Moving Beyond Gleason Scoring
Brian Miles, MD; Michael Ittmann, MD, PhD; Thomas Wheeler, MD; Mohammad Sayeeduddin, BS; Antonio Cubilla, MD;
David Rowley, PhD; Ping Bu, MD; Yi Ding, PhD; Yan Gao, MD; MinJae Lee, PhD; Gustavo E. Ayala, MD
 Context.—The combination of grading and staging is the
basis of current standard of care for prediction for most
cancers. D. F. Gleason created the current prostate cancer
(PCa) grading system. This system has been modified
several times. Molecular data have been added. Currently,
all grading systems are cancer-cell based.
Objective.—To review the literature available on host
response measures as reactive stroma grading and stromo-
genic carcinoma, and their predictive ability for PCa
biochemical recurrence and PCa-specific death.
Data Sources.—Our own experience has shown that
reactive stroma grading and the subsequently binarized
system (stromogenic carcinoma) can independently pre-
dict biochemical recurrence and/or PCa-specific death,
C ancer pathology evolved during the early part of the
20th century through the development of histogenetic
classification of tumors and grading and staging of cancer. It
was A. C. Broders from the Mayo Clinic (Rochester,
Minnesota) who first championed the grading of tumors,
in order to increase our ability to predict the behavior of
cancers.1 C. E. Dukes later introduced staging of tumors and
completed the portfolio of what was to be pathology
research for many coming decades. In fact, current standard
of care is based on these 2 concepts.2
But by the 1950s, prostate cancer (PCa) research was
behind that of tumors from other sites. Loss of ‘‘basement
membrane’’ or ‘‘basal cell layer loss’’ and perineural and
vascular invasion were identified as aggressive features for
PCa. Eventually, several histologic differentiation classifica-
Accepted for publication October 11, 2018.
Published as an Early Online Release March 13, 2019.
From the Department of Urology, The Methodist Hospital,
Houston, Texas (Dr Miles); the Departments of Pathology &
Immunology (Drs Ittmann and Wheeler and Mr Sayeeduddin) and
Molecular and Cell Biology (Dr Rowley), Baylor College of
Medicine, Houston, Texas; Instituto de Patologia e Investigacion,
Asuncion, Paraguay (Dr Cubilla); Biostatistics/Epidemiology/Re-
search Design (BERD) Core, Departments of Internal Medicine (Dr
Lee) and Pathology and Laboratory Medicine (Drs Bu, Ding, Gao,
and Ayala), University of Texas Health Sciences Center Medical
School, Houston.
Dr Ayala is owner of the company Stromont, which will hold property
over automated biomarker systems. This company is currently being
developed. The other authors have no relevant financial interest in the
products or companies described in this article.
Corresponding author: Gustavo E. Ayala, MD, Department of
Pathology and Laboratory Medicine, University of Texas Health
Sciences Center Medical School, 6431 Fannin Street, Houston, TX
77030 (email: Gustavo.E.Ayala@uth.tmc.edu).
Arch Pathol Lab Med—Vol 143, May 2019
particularly in patients with a Gleason score of 6 or 7.
Stromogenic carcinoma has been validated by 4 other
independent groups in at least 3 continents.
Conclusions.—Broders grading and Dukes staging have
been combined to form the most powerful prognostic tools
in standard of care. The time has come for us to
incorporate measures of host response (stromogenic
carcinoma) into the arsenal of elements we use to predict
cancer survival, without abandoning what we know works.
These data also suggest that our current definition of PCa
might need some revision.
(Arch Pathol Lab Med. 2019;143:565–570; doi: 10.5858/
arpa.2018-0242-RA)
tions evolved. The MD Anderson classification (MDAH) was
a 4-tiered system based on the percentage of tumor that
formed glands (based on the Broders system).3 Mostofi
proposed a 3-grade system that used both degree of
glandular differentiation and nuclear atypia.3 Bocking used
4 histologic patterns and 3 degrees of nuclear atypia.3 But it
was not until Gleason proposed his classification that
clinicians and pathologists eventually coalesced around 1
standardized system.
