The present study is of cross-sectional type, conducted over a period of four years, from January 2015 to December 2019, in the Department of Pathology, SDM College of Medical Sciences and Hospital, Shri Dharmasthala Manjunatheshwara University, Sattur, Dharwad, Karnataka, India. After obtaining ethical clearance (Ref: SDMIEC/2023/571) from the Institutional Review Board, all biopsies diagnosed as prostatic adenocarcinoma were included in the study. Consent was not mandatory due to the retrospective nature of the study. To ensure confidentiality, participants’ histopathology and clinical data were linked to a unique code number.

Inclusion and Exclusion criteria: All biopsies {Transurethral Resection of Prostate (TURP)/core needle biopsy} diagnosed as prostatic adenocarcinoma were included in the study. After excluding inadequate and/or poorly preserved tissue samples, patients who had received prior chemotherapy, radiotherapy, or any other modality of treatment, as well as those who died due to other co-morbidities unrelated to prostatic carcinoma, a total of 52 cases were included in the study.

The number of cores was counted for needle biopsy samples and all cores were submitted for histopathologic examination. The weight was measured in the case of TURP chips. If the total weight was <12 g, all chips were submitted for processing. One cassette was submitted for every additional 5 g of remaining prostatic chips. Demographic details, clinical presentations and preoperative and postoperative PSA levels were retrieved from hospital medical records.

The Haematoxylin and Eosin (H&E)-stained histopathology slides from these 52 patients were independently reviewed by two pathologists. GS was assigned for all the cases, while GG was assigned separately for each case according to the recommendations of the consensus meetings of ISUP in 2005 and 2014 [2,5]. According to the 2014 ISUP, cribriform, fused and glomeruloid glands were assigned to pattern 4 [Table/Fig-1]. GS of seven were further divided into two groups based on the proportion of patterns 3 and 4: 3+4=7 and 4+3=7. The patients were grouped into prognostic grade groups based on GS as follows: Group 1 (3+3); group 2 (GS 3+4); group 3 (GS 4+3); group 4 (GS 3+5; 4+4; 5+3); and group 5 (GS 5+4; 4+5; 5+5). Discrepancies in assigning GS and GG were resolved by consensus obtained through multiheaded microscope observation. The presence of PNI, IDC and CFP was documented. The percentage of tumour involvement (>50%) was noted separately for all cases. Cases with unusual histomorphological patterns were also observed, and GS and GG were assigned accordingly. Follow-up data regarding recurrence, treatment, metastasis and death were obtained from medical records and/or through telephonic communication. GG and GS were compared with the occurrence of metastasis and death.

[Table/Fig-1]:

Assignment of Gleason Score (GS) according to ISUP 2005 and ISUP 2014 recommendations. a) Glomeruloid pattern (Fig.a, 400X, H&E) assigned Gleason Pattern (GP) 3 in ISUP 2005 recommendation was reassigned GP 4 as per ISUP 2014 recommendations. b) Small Cribriform Pattern (CFP) (Fig.b, 400X, H&E) was assigned Gleason Pattern (GP) 3 in ISUP 2005 recommendation, was reassigned GP 4 as per ISUP 2014 recommendations.

Mean and Standard Deviation (SD) were calculated to describe continuous variables, while frequencies and percentages were used for categorical variables. Microsoft Excel was used for data entry and the Statistical Package for Social Sciences (SPSS) version 25.0 was used for descriptive statistical analysis.

