Clinical and histopathological parameters in transrectal ultrasound‐guided biopsies associated with tumor upgrading after radical prostatectomy: A comparative analysis of risk groups - Ozkaya - The Prostate - Wiley Online Library

Clinical and histopathological parameters in transrectal ultrasound‐guided biopsies associated with tumor upgrading after radical prostatectomy: A comparative analysis of risk groups - Ozkaya - The Prostate - Wiley Online Library

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Mustafa Ozkaya MD

Summary

In simple terms, this study looked at factors that might predict if a man's prostate cancer is worse than originally thought based on the initial biopsy. They studied 205 men diagnosed with prostate cancer who later had their prostate removed.

Key takeaways:

• - Men were classified as low, intermediate, or high risk. High risk men tended to be older with higher PSA levels (a blood test for prostate cancer).
• - About half had abnormal cells called HGPIN in non-cancerous parts of their biopsy. This was more common in low and intermediate risk men.
• - After surgery, the cancer grade was often worse than the biopsy suggested, especially for low risk men. Older age, having HGPIN in multiple biopsy samples, and cancer growing along nerves predicted this.
• - Having cancer growing along nerves or blood/lymph vessels was linked to finding cancer in the lymph nodes.
• - Even having HGPIN in one biopsy sample was linked to the cancer being worse at surgery. Having it in multiple samples was a strong predictor.

In summary, abnormal HGPIN cells in non-cancerous parts of a prostate biopsy, especially if found in multiple samples, along with older age and other factors may indicate the cancer is worse than the biopsy alone suggests. The authors advise reporting HGPIN when found in biopsies. 

HGPIN

High-grade prostatic intraepithelial neoplasia (HGPIN) is considered a precancerous condition of the prostate gland. It is believed to be a precursor lesion to prostate cancer, meaning that it is a cellular abnormality that may develop into cancer over time. Here are some key points about HGPIN:

1. Definition: HGPIN is characterized by abnormal cells lining the prostate ducts and acini. These cells look similar to cancer cells but are confined within the ducts and have not invaded the surrounding tissue.

2. Grading: HGPIN is considered "high-grade" because the cells appear significantly abnormal under the microscope. "Low-grade" PIN also exists but is not considered clinically significant.

3. Relationship to prostate cancer: Studies have shown that men with HGPIN are at increased risk of developing prostate cancer. However, not all men with HGPIN will develop prostate cancer.

4. Diagnosis: HGPIN is typically found during a prostate biopsy. It is not visible on imaging tests or felt on physical exam.

5. Management: If HGPIN is found on biopsy, close follow-up with repeat biopsies is often recommended to monitor for the development of prostate cancer. The presence of HGPIN does not necessarily require treatment.

6. Molecular changes: HGPIN and prostate cancer share many molecular and genetic changes, further supporting the idea that HGPIN is a precursor to prostate cancer.

7. Risk factors: The risk factors for HGPIN are similar to those for prostate cancer, including advancing age, family history, and possibly diet.

While HGPIN is not cancer, its presence indicates an increased risk for prostate cancer. Its diagnosis can be helpful in identifying men who need closer monitoring for the development of prostate cancer.

Clinical Impact

The results of this study could have several important implications for clinical practice in the management of prostate cancer:

1. Risk stratification: The presence of HGPIN in tumor-free cores, especially in multiple cores, could be used to stratify patients into higher risk categories. This could influence decisions about follow-up, additional testing, and treatment.

2. Active surveillance: Low-risk patients are often candidates for active surveillance instead of immediate treatment. However, if a patient has HGPIN, especially in multiple cores, doctors might consider more frequent monitoring or even recommend treatment due to the increased risk of tumor upgrading.

3. Biopsy interpretation: Pathologists should carefully examine prostate biopsies for the presence of HGPIN, even in cores without cancer, and include this in their report. This information could be valuable for clinical decision-making.

4. Patient counseling: When discussing biopsy results with patients, doctors should explain the potential significance of HGPIN, if present. Patients should understand that HGPIN indicates a higher risk of having more aggressive cancer than the biopsy alone suggests.

5. Surgical planning: If a patient with HGPIN chooses to undergo radical prostatectomy, surgeons might plan a more extensive operation, considering the increased likelihood of finding more aggressive cancer than expected based on the biopsy.

6. Lymph node dissection: The correlation between HGPIN, perineural invasion, lymphovascular invasion, and lymph node metastasis suggests that these findings on biopsy might guide decisions about performing lymph node dissection during surgery.

7. Adjuvant therapy: The presence of HGPIN, particularly in multiple cores, might influence decisions about adjuvant therapy after surgery, such as radiation or hormonal therapy.

While more research is needed to fully understand the clinical implications of these findings, this study provides valuable insights that could help guide prostate cancer management decisions. As always, treatment decisions should be individualized based on each patient's specific circumstances and preferences.

Questions

As a man diagnosed with prostate cancer, this study raises several important questions you should consider discussing with your physician when deciding on your course of treatment. Here are some key questions to ask:

1. HGPIN:
   - Was HGPIN found in my biopsy? If so, in how many cores?
   - How does the presence or absence of HGPIN affect my risk and prognosis?
   - Should the presence of HGPIN influence my treatment decisions?

2. Risk of tumor upgrading:
   - Based on my biopsy results, age, and other factors, what is my risk of having a higher grade cancer than what was seen on the biopsy?
   - How should this risk influence my treatment choice?

3. Active surveillance (AS):
   - Am I a candidate for active surveillance based on my biopsy results and other factors?
   - If HGPIN is present, does this change my suitability for AS?
   - If I choose AS, what monitoring schedule would you recommend?

4. Radical prostatectomy (RP):
   - If I choose surgery, how might the presence of HGPIN or the risk of tumor upgrading affect the surgical plan?
   - Should I consider a lymph node dissection based on my biopsy findings?

5. Radiation therapy:
   - If I choose radiation, would you recommend any additional therapies (such as hormonal therapy) based on my biopsy findings and risk factors?
   - How might the presence of HGPIN or risk of tumor upgrading affect the radiation plan?

