Intraductal Carcinoma of the Prostate and Invasive Cribriform Cancer: Emerging Important Prognostic Factors
By: Jennifer B. Gordetsky, MD; Kerry Schaffer, MD, MSCI; Paula J. Hurley, PhD | Posted on: 01 Sep 2022
In the era of active surveillance, prognostic pathological features play a critical role in the management of prostate cancer. Gleason score and Grade Groups on prostate biopsy remain a powerful prognostic indicator of final pathology on radical prostatectomy. Over the past few years, the practice of prostate biopsy has shifted from a systematic yet random biopsy technique to an MRI-targeted approach, with multiple cores coming from a single targeted lesion. This change in biopsy technique drove a reevaluation of prostate cancer grading and calculation of tumor extent on biopsy to allow for the most accurate pathology reporting.1–3 A new aggregate approach for prostate cancer grading and calculation of tumor extent was recommended for targeted biopsies in consensus statements by GUPS (Genitourinary Pathology Society) and ISUP (International Society of Urological Pathology).4,5 These changes helped refine the prognostic ability of prostate biopsy pathology results.
In addition to Grade Group and tumor extent, other pathological features present on biopsy can be helpful prognostic indicators. For example, the presence of perineural invasion found on prostate biopsy has been extensively studied and found to be predictive of worse histological features on radical prostatectomy, biochemical recurrence, and adverse outcomes in patients treated with external beam radiotherapy.6–8 More recently, studies have highlighted the prognostic value of cribriform morphology on prostate biopsy and its potential to impact patient management.9–12
Cribriform prostate cancer is a distinct histological morphology that consists of confluent sheets of malignant epithelial cells containing multiple glandular lumens but lacking intervening stroma or mucin.13,14 Originally, some cribriform prostate cancers were classified as Gleason Grade 3; however, emerging data indicated that cribriform growth was more aggressive than other Gleason Grade 3 patterns.15 As a result, all cribriform tumors were reclassified as Gleason Grade 4 in 2014.15 More recently, it was recommended by GUPS and ISUP to report cribriform morphology in prostate biopsies and radical prostatectomies.4,5
Cribriform growth can be seen in both invasive prostate cancer as well as intraductal carcinoma of the prostate (IDCP). IDCP is a neoplastic proliferation of epithelial cells within the glands and ducts of the prostate. This creates a marked intraductal expansion of neoplastic cells with high-grade nuclear atypia and sometimes necrosis. Most cases of IDCP are associated with high-grade invasive tumors and are thought to occur via colonization of benign prostatic acini and ducts by tumor cells.16 As both IDCP and invasive prostate cancer can have cribriform growth, often the only way to distinguish the 2 is through immunohistochemistry for basal cell markers. Although IDCP and invasive cribriform cancer often coexist, studies have shown differences between the 2 entities.17–19 PTEN expression tends to be lost more often in IDCP compared to invasive cribriform cancer, and a recent report showed that when IDCP is separated from invasive cribriform cancer, only invasive cribriform cancer was a statistically significant independent prognostic indicator for biochemical recurrence.18
The clinical significance of cribriform prostate cancer has also come under scrutiny in recent years. Numerous studies have demonstrated cribriform growth to be a poor prognostic histological feature. Cribriform architecture on prostate biopsy has been associated with higher Gleason Grade, increased pathological stage, nodal metastasis, and greater risk of biochemical failure.9–12 One study showed that in patients with Grade Group 2 tumors (Gleason score 3 + 4 = 7) on prostate biopsy, invasive cribriform cancer and/or IDCP performed better than the percentage of pattern 4 in predicting biochemical recurrence after prostatectomy.12 The authors concluded that the presence of invasive cribriform cancer and/or IDCP should act as an exclusion criterion for active surveillance in these intermediate-risk patients. Similar to the aforementioned data, most studies to date that have investigated cribriform morphology have combined both IDCP and invasive cribriform cancer in their statistical analyses, which could be problematic. It is also important to acknowledge that the field is still early in the scientific process of investigating cribriform growth as an independent prognostic indicator and understanding how these findings should best be incorporated into tumor grade assignment. For example, it is now known that many prostate cancers with tumor necrosis that would classically have been graded as Gleason Grade 5 are in fact IDCP.19 Initial investigations proposed a possible association between IDCP and BRCA2 germline mutations.20 These initial data led to the National Comprehensive Cancer Network® guideline recommendations that clinicians consider germline testing in patients with IDCP.21 However, additional investigations and characterization of IDCP have challenged this proposed association.22 Further studies are needed to definitively determine the association of pathological features including cribriform and IDCP with germline alterations.
Currently, sufficient data exist to support the presence of IDCP or cribriform architecture on prostate biopsy as a contraindication to active surveillance; thus, cribriform morphology and IDCP should be reported.4,5 However, the field continues to face several challenges including inconsistencies in defining and reporting cribriform morphology, low detection of cribriform morphology on biopsy due to tumor heterogeneity and sampling, understanding how cribriform morphology impacts active surveillance decisions for patients with Grade Group 2 prostate cancer, determining how and whether to grade IDCP, and understanding whether tumors with cribriform morphology respond differently to radiation and hormonal therapies. The molecular changes specific to cribriform prostate cancer and its tumor microenvironment continue to be explored.23–25 Ultimately, more studies are warranted to build on our current knowledge, and refine how the presence of IDCP and cribriform morphology can be optimized for prognostic and treatment stratification.
Conflict of Interest
Jennifer Gordetsky is a consultant for Jansen Inc. Paula Hurley receives royalties from Horizon Discovery for the generation of targeted cell lines. The remaining authors have no conflicts of interest to disclose.
