406
The Histologic Grading of Cancer
Marisa T. Carriaga, M.D.,* and Donald Earl Henson, M.D.t
Background. The histologic grade of a tumor pro-
vides prognostic information in addition to that provided
by stage of disease. Poorly differentiated tumors are
known to pursue a more aggressive course than their well
differentiated counterparts.
Methods. The frequency of grading and the relation-
ship of grade to outcome was investigated for 793,649
cases of cancer from 15 anatomic sites as recorded in the
Surveillance, Epidemiology, and End Results Program.
Results. For all cancers, the frequency of grading in-
creased from 1973 to 1987 and varied by anatomic site and
histologic type. Survival decreased with advancing grade,
and within each stage, grading separated cases into at
least three distinct prognostic subgroups. For some can-
cers, regional stage cases assigned Grade 1 or 2 had higher
survival rates than did localized stage cases assigned
Grade 3 or 4. Therefore, grading allowed the identifica-
tion of high and low risk subgroups within each stage
grouping.
Conclusions. The tumor grade was a strong prognos-
tic indicator for cancers of the urinary bladder, endome-
trium, and prostate-sites most often graded by patholo-
gists. The histologic grade was also an important deter-
minant of outcome for cancers of the brain, soft tissue,
and breast; however, only a small percentage of these tu-
mors were graded. The results are important because no
common criteria for grading were established among the
many contributing pathologists. Therefore, observer
variation did not alter the known relationship of histo-
logic grade to outcome. This review demonstrates that the
histologic grade is a strong predictor of outcome that re-
fines the prognostic information provided by the stage of
disease. Cancer 1995;75:406-21.
From the *Department of Pathology, Georgetown University
School of Medicine, Washington, DC; and the tNational Cancer In-
stitute, Division of Cancer Prevention and Control, Bethesda, Mary-
land.
Address for reprints: Donald Earl Henson, M.D., Program Di-
rector, Early Detection Branch, Division of Cancer Prevention and
Control, National Cancer Institute, EPN Building, Room 305, 9000
Rockville Pike, Bethesda, MD 20892.
Received August 22, 1994; accepted September 20, 1994.
Key words: cancer, epidemiology, grading, histologic
grade, histologic type, SEER, staging, survival.
The relation between the extent of differentiation of a
tumor and its biologic behavior has been known for
more than a century. Han~emannl-~ described the his-
tologic characteristics of aggressive cancers in the
1890s. In the 1920s, B r ~ d e r s and ~ - ~ Greenough7 ana-
lyzed the influence of histologic grade, a numeric ex-
pression of differentiation, on patient outcome for car-
cinomas of the lip, skin, and breast. The conclusion
drawn from these early studies has been upheld repeat-
edly in subsequent years6-’19: poorly differentiated tu-
mors pursue a more aggressive course than their well
differentiated counterparts.
B r ~ d e r s ’method
~-~ of grading, originally developed
for squamous cell carcinoma, is still in use today; tumors
are assigned one of four grades according to the per-
centage of tumor showing incomplete differentiation.
Greenough’s7 more detailed method for breast carci-
noma separated cases into three prognostic groups
based on eight histologic factors. Of these eight factors,
Patey and Scarffs4’ method underscored the impor-
tance of the degree of glandular formation, variation in
the size of cells and nuclei, nuclear hyperchromasia,
and mitotic activity. In the 1950s, Bloom and Richard-
son3l modified this grading scheme and further demon-
strated the prognostic importance of grading in relation
to breast cancer. In recent years, other investigators
have emphasized the correlation between outcome and
nuclear grade.29,30834f35 For breast cancer alone, more
than 10 methods and their modifications have been em-
ployed. Many different grading criteria have been de-
veloped for specific types of cancer, such as the Interna-
tional Federation of Gynecology and Obstetrics method
for endometrial cancer,”’ the National Cancer Institute
method for soft tissue sarcomas,’07the Daumas-Duport
method for a s t r o c y t ~ m a s and
, ~ ~ the
, ~ ~Gleason score for
prostatic carcinoma.85For all sites, the World Health
Organization four-grade system often is used, but no
universally accepted standardized system of grading
exists for any site.
Histologic Grading/Carriaga and Henson 407

