cardiac myxoma and the potential role for routine Calretinin immunohistochemical staining of all excised intracardiac tumour and retrieved embolectomy tissue to accurately confirm or exclude the diagnosis. 4. To identify if Thrombomodulin expression relates to clinicopathological thrombus (cases with documented macroscopic surface thrombus or thromboembolic sequelae) in patients with cardiac myxoma by examining Thrombomodulin expression on cardiac myxoma surface. 5. To examine the use of antithrombotic agents in patients with cardiac myxoma and make a recommendation for their use by examining Thrombomodulin expression on cardiac myxoma surface in relation to the clinical and pathological features of the tumour. METHODOLOGY Subjects with a coded diagnosis of cardiac myxoma, having undergone surgical excision, were identified from The Prince Charles Hospital (TPCH) Cardiac Surgery Research Database (CSRDB) over a 12-year period (January 1992 – December 2003). Appropriate approval from the Cardiac Surgery Research Office Chairman, TPCH Human Research Ethics Committee (HREC) and The University of Queensland HREC was sought and obtained. The medical record of each subject was examined. Patient demographics, clinical presentation, associated cardiac conditions, specific tumour data, echocardiographic and histopathological findings were recorded in addition to surgical technique, follow-up surveillance and use of antithrombotic agents. Detailed analysis of the patients was compared with experience and management worldwide with a specific focus on embolic cases and use of antithrombotic agents both in short and long-term management. Archived cardiac myxoma tissue specimens were retrieved from TPCH Department of Anatomical Pathology for review. Specimens were re-cut in triplicate for immunohistochemical (IHC) analysis. Positive and negative controls were used. Immunoreactivity of the tumours was specifically tested for Cal and TM. RESULTS Thirty patients with a diagnosis of cardiac myxoma were retrieved from TPCH CSRDB, comprising a female:male ratio 2.8:1 with the majority 96.7% adult (≥16-years-of-age). Sporadic disease accounted for 76.7%, nearly six-times more frequent than familial cases at 13.3%; another 10% represented cases suspicious for familial development. A total of 33 tumours were present in the cohort giving an annual incidence of 2.5 cases/year. Preoperative echocardiography was diagnostic in 79.3% with 90% of cardiac myxomas identified as solitary tumours in a single chamber (93.3%) (location ratio LA:RA:biatrial of 13:1:2); synchronous disease (>1 myxoma/patient) was seen in 10%. Intraoperative diagnosis was made in 20.7% of cases. The average time interval from symptom development to diagnosis was 6.4-months with a triad of clinical symptoms: intracardiac obstructive in 72.4%, embolic in 44.8% and constitutional in 34.5%; 18.6% of patients experienced more than one symptom type. Of the embolic subgroup, central embolism occurred more frequently than peripheral embolism with a ratio 2.7:1. With an interval from diagnosis to surgical intervention of 0.9-months, surgical excision of myxoma was performed in all cases with biatrial access employed in 90% either through a right atriotomy, accessing the LA transeptally (quasi-biatrial), or a combination of separate right and left atriotomies (biatrial). An associated cardiac surgical procedure was performed at myxoma operation in 33.3%. Thirty-day postoperative survival was 96.7% with one early death; a second late death occurred at >30-days postoperatively giving an overall cohort survival of 93.3%. Patient follow-up averaged 25 months with 67.9% recommended yearly TTE for life. Tumour recurrence occurred in 3.6% of subjects. In the immediate postoperative period, prophylactic oral anticoagulation was used in 82.8%; the majority 55.2% prescribed aspirin versus 34.5% Warfarin®. Patients discharged home on aspirin were advised lifelong antiplatelet therapy in 61.5%. Patients discharged home on Warfarin® were advised lifelong anticoagulation therapy in 20%. The overall use of antithrombotic agents in cases of embolic clinical presentation of cardiac myxoma was seen in 92.3%. At hospital discharge, 53.8% of the embolic subgroup were taking aspirin and at follow-up, a majority 61.5% from this clinical subset were taking an antithrombotic agent for life versus no prophylaxis in the remaining 38.5%. The major findings from this study, in relation to each aim and hypothesis, were: AIM / HYPOTHESIS 1 • age of patients at diagnosis was significantly younger for familial cardiac myxomas compared with sporadic ones p=0.04 • TTE sensitivity 94%, specificity 21% • TOE lower sensitivity and specificity but positive predictive value 81% • tumours detected by TTE significantly larger than those detected by TOE p<0.0005 • tumour prolapse correlated to the presence of a pedunculated stalk p<0.005 • tumour prolapse correlated to tumour mobility p<0.005 • tumour prolapse did not cause left ventricular outflow obstruction p=0.008 • interval from diagnosis to surgical intervention was shorter than the interval from development of symptoms to diagnosis p<0.05 • embolism relates to gelatinous myxoma feature p=0.06 • embolism relates to pedunculation myxoma feature p=0.02 Non-statistically significant results were found for: 1) relationship between tumour