Over many years Gleason created a very significant body
of work. His early work in 1966 identified that his patterns
were associated to survival rates (n ¼ 270).4 But his
collaboration with G. T. Mellinger in the Veterans Affairs
Cooperative Urological Research Group provided him with
a unique resource to validate his findings. His seminal 1974
article5 remains the only large prospective biomarker
development study for PCa. The article clearly showed the
potential of the Gleason scoring (GL). The emphasis was on
the combination with staging, and the study population
received different treatments. Gleason’s work was validated
by most of the preeminent urologic pathology groups,6–10
and the Gleason system became accepted as the preferred
grading method for PCa. There is no question that the
Gleason grading system carries significant predictive infor-
mation in the preoperative and postoperative settings.
LIMITATIONS OF THE GLEASON SYSTEM
Like most other cancer grading systems, GL concentrates
on the characteristics of the cancer cell and how it resembles
the prostate glandular differentiation. A low Gleason grade
shows the greatest similarity to the glandular tissue of
origin, while high Gleason grades show the greatest
divergence from glandular forms. The emphasis is clearly
on the cancer cell and its patterns.
Moving Beyond Gleason Scoring—Miles et al 565

Figure 1. Population of patients who have died specifically of prostate
cancer in the Baylor Prostate SPORE database. Most patients had
glandular tumors, Gleason score 6 or 7 (red).
There have been many attempts to improve the Gleason
system in the last 3 decades. Most have refined or redefined
Gleason’s criteria.6,8,9 Others have added information to the
Gleason-based models into tables or nomograms, which are
the current standard of care.11–18 Other current attempts to
improve the models use additional molecular information,
either at the DNA, RNA, or methylation level.19–22 These
have been moderately successful, because at the core, they
measure the characteristics of the cancer cell, where GL
excels. Prediction of PCa is almost exclusively based on
looking at the characteristics of the cancer cell proper, either
at its ability to resemble tissues of origin or at the molecular
level.
The validity of GL as a predictive biomarker has been
clearly demonstrated in numerous studies. It has been
repeatedly shown that having a high GL (8–10) carries a
much higher risk than having a lower GL (6–7). In other
words, a higher percentage of patients with a GL of 8 to 10
will die of PCa than those with GL 6 or 7. This risk
assessment information is clearly important for an individ-
ual with PCa. But, if we analyze the patient population that
died of PCa in our database, the results are puzzling. Almost
Figure 2. A, Adipose tissue present in the
lamina propria of most epithelia, with (D)
capturing the predominant color in (A),
namely, white. B, Reactive stroma, generic,
with (E) capturing the most common color,
namely, pink. C, Smooth muscle stroma in the
prostate, with (F) showing the predominant
color in (C), namely, magenta. The human
eye can easily identify a change from white to
pink, while the change from magenta to pink
is more difficult to detect (hematoxylin-eosin,
original magnifications 3100 [A and B] and
3200 [C]).
566 Arch Pathol Lab Med—Vol 143, May 2019
60% of those who died specifically of PCa had glandular
tumors, GL 6 or 7 (Figure 1).
This finding reflects the fact that a clear majority of
patients with PCa have a GL 6 or 7 tumor (only 10%–15%
have GL 8–10). Although a small percentage of the patients
with GL 6 or 7 die of PCa, most of the patients who die of
PCa have GL 6 or 7 tumors, as the patients with GL 6 or 7
vastly outnumber the others. We will demonstrate in
subsequent sections that stromogenic carcinoma identifies,
independently of GL, the patients at risk in the largest
category of patients with PCa. Gleason scoring allows for
variability in the GL 7 subset (3þ4 and 4þ3), but this
distinction losses predictive model significance when
incorporating stromogenic carcinoma.23 Hence, while the
Gleason scoring system has been of critical importance,
there is a need for development beyond its reach.
EARLY WORKS ON HOST RESPONSE AS A BIOMARKER
In most human cancer types, invasion is defined by the
host’s response upon extension of the cancer cells beyond
the basal membrane. But the breach of basal membrane is
not visible on hematoxylin-eosin staining at light micro-
scopic magnifications. Therefore, invasion is defined by the
desmoplastic stromal response that follows the breach of the
basement layer. The visible event is therefore modification
in host response to the cancer. And this change is
manifested to our eyes by changes in structure and color.
