Upgrading prostate cancer following proton beam therapy.

Pre- and post-radiation therapy (RT) effects on prostate histology have not been rigorously studied, but there appears to be a correlation between escalating radiation dosage and increasing post-RT histologic changes. Despite this dose-response relationship, radiation-induced changes may be heterogenous among different patients and even within a single tumor. When assessing residual tumor it is important to understand biopsy evaluation in the post-RT setting. We present the case of a poorly differentiated prostate adenocarcinoma following proton beam RT in a 45-year-old man with pre-RT Gleason 4 + 3 = 7 disease diagnosed in the setting of an elevated serum prostate-specific antigen level.

INTRODUCTION

For intermediate-risk prostate cancer, management options include active surveillance, radiation therapy (RT) ± short-term androgen deprivation therapy (ADT), adjuvant RT or radical prostatectomy ± pelvic lymph node (LN) dissection. Radiation is typically in the form of external beam (3D conformal or intensity modulated) ± brachytherapy boost or brachytherapy alone–but recently, the use of proton beam therapy is also being evaluated as a primary definitive treatment option.[1]

RT-induced changes are observed to have a dose-dependent response, but can be heterogeneous among a single tumor and patients. These changes can be so pronounced that they can affect assessment of residual disease.

CASE REPORT

A 45-year-old male was diagnosed with cT1c Gleason 4 + 3 = 7 PCa in the setting of a prostate-specific antigen (PSA) of 8.6 ng/mL and was subsequently treated with proton beam RT. His PSA level continually rose from a post-RT nadir of 3.2 ng/mL at 3 months following RT, peaking at 9.39 ng/mL 21 months later. During this observed rise in PSA, at 18 months post-RT, the patient underwent a systematic 12-core transrectal ultrasound (TRUS) biopsy that was found to be negative for cancer, displaying only atypia consistent with RT effect. This prompted multiparametric magnetic resonance imaging (MRI) evaluation of the prostate, which revealed two suspicious intraprostatic lesions and suspected seminal vesicle invasion with no evidence of nodal or bony disease. He then underwent MRI/ultrasound fusion-guided biopsy, which found all six targeted cores demonstrating high-grade disease (five cores with Gleason 4 + 5 = 9 disease) with perineural and seminal vesicle invasion [Figure 1]. He elected to undergo a robotic-assisted salvage radical prostatectomy with extended pelvic LN dissection. Grossly, the prostate gland was atrophied secondary to radiation effect and histologically demonstrated multifocal Gleason 5 + 5 = 10 disease with extracapsular extension and seminal vesicle invasion [Figure 2]. Two of 33 LNs removed were involved by PCa. Post-operative serum PSA evaluations at 1 and 3 months following salvage prostatectomy were stable at 0.07 ng/mL.

Figure 1

Core biopsy of post-proton beam prostate tissue at ×100 magnification demonstrating high-grade prostate cancer with perineural invasion

Figure 2

High-power view (×1000) of post-proton beam prostatectomy specimen showing high-grade infiltrating carcinoma with no apparent radiation effect

DISCUSSION

The current literature suggests that radiation-induced changes–regardless of RT modality–are similar when assessing tissue histology. However, given the relative newness of proton RT, these claims are not yet definitive. However, regardless of RT modality, when assessing residual tumor, it is important to identify areas within the tumor that display radiation effects as well as those areas that do not. Treatment-affected areas should not be histologically graded because of the variable radiation effects, but it is essential to grade unaffected tumor areas as local recurrences after RT tend to display increased tumor aggressiveness, as noted histologically (in the form of Gleason score) and biologically (increased DNA ploidy).[234] Cancer-affected glands that show maximal radiation changes appear as scattered isolated cells with a Gleason 10 pattern, but overall treated areas tend to show a significant increase in Gleason score.[25]

On a histologic level, neoplastic tissues show less morphologic changes than benign tissues, but can begin to lose their glandular pattern and become clustered or isolated cells. The nuclei undergo pyknosis with shape and size irregularities and, often, nucleoli are lost. An abundance of cytoplasm may be noted along with a clear and finely granular pattern and periodic acid Schiff positivity. Stromal hyalinzation–particularly in the setting of brachytherapy–may be present as stromal sclerosis is common. Paneth-like cells may also appear.

For subsequent prostate biopsies, tissue samples should be categorized based on evidence of cancer as well as presence of minimal or maximal radiation effects. Identification of residual cancer after RT can be challenging as distinguishing the untreated microacinar of cancer from the mild radiation-induced atypia is subtle. To help minimize this difficulty, it has been suggested that the most reliable marker of residual malignancy in the post-radiation setting is to look for an infiltrative pattern at least 1 year after treatment.[6] This timeframe is important to adhere by as earlier it is believed tumor regression continues for 6-12 months after radiation treatment and, thus, histologically present tumor after 12 months likely represents biologically active carcinoma.[36]

CONCLUSION

When assessing prostate histology following proton therapy RT, it is important to recognize that tissue assessment may vary from pre-RT samples. Additionally, when interpreting post-RT samples, it is important to account for the amount of radiation-induced changes observed as well as the timeframe in which evaluation occurs.