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Published in final edited form as: Urology. 2021 May 28;155:47–54. doi: 10.1016/j.urology.2021.05.028

Cribriform Prostate Cancer: Clinical Pathologic and Molecular Considerations

Amanda B Hesterberg 1, Jennifer B Gordetsky 2,3, Paula J Hurley 1,3,4,*
PMCID: PMC9165084  NIHMSID: NIHMS1723493  PMID: 34058243

Abstract

Intraductal cribriform (IDC) and invasive cribriform morphologies are associated with worse prostate cancer outcomes. Limited retrospective studies have associated IDC and cribriform morphology with germline mutations in DNA repair genes, particularly BRCA2. These findings, which prompted the National Comprehensive Cancer Network® (NCCN) Guidelines for Prostate Cancer and Genetic/Familial High- Risk Assessment to consider germline testing for individuals with IDC/cribriform histology, have been questioned in a recent prospective study. A deepened understanding of the molecular mechanisms driving disease aggressiveness in cribriform morphology is critical to provide more clarity in clinical decision making. This review summarizes the current understanding of IDC and cribriform prostate cancer, with an emphasis on clinical outcomes and molecular alterations.

Keywords: cribriform, intraductal cribriform, prostate cancer, outcomes, Grade Groups, BRCA2, germline testing, PTEN, SChLAP1, Cancer Associated Fibroblasts, ASPN, FAP, Tumor microenvironment

Introduction

Cribriform growth is a specific morphologic pattern seen across different types of neoplasms, defined as cohesive tumor cells with the presence of circular spaces, creating a sieve-like or Swiss cheese appearance. Cribriform histology can occur in invasive prostate cancer as well as intraductal carcinoma (IDC) of the prostate. Recent attention has been paid to cribriform prostate cancer and its association with clinical outcomes and genetic alterations. Herein we review the current literature on cribriform prostate cancer, including invasive tumor and IDC, with a focus on clinical outcomes, genetic implications, molecular findings, and imaging.

Gleason Grading, Grade Groups, Cribriform Morphology, and Intraductal Carcinoma

Prostate cancer is a heterogeneous disease that varies in morphology, genetics, and outcome, thereby, making treatment decisions challenging. Men with indolent disease are often effectively managed with active surveillance while some men with aggressive cancer progress to metastatic disease despite curative-intent therapy. Grade Groups, based on the original Gleason grading system, remain one of the strongest prognostic indicators of clinical outcome 1. This system stratifies individuals into one of five Grade Groups based on the overall Gleason Score (GS) 2, 3. Increased GS is associated with worse cancer outcomes. Individuals with GS ≤ 6 are more likely to have favorable outcomes while individuals with GS 8–10 have a high risk of adverse outcomes. Men with GS 7 show varied outcomes, and their risk stratification has been improved by the Grade Group system (Figure 1) 4.

Figure 1. Overview of the Gleason Grading and Grade Group System.

Figure 1.

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Representative images for each Gleason Pattern, including the respective Gleason Scores and corresponding Grade Group number. The Gleason Pattern 4 spans Grade Groups 2–5. Cancer risk and gland differentiation are inversely related as Grade Group increases.

Despite grading improvements, risk stratification remains challenging for some men due to the morphological heterogeneity present in Gleason pattern 4 cancer. Gleason pattern 4 consists of four architectural subtypes: ill-formed, fused, glomeruloid and cribriform 5. Specifically, cribriform morphology has been associated with adverse outcomes compared to other Gleason pattern 4 morphologies 6–10. Originating from the Latin word ‘cribrum,’ meaning sieve, cribriform describes the appearance of perforations within sheets of epithelial cells 2, 11. Chua et al., proposed that cribriform patterning contributes to the buildup of multiple unfavorable events (termed ‘nimbosus’, for the gathering of stormy clouds) 12 potentially leading to more adverse outcomes 7, 8, 13.