6. Androgen deprivation therapy (ADT):
   - Is ADT recommended in my situation, either alone or in combination with other treatments?
   - How might my biopsy findings, including HGPIN, influence this recommendation?

7. Monitoring and follow-up:
   - After treatment, what follow-up schedule would you recommend based on my specific pathology and risk factors?
   - What signs or symptoms should I be watchful for that might indicate a need for further evaluation or treatment?

Remember, every man's situation is unique, and treatment decisions should be individualized based on a variety of factors, including cancer grade and stage, age, health status, personal preferences, and life circumstances. A thorough discussion with your physician, considering all available information, is the best way to make an informed decision about your prostate cancer management.

Answers

Your doctor's responses will depend on your specific case details, but here's a general idea of what you might expect:

1. HGPIN:
   - If HGPIN was found, your doctor should tell you how many cores were affected.
   - They may explain that HGPIN, especially in multiple cores, suggests a higher risk of having more aggressive cancer than the biopsy alone shows.
   - The presence of HGPIN might lead your doctor to recommend more frequent monitoring or to lean towards treatment over active surveillance.

2. Risk of tumor upgrading:
   - Your doctor should assess your risk based on factors like your age, PSA level, and biopsy results, including HGPIN.
   - If your risk of upgrading is high, they may recommend treatment over active surveillance.

3. Active surveillance (AS):
   - Your doctor will consider your biopsy results, PSA, and other factors to determine if you're a candidate for AS.
   - If HGPIN is present, especially in multiple cores, they may advise that AS carries a higher risk and recommend considering treatment.
   - If you choose AS, they'll likely recommend a schedule of regular PSA tests, exams, and repeat biopsies to monitor for progression.

4. Radical prostatectomy (RP):
   - If you choose surgery, your doctor may recommend a more extensive operation, possibly including lymph node dissection, if HGPIN or other high-risk features are present.

5. Radiation therapy:
   - If you opt for radiation, your doctor may discuss adding hormonal therapy if your biopsy findings and other factors suggest higher risk.
   - The radiation plan might be adjusted to deliver a higher dose if there's a greater risk of aggressive cancer.

6. Androgen deprivation therapy (ADT):
   - Your doctor will consider your overall risk profile, including biopsy findings like HGPIN, to determine if ADT is recommended alone or with other treatments.

7. Monitoring and follow-up:
   - Your doctor should recommend a follow-up plan tailored to your risk profile, with more frequent or intensive monitoring if you have high-risk features.
   - They should advise you to report any new symptoms, like bone pain or urinary changes, that could indicate progression.

Remember, these are general expectations. Your doctor's actual responses will be specific to your individual situation and may vary depending on their experience and approach. The key is to have an open, thorough discussion where you feel your questions are being addressed and you have the information you need to make an informed decision about your care.

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Abstract

Background

Thanks to technological advances, prostate cancer (PCa) can be diagnosed at a younger age. It is known that most of these patients are in the low-intermediate risk group, and the histological grade of the tumor increases in half of those undergoing radical prostatectomy (Rp) compared to their diagnostic biopsies. This is especially important in terms of active surveillance (AS) and/or the timely evaluation of curative treatment options in patients diagnosed at an early age. Our aim was to investigate clinical and histopathological parameters that may be associated with an increase in the histological grade of the tumor in patients with acinar adenocarcinoma who were diagnosed by transrectal ultrasound-guided biopsy (TRUS-Bx) and underwent Rp.

Methods

A total of 205 patients with classical acinar adenocarcinoma diagnosed by TRUS-Bx without metastasis and who underwent Rp were grouped according to the D'Amico risk classification. Age at diagnosis, serum prostate-specific antigen (PSA), PSA density, prostate volume, Prostate Imaging Reporting and Data System (PI-RADS) score, clinical stage, Gleason Grade Group (GGG), high-grade intraepithelial neoplasia in tumor-free cores (HGPIN) (single and ≥2 cores), perineural invasion (PNI), and lymphovascular invasion (LVI) was obtained. Additionally, GGG, pathological stage, lymph node metastasis, surgical margin positivity, and tumor volume obtained from Rp were evaluated. Comparisons were made between the case groups in which the tumor grade increased and remained the same, in terms of age, serum PSA, PSA density, HGPIN in tumor-free cores (single and ≥2 cores), PNI, and LVI in all biopsies (with or without tumors), as well as risk groups. In addition, the relationships of HGPIN in tumor-free cores (single and ≥2 cores), PNI, and LVI on TRUS-Bx with age, serum PSA and PSA density, tumor volume, surgical margin positivity, pathological stage, lymph node metastasis, and risk groups were examined separately.

Results

Of the patients, 72 (35.1%) were in the low-risk group, 95 (46.3%) in the intermediate-risk group, and 38 (18.5%) in the high-risk group. Most of the patients with an increased histological grade (n = 38, 48.1%) were in the low-risk group (p < 0.05) and had an advanced median age. HGPIN in single and ≥2 tumor-free cores and PNI were more common in these patients (p < 0.01, p < 0.001, and p < 0.05, respectively). According to the multivariable analysis, advanced age (odds ratio [OR]: 1.087, 95% confidence interval [CI]: 1.029–1.148, p < 0.05), high serum PSA (OR: 1.047, 95% CI: 1.006–1.090, p < 0.05), HGPIN in ≥2 tumor-free cores (OR: 6.346, 95% CI: 3.136–12.912, p < 0.001), and PNI (OR: 3.138, 95% CI: 1.179–8.356, p < 0.05) were independent risk factors for a tumor upgrade. Furthermore, being in the low-risk group was an independent risk factor when compared to the intermediate- and high-risk groups (OR: 0.187, 95% CI: 0.080–0.437, p < 0.001 and OR: 0.054, 95% CI: 0.013–0.230, p < 0.001, respectively). The HGPIN diagnosis was more common in the low- and intermediate-risk groups. Advanced age at diagnosis, high serum PSA and PSA density values were associated with PNI on TRUS-Bx. High serum PSA and PSA density values were associated with LVI on TRUS-Bx. Surgical margin positivity was higher in cases with PNI and LVI detected by TRUS-Bx. HGPIN in ≥2 tumor-free cores, PNI, and LVI on TRUS-Bx were associated with a higher rate of lymph node metastases.

