M o r p h o l o g i c Up d a t e s i n P ro s t a t e P a t h o l o g y Adebowale J. Adeniran, MD*, Peter A. Humphrey, MD, PhD KEYWORDS Prostatic adenocarcinoma Gleason system Active surveillance Immunohistochemistry
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n the past several years, modifications have been made to the original Gleason system with resultant therapeutic and prognostic implications. Several morphologic variants of prostatic adenocarcinoma have also been described. Prostate pathology has also evolved over the years with the discovery and utility of new immunohistochemical stains. The topics discussed in this update include the Gleason grading system, prognostic grade grouping, variants of prostatic adenocarcinoma, and the application of immunohistochemistry to prostate pathology.
OVERVIEW: UPDATE ON THE GLEASON GRADING SYSTEM Since the original Gleason grading system1 was derived, so much has changed in the area of prostate pathology, with the discovery and utility of serum prostate-specific antigen (PSA), immunohistochemical stains, 18-gauge core needle biopsies, and improved surgical techniques. In 2005, the International Society of Urologic Pathology (ISUP) reviewed and made changes to the original Gleason grading system2 and these changes have had a profound impact on contemporary pathology and urology practices worldwide.3–10 A second modification to the Gleason diagram entailed placement of cribriform adenocarcinomas into pattern 4 (Fig. 1).8 Conventional and modified Gleason grading both correlate with age, serum PSA, and cancer involvement in needle biopsies. It has been shown that the stage distribution of modified Gleason grades of radical prostatectomy (RP) specimens differs from that of conventional Gleason grades, but a good
correlation exists between grade and primary tumor (pT) stage.5,10 Some of issues concerning the various Gleason grades/patterns are as follows.
GLEASON GRADE 1 Gleason grade 1 glands consist of a circumscribed nodule of closely packed but distinct, uniform, medium-sized acinar structures, which are round to oval and usually larger than glands seen in pattern 3. It is recommended that Gleason score of 1 1 1 5 2 should not be assigned to prostatic adenocarcinoma, regardless of the specimen, with rare exceptions. A majority of cases in this group are actually adenosis (atypical adenomatous hyperplasia).2,9,11–13
GLEASON GRADE 2 The glands in the Gleason grade 2 group are fairly circumscribed but may have minimal infiltration at the edge. These glands are more loosely arranged than those seen in pattern 1. This pattern is characteristic of transition zone cancers, so should rarely be seen in needle biopsy sampling that typically targets the peripheral zone. This fact along with poor reproducibility has led to the recommendation that a diagnosis of Gleason score 2 1 2 5 4 should be made “rarely, if ever” in needle biopsy.2,14,15 A majority of the cases assigned a Gleason score of 4 on core needle biopsies have a higher Gleason score on corresponding prostatectomies.
GLEASON GRADE 3 The glands in the Gleason grade 3 category are typically smaller than those seen in pattern 1 or
Department of Pathology, Yale University School of Medicine, 310 Cedar Street, LH 108, New Haven, CT 06520, USA * Corresponding author. E-mail address: [email protected] Surgical Pathology 8 (2015) 539–560 http://dx.doi.org/10.1016/j.path.2015.08.002 1875-9181/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
surgpath.theclinics.com
ABSTRACT
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Adeniran & Humphrey Fig. 1. Gleason grading diagram: 2010 modification of ISUP 2005 modified scheme. (From Epstein JI. An update of the Gleason grading system. J Urol 2010;183: 433–40; with permission.) Note that a new ISUP modification of this diagram will be published (Epstein JI, Egevad L, Amin MB, et al. 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 2015, in press).
Morphologic Updates in Prostate Pathology 2. They usually present as discrete glandular units with marked variation in size and shape and they are characterized by infiltration in and among benign glands. The consensus among urologic pathologists now is that invasive cribriform glands and glands with glomeruloid architecture more accurately reflect Gleason pattern 4 and hence should not be diagnosed as Gleason pattern 3.7,8,16 Pitfalls in grading of pattern 3 include overgrading of pattern 3 as pattern 4 with crowded pattern 3 glands (Fig. 2), atrophic pattern 3B, tangentially sectioned glands, branching glands, crush artifact, and glands with perineural invasion.17
hypernephromatoid adenocarcinoma was viewed as pattern 4 but it is vanishingly rare.18 It is now clear that invasive cribriform adenocarcinoma is more aggressive than grade 319–22 and should be included in pattern 4, as indicated by the second modification of the Gleason system (see Fig. 1).8 Ill-defined glands with poorly formed glandular lumina are now also considered as pattern 4 when a tangential section of pattern 3 glands cannot account for the histology. Diagnosis of poorly formed glands remains a significant challenge, with reproducibility an issue.