pedunculation and prolapse in tumours with an embolic profile; 2) diagnosis earlier in patients with embolism than non-embolism; 3) advice for life-long aspirin and presence of embolic profiles; 4) embolism relates to friable myxoma feature; 5) embolism relates to fragmentation myxoma feature; 6) embolism relates to prolapse myxoma feature; 7) embolism relates to villous myxoma feature; and 8) embolism relates to surface thrombus myxoma feature. AIM / HYPOTHESIS 2 & 3 • Cal staining sensitivity in cardiac myxomas 96.4% • Cal staining specificity in cardiac myxomas 83.3% • Cal staining is consistent for grade-3 readings p=0.01 • Cal staining is consistent for grade-1 readings p<0.05 • Cal staining is consistent for grade-0 readings p<0.05 • positive Cal staining correlates to cardiac myxoma diagnosis p=0.00012 The use of Cal staining to assist confirmation or exclusion of the diagnosis of cardiac myxoma was demonstrated in this study using a semi-structured grading system specifically designed for this study. Staining for Cal was positive in 93.3% of cardiac myxoma cases. The average frequency of grading was 57% for grade-3, 25% for grade-2, 14% for grade-1 and 4% for grade-0 across five readings. Examination of the Cal slides on five separate occasions assessed the quality of the IHC method and reader-reliability. A non-statistically significant result was found for Cal staining being consistent for grade-2 readings. The second hypothesis of developing a semi-structured grading system for examining Cal IHC in cardiac myxomas was supported by these findings. The semi-structured grading system for Cal demonstrated a high positive Pearson r at greater than 0.80 when comparing each reading with each reader; a perfect linear relationship evidenced on seven occasions. A low instrument error and solid test-retest reliability were demonstrated by a high Pearson r but non-significant difference of paired t-test at the various reading times. Cal staining for cardiac myxomas was highly sensitive being positive when myxoma is present. It was also specific being negative when myxoma is not present. The results were associated with a low false negative and low false positive rate. The high positive predictive value result for Cal staining (96.4%) is high enough for the presence of Cal staining to diagnose cardiac myxoma, supporting its use in diagnostic and management decision making. The strong negative predictive value (83.3%) for Cal staining is also high enough for the absence of Cal staining to exclude a diagnosis of cardiac myxoma. These results overall support the third hypothesis with implementation of Cal IHC into pathology practice. AIM / HYPOTHESIS 4 & 5 A distinct pattern of TM immunostaining was demonstrated in the myxoma specimens. Overall, TM expression was present in 85.7% of cardiac myxomas with tumour stromal cell TM expression demonstrated in 78.6%, and tumour perivascular cell expression in 75%. Surface TM expression was identified in 85.7% of tumours and 71.4% demonstrated tumour cell extension to tumour surface. Through repeated readings, results correlated (p=0.01) to prove interobserver reliability. The importance of TM expression raised in this study relates to the immunostain’s use in providing a diagnostic link for clinicopathological thrombosis (CPT) in patients with cardiac myxoma and the long-term use of antithrombotic agents in the management of cardiac myxomas with recommendations for targeting antithrombotic therapy. However, no statistically significant relation between TM expression and CPT was established. Thrombomodulin expression (surface and tumour cell) was not statistically found to be thromboprotective against clinicopathological thrombosis despite being identified in 62.1% of the cohort. Whilst TM expression did vary in the study cohort, TM expression was more associated with the presence of CPT than the absence; not supporting the fourth hypothesis. No statistically significant relationship between TM expression and low antithrombotic use nor absence of CPT and low antithrombotic use was identified in this study. The majority of antithrombotic agents were prescribed to subjects with TM expression and without evidence of CPT. The fifth hypothesis that patients with high TM expression and low incidence of CPT need less antithrombotic agents was not demonstrated. Overall, no conclusions about the importance of TM expression, CPT and long-term antithrombotic therapy can be drawn. DISCUSSION The findings from this Master of Philosophy research have the potential to impact on the clinical management of cardiac myxomas by pathologists, cardiologists, cardiac surgeons and vascular surgeons. It is the first study in Australia to examine the management of cardiac myxomas in a predominantly adult population at one of the largest cardiothoracic centres in the country, subsequent to the impact of echocardiography in the 1970s on diagnosis. It is the first study performed outside of European and American centres examining the role of IHC in the diagnosis of these tumours. It contains the largest number of cardiac myxomas from a single-unit cohort – that is, 33 tumours in a 30-patient cohort. The importance of such research being carried out in a specialised cardiothoracic, centre such as TPCH is also evident by the fact that more subjects were collected over a shorter