Grading often is considered informative for only Table 1. Frequency of Grading, 1973-87
certain types of cancer. The histologic grade is required Site Total No. graded % graded
for the assignment of stage for cancers of the prostate,
All sites* 793,649 462,136 58.2
brain, bone, and soft tissue, as specified by the tumor-
Bladder 52,135 44,561 85.5
node-metastasis (TNM)staging system of the American
Endometrium 40,734 32,774 80.5
Joint Committee on Cancer and the International Union Prostate 103,166 79,679 77.2
Against The histologic grade also is recog- Larynx 14,429 10,220 70.8
nized as an important prognostic factor for other can- Esophagus 10,972 7,555 68.9
cers, such as endometrial carcinomas, transitional cell Colon/rectum 155,305 105,816 68.1
carcinomas of the bladder, and ductal adenocarcinomas Stomach 26,198 17,072 65.2
of the breast, but currently is not required for staging Lung 147,637 90,661 61.4
these tumors in the TNM system. Ovary 21,771 10,939 50.2
In this article, the frequency of grading and grade Pancreas 22,737 10,551 46.4
distribution is presented for 793,649 cases of cancer in Uterine cervix 17,486 7,870 45.0
15 anatomic sites as recorded in the Surveillance, Epi- Braint 14,475 6,038 41.7
Adrenal 438 108 24.7
demiology, and End Results (SEER) Program. The rela-
Breast 156,798 36,152 23.1
tionship between histologic grade and patient outcome Soft tissuet 9.368 2.140 22.8
is examined for 442,476 cases.
* For all sites except brain and soft tissue, only carcinomas were included
t Includes sarcomas.
Materials and Methods

Only histologically confirmed cases of primary invasive

cancer were included in this analysis. For determining
the frequency of grading, grade distribution, and rela-
tion of grade to stage of disease, 793,649 cases were
availalble from the period 1973-1987. Five-year relative
survival rates were available for 442,476 of the 793,649
cases. These 442,476 cases, taken from the period
1978-1986, were used to analyze the relationship of
grade to outcome.
Fifteen anatomic sites were studied: esophagus,
stomach, colon/rectum, pancreas, larynx, lung, female
breast, uterine cervix, endometrium, ovary, prostate,
urinary bladder, adrenal gland, brain, and soft tissue.
For all anatomic sites except the brain and soft tissue,
only carcinomas were included. All cancers listed under
”soft tissue” were sarcomas. Lymphohematopoietic
neoplasms and Kaposi’s sarcomas were excluded from
this analysis.
The stage of disease was recorded as localized, re-
gional, or distant (LRD). Although the LRD system is
less precise than the TNM system of the American Joint
Committee on Cancer/International Union Against
Cancer, LRD staging was used because of its relative
consistency over the 15 years covered in this study.
The histologic grade was assigned by individual pa-
thologists from the nine different SEER program sites
across the country. No common criteria for grading
were established among pathologists. The method of
grading was left to the discretion of the individual pa-
thologists, and the specific grading system used in each
case was not recorded in SEER. It should be noted that
some pathologists might have used a three-grade sys-
tem, while others used four grades. Therefore, the his-
tologic grades recorded in SEER do not represent any
uniform system of grading.
The histologic grade or degree of differentiation re-
corded in SEER reflects the information provided by the
individual pathologists, as stated in the pathology re-
port. Cases described as “well-diff erentiated’ were as-
signed Grade 1; “moderately differentiated” or ”mod-
erately well-diff erentiated”, Grade 2; “poorly diff eren-
tiated”, Grade 3; and “undifferentiated”, Grade 4. If a
range was given, the higher grade was recorded. Cases
described as “low grade” were considered to be Grade
1-2 and therefore were recorded as Grade 2. Cases de-
scribed as “high grade” were considered to be Grade 3-
4 and therefore were recorded as Grade 4.
Unless otherwise stated, information given is for all
races, males and females, combined. Cases of male
breast cancer were not included in the analysis of breast
cancer.
Results
Frequency
Site. The frequency of grading varied by anatomic
site (Table 1). Overall, 58% of the 793,649 cases were
assigned a histologic grade. Among the sites most fre-
quently graded were the urinary bladder (86%), endo-
metrium (81%), and prostate (77%),but information on
grade was available for only 42% of brain tumors, 23%
of breast carcinomas, and 23% of soft tissue sarcomas.
408 CANCER Supplement January 2,2995, Volume 75, No. 1