In a fatty lamina propria (Figure 2, A), the presence of a
myofibroblastic cellular component and accumulation of
extracellular matrix (Figure 2, B) is visible as a simple change
from white to pink (Figure 2, D and E). The prostate is
different. It does not have a fatty lamina propria. The
smooth muscle fibers surround prostate glands almost
directly (Figure 2, C) (in the absence of inflammation).
The change in color associated with desmoplasia in the
prostate is not as obvious, from magenta to pink (Figure 2, E
and F). It follows that desmoplastic response in the prostate
is best identified by using structure, rather than color (Figure
3). Figure 3A shows a glandular cancer sitting in smooth
Moving Beyond Gleason Scoring—Miles et al

muscle and without host response. Figure 3B shows a
glandular cancer with exuberant desmoplastic reactive
stroma, yet the lack of significant color changes makes it
difficult to assess. The structural changes are best noted in
the black and white versions of 3A and 3B in 3C and 3D,
respectively. A detailed description of reactive stroma in PCa
is presented in the article by De Vivar et al.24 Suffice it to say
that reactive stroma has 2 main transformations. The
smooth muscle with its characteristic well-defined cytoplas-
mic borders is replaced by myofibroblasts (tumor-associated
fibroblasts), which have a syncytial growth pattern (Figure 4,
A and C). Additionally, there are deposits of varying
extracellular matrix material, which varies in color from
Arch Pathol Lab Med—Vol 143, May 2019
Figure 3. A, Prostate cancer (PCa) gland
sitting in smooth muscle, without reactive
stroma. B, A malignant prostate gland with
surrounding reactive stroma. C and D, Black-
and-white images of (A) and (B), respectively.
They demonstrate that the histologic changes
associated with reactive stroma in PCa are
best seen when based on structure, rather
than color (hematoxylin-eosin, original mag-
nification 3400 [A through D]).
pink (Figure 4, A) to blue (Figure 4, B and D). We described
3 histologic subtypes for easy identification:
1. Extracellular matrix rich, or the classically described
stromogenic carcinoma, characterized by the angularity
of the cancerous glands and the accumulation of
extensive amounts of extracellular matrix.
2. Myofibroblastic reactive stroma, characterized by the
presence of a cellular stroma, with features of muscle
differentiation organized in a wispy pattern, but at loss of
muscle architecture (bundling).
3. Edematous reactive stroma with edematous areas within
the reactive stroma.
Figure 4. Four representative cases of stro-
mogenic prostate cancer. The desmoplastic
response is at least 50% of the tumor and
characterized by the presence of myofibro-
blasts, where the well-defined cytoplasmic
borders of smooth muscle are replaced by a
syncytial growth pattern of myofibroblast
(best seen in [C]). Additionally, there are
deposits of varying extracellular matrix mate-
rial, which varies in color from pink (A) to
blue (B and D) (hematoxylin-eosin, original
magnification 3200 [A through D]).
Moving Beyond Gleason Scoring—Miles et al 567
 We have not identified any independent prognostic value
for these histologic subtypes.
The host’s response, desmoplasia or reactive stroma, is
biologically critical to PCa. The literature on biology of
reactive stroma (the myofibroblast or tumor-activated
fibroblasts in PCa) far outweighs what we have been able
to identify in the pathology literature. Reactive stromal cells
have been associated with increased tumor growth in vitro
and in vivo.25,26
In late 1998 we started collaborating with one of the
authors (D. R.) who had made significant scientific
accomplishments on the biology of prostate gland stromal
cells and myofibroblasts. However, there was no translation
to human disease. We reported that reactive stroma initiated
early, during high-grade prostatic intraepithelial neoplasia
in approximately 50% of sites, and that reactive stroma was
composed of fibroblasts and myofibroblasts with different
marker expression profiles and matrix production. This was
the first report showing that reactive stroma in prostate
cancer was defined by the presence of myofibroblasts and
altered extracellular matrix. Subsequent studies showed that
reactive stroma was associated with an elevated rate of
angiogenesis and was tumor-promoting.27
The histologic changes associated with reactive stroma in
prostate cancer are subtle, owing to the limitations stated
previously, but they are evident upon a focused examination
of the stroma. In 1990 we started a project using trichrome
stains, which make the reactive stroma changes more
visible. In this study, a priori and based on preliminary
observations, we created a reactive stroma grading (RSG)
system. We learned that reactive stroma is highly variable in
PCa, with most cases having little or no reactive stroma. In
this initial study we used the Baylor College of Medicine
cohort, with greater than 600 patients with more than 20
years of follow-up. Tumors with 0% to 5% stroma were
given an RSG of 0. Tumors with 5% to 15% reactive stroma
were assigned RSG 1 and from 15% to 50%, RSG 2. Tumors
with greater than 50% reactive stroma were given RSG 3.