- Gordetsky JB, Hirsch MS, Rais-Bahrami S. MRI-targeted prostate biopsy: key considerations for pathologists. Histopathology. 2020;77(1):18-25.
- Gordetsky JB, Schultz L, Porter KK, et al. Defining the optimal method for reporting prostate cancer grade and tumor extent on magnetic resonance/ultrasound fusion-targeted biopsies. Hum Pathol. 2018;76:68-75.
- Deng FM, Isaila B, Jones D, et al. Optimal method for reporting prostate cancer grade in MRI-targeted biopsies. Am J Surg Pathol. 2022;46(1):44-50.
- van Leenders GJLH, van der Kwast TH, Grignon DJ, et al. The 2019 International Society of Urological Pathology (ISUP) Consensus Conference on Grading of Prostatic Carcinoma. Am J Surg Pathol. 2020;44(8):e87-e99.
- Epstein JI, Amin MB, Fine SW, et al. The 2019 Genitourinary Pathology Society (GUPS) White Paper on Contemporary Grading of Prostate Cancer. Arch Pathol Lab Med. 2021;145(4):461-493.
- Truong M, Rais-Bahrami S, Nix JW, Messing EM, Miyamoto H, Gordetsky JB. Perineural invasion by prostate cancer on MR/US fusion targeted biopsy is associated with extraprostatic extension and early biochemical recurrence after radical prostatectomy. Hum Pathol. 2017;66:206-211.
- Peng LC, Narang AK, Gergis C, et al. Effects of perineural invasion on biochemical recurrence and prostate cancer-specific survival in patients treated with definitive external beam radiotherapy. Urol Oncol. 2018;36(6):309.e7-309.e14.
- Suresh N, Teramoto Y, Goto T. Clinical significance of perineural invasion by prostate cancer on magnetic resonance imaging-targeted biopsy. Hum Pathol. 2022;121:65-72.
- Haffner MC, Salles DC, Gao G, Epstein JI. Gleason pattern 4 with cribriform morphology on biopsy is associated with adverse clinicopathological findings in a prospective radical prostatectomy cohort. Hum Pathol. 2020;98:74-80.
- Greenland NY, Cowan JE, Zhang L, et al. Expansile cribriform Gleason pattern 4 has histopathologic and molecular features of aggressiveness and greater risk of biochemical failure compared to glomerulation Gleason pattern 4. Prostate. 2020;80(8):653-659.
- Chen Z, Pham H, Abreu A, et al. Prognostic value of cribriform size, percentage, and intraductal carcinoma in Gleason score 7 prostate cancer with cribriform Gleason pattern 4. Hum Pathol. 2021;118:18-29.
- Kweldam CF, Kümmerlin IP, Nieboer D, et al. Presence of invasive cribriform or intraductal growth at biopsy outperforms percentage grade 4 in predicting outcome of Gleason score 3+4=7 prostate cancer. Mod Pathol. 2017;30(8):1126-1132.
- Shah RB, Cai Q, Aron M, et al. Diagnosis of “cribriform” prostatic adenocarcinoma: an interobserver reproducibility study among urologic pathologists with recommendations. Am J Cancer Res. 2021;11(8):3990-4001.
- van der Kwast TH, van Leenders GJ, Berney DM, et al. ISUP Consensus Definition of Cribriform Pattern Prostate Cancer. Am J Surg Pathol. 2021;45(8):1118-1126.
- Epstein JI, Egevad L, Amin MB, Delahunt B, Srigley JR, Humphrey PA. The 2014 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma: definition of grading patterns and proposal for a new grading system. Am J Surg Pathol. 2016;40(2):244-252.
- Zhou M. High-grade prostatic intraepithelial neoplasia, PIN-like carcinoma, ductal carcinoma, and intraductal carcinoma of the prostate. Mod Pathol. 2018;31(S1):S71-79.
- Khani F, Wobker SE, Hicks JL, et al. Intraductal carcinoma of the prostate in the absence of high-grade invasive carcinoma represents a molecularly distinct type of in situ carcinoma enriched with oncogenic driver mutations. J Pathol. 2019;249(1):79-89.
- Spieker AJ, Gordetsky JB, Maris AS, et al. PTEN expression and morphological patterns in prostatic adenocarcinoma. Histopathology. 2021;79(6):1061-1071.
- Fine SW, Al-Ahmadie HA, Chen YB, Gopalan A, Tickoo SK, Reuter VE. Comedonecrosis revisited: strong association with intraductal carcinoma of the prostate. Am J Surg Pathol. 2018;42(8):1036-1041.
- Isaacsson Velho P, Silberstein JL, Markowski MC, et al. Intraductal/ductal histology and lymphovascular invasion are associated with germline DNA-repair gene mutations in prostate cancer. Prostate. 2018;78(5):401-407.
- Mohler JL, Antonarakis ES, Armstrong AJ, et al. Prostate Cancer, version 2.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2019;17(5):479-505.
- Lozano R, Salles DC, Sandhu S, et al. Association between BRCA2 alterations and intraductal and cribriform histologies in prostate cancer. Eur J Cancer. 2021;147:74-83.
- Elfandy H, Armenia J, Pederzoli F, et al. Genetic and epigenetic determinants of aggressiveness in cribriform carcinoma of the prostate. Mol Cancer Res. 2019;17(2):446-456.
- Hesterberg AB, Rios BL, Wolf EM, et al. A distinct repertoire of cancer-associated fibroblasts is enriched in cribriform prostate cancer. J Pathol Clin Res. 2021;7(3):271-286.
- Hesterberg AB, Gordetsky JB, Hurley PJ. Cribriform prostate cancer: clinical pathologic and molecular considerations. Urology. 2021;155:47-54.