Histopathological Study of the Prostate Cancer Growth Patterns in Relation with the Grading Systems.

Prostate adenocarcinomas are common lesions with a high incidence and variable prognosis, which can be assessed using tumor grading systems. In this study, we analyzed 329 prostate adenocarcinomas in relation to tumor variants, growth patterns, classical and updated grading systems. The study indicated statistical associations of atrophic, pseudohyperplastic and microcystic variants with low grading scores, the associations of glomeruloid, cribriform with or without necrosis and signet ring-like cell variants with high grading scores, and also of single growth patterns with intermediate scores, which supports the accordance and usefulness of existing grading systems for the identification of aggressive prostate tumor lesions.

Introduction

Although prostate adenocarcinoma (PA) has a relatively good prognosis compared with other malignant tumors, it raises major problems in clinical practice through the incidence and possible aggressive evolution of some histological subtypes.

Therefore, the individual assessment of the aggressive potential of each tumor is indispensable in the evaluation of clinical decisions in these patients.

The Gleason scoring system introduced by more than half a century ago, has remained one of the strongest prognostic and predictive factors of PA, hence of clinical therapeutic decisions [1].

One of the strengths of the traditional Gleason classification is that it takes into account the lesional heterogenity of PA.

Gleason scores (GS) are based on the classification of architectural patterns of tumors, being a sum of major and minor architectural models, appreciated on the prostate specimen, which varies from 2-10.

Due to this wide range of scores, the International Society of Urological Pathology (ISUP) and the World Health Organization (WHO) have introduced a new grading concept, with GS being assigned grade groups from 1 to 5 [2,3], to better reflect the prognostic implications, with a good reproducibility in the pathological reporting [4].

In reality, this is a different way of grouping GS than a whole new scoring system [2].

Modified Gleason grade has been shown to be one of the strongest prognostic indicators of clinically localized tumors and is one of the best factors used in establishing the management of these patients [5].

The present study aims to identify the different architectural patterns of the PA according to the modified GG and to place them in the corresponding ISUP groups.

Materials and Methods

The present study included a number of 329 cases of PA, the biological material being represented by tissue fragments obtained during prostate biopsy or prostate tumor transurethral resection (TURP), from patients hospitalized to the Urology Clinic of the Emergency County Clinical Hospital Craiova for a period of 4 years (2018-2021).

The tumor fragments were fixed in 10% buffered formalin, processed by the usual paraffin embedding technique and stained with Hematoxylin-Eosin in the Pathology Department of the same hospital.

We aimed to quantify the growth patterns in relation to the ISUP groups, according to the WHO/ISUP recommendations [2,3].

For the statistical analysis we used comparison tests (χ2 test) within the SPSS 10 software (Statistical Package for the Social Sciences), the p values <0.05 being considered significant.

The study was approved by the Ethics Committee of the University of Medicine and Pharmacy of Craiova, and written informed consents were obtained from patients.

Results

The study included 329 PAs that corresponded: 109 cases to GS 6/ISUP 1, 41 cases to GS 7/ISUP 2, 25 cases to GS 7/ISUP 2, 69 cases to GS 8/ISUP 4 and 85 cases to GS 9 and 10/ISUP 5 (Table 1).

Table 1

Distribution of cases related to PA variants and grading systems

Gleason grading scores/ growth patterns	6/ 3+3	7/ 3+4	7/ 4+3	8/ 3+5	8/ 5+3	8/ 4+4	9/ 4+5	9/ 5+4	10/ 5+5	Total
ISUP grading groups	1	2	3	4			5
Conventional (acinar)	51	23	14	12	2	22	22	7	35	188
Foamy gland	19	10	7	3	1	12	-	-	7	59
Conventional/ foamy gland	15	3	2	2	-	10	-	4	-	36
Conventional/ atrophic	14	3	2	-	-	-	-	-	-	19
Conventional/ microcystic	6	-	-	-	-	-	-	-	-	6
Conventional/ pseudohyperplastic	4	2	-	-	-	-	-	-	-	6
Conventional/ cribriform	-	-	-	-	3	-	-	-	-	3
Conventional/ glomeruloid	-	-	-	-	2	-	-	-	-	2
Conventional/ cribriform/comedonecrosis	-	-	-	-	-	-	-	3	2	5
Conventional/ signet ring-like cell	-	-	-	-	-	-	-	-	5	5

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The analysis of the architectural and cytological patterns of PA indicated in 247 (75%) cases the presence of single patterns, for the remaining 82 (25%) cases two histological patterns being associated.

In 109 cases (33.1%) we identified PAs corresponding to GS 6 (3+3)/ISUP 1.

In 70 cases we found the presence of single patterns, represented by the conventional or foamy gland type (Figure 1A).