Table 2. Frequency of Grading by Histologic Type

Total no.
Site Histologic type % graded of cases
Esophagus Squamous cell carcinoma 68.9 8,449
Adenocarcinoma 72.5 1,700
Uterine cervix Squamous cell carcinoma 44.6 13,621
Adenocarcinoma 68.9 1,857
Lung Squamous cell carcinoma 63.7 46,948
Adenocarcinoma 58.2 37,385
Small cell carcinoma 64.5 4,595
Bronchioloalveolar carcinoma 26.1 25,338
Breast Ductal carcinoma 24.9 133,141
Lobular carcinoma 9.9 9,572
Medullary carcinoma 11.3 4,479
Mucinous carcinoma 11.4 3,537
Soft tissue Liposarcoma 46.0 1,536
Fibrosarcoma 43.8 896
Leiomyosarcoma 29.2 534
Malignant fibrous histiocytoma 15.1 1,494

Histologic type. The frequency of grading also var- most cancers, Grade 3 was assigned most frequently.
ied by histologc type (Table 2). For example, adenocar- The majority of colorectal carcinomas were assigned
cinomas and squamous cell carcinomas of the esopha- Grade 2, unlike the other gastrointestinal tumors, which
gus were graded with about the same frequency (73% were most often Grade 3. Grade 2 was also the most
and 69%, respectively), but in the uterine cervix, ade- frequently assigned for carcinomas of the larynx and
nocarcinomas were graded more often than were squa- bladder. Most endometrial carcinomas, prostatic carci-
mous cell carcinomas (69% vs. 45%). Sixty-one percent nomas, and soft tissue sarcomas were assigned Grade 1.
of all lung carcinomas were graded, but bronchioloal- Approximately 70% of cancers of the lung, brain, and
veolar carcinomas were graded less often (26%). Only
25% of ductal adenocarcinomas of the breast were
graded, but an even smaller percentage of lobular, med-
ullary, and mucinous carcinomas received a histologic Table 3. Frequency of Grading Over Time
grade. Among the soft tissue sarcomas, approximately % graded
45% of liposarcomas and fibrosarcomas were assigned
Site 1973-77 1978-82 2983-87
a histologic grade, but only 15% of malignant fibrous
histiocytomas were graded. All sites* 47 60 65
Trends. The overall frequency of gradng increased Bladder 74 89 90
over the 15-year period of 1973 to 1987 (Table 3). For all Endometrium 68 86 89
Prostate 58 78 88
sites combined, the frequency increased by 18%: 65% of
Larynx 60 74 76
all cancers were graded in 1983-1987, compared with
Esophagus 57 72 76
47% in 1973-1977. The site showing the greatest increase Colon/rectum 53 70 77
was the prostate: during 1973-1977,58% of prostate can- Stomach 53 67 74
cers were graded, whereas in 1983-1987, 88% were Lung 54 64 65
graded. A 28% increase was recorded for brain tumors, Ovary 38 50 61
and a 24% increase was recorded for colorectal carcinoma. Pancreas 38 48 52
Only 16% of breast cancers were graded in 1973-1977, Cervix 38 47 51
but 30% were graded in 1983-1987. The frequency of Braint 22 49 50
grading of soft tissue sarcomas rose only 5%. Ad ren a1 21 30 23
Breast 16 20 30
Grade Distribution Soft tissuet 21 21 26
Grade distribution and anatomic site. Table 4 * For all sites except brain and soft tissue, only carcinomas were included
gives the grade distribution for each anatomic site. For t Includes sarcomas.
Histologic GradinglCarriuga and Henson 409