Conclusions

In patients diagnosed with acinar adenocarcinoma, the presence of HGPIN even in a single tumor-free core on TRUS-Bx was found to be significant in terms of showing an increase in the histological tumor grade in Rp. The diagnosis of HGPIN in ≥2 tumor-free cores on TRUS-Bx was determined as an independent risk factor for an increased Gleason score after Rp. Furthermore, an advanced age, a high serum PSA value, being in the low-risk group, and the presence of PNI were associated with a tumor upgrade. HGPIN in ≥2 tumor-free cores, PNI, and LVI were also associated with lymph node metastasis. Therefore, the diagnosis of HGPIN should be signed out on pathological reports.

1 INTRODUCTION

Prostate cancer (PCa) ranks second, after lung cancer, among the most common tumors in men worldwide, and first in Europe, America, Australia, and sub-Saharan African countries, due to geographical variations.¹ It is the fifth most common cause of cancer-related mortality.^{1, 2} Although the majority of PCa cases are seen in countries with a high socioeconomic level, mortality rates are higher in sub-Saharan African countries and among people of African descent living in countries with high socioeconomic status.^{1, 3, 4}

The serum prostate-specific antigen (PSA) level and a digital rectal examination (DRE) are the methods commonly used as the first step in the diagnosis and screening of PCa.^{5, 6} High serum PSA levels, an advanced patient age (>50 years), a history of PCa in first-degree relatives, and ethnicity are among the known risk factors for PCa development.^{7, 8} In recent years, the use of multiparametric prostate magnetic resonance imaging (MpMRI) and Prostate Imaging Reporting and Data System (PI-RADS) scoring for patients with suspected PCa has become widespread in urology practice.^{9, 10} However, a definitive diagnosis of PCa can only be made by biopsy.^{5, 9, 10} In the reporting of prostate biopsies, the histological type of the tumor detected in each core, its length or percentage in the biopsy, the Gleason score (GS), the percentages of Gleason patterns 4 and 5 (GP 4/5) in the tumor tissue, perineural invasion (PNI), and lymphovascular invasion (LVI) are specified. If present, histological patterns/variants and the cribriform pattern are also noted. The International Society of Urological Pathology/World Health Organization grade groups can be specified in composite tumor reporting.^{11, 12} In addition, high-grade prostatic intraepithelial neoplasia (HGPIN), a precursor lesion of acinar adenocarcinoma, should be reported in the absence of a tumor, especially if ≥2 cores are present. However, if a tumor is detected during the biopsy, it is optional to report HGPIN. Atypical intraductal proliferation should also be noted.¹³

Radical prostatectomy (Rp) is an effective method for the treatment of localized PCa.¹⁴ The risk classification of the European Association of Urology (EAU) and patient's life expectancy according to age and comorbidities are taken into consideration when making the treatment decision.¹⁵ The most appropriate treatment method is offered to the patient by considering the clinical and histopathological factors known to affect the prognosis of the disease. Prognostic factors include age at diagnosis, serum PSA and PSA density values, clinical/pathological stage, tumor volume, GS, histological tumor type, PNI, LVI, the presence of the cribriform pattern and intraductal carcinoma, positive surgical margins, and lymph node metastasis.^15-19

It has been reported that the histological grade of the tumor increases in approximately half of patients who have undergone Rp compared to their diagnostic prostate biopsies.^{11, 20, 21} In these patients, there is an increase in disease recurrence rates after prostatectomy and the need for additional oncological treatment.²² Although there are some studies in the literature investigating parameters that can predict an increase in histological grade, such as age at the time of diagnosis, serum PSA and PSA density values, prostate volume, the number of tumor-positive cores in biopsies, and tumor quantification), it is not yet possible to draw clear conclusions that can guide the clinical approach in this field.^19-22 Therefore, studies on the evaluation of histopathological data obtained from diagnostic prostate biopsies are needed.

The aim of our study was to investigate clinical and histopathological parameters that might be associated with a histological tumor upgrade in the final pathology results of patients who were diagnosed with prostatic acinar adenocarcinoma by transrectal ultrasound-guided biopsy (TRUS-Bx) and underwent Rp.

2 MATERIALS AND METHODS

The study included 205 patients who were diagnosed with classical acinar adenocarcinoma by TRUS-Bx, had no metastasis on cross-sectional imaging, and underwent Rp at the Urology Department of Istanbul University-Cerrahpasa, Cerrahpasa Faculty of Medicine between 2019 and 2022. Patients with histological types/variants other than classical acinar adenocarcinoma and those who underwent a magnetic resonance fusion biopsy were not included. All patients were evaluated with MpMRI. Postdiagnostic metastasis screening was performed with a bone scan or prostate-specific membrane antigen positron emission tomography/computed tomography.

Age at diagnosis, serum PSA (ng/mL), prostate volume (in mL, measured with transrectal ultrasound), PSA density (ng/mL/mL), clinical T stages, and PI-RADS scores were recorded. The results of all biopsies were reported by a single experienced uropathologist. TRUS-Bx materials were fixed with Hollande's fixative, and Rp materials were fixed with 10% buffered formaldehyde. The histological tumor type, tumor percentage (%) in biopsy, GS, PNI, LVI, GP4/5 percentage in tumor (if present), presence of the cribriform pattern for GP4, and HGPIN were reported for each core on TRUS-Bx. Composite grading (Gleason grade) and diagnoses were also noted. In prostatectomy specimens, macroscopic prostate volume, final pathological diagnosis, GS, grade group, percentage of GP4/5 in the tumor, tertiary pattern percentage (if any), intraductal component percentage (if any), cribriform pattern (focal/multifocal), LVI, PNI, tumor volume percentage, tumor localization, tumor invasion, surgical margins, pathological T stage, HGPIN, nontumour prostatic tissue, and prostatic urethra were also evaluated, and the results were recorded.