Figure 1

Prostate adenocarcinoma. A. Conventional and atrophic patterns, GS 6 (3+3)/ISUP 1, HE staining, ×200; B. Conventional pattern, GS 7 (3+4)/ISUP 2, HE staining, ×400; C. Foamy gland pattern, GS 7 (3+4)/ISUP 2, HE staining, ×400; D. Conventional pattern, GS 7 (4+3)/ISUP 3, HE staining, ×200; E. Foamy gland pattern, GS 8 (4+4)/ISUP 4, HE staining, ×400; F. Conventional and cribriform patterns GS 8/ISUP 4, HE staining, ×200; G. Conventional and glomeruloid patterns GS 8/ ISUP 4, HE staining, ×200; H. Conventional and cribriform wirh comedonecrosis patterns, GS 10/ ISUP 5, HE staining, ×200

In 39 cases associated patterns were present, respectively conventional and foamy gland, conventional and atrophic, conventional and microcystic, conventional and pseudohyperplastic.

We found 41 cases (12.5%) for PAs corresponding to GS 7 (3+4)/ISUP 2.

The single patterns were present in 33 cases, also with conventional or foamy gland appearance (Figure 1B,1C).

We identified the associated patterns in 8 cases, represented by the coexistence of the conventional pattern with foamy gland, conventional and atrophic, conventional and pseudohyperplastic.

For the PAs corresponding to GS 7 (4+3)/ISUP 3 we identified 25 cases (7.6%).

The single patterns were present in 21 cases, with a conventional or foamy gland appearance (Figure 1D).

We observed the associated patterns only in 4 cases, represented by the coexistence of the conventional with foamy gland or atrophic patterns.

For PAs corresponding to GS 8/ISUP 4 we found 69 cases (21%), which included for GS (3+5) 17 cases, GS (5+3) 8 cases and GS (4+4) 22 cases.

Single tumor patterns were observed in 57 cases, which had a conventional or foamy gland appearance (Figure 1E).

The associated patterns were present in 17 cases, in which there were conventional aspects with foamy gland, conventional and cribriform, conventional and glomeruloid (Figure 1F,1G).

For PAs corresponding to GS 9 and 10/ISUP 5 we found 85 cases (25.8%), which included for GS (4+5) 22 cases, GS (5+4) 14 cases and for GS (5+5) 49 cases.

Single tumor patterns were observed in 71 cases, which present a conventional or with foamy gkland pattern.

The associated patterns were present in 14 cases, in which there were conventional aspects with foamy gland, conventional and cribriform with comedonecrosis, conventional and with signet ring-like cells (Figure 1H).

Statistical analysis of the investigated PA typs indicated the association of low 6/7 Gleason scores with adenocarcinomas with atrophic, pseudohyperplastic and microcystic patterns and of high Gleason scores 8-10 with those with glomeruloid component, cribriform with or without comedonecrosis and signet ring-like cell, while single pattern conventional tumors or those with foamy gland showed variable scores (p<0.001, test χ2) (Figure 2A), aspects that were also observed in the case of associations with growth patterns (p<0.001, test χ2) (Figure 2B) and with ISUP grading groups (p<0.001, test χ2) (Figure 2C).

Figure 2

A. Distribution of cases in relation to the PA variants and Gleason Score; B. Distribution of cases in relation to the PA variants and the growth pattern; C. Distribution of cases in relation to PA variants and ISUP grading groups; D. Distribution of cases in relation to the Gleason Score and ISUP grading groups

Note* C=conventional; C/A=conventional/atrophic; C/C=conventional/cribiform; C/C/C=conventional/cribiform/ comedonecrosis; C/FG=conventional/foamy glands; C/G=conventional/glomeruloid; C/M=conventional/microcystic; C/P=conventional/pseudohyperplastic; C/SR=conventional/signet ring-like cells; FG=foamy glands

At the same time we found the association of low Gleason scores 6/7 with ISUP groups 1-3 and of the Gleason high scores 8-10 with ISUP groups 4-5 (p<0.001, test χ2) (Figure 2D), which supports the utility of these systems for identifying aggressive PAs.

Discussion

Despite the interobserver variation between pathologists, the histopathological gradation of PA remains the strongest prognostic indicator of disease recurrence and death, as well as the main tool for stratifying patients for different treatment options [6].

The classification of PA has changed considerably over time, mainly due to major advances in diagnostic approaches and procedures, as well as early detection of the disease.

Several changes have been made to improve the prognostic significance of various tumor groups, in order to reduce interobserver variability and to increase the agreement between prostate biopsy and radical prostatectomy [7].

During the 2014 ISUP Consensus Conference on PA Classification, a number of amendments were adopted and subsequently included in the 2016 WHO Classification [3].

Thus, the latest classification according to the groups of degrees recommended by the WHO/ISUP is based on GS, which is evaluated on the basis of architectural models.

The prognostic use of ISUP degrees has been validated by several studies [8,9,10,11,12,13,14].

One of the most important reasons of using ISUP terminology, is the acceptance of active surveillance by patients with PAs with ISUP grade 1, equivalent to GS 6.

In the case of PAs with GS 6, the assessment is made on a scale between 1-10 which suggests an intermediate grade, these tumors being more suitable classified by ISUP grading in the lowest grade group, respectively group 1 out of 5.