Table 4. Grade Distribution,All Stages Combined corded as low grade tumors would be associated with
O/O of total graded cases
longer survival than those assigned a high histologic
grade. Furthermore, within each stage grouping, the
Site* GRl GR2 GR3 GR4 n difference in survival between Grades 1 and 4 repre-
Esophagus 12 7 7,555 sents the additional prognostic information provided by
determining the grade of a tumor, beyond that pre-
Stomach 10
& -
9 17,072
Colon/rectum
Pancreas
22
19 30 -
20
I 43 I
2
9
2
105,816
10,551
10,220
dicted by the stage alone.
For all cancers, the 5-year survival rate decreased
with advancing grade (Table 6): tumors assigned Grade
Larynx
Lung
Breast
30
6
9
16
33
@ 34
11
90,661
36,152
1 were associated with the highest survival rates, and
those assigned Grade 4 were associated with the worst
Uterine cervix 15 37 I 42 1 6 7,870 outcome. For many cancers, however, no significant
Endometrium 2 32,774 difference in outcome was observed between Grades 3
Ovary 11 10,939
and 4, specifically, cancers of the esophagus, stomach,
Prostate
Bladder
Brain
22
6
- 35 25
30
3
9
31
79,679
44,561
6,038
pancreas, breast, ovary, and brain.
Tables 7, 8, and 9 list the survival according to
Adrenal 19 16 32 108 grade for localized, regional, and distant stage disease.
-
Soft tisijue 26 24 19 2,140 For all stages, histologic grading stratified cases into dis-
tinct prognostic subgroups. For comparison, the sur-
G R grade; n: total number of graded cases.
* For all sites except brain and soft tissue, only carcinomas are included
vival rate for all grades combined also is provided for
t Boxes indicate the grade most frequently assigned. each stage; this number represents the survival infor-
mation available if one considered the stage of disease
alone.
Esophagus. Of the esophageal carcinomas, 69%
adrenal glands were assigned a high histologic grade, were graded. Grade 3 was assigned most frequently.
and greater than 30% were recorded as Grade 4. Survival decreased with advancing grade (Tables 6-9),
Grade distribution and histologic type. The grade except for distant stage disease, for which the 5-year
distributions for common histologic types in selected survival was essentially zero. Cases assigned regional
sites are shown in Table 5. In the breast, almost 50% stage Grade 1had the same 5-year survival rate as cases
of ductal and lobular adenocarcinomas were assigned assigned localized Grade 3 (approximately 11YO).
Grade 3. The majority of medullary carcinomas were The difference in survival between low and high
assigned Grade 3 or 4, whereas 76% of mucinous carci- grade disease was greater for adenocarcinomas than for
nomas were recorded as Grade 1 or 2. squamous cell carcinomas (Table 10). For localized
Of liposarcomas, 60% were listed as Grade 1. In stage disease, the difference between Grades 1 and 3
contrast, Grade 2 was the most frequently assigned was 10% for squamous cell carcinomas, whereas the
grade for fibrosarcomas and leiomyosarcomas. Many difference in survival between Grade 1 and Grade for 3
cases of malignant fibrous histiocytoma were recorded adenocarcinomas was 27%. No survival rates are re-
as Grade 3 or 4, but Grade 2 was also the most fre- corded for localized stage Grade 4 tumors because too
quently assigned. few were recorded. For regional and distant stage dis-
The majority of squamous cell carcinomas and ad- ease, the differences in 5-year survival among the
enocarcinomas of the lung were assigned Grade 3 . As grades were not clinically significant because the rates
expected, 70% of bronchioloalveolar carcinomas were were so low.
assigned Grade 1 or 2, and the vast majority of small Stomach. According to SEER data, 65% of gastric
cell carcinomas were assigned Grade 4 (91%). Never- carcinomas were graded. Again, Grade 3 was the most
theless, 1243 cases were assigned Grade 3, and 200 frequently assigned. Grading identified three sub-
cases of small cell carcinoma were assigned Grade 1 groups with different survival rates; the outcome for
or 2. Grades 3 and 4 were similar (Tables 6-9). The differ-
ences in survival between Grade 1 and Grade 4 tumors
Grade and Survival were 20% for localized disease and 11% for regional
stage disease. The 5-year survival for distant stage dis-
The prognostic value of histologic grade can be assessed ease was less than 4%, regardless of grade.
by examining the relationship between grade and out- Colon. All histologic subtypes of colorectal carci-
come. If grading has prognostic value, then cancers re- noma were included. Of the colorectal carcinomas, 68%
410 CANCER Supplement January 1,1995, Volume 75, No. 1

