Osteosclerosis is associated to low anaplastic histological patterns in prostate cancer bone metastasis

First-line therapies for prostate cancer (PC) rely on the inhibition of androgen receptor signaling. Eventually, PC cells develop resistance to AR-directed therapies and various androgen independent phenotypes arise. Thus, advanced PC patients may present a variety of phenotypically diverse tumors, consistent with cell lineage plasticity. As most patients present with PC bone metastasis (PCBM), determining whether specific PC phenotype preferentially targets bone is of paramount importance to guide appropriate PC treatment.In the localized disease setting, Gleason grading is the standard for histopathological classification of PC. It links histological characteristics of the neoplasm with the biological tendency to metastasize. However, as this framework only applies to primary tumors, there is a need to characterize the histological patterns of PCBM to inform future therapeutic strategies.Here, we perform histological analysis of PCBM and evaluate if histopathological characteristics of metastatic PC in bone are related to different PC phenotypes and/or the bone histoarchitectural phenotype.We obtained vertebral samples from the University of Washington rapid autopsy program. We performed histopathological classification of 76 PCBM from 48 patients according to cell organization, cell morphology, nuclear size and shape and nucleoli following a framework established by our groups. Immunohistochemistry was used to determine molecular tumor phenotypes. Histopathological patterns and molecular phenotypes were correlated with results of micro-computed tomography (micro-CT) of the specimens.We observed that most PCBM were adenocarcinoma (24% of the samples) followed by cribriform adenocarcinoma (13%) and poorly differentiated adenocarcinoma (13%), while high grade carcinoma types have a lower representation. Twenty-one percent of the samples had no tumor evidence and exhibited an osteopenic pattern. More importantly, we observed intra-vertebral heterogeneity of PCBM, as 9 samples showed different histological patterns within a single histological section. Interestingly, different histopathological patterns are not fully linked to PC molecular phenotypes since 7 adenocarcinomas were synaptophysin (+) and 3 were chromogranin (+).Comparing the histopathological pattern of PCBM with micro-CT bone volume/total volume (BV/TV) measurements, we observed that most of the highly osteosclerotic PCBM corresponded to adenocarcinoma, while the more anaplastic histological patterns are related to lower BV/TV.Less anaplastic PCBM are associated with higher androgen dependency phenotypes and higher osteosclerosis. This is in the context of high intra-vertebrae and intra-patient heterogeneity.