What is the role of biological cancer markers in the workup of postradiation therapy pathology?

Updated: Dec 30, 2020
  • Author: Kenneth A Iczkowski, MD; Chief Editor: Liang Cheng, MD  more...
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Benign acini with no residual cancer are positive for high–molecular-weight basal cell cytokeratin 34ßE12, prostate-specific antigen (PSA), and prostatic acid phosphatase (PAP). The absence of basal cell cytokeratin staining is most reliable in diagnosing residual cancer, provided that good internal positive control exists. The intensity and percentage of nonneoplastic epithelium staining with this marker can be optimized with methods that involve steam heat and ethylenediaminetetra-acetic acid (EDTA) for antigen retrieval. [5]

In a study by Yang et al to test the usefulness of the marker α-methylacyl-coenzyme A (CoA) racemase (AMACR, P504S) in diagnosing postirradiation cancer, the authors found that the marker was consistently reactive in 28 cancers and was nonreactive in 12 benign postbiopsy cases. [6] However, the authors also found that, when used in conjunction with cytokeratin 34ßE12, P504S was not considered to increase recognition of postirradiation cancer, compared with cytokeratin 34ßE12 alone. [7]

If cancer cells are present, their viability can be assessed by positive staining with pan-cytokeratin and PSA. [8] In positive biopsy specimens obtained 12 months after radiotherapy, pan-cytokeratin staining is useful. A negative result predicts resolution of tumor in 83-97% of cases by 36 months. Positive pan-cytokeratin findings correlate with local failure in 49-79% of cases, but when pan-cytokeratin is present in an early biopsy specimen (12-18 months), it still may subsequently disappear. [9]

Preradiation expression of MIB-1 [10] and TP53 [11] predicts postradiation recurrence. Increased TP53 expression occurs after radiation, indicating that cells with abnormal overexpression were protected from cell death. TP53 expression in radioresistant cancer (postradiation) is less likely if patients receive neoadjuvant hormonal treatment. [12, 13] No significant changes in BCL2 or P21WAF1 are found.

Jackson et al conducted a retrospective review to assess whether the presence of Gleason pattern 5 (GP5) is associated with worse clinical outcomes for patients receiving salvage radiation therapy after experiencing an increase in prostate-specific antigen level after undergoing treatment. [14] Their review included a total of 575 patients who underwent primary radiation therapy for localized prostate cancer and who subsequently received salavage radiation therapy. Biochemical failure, distant metastasis, and prostate cancer–specific mortality were assessed using univariate analysis and Fine and Grays competing risks multivariate models.

On pathologic evaluation, 563 (98%) patients had a documented Gleason score. [14] The median follow-up period after salvage radiation therapy was 56.7 months. A total of 60 patients (10.7%) had primary, secondary, or tertiary GP5. On univariate analysis, the presence of GP5 was prognostic of biochemical failure, distant metastasis,andprostatecancer–specificmortality.Restratification of the Gleason score to include GP5 as a distinct entity resulted in improved prognostic capability. On multivariate analysis, the presence of GP5 was the most adverse pathologic predictor of biochemical failure, distant metastasis, prostate cancer–specific mortality. The investigators concluded that for patients with prostate cancer who undergo salvage radiation therapy, the presence of GP5 is a critical pathologic predictor of biochemical failure, distant metastasis, and prostate cancer–specific mortality. [14]

Lilleby et al conducted a study to determine whether the presence of pretreatment disseminated cells in bone marrow aspirates that were sampled before initiation of primary therapy for patients with prostate cancer has a bearing on prognosis and long-term survival. [15] Their study included 129 patients with T1–3N0M0 prostate cancer for whom long-term follow-up data were available. Pretreatment bone marrow aspirates were available for 100 of those patients. Patients received either combined therapy, radiotherapy with hormone treatment of differing duration, or monotherapy with radiation therapy or hormone therapy alone [n = 48 (37%)]. Mononuclear cells were deposited on slides according to the cytospin methodology. The median age of the patients at diagnosis was 64.5 years (range, 49.5-73.4 years). The median long-term follow-up from the first bone marrow sampling to the last observation was 11 years. On multivariate analysis, the presence of pretreatment disseminated cells in bone marrowwastheonly statistically independent parameter for survival. The investigators concluded that for patients with nonmetastatic prostate cancer, the presence of pretreatment disseminated cells in bone marrow is significantly associated with clinically relevant outcomes independently of the patient's treatment. [15]

Stone et al conducted a literature review to assess the degree to which local recurrence occurs after prostate brachytherapy, as well as the treatment options available after such recurrence. [16] In their review, they identified 6 patients who experienced an increase in prostate-specific antigen levels after undergoing brachytherapy. The patients were subsequently treated with targeted, focused cryoablation. Local recurrence after prostate brachytherapy occurred in 2-20% of patients and was dose dependent. The biologic effective dose greater than 200 Gy2 was associated with a less than 2% recurrence rate. The investigators recommended that the pathologist be experienced in evaluating postirradiation tissue, owing to the difficulty in distinguishing benign irradiated prostate from residual or recurrent tumor. They also recommended that confirmatory biopsy include both the prostate and seminal vesicles. They found that whole-gland salvage, whether by prostatectomy or cryoablation, wasassociatedwith high complication rates. Focal therapy had fewer complications, although targeting was less accurate. They found that multiparametric MRI and transperineal mapping biopsy were advantageous in lesion identification and ablation. They concluded that improved lesion identification and targeting may be associated with better cancer control and lower morbidity, and they suggested that transperineal mapping biopsy with interactive targeting software may offer the best approach to focused therapy. [16]

In a 2018 retrospective study (1990-2010) that assessed data from 776 patients with prostate adenocarcinoma treated with dose-escalated external beam radiation therapy (DE-EBRT), Romesser et al found PSA bounce was independently associated with a decreased risk for PSA relapse, distant metastases, and all-cause mortality, as well as improved cancer-specific survival. [17]  Another 2018 retrospective study (2005-2015) that reviewed data from 113 patients with localized prostate cancer who underwent three-dimensional conformal radiotherapy with various durations of androgen deprivation therapy found that a postradiation PSA rate of decline of at least 90% was significantly prognostic for biochemical recurrence. [18]

Barchetti et al conducted a study to assess the role of multiparametric MRI in the detection of locoregional recurrence of prostate cancer after radical prostatectomy and radiation therapy. [19] They undertook a systematic review of the literature using the Medline and Cochrane Library databases to identify relevant studies published from January 1995 to November 2013. They found that multiparametric MRI makes it possible to differentiate between residual glandular healthy tissue, scar/fibrotic tissue, granulation tissue, and tumor recurrence and that it may be useful in assessing the aggressiveness of nodule recurrence. They suggested that multiparametric MRI could be used to boost the dose of salvage radiation therapy to the recurrent nodule, thereby improving control of local disease and avoiding eventual locoregional recurrence, and that hybrid PET/MRI scanners may further improve diagnostic accuracy by depicting local recurrence in postprostatectomy fossa. [19]

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