The patients were grouped using the D'Amico risk classification in locally and locally advanced PCa.¹⁵ Accordingly, PSA < 10 ng/mL, T1–T2a, and Gleason grade group (GGG) 1 were defined as low risk; PSA 10–20 ng/mL, T2b, or GGG 2–3 as intermediate risk; and PSA > 20 ng/mL, T2c-T4, or GGG 4-5 as high risk. Clinical stages were defined according to the data obtained from the DRE reports. Radiological evaluation was performed according to the data obtained from the mpMRI reports. Age at the time of diagnosis, serum PSA, PSA density, prostate volume, PI-RADS scores, and clinical stages were compared according to the risk groups.

The distributions of parameters evaluated in TRUS-Bx materials, such as GGG, HGPIN in tumor-free cores (single core and ≥2 cores), PNI, and LVI, were analyzed and compared according to the risk groups. In addition, pathological stage, GGG, lymph node metastasis, surgical margin positivity, and tumor volume were obtained from Rp reports and compared between the risk groups.

Histological upgrade was defined as an increase in the total GS of the tumor in Rp specimens compared to TRUS-Bx findings or a change from primary/secondary to higher grades. The case groups in which tumor grade increased and remained the same were compared in terms of age, serum PSA, PSA density, HGPIN in tumor-free cores (single core and ≥2 cores), PNI and LVI in all biopsies (with and without tumors), and risk groups.

The relationships of HGPIN in tumor-free cores (single core and ≥2 cores), PNI, and LVI on TRUS-Bx with age, serum PSA and PSA density values, tumor volume, surgical margin positivity, pathological stage, and lymph node metastasis were also examined separately between each other.

2.1 Statistical analysis

All data were statistically analyzed using the SPSS Statistics (Version 21.0; IBM Corp) package program. Numerical values were expressed as mean ± standard deviation and median (interquartile range). Categorical data were expressed as frequencies and percentages. The suitability of quantitative data for a normal distribution was evaluated using the Kolmogorov–Smirnov normality test. The Kruskal–Wallis test was used to compare the quantitative data that did not fit a normal distribution in triple-group analyses. In paired-group analyses, the Mann–Whitney U test was conducted to compare data without a normal distribution, and the independent-samples t test was used to compare normally distributed data. χ² and Fisher's exact test were employed in the analysis of categorical variables. Upgrade rates were examined using backward logistic regression in univariate and multivariate analyses. The statistical significance limit of all evaluations was accepted as p < 0.05.

3 RESULTS

Of the 205 patients included in the study, 72 (35.1%) were in the low-risk group, 95 (46.3%) in the intermediate-risk group, and 38 (18.5%) in the high-risk group. The median age of all patients was 65 (58–69) years. Table 1 summarizes the data on age at diagnosis, serum PSA, PSA density, prostate volume, PI-RADS scores, and clinical stages according to the risk groups. There was a significant increase in age, serum PSA, and PSA density as the risk group increased (p < 0.001, p < 0.05, and p < 0.001, respectively). No statistically significant difference was found between the risk groups in terms of prostate volume or clinical stage (p = 0.589 and p = 0.075, respectively). Of the 83 (40.6%) cases classified as PI-RADS ≤ 4, 33 (55.7%) were in the low-risk group, 42 (44.2%) in the intermediate-risk group, and eight (23%) in the high-risk group. The rate of PI-RADS 3 lesions was significantly higher in the low-risk group (p < 0.05) (Table 1).

Table 1. Demographic and clinical characteristics of all patients.

	Groups
	Overall (n = 205)	Low-risk patients (n = 72)	Intermediate-risk patients (n = 95)	High-risk patients (n = 38)		p Value
Age (year)	65 (58–69)	62 (56–67)	66 (59–71)	66 (62–73)		<0.001a, a
PSA (ng/mL)	7.1 (5–11.35)	5.7 (4.6–7.2)	8.9 (5.4–12)	19 (8.2–30.5)		<0.05a, a
PSA density (ng/mL/mL)	0.17 (0.11–0.29)	0.12 (0.9–0.19)	0.19 (0.11–0.33)	0.42 (0.14–1.02)		<0.001a, a
Prostate volume (mL)	45 (35–56.5)	45 (40–57.2)	53 (35–55)	43.5 (35–60)		<0.589a, a
PI-RADS score, overall (%)						<0.05b
2	6 (2.9)	2 (2.7)	3 (3.2)	1 (2.6)
3	23 (11.3)	13 (18)	8 (8.4)	2 (5.2)
4	54 (26.4)	18 (35)	31 (32.6)	5 (15.2)
5	29 (14.2)	5 (6.9)	15 (15.8)	9 (23.7)
NA	93 (45.5)	34 (47.2)	38 (40)	21 (55.3)
Clinical stage, overall (%)						0.075b
1	130 (63.4)	52 (72.2)	55 (67.9)	23 (60.5)
2	69 (33.7)	20 (27.8)	37 (38.9)	12 (31.6)
3	6 (2.9)	0 (0)	3 (3.2)	3 (7.9)

• Note: Data are expressed as median (interquartile range) or number (percentage), where appropriate. Bold values indicate statistical significance (p < 0.05).
• Abbreviations: NA, not applicable; PI-RADS, prostate imaging-reporting and data system; PSA, prostate-specific antigen.

GGG distributions determined on TRUS-Bx and Rp are summarized in Table 2. HGPIN in tumor-free cores was reported in 102 (49.8%) patients in TRUS-Bx. The HGPIN diagnosis was significantly higher in the low- and intermediate-risk groups (p < 0.05). HGPIN in ≥2 tumor-free cores was present in 83 (40.5%) patients and did not significantly differ between the risk groups (p = 0.077). The rates of PNI, LVI, the number of positive cores, maximum tumor core percentage, cribriform pattern and presence of intraductal carcinoma were significantly higher in the high-risk group (p < 0.001, p < 0.05, < 0.001, p < 0.001, p < 0.001, p = 0.005, respectively) (Table 2).