period of time than the largest of the European studies – that is, 30 patients over 12-years (incidence of 2.5 cases/year) in this study versus 23 patients over 27-years (incidence of 0.9 cases/year) (Acebo et al 20011). The information contained is unique and educative to cardiac surgery and IHC practice in Australia. Detailed analysis of the patients with this diagnosis is comparable and on par with experience and management worldwide. A semi-structured grading system for Calretinin IHC was successfully developed with consistency, reliability (high interobserver, low instrument error and solid test-retest), validity (content and construct), sensitivity and specificity with high predictive values with the designed semi-structured grading system for Cal. The use of Cal staining to assist confirmation or exclusion of the diagnosis of cardiac myxoma has been demonstrated in this study. Introduction into the pathology community of Cal as a diagnostic tissue marker test should be implemented. The thromboprotective role of TM expression for prevention of surface thrombus in cardiac myxomas has not been demonstrated in this study. The naturally low incidence of cardiac myxoma in the general population would require a much larger number of cases than in this study to be examined for statistical significance to be approached. However, as a secondary benefit, TM expression may aid in confirming cardiac myxoma diagnosis with its distinct pattern of staining despite the immunostain having no significant use as a specific tumour marker in myxomas. RECOMMENDATIONS The results from this study support a recommendation that Cal IHC be performed on all excised intracardiac masses and all retrieved embolectomy tissue. The finding of Cal positive tissue would confirm the diagnosis (provisional or otherwise) in the case of intracardiac mass, and expedite clinical examination for a cardiac myxoma in the case of peripheral embolisation presenting as acute limb ischaemia. In addition, the results support a recommendation that Cal IHC would contribute to more accurate tissue diagnosis in the pathology laboratory as these are rare tumours and individual pathologists will have limited experience in their diagnosis. Benefit also exists in situations where excised intracardiac masses have macroscopically similar appearances. To assist in the implementation of these recommendations, is the introduction into the pathology community of the semi-structured grading system for Cal IHC that was designed and tested in this study. The results from this study demonstrated its consistency, reliability, validity, sensitivity and specificity with high predictive values – all in support of this proposal. This study supports a recommendation that antithrombotic agents should be prescribed for life in all patients presenting with embolic clinical features of cardiac myxoma or familial disease. The antiplatelet agent aspirin would be sufficient. In addition, this study supports a recommendation that antithrombotics should be considered in all patients with cardiac myxoma regardless of presenting features because of the morphological nature of the tumour. These immunohistochemistry and antithrombotic therapy recommendations could impact significantly on the postoperative clinical management of these tumours by cardiologists, cardiac surgeons, vascular surgeons and pathologists. LIMITATIONS The limitations of this study include: 1) retrospective design – reliance on previously collected data allows for variable recording of information and human error in information transfer; 2) cardiac myxoma topic – the uncommon diagnosis means small subject numbers and requires the research to be carried out in a specialised cardiothoracic centre to enhance capture of a continuous patient pool; 3) small and specific subject number – increases the probability of type II errors in the statistical analysis, analogous to a false-negative result but makes calculation of study power difficult; 4) retrospective tissue analysis – potential affect on stored tissue cellularity and antigen avidity for IHC markers in addition to the need for heat-induced epitope-retrieval prior to staining which may reduce epitope concentration after long-periods of storage. AREAS OF FUTURE RESEARCH Future expansion of this study would need prospective design and multicentre involvement. Prospective data collection would reduce the first limitation of variable recording of information in reviewing clinical presentation and management of cardiac myxomas within a cardiothoracic unit and across multiple units. It would also allow for pre-selection of the datasets so that the same information was collected on all subjects. Multicentre involvement would be important to increase subject numbers at a national and international level, incorporating cardiothoracic surgery for cardiac myxoma results and vascular surgery for peripheral embolectomy results. At a national level, a cardiac myxoma registry could be readily established permitting monitoring of tumour development, familial cases as well as obtaining accurate tumour incidence. Employment of the semi-structured grading system for examining Cal immunohistochemistry developed in this study would also allow multicentre data to be collected. The primary centres would be those with cardiothoracic and vascular surgical services, secondary