Hence, RSG 3 exhibits at least a 1:1 ratio of reactive stroma
to epithelium. We identified that patients with RSG 0 (no
stroma) or patients with RSG 3 had a mean survival time of
69.02 months as compared to 106.33 months for RSG 1 or
2.28 This distinction was independently significant in the
patients with GL 7.
We concentrated our efforts on RSG 3, since the clear
majority of patients with RSG 0 had a high Gleason grade.
We consequently converted a 4-tiered grading system into a
binary system. RSG 3 was either present or not. We
subsequently termed the RSG 3 as stromogenic carcinoma.
Stromogenic carcinoma is a rare event, and cases with more
than 50% reactive stroma are even more rare, but so are
patients who die of PCa using our current definition of
cancer. It is important to note that we have tested other
thresholds such as 30% and the presence of any reactive
stroma, without success.
We used quantification of stromogenic carcinoma on
hematoxylin-eosin sections (Figure 4) to demonstrate that it
was an independent predictor of recurrence (hazard ratio ¼
1.953; P ¼ .02) on preoperative biopsies, independent of
Gleason subset 4þ3 and 3þ4 in patients with a GL of 7.23
Finally, we measured the percentage of stromogenic
carcinoma on more than 800 whole-mounted radical
prostatectomy specimens to identify the percentage of
tumor that had stromogenic carcinoma. Patients with higher
RSG 3 percentages (larger tumor areas with RSG 3) had a
568 Arch Pathol Lab Med—Vol 143, May 2019
significantly decreased biochemical recurrence-free survival
and PCa-specific death-free survival than those with a lower
RSG 3 percentage, even within the GL 7 subset of patients.29
We created nomograms for both biopsies and radical
prostatectomies. We later described the transcriptomic
changes found in reactive stroma.30 This is the scope of
our published data on stromogenic carcinoma, with other
validation studies of our own in new populations forth-
coming soon.
VALIDATION OF STROMOGENIC CARCINOMA
These data, although substantial, need external validation.
And this validation has come from several independent
studies. The most recent is from the Canary group.
McKenney and colleagues31 showed, in 1275 patients with
GL 6 and GL7 carcinomas, that reactive stromal patterns
were associated with worse recurrence-free survival. They
concluded that ‘‘a reactive stromal response was the
strongest histologic prognostic factor in grade 3þ3¼6 and
3þ4¼7 groups by multivariable analysis’’ and that ‘‘As
stromal response is not currently evaluated in the routine
histologic assessment of prostate cancer, its unrecognized
presence leads to a significant underestimate of risk in this
aggressive set of prostate cancers.’’31
Another excellent study from Norway used a population
strategy approach, this being one of the most difficult tasks
in biomarker development. The authors32 identified 318
patients with biopsy-proven PCa and without evidence of
systemic metastasis at the time of diagnosis in Aust-Agder
County (100,000 inhabitants) in the period 1991–1999. The
10-year PCa-specific survival rate for RSGs of 0, 1, 2, and 3
was 96%, 81%, 69%, and 63%, respectively (P , .005). RSG
remained independently associated with PCa-specific death
in a multivariate Cox regression analysis adjusting for
prostatic specific antigen (PSA), clinical stage, Gleason
score, and mode of treatment.32 The authors also published
on the relationship between reactive stroma grading and
perineural invasion33 and lymphovascular invasion.34 Like
our results, a group from Brazil35 found that stromogenic
carcinoma predicts biochemical recurrence on univariate but
not multivariate analysis (266 patients). Unfortunately, a
GL7 subset was not included in their analysis. Finally, a
group from China36 has shown a significant association
between reactive stroma grade in tumors and the occurrence
of castration-resistant PCa in patients with a Gleason score
of 6 or 7 (P , .00).