Table 2. Tumor characteristics of all patients according to the examination of TRUS-Bx and Rp specimens.

	Groups
	Overall (n = 205)	Low-risk patients (n = 72)	Intermediate-risk patients (n = 95)	High-risk patients (n = 38)	p Value
Tumor characteristics in TRUS-Bx specimens
Grade group,a overall (%)
1	89 (43.4)	72 (100)	13 (13.7)	4 (10.5)
2	53 (25.9)	0 (0)	45 (47.4)	8 (21)
3	39 (19)	0 (0)	37 (38.9)	2 (5.2)
4	15 (7.3)	0 (0)	0 (0)	15 (39.4)
5	9 (4.4)	0 (0)	0 (0)	9 (23.6)
HGPIN in tumor-free cores	102 (49.8)	41 (56.9)	49 (51.6)	12 (31.6)	<0.05b
HGPIN in ≥2 tumor-free cores	83 (40.5)	35 (48.6)	38 (40)	10 (26.3)	0.077b
PNI	162 (79.0)	45 (62.5)	80 (84.2)	37 (97.4)	<0.001b
LVI	25 (12.2)	4 (5.5)	11 (11.6)	10 (26.3)	<0.05b
Tumor characteristics in Rp specimens
Grade group,a overall (%)
1	51 (25)	34 (47.2)	15 (15.8)	2 (5.2)
2	78 (38)	26 (36.1)	42 (44.2)	10 (26.3)
3	47 (22.5)	9 (12.5)	27 (28.4)	11 (28.9)
4	20 (9.9)	2 (2.7)	7 (7.3)	11 (28.9)
5	9 (4.5)	1 (1.3)	4 (4.2)	4 (10.5)
Pathological T stage, overall (%)					<0.05c
1	5 (2.4)	0 (0)	5 (5.3)	0 (0)
2	124 (60.5)	40 (55.6)	66 (69.5)	18 (47.4)
3	76 (37.1)	32 (44.4)	24 (25.2)	20 (52.6)
Pathological N stage, overall (%)					<0.001c
0	59 (28.8)	8 (11.1)	33 (34.7)	18 (47.4)
1	14 (6.8)	2 (2.8)	10 (10.6)	2 (5.3)
NXd	132 (64.4)	62 (86.1)	52 (54.7)	18 (47.4)
Tumor volume,e overall (%)	1.4 (0.7–4.9)	0.72 (0.45–1.23)	1.8 (1.0–3.4)	6.5 (2.4–10.5)	<0.001f, f
Surgical margin positivity	119	20 (27.8)	44 (46.3)	22 (57.9)	<0.05b

• Note: Data are expressed as median (interquartile range) or number (percentage), where appropriate. Bold values indicate statistical significance (p < 0.05).
• Abbreviations: HGPIN, high-grade prostatic intraepithelial neoplasia; LVI, lymphovascular invasion; PNI, perineural invasion; Rp, radical prostatectomy; TRUS-Bx, transrectal ultrasound-guided prostate biopsy.

When the pathology reports of Rp were examined, it was observed that pT2 tumors were more common in the intermediate-risk group (p < 0.05). In addition, lymph node dissection was performed at a higher rate in the intermediate- and high-risk groups. N0 was found to be more common in the intermediate-risk group, while N1 was more prevalent in the high-risk group (p < 0.001). Tumor volume and surgical margin positivity were more common in the high-risk group (p < 0.001 and p < 0.05, respectively) (Table 2).

Most of the patients with a histological tumor upgrade (n = 38, 48.1%) were in the low-risk group (p < 0.05). An advanced median age, HGPIN in a single core or ≥2 tumor-free cores, percentage of cores with HGPIN and PNI were also more common in these patients (p < 0.05, p < 0.001, p < 0.001, p < 0.001 and p < 0.05, respectively). No significant difference was observed in terms of serum PSA, PSA density, or LVI (p = 0.25, p = 0.626, and p = 0.140) (Table 3).

Table 3. Presence of tumor upgrading according to age, PSA, PSA density, HGPIN diagnosis in tumor-free cores (single core or ≥2 cores), PNI, LVI, and D'Amico Risk classification of all patients who underwent Rp.

	Groups
	Not upgraded (n = 126)	Upgraded (n = 79)	p Value
Age (year)	63.5 (57–68)	67 (62–70)	<0.05a
PSA (ng/mL)	7 (5–11.1)	7.5 (5.6 –11.4)	0.25b, b
PSA density (ng/mL/mL)	0.16(0.1–0.33)	0.18 (0.11–0.26)	0.626b, b
HGPIN in tumor-free cores	33 (26.2)	69 (87.34)	<0.001c
HGPIN in ≥2 tumor-free cores	30 (23.81)	53 (67.09)	<0.001c
PNI	92 (70.02)	70 (88.6)	<0.05c
LVI	12 (9.52)	13 (16.46)	0.140c
D'Amico risk group classification, overall (%)			<0.05c
Low	34 (27)	38 (48.1)
Intermediate	64 (50.8)	31 (39.24)
High	28 (22.2)	10 (12.66)

• Note: Data are expressed as median (interquartile range) or number (percentage), where appropriate. Bold values indicate statistical significance (p < 0.05).
• Abbreviations: HGPIN, high-grade prostatic intraepithelial neoplasia; LVI, lymphovascular invasion; PNI, perineural invasion; PSA, prostate-specific antigen; Rp, radical prostatectomy.

In multivariate logistic regression analysis, the factors that could affect tumor upgrade were determined to be an advanced age (odds ratio [OR]: 1.087, 95% confidence interval [CI]: 1.029–1.148, p < 0.05), high serum PSA (OR: 1.047, 95% CI: 1.006–1.090, p < 0.05), HGPIN in ≥2 tumor-free cores (OR: 6.346, 95% CI: 3.136–12.912, p < 0.001), and PNI (OR: 3.138, 95% CI: 1.179–8.356, p < 0.05). LVI did not have any effect on tumor upgrade (p = 0.529). In this analysis, the rate of tumor upgrading was higher in the low-risk group compared to the intermediate- and high-risk groups (OR: 0.187, 95% CI: 0.080–0.437, p < 0.001 and OR: 0.054, 95% CI: 0.013–0.230, p < 0.001, respectively) (Table 4).