The Gleason Grading system has evolved to reflect the aggressive phenotype observed with cribriform morphology. Originally, cribriform patterns were assigned to Gleason pattern 3. In 2005, most cribriform patterns were re-assigned to Gleason pattern 4, with only small, rounded, and well-circumscribed cribriform patterns remaining as Gleason pattern 3 3. The 2014 revisions by the International Society of Urological Pathology (ISUP) recommended that all cribriform patterns be recognized as Gleason pattern 4 regardless of size or morphology 1. The 2014 revisions also introduced Grade Groups, which further stratified men with GS 7. Men with GS 7 (3+4) were assigned to Group 2 and GS 7 (4+3) assigned to Group 3, suggesting increased aggressiveness in men with more prominent pattern 4 prostate cancer 1, 3. Despite these advancements, cribriform architecture still spans groups 2–5 14, leading to variability in patient outcome and treatment decisions 1. In addition, there is still ambiguity in how to categorize the invasive cribriform morphological mimicker, prostate IDC. IDC features the proliferation of malignant epithelial cells with similar morphology as invasive cribriform cancer but within prostatic ducts 15. Histological staining of basal markers is the definitive assay to distinguish IDC from invasive cribriform tumors, which lack basal cell markers 5, 16. Co- occurrence between these morphological features is common, with 47% of cribriform prostate cancer containing areas of IDC and 68% of IDC containing cribriform patterns 6. Other morphologic patterns of IDC include comedo necrosis, solid growth, and extreme nuclear atypia. Both invasive cribriform tumors and IDC in prostate adenocarcinoma are associated with worse outcomes 6, 15, 17, 18. Due to the strong morphological and biological overlap, many studies combine these subtypes into a single prognostic group for analysis. The current ISUP guidelines recommend incorporating the grade of IDC into the GS when invasive cancer is present 19, while the GUPS recommends against including IDC in the final GS 20. However, both societies recommend reporting the presence of cribriform morphology and IDC and hold that cribriform morphology should be an exclusion criterium for active surveillance.

Clinical Outcomes

A growing body of evidence suggests that cribriform morphology contributes to adverse outcomes and has potential to impact clinical decisions. Several studies have investigated the clinical implication of cribriform tumor found on prostate biopsy. Cribriform growth detected at initial biopsy corresponds with higher Gleason Grade and tumor stage at radical prostatectomy 21. In addition, Kweldam et al. showed that in men with Grade Group 2 (GS 3+4) prostate cancer at biopsy, cribriform morphology or IDC, and not percent Gleason pattern 4 was an independent predictor of biochemical recurrence 22. Few studies have reported the impact of cribriform tumor on therapy resistance, however, a recent study of neoadjuvant androgen blockade in men with locally high-risk prostate cancer identified an association of cribriform morphology at biopsy with a worse response to therapy, suggesting that cribriform tumor may contribute to hormone ablation therapy resistance 23.

Additional studies have also investigated the clinical impact of cribriform morphology detected at radical prostatectomy. Increased lymph node positive status at prostatectomy has been reported in men with IDC or cribriform morphology 24. Additionally, cribriform morphology detected at radical prostatectomy is associated with an increased risk of biochemical recurrence 6–9 and a shorter time to biochemical recurrence, with an average time of 34 months compared to 120 months for men without cribriform morphology 7. The association of cribriform morphology at radical prostatectomy with worse biochemical and metastasis-free survival is independent of Grade Group in patients with Grade Group 4 (Gleason grade 8) prostate cancer 25. Consistent with this, studies have reported that men with cribriform morphology at the time of prostatectomy are more likely to develop metastases 9 and experience a shorter time to metastasis 7. Studies have also shown that men with cribriform morphology at biopsy or radical prostatectomy have decreased overall survival and increased disease- specific death 7, 10, 15, 26.

Due to the association of cribriform morphology and IDC with adverse outcomes, Van Leenders et al. proposed a new grading system, cGrade, which incorporates both cribriform and IDC into the Grade Group system to increase prognostic value 18. According to this modified system, for patients with Grade Group 2–5 prostate cancers, the cGrade is the same as the current Grade Group if cribriform morphology and IDC are present, however, the absence of these morphologies results in a cGrade of the current Grade Group minus 1. In the European Randomized Study of Screening for Prostate Cancer cohort, cGrade improved prognostication of both disease-specific survival and metastasis-free survival compared to the current Grade Group system. To date, cGrade has not been incorporated into ISUP or GUPS prostate cancer grading consensus statements.