The present study had a total of 52 cases. The age distribution ranged from 52 to 88 years, with the mean age of presentation being 70.21 years. There were a total of 30 core needle biopsy specimens and 22 TURP specimens, with none being radical prostatectomy specimens. The histopathological diagnosis was adenocarcinoma in all the cases, which also included three unusual variants. The special variants were one case each of SRCC, pseudo-hyperplastic adenocarcinoma and intraductal foamy gland carcinoma [Table/Fig-2]. PSA levels were documented in all the cases during the preoperative and postoperative follow-up periods. Preoperative PSA levels ranged from 0.69 ng/mL to 1745 ng/mL, with an average of 173.48 ng/mL. All cases were classified according to ISUP 2005 and then regrouped according to the newer grading system as per the ISUP 2014 consensus. The grades of the cases studied in the current study were as follows: 7 (13.46%) in grade 1, 5 (9%) in grade 2, 6 (11.5%) in grade 3, 8 (15.38%) in grade 4 and 26 (50%) in grade 5, as shown in [Table/Fig-3]. The score was upgraded in 14 cases (26.92%) with the advent of the newer grading system. After re-evaluating with the revised score, seven cases were reassigned from group 4 to group 5. Three cases from group 2 were reallocated to group 5 and two cases from group 2 were moved to group 3. One case was reassigned from group 1 to group 4. There were 7 cases (13.46%) that were downgraded from the original scores to lower scores. In this, two cases were reassigned from group 5 to group 3, one from group 3 to group 2 and one from group 2 to group 1. One case was moved from group 4 to group 5. Follow-up details are tabulated and presented in [Table/Fig-4]. Metastatic deposits were observed in 23 (44.23%) cases in different parts of the body. The most common site was found to be the vertebrae (13 cases). Other sites of involvement included multiple bones (long bones, ribs, pelvic bones), the urinary bladder, liver and pelvic and paraaortic lymph nodes. The majority (14 cases) belonged to GG5 (10 cases) and GG4 (4 cases). The remaining cases belonged to GG3 (3 cases), GG2 (4 cases) and GG1 (2 cases). There were a total of 8 (15.38%) patients who died during the study period, with the majority of these (6 cases) being in GG5. Three of these patients also had metastasis. A comparison of GS (ISUP 2005) and GG (ISUP 2014) with the presence or absence of metastasis in these patients was tabulated [Table/Fig-5]. PNI was observed in 34 (65.38%) cases. The tumour involvement by tissue cores ranged from 20% to 85%. CFP was present in 25 (48.07%) cases. Tissue cores with over 50% tumour involvement were seen in 32 cases (61.53%). These histomorphology parameters were compared with the occurrence of metastasis [Table/Fig-6].

[Table/Fig-2]:

Unusual histopathologic variants of prostatic adenocarcinoma. a) Diffuse sheets of signet ring cells in case of signet ring cell adenocarcinoma (400x, H&E); b) Intraductal pseudohyperplastic tumour cells in glands, cords and Cribriform Pattern (CFP) (100x) in a case of pseudohyperplastic prostatic carcinoma.

The incidence of prostate cancer varies across different regions of the world, representing 7.1% of all cancers in men [13]. Prostate cancer incidence rates are highly variable worldwide. Africa (26.6%) and Asia (11.5%) account for lower incidence rates compared to developed countries such as North America (73.7%), followed by Europe (62.1%). Age plays a significant role in the incidence and mortality rates of prostatic carcinoma, with almost 55% of all deaths occurring after 65 years of age [1]. The mean age of the patients in this study was 70 years. In a study by Ceyhan E et al., the mean age was found to be 63.1±6 years, which also included radical prostatectomy specimens [14]. The mean PSA value was 173.40 ng/mL, while a lower mean value of 14.8±6.7 was reported. The presence of a proportion of pattern 4 had a significant impact on assigning grades. The separation of GS 7 into 3+4=7 (GG2) and 4+3=7 (GG3) has different implications for management and treatment. For example, a prostatic core with a GS of 3+4=7, where pattern 4 accounted for <5%, behaved like 3+3=6 regarding BCR-free survival rate and had similar prostatectomy findings, thus qualifying it for active surveillance [9]. There were a total of 14 cases assigned GS 7 according to the 2005 ISUP guidelines. As per the 2014 ISUP guidelines, this was decreased to 11 cases (3+4=5 cases, GG2; 4+3=6 cases, GG3). Total of 66.66% (4 cases) with 4+3 and 60% of cases with 3+4 presented with metastasis. Even though this difference is not statistically significant due to a smaller sample size and limited duration of follow-up, it underscores the importance of segregating GS 7 into 3+4 and 4+3. GS of 10 was assigned to 5 cases according to ISUP 2005 and was outnumbered by 1 according to ISUP 2014. GG5 constituted 50% of cases, which included GP 4+5 (12 cases), 5+4 (8 cases) and 5+5 (6 cases). A 31.57% of the cases assigned with GS 9 and 10 presented with metastasis when compared to 38.4% of GG5 cases that had metastasis. The examination of radical prostatectomies, targeted biopsies with radiologic assistance, along with core needle biopsies, could better delineate the prognostic differences [15-18].