GLEASON GRADE 4
In pattern 5, there is essentially no glandular differentiation, with tumor consisting of solid sheets, cords, or single cells. The presence of comedonecrosis surrounded by papillary, cribriform, or solid masses, also falls into the pattern 5 category. Small solid nests (Fig. 5), linear arrays (Fig. 6), and solid cylinders should also be considered grade
The glands in the Gleason grade 4 category are characterized by fused microacinar glands, cribriform glands (Fig. 3), ill-defined glands with poorly formed glandular lumina (Fig. 4), and glands with glomeruloid pattern. In the past, the Fig. 2. Crowded Gleason grade 3 adenocarcinoma of the prostate (hematoxylin-eosin, original magnification 200).
GLEASON GRADE 5
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Adeniran & Humphrey Fig. 3. Cribriform Gleason grade 4 adenocarcinoma of the prostate (hematoxylin-eosin, original magnification 200).
5.18 One pitfall is that the presence of signet ringlike cells is indicative of pattern 5 and these should be distinguished from clear vacuoles, which are typically seen in pattern 4 tumors, but which can also be found in pattern 3 glands. Grade 5 is readily underdiagnosed, particularly when it is not the primary pattern.23 A challenge for the future for diagnosis of pattern 5 is the
determination of how many single cells are needed to assign pattern 5 (Fig. 7). This is currently unsettled.
PROGNOSTIC GLEASON GRADE GROUPS Based on the clinical outcome and excellent prognosis for patients with low Gleason scores, 5
Fig. 4. Poorly formed glands of Gleason grade 4 adenocarcinoma of the prostate (hematoxylin-eosin, original magnification 100).
Morphologic Updates in Prostate Pathology Fig. 5. Small solid nests of Gleason grade 5 adenocarcinoma of the prostate (hematoxylineosin, original magnification 200).
prognostic groups have been proposed, and these accurately reflect tumor behavior and prognosis in prostate cancer.24 Additionally, by defining Gleason score 6 carcinoma as group 1 of 5, rather than 6 of 10 using the Gleason system, physicians and patients can appreciate the indolent and lowrisk nature of this common score, where it is in the lowest-risk grade group (1/5) rather than considered intermediate (6/10) in the Gleason system. The 5 prognostic groups are defined as follows: Grade group 1 (Gleason score 2–6) Grade group 2 (Gleason score 3 1 4 5 7) Grade group 3 (Gleason score 4 1 3 5 7)
Fig. 6. Linear array growth pattern of Gleason grade 5 adenocarcinoma of the prostate (hematoxylin-eosin, original magnification 200).
Grade group 4 (Gleason score 4 1 4 5 8) Grade group 5 (Gleason score 9–10) Several studies have shown that in the modified Gleason system, Gleason score 6 has an excellent prognosis.24–26 In 1 of the studies, Gleason score 6 tumor was associated with an extremely low risk of progression after RP.25 In that study, 94.6% and 96.6% of patients with pure Gleason 6 cancer at biopsy and RP, respectively, were biochemically free of tumor 5 years after RP. Additionally, in a multi-institutional study of more than 14,000 RP cases of modified Gleason score 6, there was not a single patient with lymph node
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Adeniran & Humphrey Fig. 7. Single cell Gleason grade 5 adenocarcinoma of the prostate (hematoxylin-eosin, original magnification 40).
metastasis.27 Best evidence using various parameters, such as competing risk analyses, surgical series, nonrandomized cohort studies, and randomized trials, has shown similar outcomes for patients with Gleason score 2 to 6 tumors treated or not in the PSA era.28–32 An analysis of these data shows that using a time frame of 10 to 15 years, less than 3% of men diagnosed with Gleason score less than or equal to 6 and classified as low risk (based on a PSA
I
n the past several years, modifications have been made to the original Gleason system with resultant therapeutic and prognostic implications. Several morphologic variants of prostatic adenocarcinoma have also been described. Prostate pathology has also evolved over the years with the discovery and utility of new immunohistochemical stains. The topics discussed in this update include the Gleason grading system, prognostic grade grouping, variants of prostatic adenocarcinoma, and the application of immunohistochemistry to prostate pathology.