centres those with vascular surgery alone. Using Cal IHC and the grading system to examine all excised intracardiac masses and embolectomy tissue would further test this IHC marker’s consistency on more tissue specimens and the system’s reliability. Increased patient numbers would also support Cal‘s routine use in IHC to confirm or exclude the diagnosis of cardiac myxoma. As a consistent tissue marker in cardiac myxomas, Cal may also be helpful in differentiating the glandular-type of cardiac myxoma as a primary intracardiac tumour from other tumours representing secondary deposits, especially those sharing glandular components (eg. adenocarcinomas). Previous work has not identified IHC markers to enable tissue differentiation (Lindner et al 1999). The potential immunoreactivity of Cal in this sub-group of tumours would require further investigation in a future study. Cal also has a potential role in serum monitoring in cases of cardiac myxoma. A future area of research would be developing a serum assay for Cal. With the establishment of levels of significance, instances of recurrence may be able to be detected before the tumour is of a size large enough for visualisation by echocardiography or of a size large enough to produce clinical symptoms; this would surely impact on patient care. An area that might also warrant further investigation is the relationship between Cal expression by myxomas and development of surface thrombus. As a calcium-binding protein, Cal is thought to be involved in the cellular transport of calcium (Terracciano et al 2000; Val-Bernal et al 2003). Perhaps its dominant expression on these tumours predisposes or is involved in the development of surface thrombus by aiding the coagulation cascade. To identifying if TM expression relates to clinicopathological thrombus and use of antithrombotic agents in cardiac myxoma patients, a future study would again need prospective design and randomisation of antithrombotic therapy to attempt to measure the impact of antithrombotic agents on thrombosis and its relation to TM expression. Multicentre (national and international) cardiothoracic surgery participation would increase capture of cases. Secondarily, TM may also aid in confirming cardiac myxoma diagnosis, with its distinct pattern of staining, despite having no significant use as a specific tumour marker in myxomas; another focus of IHC future study. Intra-arterial thrombolysis in patients with embolic features of cardiac myxoma may offer an option in cases of brain ischaemia / infarction related to this diagnosis. Cases that may be responsive include those with cerebral vessel occlusion by composite tumour and thrombus, surface thrombus or thrombus as a consequence of tumour blockage (Bekavac et al 1997). Whilst only trialled in a single case study (Bekavac et al 1997), further investigation may be warranted. Finally, a future expansion on this study could include tumour gene analysis. With evidence for familial cases linked to an autosomal dominant pattern of inheritance (Shinfeld et al 1998; Chopra et al 1999; Schoen 1999; Morton-Bours et al 2000; Kamiya et al 2001; Vohra et al 2002), a link could positively contribute to myxoma screening in familial cases and definitive identification of familial lineage of disease. Echocardiographic monitoring of these patients and their first-degree relatives would also be more directed. It would also alert the clinician to the potential of these patients having Carney Complex / Carney Syndrome – extracardiac manifestations of cardiac myxoma. CONCLUSIONS This is the first detailed study of cardiac myxomas in a predominantly adult population to be performed at The Prince Charles Hospital (TPCH) and the first detailed study of cardiac myxomas in Australia, with a large single-unit cohort (33 tumours in 30 patients). It is also the first study examining the role of IHC in the diagnosis cardiac myxomas using Cal and TM IHC to be performed outside of large European and American clinical centres. A retrospectively review of the experience with cardiac myxomas at The Prince Charles Hospital was performed assessing clinical presentation and management of cases. This was compared with worldwide experience and found to be on par. Therefore, from the results of this study, the first aim and hypothesis of this Master of Philosophy research has been supported. A semi-structured grading system for examining Cal IHC marking was designed specifically for this study in the absence of any other objective measures in the literature. Four grades (0 to 3) of immunohistochemical staining intensity were determined by microscopic examination. Multiple examinations of the Cal stained cardiac myxoma slides were made. Overall, the semi-structured grading system demonstrated: 1) consistency – the higher the staining grade, the more consistent and less variable were the readings so that at grade-2 and grade-3 there was only an 11% variation across the readings; 2) reliability – Cal-grades recorded at one reading were statistically similar to the grades at another reading (p=0.01) with Pearson r ≥0.80 on all comparisons; 3) validity – the Cal grading is an objective measure for assessing cardiac myxoma tumour markers with published evidence relating Cal to cardiac myxomas; 4) high sensitivity at 96.4% and specificity at 83.3% with a high predictive