Inconsistencies Diagnosing and Reporting Cribriform Prostate Cancer and IDC

Although studies suggest that inclusion of cribriform morphology improves risk stratification, reporting inconsistencies limit the clinical utility of cribriform morphology to identify at-risk individuals. Specifically, a 2019 pre-meeting survey for the Genitourinary Pathology Society (GUPS) revealed only 40% of U.S. pathologists reported the presence of cribriform glands on patient biopsies 20. Amongst pathologists who do report the presence of cribriform morphology, inconsistencies remain, including differences in size cutoffs and reporting style (i.e., presence/absence versus overall tumor percent) 20. Currently there is not a strong consensus on sizing criteria when distinguishing small (simple) and large (expansile) cribriform glands. Some groups define large cribriform glands as having more than 12 luminal spaces 27–29, with other groups using benign glands as a reference 6, 30. It is unclear if cribriform gland size leads to outcome differences. Hollemans et al. reported that only large cribriform patterning was an independent predictor of biochemical recurrence and metastasis in patients with Grade 2 prostate cancer 30 while other studies suggest both small and large cribriform glands lead to adverse outcomes and increased PSA failure 27, 31. Ambrosini et al. proposed the use of an automated reporting system for patient biopsies to reduce inter-observer variability and to increase the detection of cribriform 32. Taken together, these data suggest that interobserver variability could lead to inconsistences in cribriform morphology reporting, emphasizing the importance of refining current definitions to reduce reporting discrepancies.

Biopsy under sampling also contributes to differences in cribriform morphology reporting between biopsy and radical prostatectomy. Hollemans et al. assessed under sampling in patient biopsies through matched radical prostatectomy sections, revealing that 40% of men were false negative for cribriform at initial biopsy 33. Recent studies support these findings, suggesting biopsies have high specificity (87.2–94.9%) but low sensitivity (47.2–56.6%) in detecting cribriform morphology (Table 1) 34, 35. Discordant results between biopsy and prostatectomy led to significant tumor upstaging following radical prostatectomy. These findings emphasize the importance of both improving detection methods and considering the implementation of multimodal detection methods for men negative for cribriform morphology at biopsy to better assess treatment decisions.

Table 1. Cribriform-specific Sensitivity and Specificity for Various Detection Methods.

Sensitivity and specificity of various prostate cancer detection methods in identifying cribriform morphology are outlined. In general, techniques have high specificity and low sensitivity.

Detection Method Sensitivity (cribriform specific) Specificity (cribriform specific)
Systematic Biopsy (SB) 20.7% 37
43% 33
44.7% 35
56.5% 34 		29.2% 37
97% 33
93% 35
87.2% 34
Targeted biopsy (TB) (Fusion Biopsy/MRI-TBx) 28.6% 37
53.5% 34 		32.4% 37
76.5% 34
68Ga-PSMA PET/CT 76% 43 86% 43
Nomogram 79.2% 44 84% 44
Mp-MRI 90.5% 41 *Specificity not calculated due to all MRIs being performed in men with prostate cancer (no control)
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Imaging Cribriform Prostate Cancer

Improved imaging modalities to identify cribriform morphology at disease onset are needed. Currently, multiparametric magnetic resonance imaging (mpMRI), a non- invasive 3D imaging technique, has risen to prominence in prostate cancer detection. Small retrospective studies suggested cribriform morphology is invisible to mpMRI 36–38 with only 17% of cribriform patterning detected upon analysis 37. However, recent studies contradict these findings. Van Houdt et. al. determined cribriform was not an indicator of mpMRI invisible regions 39. Instead, invisible tumors were more likely to contain lower grade (GG1–2) prostate cancer and heterogeneous morphology compared to visible tumors 39. Other studies suggest mpMRI improves detection of cribriform morphology compared to standard biopsy methods 40, 41 with a cribriform-specific sensitivity of 90.5% 41. Consistent with these findings, cribriform morphology was identified as an independent factor associated with increased PI-RADS score derived from MRI analysis 42. Cumulatively, these studies suggest that mpMRI may serve as a promising diagnostic tool for detection of cribriform morphology.

Other novel detection methods include positron emission tomography (PET) scans with nuclear labeled prostate-specific membrane antigen ligands (PSMA), termed 68Ga- PSMA PET/CT 43. Cribriform morphology had increased uptake, supporting the utility of 68Ga-PSMA PET/CT as a less invasive prediction tool, especially when combined with other detection techniques such as MRI. Lastly, Gao et al. 2020 developed of a novel risk-nomogram that combines clinical characteristics with mpMRI analysis to serve as an improved prognostic indicator of cribriform morphology 44. The three independent predictors that increased accurate detection of cribriform morphology were prostate specific antigen density (PSAD), PI-RADS score, and overall biopsy GS. Although further validation is needed to assess clinical utility, these results emphasize the importance of assessing multiple factors when predicting risk of cribriform morphology and highlight promising future developments to prostate cancer imaging techniques.