Stromogenic carcinoma occurs with high Gleason grades
but data are inconsistent as to its risk profile, at our current
definition (50%). It is likely that higher Gleason grades will
need greater reactive stroma to be clinically significant, as
our unpublished data suggest. Therefore, at this time we
suggest that the proven value of stromogenic carcinoma is
best identified in patients with GL 6 and 7, and therefore
this is the patient population that would benefit most from
its use.
There are sufficient data, currently published, or to be
published soon, about reactive stroma grading or stromo-
genic carcinoma to support its incorporation in clinical
practice. Stromogenic carcinoma has been validated by 5
independent groups, in at least 3 continents (Europe, Asia,
and the Americas) and with more than 4000 patients.
Clearly, stromogenic carcinoma has predictive ability for
PCa. The presence of stromogenic carcinoma in a biopsy
Moving Beyond Gleason Scoring—Miles et al

specimen significantly increases risk recurrence or PCa-
specific death.
ON THE RATIONALE FOR COMBINING GLEASON AND
STROMOGENIC CARCINOMA
We conclude that differential alterations in the tumor
microenvironment may explain PCa diversity and aggres-
siveness. We have shown that the microenvironment
provides significant predictive information that can help
define indolent and lethal phenotypes of PCa. Distinction of
indolent PCa (GL 6–7 without stromogenic carcinoma) from
stroma-independent (GL 8–10) and stroma-dependent or
stromogenic PCa (Gleason 6–7 with stromogenic pattern)
can only be done by incorporating measures of the stromal
response to current predictive tools (Figure 5). Neither
system alone can capture information that is present in
both. More importantly, lack of recognition of stromogenic
carcinoma in GL 6 or 7 tumors greatly underestimates the
risk of patients with PCa.
Further studies will look at the reproducibility of this
biomarker. We believe that recognizing stromogenic carci-
noma is straightforward, since we have made it into a binary
test with an easily recognizable cutoff, at least a 1:1 ratio
between the amount of reactive stroma and cancer cells. The
Canary cohort slides were reviewed independently at The
Cleveland Clinic (Cleveland, Ohio) and the McGovern
School of Medicine (Houston, Texas). We individually
reached almost identical statistical results. However, like
all other semiquantitative studies they will have known
limitations. Most other semiquantitative biomarkers have
issues with reproducibility, including high grade prostatic
intraepithelial neoplasia and GL.7,37 For this reason, our
current studies are looking at technologic advancements to
improve on reproducibility. The results are very encourag-
ing.
The biological reasoning behind developing a predictive
model of PCa, based on the tumor microenvironment, is
based on several key publications. So was D. F. Gleason’s
work. We propose that combining the information from the
cancer and the host response is critical for improving
prediction. We find a strong historical background to
support this merger. Broders’ response to Dukes’ article
on cancer staging was to publish a new article showing that
the combination of his cancer grading and Dukes’ cancer
staging provided better prognostication than either method
alone.38 The time has come for us to incorporate measures
of host response into the arsenal of elements we use to
predict cancer survival, without abandoning what we know
works.
Arch Pathol Lab Med—Vol 143, May 2019
Figure 5. Indolent prostate cancer (PCa) is
characterized by glandular tumors, sitting in
muscle, without a host response. In contrast,
there are 2 types of lethal PCas. The classic
lethal PCa can be identified by Gleason
scoring and molecular tests and is character-
ized by loss of glandular differentiation.
Additionally, glandular tumors (Gleason score
6–7) with intense stromal response, or stro-
mogenic carcinoma, are as lethal as the
previous category. Lack of recognition of this
category greatly underestimates the risk of
patients with PCa.
Finally, the Surveillance, Epidemiology, and End Results
Program (SEER) data for cancer-type death rates show that
PCa has one of the lowest cancer-specific mortalities of all
cancers (1.4% at 5 years). We must wonder if the lack of
host response elements to define a cancer as truly invasive,
as happens in most other cancers, could be hindering our
ability to define actual prostate cancer. Further studies are
required.
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Moving Beyond Gleason Scoring—Miles et al