Table 5. Grade Distribution by Histologic Type for Selected Sites,

All Stages Combined
% of total graded cases

Site GR1 GR2 GR3 GR4 n

Breast
Ductal carcinoma 10 34 10 33,207
Lobular carcinoma 5 26 19 944
Medullary carcinoma
Mucinous carcinoma
Soft tissue
3
34 & 20
26
4
507
404

rn
pj
Liposarcoma 17 7 706
Fibrosarcoma 31 12 10 234
Leiomyosarcoma 27 21 10 262
Malignant fibrous histiocytoma 11 29 27 225
Lung
Squamous cell carcinoma 9 31 6 29,897
Adenocarcinoma
Bronchioloalveolar carcinoma
Small cell carcinoma
&0.1
22
30
1
25
8
6 21,740
1,201
16,352
Othert 0.1 1 37 21,471
GR grade
* Boxes indicate the grade most frequently assigned.
t Includes large cell, giant cell, pleomorphic, etc.

were assigned a histologic grade, and the majority were
assigned Grade 2. The difference in 5-year survival be-
tween Grades 1 and 4 was 37% for all stages combined
(Table 6). Grading divides localized and regional stage
cases into four subgroups (Table 11). Although the
difference in survival between Grades 1 and 2 was only
2-3%, the rates were significantly different because of
the large number of cases. Localized cases assigned
Grade 4 were associated with a lower 5-year survival of
699'0, but the small number of cases resulted in a high
standard error (0.5 < standard error I0.10). The great-
est difference in survival between low grade (Grade 1
and 2) and high grade (Grade 3 and 4) disease is seen
for regional stage cases.
Pancreas. Fewer than half of all pancreatic carcino-
mas were graded. Figure 1 shows monthly survival
rates for pancreatic cancer according to grade for all
stages combined. Low grade tumors were associated
with higher monthly survival rates than were high
grade tumors, but the differences were smaller at 1 year,
and at five years, the differences were not clinically sig-
nificant (Table 6). The 5-year survival was less than
lo%, regardless of histologic grade or stage of disease.
Larynx. Of the laryngeal carcinomas, 97% were
squamous cell carcinomas. Compared with carcinomas
of other sites, cases of laryngeal carcinoma were graded
quite frequently, and almost half were assigned Grade
2. Grading divided cases into three subgroups on the
basis of outcome (Tables 6-9). The differences in sur-
vival between Grades 1 and 3 were 15% for localized
stage cases and 21% for regional stage cases. For local-
ized and regional stage disease, high grade tumors were
associated with approximately 10% poorer survival
than that expected based on stage alone.
Lung. The frequency of grading and the grade dis-
tribution for the different histologc types of lung cancer
are presented in Tables 2 and 5. In the lung, as in the
esophagus, grading was more useful for localized ade-
nocarcinomas than for squamous cell carcinomas (Table
10). For unexplained reasons, localized and regional
stage squamous cell carcinomas assigned Grade 2 had a
slightly higher 5-year survival rate than did cases as-
signed Grade 1, and the survival rates for Grades 1 and
3 were similar. In contrast, adenocarcinomas assigned
localized stage Grade 1 had a 5-year survival rate 24%
higher than that listed for localized stage Grade 3, and
approximately 35% higher than that for Grade 4 tu-
mors.
The survival rates for localized stage bronchioloal-
veolar carcinomas assigned Grade 1 and 2 were similar,
67% and 69%, respectively, and the survival for local-
ized disease, all grades combined, was 65%. Cases as-
signed Grade 3, however, had a survival rate of only
41%. Therefore, grading identified a subset of localized
stage cases with 24% poorer survival than that pre-
dicted by stage alone. In addition, regional stage cases
Histologic Grading/Carriaga and Henson 41 1