Authors observed that 70.58% of the present cases displayed PNI, 71% of cases with CAF were present and 42.85% of cases with more than 50% tumour involvement on histopathology presented with metastasis. The measurement of the extent of a tumour, such as the total length of cancer in millimeters and/or the percentage of the core involved by the tumour, serves as a potential prognostic factor in prostatic carcinoma [19,20]. In a study by Zelic R et al., the number of cores with more than or equal to 50% cancer independently predicted cancer death, regardless of the GG [10]. They also proposed that comedo necrosis is an independent prognostic factor. The presence of other histomorphological features such as CFP, PNI and the percentage of GP4 may aid in patient prognostication along with GG [19,21-25]. In a study examining the statistical correlation between PNI and PSA recurrence, disease-free survival rates were higher in patients without PNI (64% versus 24%) [25]. Out of the eight cases that died during the study period, six belonged to GG 9 and 10, indicating an association of higher GG with poor prognosis. The remaining two cases that died belonged to lower grades. In these cases, the confounding factors of other co-morbidities could not be ruled out. The authors encountered 23 patients (44.23%) with metastasis. The average age of metastasis was 67.63 years and only one case presented with metastasis at less than 55 years. Over 50% of patients (14 cases) belonged to GS 9 and 8, with two cases assigned GS 10. Bone was the most common site, with a predilection for the lumbar vertebra (13 cases) and pelvic bones. Multiple sites of bone involvement (long bones, ribs, pelvic bones) were seen in seven cases. Urinary bladder involvement was noted in two cases, while liver metastasis, as well as pelvic and para-aortic lymph node metastasis, was observed in one case. Similar findings were reported by Ondo CZ et al., [26]. SRCC of the prostate is a rare tumour first described in 1981, characterised by sheets of tumour cells displaying intracytoplasmic vacuoles (GS 5) with compressed, crescent-shaped, eccentrically placed nuclei [27,28]. This rare variant accounts for 2.5% of cases of prostate adenocarcinoma. The diagnosis of primary prostatic SRCC is challenging, as a complete work-up is needed to rule out metastasis from gastrointestinal origins. Correct diagnosis of pseudo-hyperplastic carcinoma may be challenging, as it mimics benign prostatic hyperplasia. Immunohistochemistry is essential for the correct diagnosis and GS should be assigned according to standard definitions [29]. Foamy gland carcinoma is a unique variant of prostatic adenocarcinoma, first described in 1996. It is characterised by a 3+3 pattern, displaying well-formed discrete glands with relatively bland nuclei, inconspicuous nucleoli and frequent intraluminal dense pink secretions [30]. In the present study, the authors observed a GS of 4+4 with higher grade presentation.

The present study has some limitations. The regrouping of prostate biopsies according to the 2005 ISUP guidelines was prone to observer bias, as the pathologists were already accustomed to the newer 2014 ISUP recommendations as part of their routine institutional reporting. The findings from core biopsies and TURP chips were not correlated with the radical prostatectomy specimens. Additionally, the limited sample size and duration of follow-up may have interfered with the study results. Implementing optimal biopsy techniques, using an adequate number of cores, incorporating radiologic assistance and evaluating the role of confounding factors would greatly enhance the strength of the present study.

The current study underscores the prognostic importance of the ISUP 2014 GG system over the ISUP 2005 GS system. Rare histopathologic variants of prostatic adenocarcinomas pose diagnostic challenges in assigning the GS and establishing the correct diagnosis. Histomorphological parameters such as PNI, CFP and the percentage of tumour involvement (greater than 50% involvement) significantly influence prostate cancer prognosis. These factors may provide valuable information for optimal clinical management.