value of 96.4%. Therefore, from the results of this study, the second aim and hypothesis of this Master of Philosophy research has been supported; the purpose-designed semi-structured grading system for Cal IHC has validity, reliability, repeatability and the characteristics of a diagnostic test such that it could be introduced into the pathology community to guide clinical decision making. The consistency of Cal as a tissue marker in cardiac myxoma was examined. Positive Cal staining was evidenced in 93.3% of the cardiac myxoma specimens in this study. As mentioned above, the high sensitivity and specificity, coupled with a low false negative rate (3.6%) and false positive rate (16.7%), indicates Cal IHC is positive when cardiac myxoma is present and negative when cardiac myxoma is not. The high positive predictive value calculated in this study (96.4%) also supports a diagnosis of cardiac myxoma when Cal IHC is positive. The negative predictive value (83.3%) is sufficiently high enough for an absence of Cal staining to exclude a diagnosis of cardiac myxoma. Therefore, this research has confirmed in a larger cohort than previously published studies, that Cal IHC is a consistent tissue marker in cardiac myxoma and would be able to assist with the diagnosis of cardiac myxoma. Given this consistency, benefit exists in its implementation into pathological practice for all excised intracardiac tumour and retrieved embolectomy tissue; benefit to accurately diagnose rare tissue with which pathology experience may be limited outside of major cardiothoracic centres and where excised intracardiac masses or embolectomy material may have macroscopically similar appearances. A recommendation for examining all retrieved embolectomy tissue in cases of cardiac myxoma already exists in the literature (Val-Bernal et al 2003). This study recommends routine IHC analysis with Cal of all retrieved embolectomy tissue and excised intracardiac tumour tissue to accurately diagnosis or exclude cardiac myxoma, with the added support of the developed semi-structured grading system for Cal IHC. Therefore, from the results of this study, the third aim and hypothesis of this Master of Philosophy research has been supported. TM expression in cardiac myxomas related to CPT (cases with documented macroscopic surface thrombus or thromboembolic sequelae) was examined. TM expression was identified in 85.7% of the overall cohort and in 62.1% of those with CPT. Whilst TM expression was variable it did not demonstrate statistical significance as thromboprotective against CPT. Therefore, from the results of this study, the fourth aim and hypothesis of this Master of Philosophy research has not been supported. Studying this theoretical link is difficult in a retrospective study and with the naturally low incidence of cardiac myxoma in the general population. Antithrombotic agents carry a risk of bleeding complications related to therapy. Currently, the use of antithrombotics in patients with cardiac myxoma is empiric but recommended in high-risk cases. Therefore, an ability to target antithrombotic therapy to a sub-group would be advantageous in reducing both the risk of thromboembolic events and bleeding complications related to their ingestion. The use of antithrombotic agents in patients with cardiac myxoma was examined. In 82.8% of patients, aspirin was prescribed in preference to warfarin. Approximately 60% were advised aspirin for life in the general cohort and in those with embolic clinical features. However, no statistically significant relationship between TM expression and low antithrombotic use nor absence of CPT and low antithrombotic use was identified in this study. The majority of antithrombotic agents were prescribed to subjects with TM expression and without evidence of CPT. Therefore, from the results of this study, the fifth aim and hypothesis of this Master of Philosophy research has not been supported. No conclusions about the importance of TM expression, CPT and long-term antithrombotic therapy can be drawn from the results of this research. A recommendation for anticoagulant/antiplatelet therapy can only be drawn from the published literature (Kapral and Silver 1999; Álvarez-Sabín et al 2001; Bienfait and Moll 2001). Based on these, this research recommends that following surgical excision of cardiac myxomas, patients should be prescribed an antithrombotic agent with the added recommendation of continuing on low-dose aspirin for life; an alternative being clopidogrel. The beneficiaries of such practice would be diverse and include instances of: 1) embolism/embolic complications; 2) recurrence; 3) multiple embolic events before diagnosis; 4) younger patients; 5) female patients; 6) familial cases of development; 7) biatrial tumours; and 8) multicentric tumours (synchronous or metachronous).
Keyword Cardiac myxoma, Calretinin, Thrombomodulin, Immunohistochemistry, Semi-structured Grading System, Clinicopathological Correlation, Embolism, Intracardiac Obstructive, Constitutional, Transthoracic Echocardiography, Transoesophageal Echocardiography
Additional Notes COLOUR PAGES: 49-50, 55-60, 63, 68-69, 77-78, 85, 88-89, 100, 110-113, 115-119, 121-124, 126, 131-132, 134-135, 139, 141, 150-151, 155, 171-172, 178, 192, 229, 232, 234, 243-246, 248, 250-251

 
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