Postradiation Therapy Pathology of Prostate Cancer

The early published literature on post–radiation therapy pathology in patients with prostate cancer was based on treatment with external beam radiation. However, brachytherapy techniques produce the same pathologic changes.

Radiotherapy

About one quarter of men with prostate cancer choose radiotherapy. ^[1] Prostate radiotherapy can be delivered by brachytherapy or external beam therapy. In external beam therapy, a beam delivers radiation to the whole pelvis, with a boost to the prostate.

In brachytherapy, interstitial radiation is delivered by implanted seeds containing a radioisotope (iodine-131 (¹³¹ I), iridium-192 [¹⁹² Ir], or gold-198 [¹⁹⁸ Au]).

Serum prostate-specific antigen (PSA) and a rectal examination may suggest whether or not radiotherapy has eradicated the entire prostate tumor. ^[2]

Following irradiation, the benign prostate shows acinar atrophy, with acinar distortion and decreased number and size of acini. In the most extreme form, only single cells may remain. Cytoplasm is usually decreased. Some nuclei are pyknotic, while others may be enlarged and atypical, exceeding the atypia of cancer. Basal cell hyperplasia or squamous metaplasia may exist. (See the images below.)

Postradiation Therapy Pathology of Prostate Cancer. In the nonneoplastic, irradiated prostate, nuclear enlargement and smudged chromatin are the most notable changes.

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Postradiation Therapy Pathology of Prostate Cancer. This nuclear enlargement may be extreme, but no prominent secretory cell nucleoli exist.

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In either benign or malignant prostate tissue, stromal fibrosis may occur following radiation therapy. Vascular changes include myointimal proliferation, luminal narrowing, and foamy macrophages. The hyalinized and thickened vessels provide a clue that the patient previously received radiation therapy, even if the clinician has not specified this. (See the image below.)

Postradiation Therapy Pathology of Prostate Cancer. In cases in which the history of irradiation is not given or is uncertain, stromal and vascular changes can cue the pathologist to recognize radiation effect. The stroma becomes fibrotic, and the cellularity of normal vessel walls (normal: left) increases because of smooth muscle proliferation (right).

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Histologic features of irradiated cancer and reactive prostate, however, can overlap, regardless of the form of radiotherapy. Thus, it is reasonable to label some cases as indeterminate or atypical suspicious acinar proliferation (ASAP), a designation applied to most of the 20% of nonnegative biopsies in one study. ^[3] Microscopic findings following prostate irradiation are demonstrated in the images below.

Postradiation Therapy Pathology of Prostate Cancer. The preservation of at least a focal basal cell layer is a key finding (upper left).

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Postradiation Therapy Pathology of Prostate Cancer. In basal cells, normally a single-layer (left), nuclear enlargement can be found. The cells may become so hyperplastic that they form several layers and secretory cells are inconspicuous (right). Irregular, potato-shaped nuclei are pathognomonic for basal cells.

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Postradiation Therapy Pathology of Prostate Cancer. Identification of irradiated cancer is a problematic area in pathology now that increased numbers of posttreatment biopsies are being performed. Early changes include cytomegaly, vacuoles, and nucleomegaly with persistent single and, occasionally, double nucleoli in each nucleus (left). Later changes include atrophy and, sometimes, cytoplasmic vacuolation, with the nucleoli now being inconspicuous.

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Postradiation Therapy Pathology of Prostate Cancer. In this matched set of photomicrographs from the same patient, compared with pretreatment grade 3 cancer (left), the main posttreatment change is atrophy (right). Note, however, the maintenance of an infiltrative pattern, angulated acini, absence of basal cells, and inspissated luminal blue mucin characteristic of cancer. Depending on the duration of irradiation, one may see all atrophic cancer acini, unchanged acini, or a combination of atrophic and unchanged acini.

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Postradiation Therapy Pathology of Prostate Cancer. Needle biopsy specimen with postirradiation grade 3 cancer (left), a focus of high-grade prostatic intraepithelial neoplasia (PIN; center), and grade 4 cancer (right).

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Postradiation Therapy Pathology of Prostate Cancer. The residual neoplasm loses architectural differentiation while retaining the cytologic features of cancer. The acini are decreased in number and smaller in size, with a haphazard arrangement.

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Postradiation Therapy Pathology of Prostate Cancer. In the grade 4 component of cancer, the acinar luminal structure breaks down; overgrading the apparent single cells as grade 5 is a temptation. The nucleoli have disappeared, indicating maximal effect. Some cases have increased Paneth cells (Siders, 1992).