Table 6. Survival According to Grade All Stages Combined

Five-vear relative survival rate (%) (1978-86)
~~~~~~~ ~~

Site GR 1 GR2 GR3 GR4 All GR * UNGRt n

Esophagus 13 8 4 5 7 7 7 5,954
SCC 13 7 5 6 7 7 8 4,489
Adeno 15 12 3 143 8 8 7 1,055
Stomach 33 21 13 11 17 17 17 14,321
Colon/rectum 67 59 41 30 56 57 55 85,152
Pancreas 4 2 1 1 3 2 3 12,648
Larynx 77 65 50 44$ 66 65 70 8,135
Lung 31 25 14 7 14 14 13 85,251
SCC 20 22 16 11 15 18 10 26,384
Adeno 38 29 14 14 17 19 12 22,468
Bronch-ah 50 44 26 - 42 41 42 2,382
Small cell - 6 6 5 5 5 5 15,656
Breast 92 83 65 66 77 73 78 85,927
Ductal 93 83 64 66 76 73 77 72,835
Lobular - 82 79 70* 84 77 84 5,296
Medullary - 85* 78 72 80 78 80 2,372
Mucinous 81* 9 6* 61+ - 91 83 92 1,834
Uterine cervix 74 64 52 36 67 59 74 9,313
SCC 66 62 53 46 67 58 74 7,330
Adeno 85 67 51 - 69 69 70 1,035
Endometrium 97 88 61 46 86 87 78 21,531
Ovary 80 50 24 23 39 40 37 11,855
Prostate 93 79 49 41 74 76 68 59,515
Urinary bladder 96 89 58 44 78 78 72 28,831
Brain 62 52 13 12 24 26 22 8,507
Adrenal - - 0 - 31 11 39 244
Soft tissue 89 73 42 27 47 62 42 5,292
SCC: squamous cell carcinoma; Adeno: adenocarcinoma; Bronch-ah: bronchioloalveolar carcinoma; GR: grade; ALL: all grades combined (includes ungraded
cases); --: fewer than 25 cases.
* Graded cases only.
t Ungraded cases only.
t 0.05 <: SE I0.10; + SE 0.10.

assigned Grade 1 were associated with a survival rate
12% higher than that for regional stage, all grades com-
bined. The 5-year survival rate for cases staged "dis-
tant" was zero.
No significant relationship between grade and out-
come was observed for small cell carcinomas of the
lung, because all small cell carcinomas are considered
undilferentiated tumors that therefore should be as-
signed Grade 4. The 5-year survival for the 15,656 cases
of Grade 4 small cell carcinoma was 5% (Table 6).
Breast. Table 12 lists the survival rates for ductal
adenocarcinomasof the breast according to stage of dis-
ease and histologic grade. For all stages, survival rates
decreased with advancing grade, but no difference in
outcome was observed between Grades 3 and 4. Local-
ized :stage cases assigned Grade 1 had 11YO higher sur-
vival than did those assigned Grade 3 . For regional
stage cases, the difference in survival between Grade 1
and Grade 4 was 26%. Furthermore, regional stage
cases assigned Grade 1 had the same survival as local-
ized stage cases assigned Grade 3 or 4. Distant stage
cases assigned Grade 1 had a survival rate of 3370, com-
pared with 18% recorded for distant stage, all grades
combined.
The survival rates for medullary and mucinous car-
cinomas also decreased with advancing grade, all stages
combined (Table 6). Too few cases were recorded to
evaluate grade and outcome for the individual stages.
Only 9% of lobular carcinomas were graded. For
localized stage lobular carcinomas, the survival gradient
was reversed: the 5-year survival rate for Grade 2 cases
was 92% and that for Grade 4 was 96%. Regional stage
cases assigned Grade 3 had a better outcome than did
the same stage Grade 2 cases (Table 8). The standard
412 CANCER Supplement January I , 2995, Volume 75, No. 1