Genetic, Genomic, and Molecular Alterations

Much research has focused on identifying the genetic, genomic, and molecular underpinnings of cribriform prostate cancer and IDC aggressiveness. Retrospective studies have associated IDC with germline mutations in DNA repair genes, particularly BRCA2 45–47. Pathogenic germline alterations in BRCA1/2 correspond with higher risk of metastases and worse survival 48, 49, and additionally have implications for both familial testing and therapeutic selection. This association of BRCA2 and IDC in these studies prompted the National Comprehensive Cancer Network® (NCCN) guidelines for prostate cancer IDC 50 and Genetic/Familial High-Risk Assessment 51 to include a consideration for germline testing in men who have prostate cancer with cribriform morphology or IDC. Recently, a prospective study by Lozano et al., found no association between germline BRCA2 mutations and cribriform/IDC histology when analyzing primary prostate tumor samples 52. These new findings call into question the current guidelines and demonstrate the need for further investigation into the role of germline BRCA2 alterations in cribriform morphology prostate cancer.

In contrast to germline mutations, Lozano et al. reported an association of biallelic somatic loss of BRCA2 with both cribriform and IDC histological subtypes 52, thereby, supporting a role for BRCA2 in the development of cribriform morphology and IDC. Additionally, cribriform morphology has been reported to have increased genomic instability and copy number alterations when compared to other Gleason pattern 4 morphologies 10 and non-cribriform prostate cancers 16. Cribriform morphology is also associated with deletions in common tumor suppressor genes including CHD1, TP53, NKX3–1, MAP3K7, RB1 and PTEN 10, 16. PTEN, TP53, and RB1 loss are increased in metastatic castration-resistant prostate cancer (mCRPC) and are associated with therapy resistance 53–57. Genetic amplifications in cribriform prostate cancer are less common, with gain of MYC and LY6 being reported 16. Genetic rearrangements of the ETS-related gene (ERG) have also been reported 58; however, Elfandy et al. found that ERG fusions were not significantly different in men with cribriform morphology compared to other non- cribriform patterns when analyzed in the prostate TCGA cohort 10. In addition to chromosomal abnormalities, point mutations have also been reported, impacting genes involved in DNA repair (TP53, ATM), ubiquitination (SPOP), and transcription (FOXA1)10.

Few studies have assessed the association of cribriform morphology with epigenetic alterations. DNA methylation signatures are of interest as altered DNA methylation is common in aggressive prostate cancers, including mCRPC 53. Elfandy et al. found that patients in the TCGA prostate cohort with cribriform morphology also showed increased methylation, resulting in a molecular phenotype that closely resembled metastatic prostate cancer 10. Increased methylation of several genes corresponded to decreased expression of some genes including those associated with aggressive prostate cancer (EVX1, EPHX3, ABDH9, IRAK3), while hypermethylation of EZH2 led to increased expression. Oklhov-Mitsel et al., previously reported the hypermethylation of APC, RASSF1 and TBX15 in samples with cribriform morphology 59; however, Elfandy et al. did not detect a difference in the methylation profile of these genes in the TCGA cohort. Thus, future studies will be informative in further elucidating the epigenetic signature of cribriform prostate cancer and to determine if these alterations serve as useful biomarkers for the identification of at-risk patients.

Genomic instability likely contributes to the dysregulation of important regulatory pathways enriched in prostate cancers with cribriform morphology including mTORC1, MYC, MAPK, KRAS and JAK-STAT 10. Aberrations in RNA have also been described in prostate cancer with cribriform morphology. Increased expression in the long noncoding RNA SChLAP1 was recently reported 12. SChLAP1 overexpression is strongly associated with increased metastases 60, suggesting it could serve as a valuable marker of aggressive disease. Patients with cribriform prostate cancer also score worse in RNA- based screening tests including the OncotypeDx Genomic Prostate Score® (GPS) assay 31 and the Decipher test 17. As the NCCN guidelines recommend these assays for men with low or intermediate-risk disease 50, their association with cribriform morphology could serve to further assess patient risk and improve prognostic decisions.

