Biopsies, diagnosis and prognosis in prostate cancer

Prostate cancer is the third most common cancer in men worldwide, and poses a challenge both for patients and health care systems. Many aspects of prostate cancer are controversial, from screening for early detection to the concept of insignificant cancer that does not need curative treatment. This study deals with different aspects of the diagnostic process, including biopsy procedures, histopathological diagnosis and biomarkers for carcinogenesis and progression.

Biopsies of the prostate are the prerequisite for histopathological diagnosis of cancer. The standard biopsy instrument uses an inner needle with a side-notch. The tissue yield of a novel end-cutting instrument was investigated and compared with that of the standard instrument. The new instrument provided thicker biopsies, flatter embedding in paraffin blocks and an optional greater stroke length. These advantages were countered by loss of some biopsy cores. The new instrument can be recommended primarily for men with large prostates or repeat biopsies when there is a persistent serum PSA elevation and suspicion of anterior tumour.

Tumour volume of prostate cancer correlates with progression after radical prostatectomy, but its clinical utility is limited by difficulties in the preoperative assessment. The prediction of large volume prostate cancer by prostate biopsies was studied. Biopsy cancer length and percentage cancer length predicted large tumours better than number and percentage of cores positive for cancer. A cancer length of 30 mm predicted a tumour volume of >4 ml in 95% of cases. Gleason score and serum PSA were weaker predictors. Tumour volumes of <4 ml were found in as many as 35% of men with 6 biopsy cores, indicating that number of positive cores is less useful than linear cancer extent as predictor of large tumours. DNA ploidy status correlates to stage and outcome, but studies on its clinical utility have shown divergent results. The impact of tumour heterogeneity on preoperative ploidy assessment in prostate cancer was investigated by comparing DNA ploidy of prostate biopsies with radical prostatectomy specimens that had been mapped for ploidy heterogeneity. Ploidy was both under- and overestimated in biopsies, and this finding was more pronounced in tumours with heterogeneous ploidy status. Accuracy increased with multiple biopsies.

Oxidative stress is considered to be of great importance in the development of prostate cancer. The expression of three proteins in the redox control system was investigated, in order to evaluate their involvement in prostate cancer. By immunohistochemistry on prostate tissue microarrays all three proteins showed similar expression patterns with the highest immunoreactivity in HGPIN followed by atrophy, cancer and benign tissue. No correlation with biochemical recurrence was found.

In patients with metastatic cancer it is important for treatment and prognosis to assess the site of tumour origin. The origin of certain tumour types is difficult to identify by morphology alone or with existing biomarkers. In a database search for new prostate-specific markers, GAD1 was identified. Its tissue specificity was investigated in a tissue microarray and compared with PSA and PSMA. GAD1 showed a high specificity and sensitivity to benign and malignant prostate tissue and was almost entirely negative in cancers from lung, rectum and urinary bladder, i.e. tumours that may be considered as differential diagnoses to advanced prostate cancer.

In a database search for diagnostic markers with ability to discriminate between malignant and benign prostate tissue, four proteins were identified: AMACR, CYCS, ICK and IKBKB. AMACR is a well- established diagnostic biomarker, but is negative in some prostate cancers and may also be false positive. The expression was analysed in a tissue microarray of benign prostatic tissue, precursor lesions and cancer from the same cases. All four markers showed a stronger expression in prostate cancer and HGPIN than in benign tissue. A panel of diagnostic biomarkers may serve as an adjunct tool for diagnosis of difficult cases.

List of scientific papers

I. Häggarth L, Ekman P, Egevad L. A new core-biopsy instrument with an end-cut technique provides prostate biopsies with increased tissue yield. BJU Int. 2002; 90(1):51-5.
https://pubmed.ncbi.nlm.nih.gov/12081770

II. Häggarth L, Busch C, Norberg M, Norlén B J, Egevad L. Prediction of the volume of large prostate cancers by multiple core biopsies. Scand J Urol Nephrol. 2005; 39(5):380-386.
https://doi.org/10.1080/00365590500202436

III. Häggarth L, Auer G, Busch C, Norberg M, Häggman M, Egevad L. The significance of tumor heterogeneity for prediction of DNA ploidy of prostate cancer. Scand J Urol Nephrol. 2005; 39(5):387-92.
https://doi.org/10.1080/00365590500239883

IV. Valdman A, Häggarth L, Cheng L, Lopez-Beltran A, Montironi R, Ekman P, Egevad L. Expression of redox pathway enzymes in human prostatic tissue. Anal Quant Cytol Histol. 2009, Dec; 31(6):367-74.
https://pubmed.ncbi.nlm.nih.gov/20698352

V. Jonmarker Jaraj S, Augsten M, Häggarth L, Wester K, Pontén F, Östman A, Egevad L. GAD1 is a biomarker for benign and malignant prostatic tissue. Scand J Urol Nephrol. 2011 Feb; 45(1):39-45
https://doi.org/10.3109/00365599.2010.521189

VI. Häggarth L, Hägglöf C, Jaraj SJ, Wester K, Pontén F, Östman A, Egevad L. Diagnostic biomarkers of prostate cancer. Scand J Urol Nephrol. 2011 Feb; 45(1):60-7
https://doi.org/10.3109/00365599.2010.526141