Table 7. Survival According to Grade, Localized Stage mous cell carcinomas assigned Grade 2 had a better out-
Five-year relative survival rate (YO) come than did cases assigned Grade 1, and the differ-
ence between Grades 1and 3 was only 4%. For regional
Site GR1 GR2 GR3 GR4 All stage adenocarcinomas, however, the difference be-
Esophagus 25 17 11 9 15 tween Grades 1 and 3 was 31% (Table 8).
SCC 20 14 10 - 13 Endometrium. Only carcinomas of the urinary
Adeno 42 37 15 - 27 bladder were graded more often than endometrial car-
Stomach 66 58 51 46 57 cinomas. Almost 80% of the graded cases were assigned
Colon/rectum 89 86 82 69* 86 Grade 1 or 2. Within each stage, grading separated cases
Pancreas 8 5 2 - 6 into four subgroups whose survival rates decreased
Larynx 87 80 72 - 82
with advancing grade. The differences in survival be-
Lung 56 49 38 23 40
tween Grades 1 and 3 were 22% for localized stage dis-
SCC 37 45 36 25 34
Adeno 69 55 45 34* 50
ease, 32% for regional stage, and 44% for distant stage
Bronch-alv 67 69 41 - 65
disease. Cases assigned Grade 4 had an even poorer
Small cell - - 31 10 12 outcome than did those assigned Grade 3, but standard
Breast 96 93 87 87 91 errors were high because so few endometrial carcino-
Ductal 97 93 86 86 91 mas were assigned Grade 4. Stage for stage, a high his-
Lobular - 92* 94 96* 97 tologic grade was associated with a poor outcome.
Medullary - - 87 79 87 Therefore, in localized and regional stage cases, grading
Mucinous 81t 99 - - 97
Uterine cervix 91 84 80 67* 89
SCC 87 83 79 79* 88
Adeno 95 87 87* - 90 Table 8. Survival According to Grade, Regional Stage
Endometrium 99 94 77 68 93 Five-year relative survival rate (YO)
Ovary 94 90 73 76* 87
Prostate 97 87 66 54 88 Site GRl GR2 GR3 GR4 Allt
Urinary bladder 97 93 75 69 89 Esophagus 11 4 2 4 5
Brain 61 54 12 12 23 SCC 14 4 2 - 4
Soft tissue 99 85 71* 49* 73 Adeno - 8 4 - 6
SCC: squamous cell carcinoma; Adeno: adenocarcinoma; Bronch-alv: bronchi- Stomach 26 18 15 15 17
oloalveolar carcinoma; GR: grade; ALL: all grades combined (includes ungraded
Colon/rectum 61 59 47 43 56
cases); -: fewer than 25 cases.
* 0.05 < SE I 0.10. Pancreas 5 4 2 4 4
t SE > 0.10. Larynx 61 54 40 39 53
Lung 22 21 15 10 14
SCC 17 19 16 13 15
Adeno 24 26 15 21 16
Bronch-alv 44 31 25 - 32
errors were high, however, because of the small number
Small cell - 13 8 8 8
of graded cases for which survival data were available
Breast 87 77 60 59 70
(n = 514).
Ductal 86 77 59 60 69
Uterine cervix. In the uterine cervix, adenocarcino- Lobular - 78* 84* 61* 78
mas were graded more often than were squamous cell Medullary - - 71* - 72
carcinomas. The difference in outcome between high Mucinous - - - - 83
and low grade disease was greater for adenocarcinoma Uterine cervix 57 56 45 3Y* 52
than for squamous cell carcinoma, but the survival for SCC 51 57 47 47% 54
squamous cell carcinoma also decreased with advanc- Adeno 70* 46* 39* - 49
ing grade. Endometrium 86 79 54 34* 71
For all stages combined, the difference in survival Ovary 75* 45 36 34* 41
between Grades 1and 3 was 34% for adenocarcinomas, Prostate 92 86 60 49 77
Urinary bladder 77 61 42 38 45
compared with a 13% difference between Grades 1 and