Such an approach informs both physicians and patients about the relatively indolent nature of this PA group [11], therefore, it reduces the overtreatment of indolent prostate cancer.

Also, the application of these groups is helpful to clinicians in the management of heterogeneous PAs with variable prognosis, such as those with GS 7 that can be included in ISUP groups 2 or 3, groups associated with different prognosis and therefore with different therapeutic approaches [7].

ISUP grade 3 is defined by the presence of well-differentiated glands, often with variable-sized and tubular architecture, separated from each other by stroma.

A particular aspect of this group, which should not be underestimated, is the evaluation of specific PA variants, which can look deceptively benign, respectively the atrophic, pseudohyperplastic or foamy gland variant, similar situations being observed in the case of micronodular architecture, or similar variants of PIN (prostate intraepithelial neoplasia), mucinous or collagenous (mucinous fibroplasia) [11,15,16,17,18].

The most recent WHO classification emphasizes that atrophic, pseudohypertrophic, with foamy and microcystic glands, which may have a deceptively benign appearance, are attributed to pattern 3 [3,18].

In our study, the atrophic, pseudohyperplastic and microcystic variants were identified only in patterns associated with the conventional acinar appearance, which imposed the final Gleason score, most cases being ISUP group 1 or 2.

The same ISUP classification was present in the case of the foamy gland variant, which was observed as a single pattern in 17.9% of cases, and in a pattern associated with the conventional one in 10.9% of cases.

ISUP grade 4 includes fused glands with small and large sizes, poorly formed, as well as tumors with glomeruloid and cribriform architecture [11,19].

In one study, the prevalence of pattern 4 submodels in prostate biopsies it was: 75% merged pattern, 64% undefined, 48% cribriform and 25% glomeruloid [6].

Several models of tumor growth initially considered as pattern 3, have been redefined as pattern 4 [20].

Thus, the small cribriform glands and the glomeruloid appearance were reconsidered and it is recommended that both models be classified as pattern 4 [21,22,23].

Several studies have shown that the glomeruloid model, considered specific for PA, is associated with a reduced risk of biochemical recurrence after radical prostatectomy [24,25], but compared with pure pattern 3 the prognosis was unfavorable, justifying the inclusion in pattern 4 category [20,25].

In our study, in the ISUP 4 group, the single or associated conventional or with foamy glands patterns predominated, as well as a limited number of PAs that associated to the conventional pattern the cribiform or glomeruloid aspects.

Several studies have indicated a more unfavorable evolution and biochemical recurrence for GS 4+3 compared to GS 3+4 [11,26].

As a result, by separating PA with GS 7 into 2 categories, 3+4=7 (ISUP grade 2) and 4+3=7 (ISUP grade 3), the proportion of ISUP grade 4 was at least partially included in the patient management algorithms [26,27,28], several studies reporting clinical significance for ISUP group 4 quantification [29,30,31,32,33,34].

A number of studies have shown that patients with the cribriform model [35] have survival without biochemical relapses, survival without metastases, and cancer-specific survival is more unfavorable than those without this pattern [19].

The value of this pattern has been studied especially for patients with GS 7, but has been shown to have independent prognostic value in PA GS 8 with pattern 4 [36], unlike PA with GS 9 in which its role remains uncertain [33].

ISUP grade 5 includes PAs without glandular features or lumen formation.

Several particular patterns can be distinguished, such as comedonecrosis, infiltrative cords, and the solid pattern [37,38].

The presence of comedonecrosis even in a single gland (focal comedonecrosis) [37], as well as signet ring-like cell with unicellular aspects or in larger cell groups, are also considered pattern 5.

In prostate biopsies the patterns with infiltrative cords without formation of lumens and single cells have been reported as the most common grade patterns 5, the most uncommon being comedocarcinoma [39].

With the reclassification of PA with GS 8-10 (considered a single high-grade subgroup), in two specific 4-5 patterns, clinicians can better differentiate the prognosis and clinical risk associated with the disease [11,26].

In this study, in the ISUP 5 group, in addition to the conventional pattern, we found a significant number of cases of PA with mixed patterns, rspectively conventional in association with cribriform with comedonecrosis and signet ring-like cell patterns.

While for less than half of patients with PA, the tumor can be life-threatening (Gleason score ≥7), many patients have low-risk disease and are still undergoing radical prostatectomy [3].

For the latter, active surveillance has become a widely used alternative after the diagnosis of PA, even if up to 33% of patients in active surveillance need therapeutic intervention after a period of 1.2-3.5 years [4,5,6,7,8].

Therefore, a better stratification of PA patients in terms of clinical decision is needed, especially in the predominant group of low-and medium-risk of the PA.

Conclusion

In this study, we found the association of prostate adenocarcinoma variants with classic and updated Gleason growth patterns and ISUP grading systems.

Statistical concordance of lesion grading systems indicates their usefulness for identifying aggressive prostate tumors in determining the management of these patients.

Conflict of interests

None to declare.