Protein alterations have also been reported in cribriform morphology. IHC analysis of primary prostate cancers demonstrated increased phosphorylation of the proto- oncogene MET 61, which has been associated with resistance to androgen deprivation therapy in preclinical models 62. Other enriched proteins include EGFR 63 and Ki-67 64, suggesting cribriform patterning has a higher number of actively proliferating cells compared to other morphologies. Downregulated proteins include PTEN 65, 66, p27 65, and CD44 63. Chen et al., also reported the dysregulation of important AR-interacting proteins, NRIP and DDB2 67. NRIP and AR expression positively correlated while DDB2 showed decreased expression in prostate cancer tissues. This pattern occurred more frequently in men with cribriform morphology, suggesting that cribriform could alter AR signaling to drive cancer aggressiveness.

Collectively, these data suggest that cribriform prostate cancer has a unique molecular repertoire compared to other prostate cancer morphologies that may contribute to worse outcomes. Although many of these molecular alterations have expression profiles associated with cribriform morphology, the biomarkers are not solely cribriform- specific. The discovery of new biomarkers that are unique to cribriform morphology would be valuable in increasing the detection and treatment options for cribriform prostate cancer (Figure 2).

Figure 2. Summary of Factors Altered in Cribriform Morphology Prostate Cancer.

Figure 2.

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Factors associated with cribriform morphology prostate cancer and IDC. Figure created with BioRender.com.

Tumor Microenvironment

Less is known about how the tumor microenvironment impacts cribriform prostate cancer. The tumor microenvironment consists of a heterogeneous cellular population and a diverse connective tissue composition, both of which can influence tumor progression and metastasis. Alterations within integrin signaling have been observed in patients with cribriform prostate cancer 68. Connell et al., revealed cribriform patterning had aberrant and increased expression of the Integrin αv (ITGAV). ITGAV expression formed a dense stromal ring around cribriform glands, leading to the hypothesis that ITGAV serves as a mediator of crosstalk between stromal cells and cancer cells, resulting in signaling regulation, stem-cell maintenance, and tumor survival 68. Increased integrin expression has been suggested to increase cancer cell migration, as increased expression has been reported in bone metastases in prostate cancer patients 68.

Hypoxia is thought to occur in cribriform cancer due to the 3D architecture of cribriform glands. And indeed, central comedo necrosis is often seen with cribriform IDC. Most cribriform glands do not directly contact the surrounding stroma and contain limited intervening stroma, thus restricting the amount of oxygen able to penetrate the dense gland architecture 69. The architecture of most other prostate morphologies contain tumor cells in direct contact with the stroma, thereby, limiting this hypoxic effect 69. In support of this, Chua et al., reported increased hypoxia in patients with cribriform patterning, which corresponded with increased disease recurrence and resistance to therapy 12.

The stroma surrounding cribriform glands was recently reported to be highly heterogenous and enriched in cancer associated fibroblasts (CAFs) subtypes expressing markers associated with worse outcomes 70. Specifically, ASPN+ and FAP+ CAFs were elevated in cribriform morphology prostate cancer compared to other Gleason pattern 4 morphologies and lower Gleason patterns 70. Altogether, these findings suggest cribriform prostate cancer contains a heterogenous and reactive stroma that may contribute to worse cancer outcomes. Further studies are needed to determine mechanistically how specific fibroblast subtypes contribute to cancer progression and disease aggressiveness (Figure 2).

Concluding Remarks

Cribriform prostate cancer remains an aggressive form of prostate cancer. Although current research has improved our understanding of the nature of cribriform prostate cancer, the specific mechanisms driving cribriform aggressiveness are unknown. Future studies should focus on discovering cribriform specific biomarkers, enhancing the current model systems, and increasing early detection methods. Combined, these findings will provide increased understanding to the specific mechanisms driving cancer aggressiveness in men with cribriform morphology as well as unveil novel biomarkers that could lead to earlier disease detection and therapeutic targets. By improving disease detection, reporting, and enhancing therapeutic outcome, this could not only lead to increased risk stratification but also improve quality of life in men impacted with cribriform prostate cancer.

Acknowledgements:

This work was supported by the American Cancer Society 131356-RSG-17-160-01-CSM (PJH, JG), the National Cancer Institute/National Institute of Health RO1CA211695-01A1 (PJH, JG), the Eckstein Foundation (PJH), Microenvironmental Influences in Cancer Training Program T32CA009592 (ABH).

Footnotes

Conflict of interest: Paula Hurley receives royalties from Horizon Discovery for the generation of targeted cell lines. No potential conflicts of interest were disclosed by the other authors.

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