Table 4. Univariate and multivariate analyses of factors affecting tumor upgrading.

Variables	Univariate analysis			Multivariate analysis
	Odds ratio	Confidence interval	p Value	Odds ratio	Confidence interval	p Value
Age (year)	1.058	1.014–1.103	<0.05	1.087	1.029–1.148	<0.05
PSA (ng/mL)	1.01	0.986–1.035	0.418	1.047	1.006–1.090	<0.05
HGPIN in ≥2 tumor-free cores	6.523	3.498–12.164	<0.001	6.346	3.136–12.912	<0.001
PNI	2.874	1.294–6.383	<0.05	3.138	1.179–8.356	<0.05
LVI	1.817	0.807–4.339	0.144	1.525	0.474–4.285	0.529
D'Amico risk group classification, overall (%)
Low	Reference	Reference	Reference	Reference	Reference	Reference
Intermediate	0.433	0.231–0.814	<0.05	0.187	0.080–0.437	<0.001
High	0.32	0.136–0.753	<0.05	0.054	0.013–0.230	<0.001

• Note: Bold values indicate statistical significance (p < 0.05).
• Abbreviations: HGPIN, high-grade prostatic intraepithelial neoplasia; LVI, lymphovascular invasion; PNI, perineural invasion; PSA, prostate-specific antigen.

PNI on TRUS-Bx was significantly higher in patients with an advanced age and high serum PSA and PSA density values (p < 0.05, p < 0.05, and p < 0.001, respectively). LVI on TRUS-Bx was associated with high serum PSA and PSA density values (p < 0.05 and p < 0.05, respectively). Both PNI and LVI were significantly higher in cases with a higher tumor volume and surgical margin positivity (p < 0.05 and p < 0.001, respectively, for PNI and LVI). Lymph node metastasis was found to be higher in patients with HGPIN in ≥2 tumor-free cores, PNI or LVI on TRUS-Bx (p < 0.05, p < 0.001, and p < 0.001, respectively). When evaluated according to the risk groups, HGPIN in a single tumor-free core was significantly higher in low- and intermediate-risk cases (p < 0.05), while PNI and LVI were higher in the high-risk group (p < 0.001 and p < 0.05, respectively). No parameter was associated with the pathological stage (Table 5).

Table 5. Correlation between prognostic factors and baseline parameters of the study.

Prognostic factors/baseline parameters
	HGPIN			≥2 HGPIN			PNI			LVI
	Absent (n = 103)	Present (n = 102)	p Value	Absent (n = 122)	Present (n = 83)	p Value	Absent (n = 43)	Present (n = 162)	p Value	Absent (n = 180)	Present (n = 25)	p Value
Age (year)	64 (57–68)	66 (60–70)	0.052a	64 (58–69)	65 (58–69)	0.549a	61 (57–65)	65.5 (59–70)	<0.05a	64 (58–69)	66 (64–73.5)	0.055a
PSA (ng/mL)	7 (5–11.8)	7.2 (5.5–11.1)	0.503a	7.1 (5–12.3)	7 (5.1–11)	0.869a	6.7 (4.6–8.4)	7.5 (5.1–13.5)	<0.05a	6.9 (5–11)	10.7 (8.8–15.1)	<0.05a
PSA density (ng/mL/mL)	0.15 (0.10–0.31)	0.19 (0.12–0.29)	0.155a	0.15 (0.10–0.33)	0.19 (0.11–0.28)	0.378a	0.12 (0.9–0.2)	0.19 (0.12–0.33)	<0.001a	0.16 (0.1–0.26)	0.25 (0.15–0.39)	<0.05a
Surgical margin positivity	42 (40.8)	44 (43.1)	0.732b	51 (41.8)	35 (42.11)	0.958b	12 (28)	74 (45.7)	<0.05b	69 (38.4)	17 (68)	<0.05b
Rp tumor volume (%)	9 (3–20)	9.3 (3.7–17.4)	0.657a	9.4 (3.4–20.1)	8.9 (3.5–17.4)	0.903a	2 (1–4)	11.2 (5.6–21)	<0.001a	7.8 (3–15)	26.2 (17.4–48.8)	<0.001a
D'Amico risk group classification, overall (%)			<0.05b			0.076b			<0.001b			<0.05b
Low	31 (30.1)	41 (40.2)		37 (30.3)	35 (42.2)		27 (62.8)	45 (27.7)		68 (37.7)	4 (16)
Intermediate	46 (44.7)	49 (48.0)		57 (46.7)	38 (45.8)		15 (34.9)	80 (49.4)		84 (46.6)	11 (44)
High	26 (25.2)	12 (11.8)		28 (23)	10 (12)		1 (2.3)	37 (22.8)		28 (15.5)	10 (40)
Lymph node metastasis	10/53 (18.8)	4/50 (8)	0.258b	10/73 (13.6)	4/30 (13.3)	<0.05b	0/8 (0)	14/95 (14.7)	<0.001b	5/84 (5.9)	9/19 (47.3)	<0.001b
Pathological T stage. overall (%)			0.927c			0.919c			0.617c			0.117c
1	2 (1.9)	3 (2.9)		3 (2.5)	2 (2.4)		0 (0)	5 (3.1)		5 (2.7)	0 (0)
2	62 (60.2)	62 (60.8)		75 (61.5)	49 (59.0)		25 (58.1)	99 (61.1)		113 (62.7)	11 (44)
3	39 (37.9)	37 (36.3)		44 (36.0)	32 (38.6)		18 (41.9)	58 (35.8)		62 (34.4)	14 (56)

• Note: Data are expressed as median (interquartile range) or number (percentage), where appropriate. Bold values indicate statistical significance (p < 0.05).
• Abbreviations: HGPIN, high-grade prostatic intraepithelial neoplasia; ≥2 HGPIN, diagnosis of HGPIN in two or more tumor-free cores; LVI, lymphovascular invasion; PNI, perineural invasion; PSA, prostate-specific antigen; Rp, radical prostatectomy.

