Genetic and morphological studies of tumor heterogeneity, multifocality and outcome in locally advanced prostate cancer

Prostate cancer is a leading cause of mortality worldwide. Patients with locally advanced disease have a higher risk of relapse after treatment with curative intent. Examples of risk factors are seminal vesicle invasion (SVI) and lymph node metastases. However, not all patients with adverse pathology experience recurrence. It is not fully understood how histopathological features are associated with progressive capacity and how to best identify them before treatment. The aim of this thesis was to evaluate histopathological and genetic prognostic factors of locally advanced prostate cancer and to correlate findings in preoperative biopsy with radical prostatectomy (RP) specimens.

In Study I we evaluated 1050 RP specimens. SVI was found in 60 cases, which were further analyzed regarding pathological factors such as route of invasion, tumor area and Gleason score of the cancer component invading the seminal vesicles. We confirmed that patients with SVI have a higher risk of biochemical recurrence. The prognosis was poorer if cancer invaded the mucosa of the seminal vesicle compared to when cancer invasion was restricted to the muscular wall. The aim of Study II was to evaluate 45 morphologically distinct tissue areas in a RP specimen with lymph node metastases in order to identify the clone that gave rise to the metastases. We analyzed break-point regions, which marks a start of an amplification or a deletion event, to construct a phylogenetic tree showing the somatic relationship between samples. The greatest similarity with metastases was seen in three samples with intraductal carcinoma. This lesion has previously been associated with poor prognosis, although this study was the first to indicate a metastatic potential. In Study III we analyzed the prognosis of patients with SVI compared to patients with extraprostatic extension alone (stage categories pT3b and pT3a, respectively). Data from 4063 pT3a cases and 1371 pT3b cases were retrieved from the National Prostate Cancer Register. We found that patients with stage category pT3b had a higher risk of death from prostate cancer and were more likely to receive postoperative treatment with androgen deprivation therapy or radiotherapy. They also had a greater tumor burden as measured by tumor length and number of positive cores and a higher Gleason score. In Study IV we evaluated several tumor foci and biopsy cores from 11 patients. The samples were sequenced and somatic profiles of the tumor foci compared with those of the biopsies. We found a high degree of genomic heterogeneity between foci within the same prostate. In eight patients the biopsies represented at least one of the tumor foci of the RP specimen. In only one case two somatically distinct tumors were identified in the biopsies.

In conclusion, these studies show that prostate cancer is a morphologically and genetically heterogeneous disease. The poor representation of somatically different tumors in core biopsies suggests a diagnostic challenge as we move towards more individualized treatment.

List of scientific papers

I. Kristiansen A, Wiklund F, Wiklund P, Egevad L. Prognostic significance of patterns of seminal vesicle invasion in prostate cancer. Histopathology. 2013 Jun;62(7):1049-56.
https://doi.org/10.1111/his.12104

II. Lindberg J, Kristiansen A, Wiklund P, Grönberg H, Egevad L. Tracking the origin of metastatic prostate cancer. European Urology. 2015 May;67(5):819-22.
https://doi.org/10.1016/j.eururo.2014.09.006

III. Kristiansen A, Drevin L, Delahunt B, Samaratunga H, Robinson D, Franck Lissbrant I, Stattin P, Egevad L. Prognostic significance and biopsy characteristics of prostate cancer with seminal vesicle invasion on radical prostatectomy: a nationwide population-based study. Pathology. 2017 Dec;49(7):715-720.
https://doi.org/10.1016/j.pathol.2017.08.008

IV. Kristiansen A, Bergström R, Delahunt B, Samaratunga H, Guðjónsdóttir J, Grönberg H, Egevad L, Lindberg J. Somatic alterations detected in diagnostic prostate biopsies provide an inadequate representation of multi-focal prostate cancer. The Prostate. 2019;1-9.
https://doi.org/10.1002/pros.23797