OVERVIEW: UPDATE ON THE GLEASON GRADING SYSTEM Since the original Gleason grading system1 was derived, so much has changed in the area of prostate pathology, with the discovery and utility of serum prostate-specific antigen (PSA), immunohistochemical stains, 18-gauge core needle biopsies, and improved surgical techniques. In 2005, the International Society of Urologic Pathology (ISUP) reviewed and made changes to the original Gleason grading system2 and these changes have had a profound impact on contemporary pathology and urology practices worldwide.3–10 A second modification to the Gleason diagram entailed placement of cribriform adenocarcinomas into pattern 4 (Fig. 1).8 Conventional and modified Gleason grading both correlate with age, serum PSA, and cancer involvement in needle biopsies. It has been shown that the stage distribution of modified Gleason grades of radical prostatectomy (RP) specimens differs from that of conventional Gleason grades, but a good
correlation exists between grade and primary tumor (pT) stage.5,10 Some of issues concerning the various Gleason grades/patterns are as follows.
GLEASON GRADE 1 Gleason grade 1 glands consist of a circumscribed nodule of closely packed but distinct, uniform, medium-sized acinar structures, which are round to oval and usually larger than glands seen in pattern 3. It is recommended that Gleason score of 1 1 1 5 2 should not be assigned to prostatic adenocarcinoma, regardless of the specimen, with rare exceptions. A majority of cases in this group are actually adenosis (atypical adenomatous hyperplasia).2,9,11–13
GLEASON GRADE 2 The glands in the Gleason grade 2 group are fairly circumscribed but may have minimal infiltration at the edge. These glands are more loosely arranged than those seen in pattern 1. This pattern is characteristic of transition zone cancers, so should rarely be seen in needle biopsy sampling that typically targets the peripheral zone. This fact along with poor reproducibility has led to the recommendation that a diagnosis of Gleason score 2 1 2 5 4 should be made “rarely, if ever” in needle biopsy.2,14,15 A majority of the cases assigned a Gleason score of 4 on core needle biopsies have a higher Gleason score on corresponding prostatectomies.
GLEASON GRADE 3 The glands in the Gleason grade 3 category are typically smaller than those seen in pattern 1 or
Department of Pathology, Yale University School of Medicine, 310 Cedar Street, LH 108, New Haven, CT 06520, USA * Corresponding author. E-mail address: [email protected] Surgical Pathology 8 (2015) 539–560 http://dx.doi.org/10.1016/j.path.2015.08.002 1875-9181/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
surgpath.theclinics.com
ABSTRACT
540
Adeniran & Humphrey Fig. 1. Gleason grading diagram: 2010 modification of ISUP 2005 modified scheme. (From Epstein JI. An update of the Gleason grading system. J Urol 2010;183: 433–40; with permission.) Note that a new ISUP modification of this diagram will be published (Epstein JI, Egevad L, Amin MB, et al. 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 2015, in press).
Morphologic Updates in Prostate Pathology 2. They usually present as discrete glandular units with marked variation in size and shape and they are characterized by infiltration in and among benign glands. The consensus among urologic pathologists now is that invasive cribriform glands and glands with glomeruloid architecture more accurately reflect Gleason pattern 4 and hence should not be diagnosed as Gleason pattern 3.7,8,16 Pitfalls in grading of pattern 3 include overgrading of pattern 3 as pattern 4 with crowded pattern 3 glands (Fig. 2), atrophic pattern 3B, tangentially sectioned glands, branching glands, crush artifact, and glands with perineural invasion.17
hypernephromatoid adenocarcinoma was viewed as pattern 4 but it is vanishingly rare.18 It is now clear that invasive cribriform adenocarcinoma is more aggressive than grade 319–22 and should be included in pattern 4, as indicated by the second modification of the Gleason system (see Fig. 1).8 Ill-defined glands with poorly formed glandular lumina are now also considered as pattern 4 when a tangential section of pattern 3 glands cannot account for the histology. Diagnosis of poorly formed glands remains a significant challenge, with reproducibility an issue.