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Postradiation Therapy Pathology of Prostate Cancer. In this biopsy specimen, high-grade prostatic intraepithelial neoplasia (PIN) with radiation effect is a helpful feature that should prompt a search for cancer. However, the frequency of PIN in irradiated prostate cancer (based on salvage prostatectomy findings) is reduced to 60% of cases (Cheng, 1998). In contrast, 82% of nonirradiated, step-sectioned prostates show high-grade PIN (McNeal, 1986).

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Postradiation membranous urethral stenosis may occur in men treated for prostate cancer. Histologic findings may include vascular loss, higher collagen density/organization and increased hyalinized fibrosis (scarring), fat entrapment, and spindle cell change. ^[4]

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 P21^WAF1 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]

Postradiotherapy grading of cancer was not endorsed by the International Consultation Meeting on Prostatic Intraepithelial Neoplasia & Pathologic Staging of Prostatic Carcinoma, November 1995. This issue remains controversial, with conflicting data. ^[20] The Gleason score in needle biopsy specimens from nonirradiated prostates matches the score by ±1 in the prostatectomy specimen 74% of the time. ^[21] A Mayo Clinic study evaluating patients treated with radiation and salvage prostatectomy showed a mean Gleason score of 6.2 in biopsy samples and 6.8 in prostatectomy samples. ^[22]

However, other studies have shown posttherapy upgrading. Siders and Lee found a 24% increase in the number of poorly differentiated tumors (Gleason score 8-10) after radiotherapy. ^[23]

The strongest argument for grading is for doing so by multivariate analysis; Gleason score and deoxyribonucleic acid (DNA) ploidy predicted cancer-specific survival in the Mayo Clinic study. ^[22]

Tumor dedifferentiation

Wheeler et al found that patients with dedifferentiation of locally recurrent prostate cancer after radiation therapy had poorer survival than did patients who retained their original tumor grade. On multiple variable logistic regression, time since treatment was the only factor predictive for dedifferentiation; thus, these researchers concluded that the dedifferentiation reflected time-dependent progression. ^[24]

Timing of postirradiation biopsy

The recommended timing of a prostate biopsy after irradiation is a minimum of 1 year after completion of radiation therapy. This approach reliably discloses residual cancer. ^[25] Biopsy samples should be taken from as many sites as possible.

Crook et al reported that ultrasonographically guided biopsies beginning 12 months after radiation therapy revealed failure in 103 (21%) of 479 of patients; however, in 67 of these patients, biopsy results converted to negative after a mean of 28 months. ^[26] Thus, the tumor may take up to 28 months to resolve.

In a study of 160 patients, at a median 6.7-year follow-up, 21% of patients had a positive biopsy result. ^[27] The radiation therapy failure rate has been found to be 25-90%, depending on whether failure is based on biochemical or biopsy evidence. Notably, in a study by Miller et al, 17% of patients with positive biopsy findings remained clinically free of disease at more than 10 years of follow-up. ^[28] It has also been reported that in patients undergoing salvage radical prostatectomy after failure, recurrence was detected by biopsy after a mean of 3.5 (0.5-17) years.

A study by Marinelli et al found that in patients with stage II prostate cancer, 95% of postradiation biopsy specimens were negative for cancer; this figure was 55% for stage III cancer. ^[29]

In a study by Cheng et al, salvage prostatectomy after radiation failure produced a 5-year, cancer-specific survival rate of 91%; 83% of patients were free of metastases. ^[30]

Findings from Radiation Therapy Oncology Group (RTOG) study 94-08 comprising data from 831 men who underwent postradiation therapy (n = 398 radiation alone; n = 422 radiation + total androgen suppression) for localized prostate cancer revealed postive postradiation biopsy was associated with higher rates of biochemical failure, distant metastases, and inferior overall survival in those with high-grade tumors (Gleason score ≥7). ^[31]

Quality of life

About 50% of men undergoing high-dose-rate brachytherapy followed by external beam radiotherapy reported a significant decrease in Expanded Prostate Cancer Index Composite (EPIC) urinary, bowel, sexual, and hormonal domain scores by 12 months. In comparison, those undergoing a dose of radiation directed at the urethra had a greater deterioration in quality of life. ^{[32, 33]}  Radiotherapy seems to be the treatment of choice for Gleason score 7 prostate cancer patients; this modality has been associated with superior disease-free survival at 5 years compared to RP alone ^[34]