Análisis descriptivo de la ejecución.

Staging and grading of a cancer describes how far along a cancer may have progressed and is useful for deciding the type of treatment which is necessary. For prostate cancer detection, the TNM system is used (Table 1.1), standing for Tumour (T), Node (N) and Metastases (M) (ProstateCancerUK, 2016e). The early stages (T

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stages) represent the initial developments which occur when a tumour is formed in the prostate gland (Figure 1.3). Node stages demonstrate tumour stages with nodal involvement, and Metastases stages illustrate advanced stages of tumour development where metastases are present. Table 1.1 illustrates the differences in staging and how each stage is identified.

12 Table 1.1 Prostate cancer TNM staging. Adapted from (CancerResearchUK, 2016f).

Stage Description

T1 Localised prostate cancer, small tumours, too small to be seen/felt during prostate examination, possible to be identified by needle biopsy or seen under microscope

T2 Localised prostate cancer, cancer is big enough to be seen on scans but is contained inside the prostate gland. Stage T2 can be divided into 3 sub-stages; T2a, T2b and T2c.

T2a Localised prostate cancer, the tumour is in only half of one of the lobes of the prostate gland

T2b Localised prostate cancer, the tumour is in more than half of one of the lobes of the prostate gland

T2c Localised prostate cancer, the tumour is in both of the lobes of the prostate gland

T3 Locally advanced prostate cancer, the cancer starts to break away through the capsule of the prostate; this can be felt/seen on a scan. The cancer is yet to spread to additional organs. Stage T3 can be divided into 2 sub-stages; T3a and T3b.

T3a Locally advanced prostate cancer, the cancer has broken through the capsule of the prostate but is yet to spread to the seminal vesicles. T3b Locally advanced prostate cancer, the cancer has broken through the

capsule of the prostate and has spread to the seminal vesicles.

T4 Locally advanced prostate cancer, the cancer has penetrated the capsule of the prostate and began to infiltrate organs of the body in the immediate area, such as the bladder and the rectum.

NX Locally advanced prostate cancer. Stage NX is when the lymph nodes cannot be measured.

N0 Locally advanced prostate cancer. Stage N0 is when the lymph nodes can be measured and reveals there are no cancer cells in lymph nodes surrounding the prostate.

N1 Locally advanced or metastatic advanced prostate cancer. Stage N1 is when the lymph nodes surrounding the prostate are measured and contain cancer cells.

MX Locally advanced or advanced metastatic prostate cancer. Stage MX may indicate results were unclear as to whether metastases were present or not.

M0 Locally advanced or advanced metastatic prostate cancer. Stage M0 means the cancer hasn’t progressed outside of the pelvic region.

M1 Locally advanced or advanced metastatic prostate cancer. Stage M1 means the cancer has progressed outside of the pelvic region.

M1a Advanced metastatic prostate cancer. Stage M1a indicates there are cancer cells in lymph nodes outside of the pelvic region.

M1b Advanced metastatic prostate cancer. Stage M1b indicates there are cancer cells present in the bone.

M1c Advanced metastatic prostate cancer. Stages M1c indicates there are cancer cells in other organs such as the liver, brain or lungs.

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Figure 1.3 Schematic representation illustrating early stages of prostate cancer development.

The prostate gland is situated below the bladder. The proximity to the bladder and urinary organs can lead to bladder related issues when cancer is present. T1 prostate cancer is the first stage of prostate cancer where the cancer is difficult to observe during a prostate examination. The next stage, T2, is when the cancer has grown slightly larger and can now be clearly identified on prostate scans. Stage T3 is where the cancer first starts to penetrate the lining of the prostate. This stage can be both felt during a prostate examination and seen on a prostate scan. During T3 the cancer has yet to reach other organs of the body but may have reached the seminal vesicles near the prostate.

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Figure 1.4 Illustration of Gleason Grading System, a microscopic based grading method for prostate cancer (Gleason et al 1974).

The total Gleason score is generated from the sum of two key scoring: The appearance of the most common cell morphology and the appearance of the second most common cell morphology are each assigned to grade 1-5. Using this system the most well-differentiated tumours have a Gleason score/grade of 2, and the least- differentiated tumours a score of 10. Grade 2-4 being well-differentiated neoplasm, Grade 5-6 intermediate-grade neoplasm, Grade 7 moderately - poorly differentiated grade neoplasm, Grade 8-10 high-grade neoplasm.

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The prostate cancer staging system is used to describe how far the cancer has spread, starting with primary localised prostate cancer and finalising with advanced metastatic cancer. Additionally, a method to determine how aggressive the cancer will be is calculated using the Gleason score and Gleason grade, named after David Gleason who initiated the scoring method (Gleason and Mellinger, 1974) and modified in the following decades (Brimo et al., 2013) (Figure 1.4). Once the tissue biopsy has been evaluated under a microscope in the laboratory, a Gleason score is determined using a total of Gleason grades, and this illustrates the level of differentiation to the cells. The morphology or pattern of the tumour is given a Gleason grade by numbering from 1-5, depending on the extent of abnormality to the cells, with 1 being the lowest and 5 the highest, then varying Gleason grades are added together to give an overall Gleason score (ProstateCancerUK, 2016c). The two most common morphologies of tissue are graded, then added together to give the Gleason score. The higher the Gleason score, the more aggressive the tumour is and more likely it is to spread to distinct areas of the body (TackleProstateCancer, 2016). The tests described above provide significant clues on whether the cancer will metastasise and become more aggressive, infiltrating other areas of the body, in addition to providing aspects on patient morbidity and mortality. However, the main disadvantage for the tests in use for prostate cancer diagnosis and prognosis is the specificity of the test; currently, there is no single diagnostic assay which can give a definitive result for presence of prostate cancer and whether a cancer will metastasise or not. For this to be achieved, a specific, molecular target which correlates with prostate cancer progression is therefore required. A crucial part of this PhD will be to evaluate EPLIN for its role in prostate cancer and to establish whether EPLIN can be

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successfully utilised as a suitable prognostic marker or therapeutic strategy for prostate cancer development and progression.