4 DISCUSSION

The most important parameter that has consistently maintained its relevance throughout the years in assessing the treatment and prognosis of PCa is GGG that determined by the histopathological examination of the tumor.²³ Technological developments in imaging methods have led to the diversification of biopsy techniques and to the diagnosis of PCa at an earlier age and at a higher rate. Moreover, studies have shown that in approximately half of patients, tumor grades reported in diagnostic biopsies are lower than those determined in prostatectomy specimens.^{11, 20, 21} This is of vital importance in terms of active surveillance (AS) and/or the timely evaluation of curative treatment options, especially in patients diagnosed at an early age.²⁴ Although there are studies in the literature on the parameters that can predict a histological upgrade, clear conclusions that can guide the clinical approach have not yet been reached.^19-22 Flammia et al. conducted a comprehensive study, revealing that parameters routinely utilized for predicting a tumor upgrade are not adequate.²⁰ Therefore, there is a need for studies to evaluate histopathological data that can predict tumor upgrade in prostatectomy specimens derived from diagnostic prostate biopsies.

Another parameter used to assess PCa prognosis, biochemical recurrence, and the need for additional treatment is the D'Amico risk group, of which GGG is a component.¹⁵ In a multicentre study conducted by Bullock et al. with a large number of patients, it was shown that the histological upgrade was higher in low-risk patients than in intermediate- and high-risk patients. In addition, it was concluded that patients with higher GGG on the diagnostic biopsy had a lower risk of histological upgrade.²⁵

In another study evaluating a low-risk group, Schiffmann et al. found that patients who did not meet the criteria for active surveillance according to the EAU and German guidelines had a higher tendency of histological upgrade.²⁶ However, the AS criteria utilized in that study exhibited significant similarities with the National Comprehensive Cancer Network criteria for highly selected and very low-risk cases of PCa. Therefore, a higher histological upgrade may be expected in patients who do not meet the AS criteria.

In our study, 38 (48.1%), 31 (39.24%), 10 (12.66%), and 10 (12.66%) of the patients with a histological upgrade were in the low-, intermediate- and high-risk groups, respectively. The rate of patients in the low-risk group was significantly higher (p < 0.05), and being in the low-risk group was determined to be an independent risk factor when compared to the remaining risk groups (intermediate risk OR: 0.187, 95% CI: 0.080–0.437, p < 0.001 and high risk OR: 0.054, 95% CI: 0.013–0.230, p < 0.001).

In addition to GS, patient age at diagnosis, serum PSA, PSA density, PNI, LVI, tumor volume, surgical margin positivity, lymph node metastasis, and stage have been shown to be important prognostic parameters for PCa in many studies.^15-22 Jung et al. compared the presence of PNI, LVI, and HGPIN in Rp specimens between risk groups and showed that PNI and LVI were more common in the high-risk group, but there was no significant difference in terms of HGPIN.²⁷ In various studies investigating the relationship of PNI with other known prognostic parameters, although high PSA was found to be associated with tumor volume, surgical margin positivity, and pathological stage, the data on age and lymph node metastasis were contradictory.^{27, 28}

In the literature, there are fewer studies investigating prognostic parameters in diagnostic biopsies. In a study on the prognostic significance of PNI in prostate biopsies, Lee et al. showed that patients without PNI were in the low-risk group, and those with PNI were in the intermediate-risk group. In the same study, the risk groups were also compared in terms of histological upgrade, but no significant difference was found.²⁹ When HGPIN, PNI, and LVI, which are among the parameters we examined in diagnostic biopsies in our study, were compared between the risk groups, PNI and LVI were found to be significantly higher in the high-risk group, while HGPIN (single tumor-free core) was found to be significantly higher in the low- and intermediate-risk groups (p < 0.001, p < 0.05, and p < 0.05, respectively). However, there was no significant difference between the groups in terms of the diagnosis of HGPIN in ≥2 tumor-free cores.

In studies conducted to determine the clinical parameters that may affect histological upgrade, advanced patient age and high serum PSA and PSA density values have been shown to be effective.^{19, 20, 25, 26} Although our sample size was smaller than in previous studies, our findings pertaining to advanced patient age and high serum PSA are consistent with the literature (age OR: 1.087, 95% CI: 1.029–1.148, p < 0.05 and PSA OR: 1.047, 95% CI: 1.006–1.090, p < 0.05).

The effect of histological parameters LVI and PNI on tumor upgrade remains unclear. In a large series of 2529 patients, Athanazio et al. examined at least one GS value change between prostate biopsies and Rp specimens and found that PNI was associated with the histological upgrade in patients with GS (3 + 3) 6.³⁰ On the other hand, Barsky et al. analyzed the effect of the presence of PNI in prostate biopsies on the final GS in prostatectomy specimens and found that the absence of PNI was associated with increased GS.³¹ In our study, an increase in the GS of the tumor was found in the Rp of cases with PNI on TRUS-Bx (p < 0.05). In addition, the presence of PNI had a positive correlation with advanced age, high serum PSA, PSA density, surgical margin positivity, high tumor volume, and lymph node metastasis, but not with the pathological stage.

In the literature, there is no study examining the effect of LVI on histological upgrade. Comprehensive meta-analysis studies have not shown an association between LVI and advanced patient age, but they have revealed that LVI is correlated with high GS, high serum PSA, surgical margin positivity, lymph node metastasis, and advanced pathological stage.^32-35 We observed no effect of LVI on the histological upgrade. However, we determined that it was associated with high serum PSA and PSA density values, surgical margin positivity, high tumor volume, and lymph node metastasis, but not with pathological stage.