GLEASON GRADE 4
In pattern 5, there is essentially no glandular differentiation, with tumor consisting of solid sheets, cords, or single cells. The presence of comedonecrosis surrounded by papillary, cribriform, or solid masses, also falls into the pattern 5 category. Small solid nests (Fig. 5), linear arrays (Fig. 6), and solid cylinders should also be considered grade
The glands in the Gleason grade 4 category are characterized by fused microacinar glands, cribriform glands (Fig. 3), ill-defined glands with poorly formed glandular lumina (Fig. 4), and glands with glomeruloid pattern. In the past, the Fig. 2. Crowded Gleason grade 3 adenocarcinoma of the prostate (hematoxylin-eosin, original magnification 200).
GLEASON GRADE 5
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Adeniran & Humphrey Fig. 3. Cribriform Gleason grade 4 adenocarcinoma of the prostate (hematoxylin-eosin, original magnification 200).
5.18 One pitfall is that the presence of signet ringlike cells is indicative of pattern 5 and these should be distinguished from clear vacuoles, which are typically seen in pattern 4 tumors, but which can also be found in pattern 3 glands. Grade 5 is readily underdiagnosed, particularly when it is not the primary pattern.23 A challenge for the future for diagnosis of pattern 5 is the
determination of how many single cells are needed to assign pattern 5 (Fig. 7). This is currently unsettled.
PROGNOSTIC GLEASON GRADE GROUPS Based on the clinical outcome and excellent prognosis for patients with low Gleason scores, 5
Fig. 4. Poorly formed glands of Gleason grade 4 adenocarcinoma of the prostate (hematoxylin-eosin, original magnification 100).
Morphologic Updates in Prostate Pathology Fig. 5. Small solid nests of Gleason grade 5 adenocarcinoma of the prostate (hematoxylineosin, original magnification 200).
prognostic groups have been proposed, and these accurately reflect tumor behavior and prognosis in prostate cancer.24 Additionally, by defining Gleason score 6 carcinoma as group 1 of 5, rather than 6 of 10 using the Gleason system, physicians and patients can appreciate the indolent and lowrisk nature of this common score, where it is in the lowest-risk grade group (1/5) rather than considered intermediate (6/10) in the Gleason system. The 5 prognostic groups are defined as follows: Grade group 1 (Gleason score 2–6) Grade group 2 (Gleason score 3 1 4 5 7) Grade group 3 (Gleason score 4 1 3 5 7)
Fig. 6. Linear array growth pattern of Gleason grade 5 adenocarcinoma of the prostate (hematoxylin-eosin, original magnification 200).
Grade group 4 (Gleason score 4 1 4 5 8) Grade group 5 (Gleason score 9–10) Several studies have shown that in the modified Gleason system, Gleason score 6 has an excellent prognosis.24–26 In 1 of the studies, Gleason score 6 tumor was associated with an extremely low risk of progression after RP.25 In that study, 94.6% and 96.6% of patients with pure Gleason 6 cancer at biopsy and RP, respectively, were biochemically free of tumor 5 years after RP. Additionally, in a multi-institutional study of more than 14,000 RP cases of modified Gleason score 6, there was not a single patient with lymph node
543
544
Adeniran & Humphrey Fig. 7. Single cell Gleason grade 5 adenocarcinoma of the prostate (hematoxylin-eosin, original magnification 40).
metastasis.27 Best evidence using various parameters, such as competing risk analyses, surgical series, nonrandomized cohort studies, and randomized trials, has shown similar outcomes for patients with Gleason score 2 to 6 tumors treated or not in the PSA era.28–32 An analysis of these data shows that using a time frame of 10 to 15 years, less than 3% of men diagnosed with Gleason score less than or equal to 6 and classified as low risk (based on a PSA