In a review by Epstein et al. on the importance of HGPIN, which is the precursor lesion of prostatic acinar adenocarcinoma, in prostate biopsies, it was revealed that patients with HGPIN in the first diagnostic biopsy had an average tumor rate of 31.5% in subsequent biopsies and a tumor rate of 58-70% in patients with HGPIN in ≥2 cores. However, although these rates were high, there was no significant difference in the rates of tumor detection in the subsequent biopsies of patients with HGPIN when compared to those with initially benign diagnostic biopsies.³⁶ In a similar study by Gokden et al., the rates of cancer detection in repeated biopsies after HGPIN were 30.5% and 26.2% after benign biopsies. No significant difference was found between the groups. Furthermore, it was shown that patients with HGPIN in the second biopsy were diagnosed with cancer at a higher rate during the follow-up compared to those with benign pathologies.³⁷ Other recent studies have shown that patients with HGPIN in ≥2 cores in the first biopsy have a high rate of invasive cancer (30.5%–80%) in subsequent biopsies and have a higher risk compared to those with benign pathologies.^{38, 39}

There are studies investigating the effect of HGPIN on GS in the final pathology. Pietzak et al. showed that patients who met the criteria for active surveillance but were treated with Rp and were diagnosed with HGPIN based on prostate biopsies had no increase in GS in the final pathology.⁴⁰ Prathibha et al. compared the rate of adenocarcinoma detected in the repeat biopsies of patients with HGPIN and/or atypical small acinar proliferation (ASAP) with patients with no tumors detected in the first biopsy. Although the rate of adenocarcinoma detection (43.7%) and the rate of clinically significant (GS ≥ 7) cancer detection (16.7%) were higher in the repeat biopsies of patients with an HGPIN/ASAP diagnosis in biopsies, there was no statistically significant difference.⁴¹ Erdem et al., who examined the increase in GGG in Rp specimens, found that the presence of HGPIN in the tissue around the tumor was associated with the GGG increase.⁴²

Our study holds significance in terms of examining the effect of the presence of HGPIN in tumor-free cores in diagnostic biopsies on the GS increase of the tumor in Rp. The presence of HGPIN even in a single core in tumor-free cores on TRUS-Bx in patients with a diagnosis of acinar adenocarcinoma is important in showing the histological upgrade of the tumor in Rp (p < 0.001). In addition, the diagnosis of HGPIN in ≥ 2 tumor-free cores was determined as an independent risk factor for an increased GS (OR: 6.346, 95% CI: 3.136–12.912, p < 0.001). The existing literature does not establish a correlation between HGPIN and other prognostic parameters, such as advanced patient age, high serum PSA, tumor volume, surgical margin positivity, advanced pathological stage, and lymph node metastasis.^{27, 40} Although our findings were similar to the literature, only HGPIN in ≥2 tumor-free cores were associated with a higher rate of lymph node metastasis (p < 0.05).

Studies have shown that it is important and necessary to report HGPIN in prostate biopsies. Our study reveals the importance of an HGPIN diagnosis in tumor-free cores of TRUS-Bx in cases of acinar adenocarcinoma. In addition to PNI, we consider HGPIN to be a useful parameter to predict tumor upgrade on TRUS-Bx.

In our center, HGPIN is routinely reported in TRUS-Bx. Given that we are a reference center, HGPIN is not always reported in the pathology reports of biopsies submitted for consultation. Hollande's fixative solution has been used in our laboratory for TRUS-Bx for 26 years. This fixative preserves the nuclear detail of cells and better reflects cytoplasmic changes. The diagnosis of HGPIN is almost always made morphologically, and additional staining is rarely needed. Biopsies from external centers are formaldehyde-fixed tissues, which presents challenges in conducting morphological evaluations. Therefore, immunohistochemical studies, especially alpha-methylacyl-CoA racemase, and basal cell markers (p63 or high-molecular-weight keratin) are required to evaluate HGPIN and sometimes even tumors. Although the cost of Hollande's fixative solution is higher compared to that of formaldehyde, it is possible to mitigate the rise in cost and reporting time by avoiding additional tests. Owing to its superiority over formaldehyde, we recommend the use of Hollande's fixative solution in TRUS-Bx.

In recent years, artificial intelligence algorithms have been investigated for the purpose of determining clinical approaches. These algorithms encompass a wide range of patient data, medical records, a family history of cancer, laboratory test results, radiological and pathological findings, treatment details, and clinical follow-up data. In such studies that are important for patient management, the diagnosis of HGPIN in tumor-free cores of TRUS-Bx samples diagnosed with tumors may also have significant implications for patient care.

Since interventional procedures are carried out by a team in our center, it is possible for the practitioners involved to consist of different physicians. Although this situation may initially appear to be a limitation for our retrospective study, a similar situation or pattern occurs for applications performed by different physicians worldwide. Another limitation of our study is that the results were not supported by molecular biomarker analyses that have been shown to be useful in demonstrating the histological upgrade.

5 CONCLUSION

PCa can now be diagnosed at younger ages thanks to technological advances in imaging and diagnostic methods. According to diagnostic biopsies, active surveillance is recommended more frequently for these patients, who are mostly in the low-intermediate risk group, in order not to affect their quality of life. However, it has been shown that tumor grade increases in approximately half of this group of patients who have undergone prostatectomy. This is especially important for the timely evaluation of curative treatment options for patients diagnosed at an early age.

The presence of HGPIN even in a single core in tumor-free cores on TRUS-Bx samples with a diagnosis of acinar adenocarcinoma was found to be significant in terms of the histological upgrade of the tumor in Rp, and HGPIN in ≥2 tumor-free cores was determined as an independent risk factor in determining an increase in GS. The diagnosis of HGPIN is more common in low- and intermediate-risk groups. In addition, advanced age, high serum PSA values, being in the low-risk group, and PNI were associated with a tumor upgrade. PNI, LVI, and HGPIN in ≥2 tumor-free cores were also correlated with lymph node metastasis. Our study is unique and important in terms of examining the effect of the presence of HGPIN in tumor-free cores in diagnostic biopsies on the GS increase of the tumor in Rp.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

REFERENCES