Brain 69* 46* 14 13 26
3 for squamous cell carcinomas (Table 10). Nonetheless, h3* 3n* 36
Soft tissue 69* .. 23* - _.
it should be noted that Grade 4 squamous cell carcino-
SCC: squamous cell carcinoma; Adeno: adenocarcinoma; Bronch-alv: bronchi-
mas was associated with a 20% poorer survival than oloalveolar carcinoma; GR: grade; -: fewer than 25 cases; ALL: all grades com-
were cases assigned Grade 1. bined (includes ungraded).
In the cervix, as in the lung, regional stage squa- * 0.05 < SE 5 0.10.
Histologic Grading/Carriaga and Henson 413

Table 9. Survival According to Grade, Distant Stage Table 10.Squamous Cell Carcinoma and
Adenocarcinoma: Survival by Stage and Grade
Five-year relative survival rate (%)
Five-year relative
Site GRl GR2 GR3 GR4 Allt survival rate (%)
Esophagus 0 1 0 2 1
Stage Grade SCC Adeno
SCC 0 1 1 0 1
Adeno - 0 0 - 1 Esophagus
Stomach 3 4 2 1 2 Localized 1 20 42
Colon,lrectum 7 7 5 4 6 Localized 2 14 37
Pancreas 1 1 1 0 1 Localized 3 10 15
Larynx 34* 30* 27 - 27 Localized 4 - -
Lung 3 2 1 1 2 Localized All 13 27
SCC 3 2 1 1 2 Lung
Adeno 3 2 2 2 2 Localized 1 37 69
Bronch-alv 0 0 0 - 4 Localized 2 45 55
Small cell - 0 1 1 1 Localized 3 36 45
Breast 33* 23 11 17 18 Localized 4 25 34*
Ductal 34 23 11 17 18 Localized All 34 50
Lobular - - 15* - 23 Uterine cervix
Medullary - - - - 27 All stages 1 66 85
Mucinous - - - - 30 All stages 2 62 67
Uterine cervix 18* 20 7 5 14 All stages 3 53 51
SCC 16 18 9 6* 15 All stages 4 46 -
Adeno - - 0 - 13 All stages All 67 69
Endometrium 61 40 16 7 29 SCC: squamous cell carcinoma; Adeno: adenocarcinoma; All: all grades com-
Ovary 52 25 15 15 19 bined (includes ungraded cases); -: fewer than 25 cases.
Prostate 46 38 22 25 * 0.05 < SE I0.10.
30
Urinary bladder - 12 9 5 9
Brain - - - - 17
Soft tissue - 21* 9 4 8
Survival decreased with advancing grade, but rates for
SCC: squamous cell carcinoma; Adeno: adenocarcinoma; Bronch-alv: bronchi-
oloalveolar carcinoma; G R grade; All: all grades combined (includes ungraded Grades 3 and 4 were similar. Within each stage, Grade
cases); -: fewer than 25 cases. 1 cases had better survival than did cases graded 2,3, or
* 0.05 <: SE I0.10. 4. Regional stage Grade 1 cases had the same survival
as did localized stage high grade cases, whereas distant
stage Grade 1 cases had higher survival rates than did
allowed the identification of high risk subgroups, regional stage cases assigned Grade 2, 3, or 4. The 5-
whereas among distant stage cases, those assigned year survival rate for distant stage Grade 1 cases was
Grade 1 had much higher survival compared with that 52%, much higher than the 19% survival recorded for
expected based on stage alone (Tables 7-9). distant stage, all grades combined. Furthermore, the
Figure 2 shows the 5-year survival according to survival rate for serous cystadenocarcinomas assigned
grade and stage for 18,840 cases of endometrial carci- distant stage Grade 1 was 76%.
noma. Regional stage cases assigned Grade 1 or 2 had Similar results were observed for the different his-
higher survival rates than did localized stage cases as-
signed Grade 3 or 4. Distant stage Grade 1 cases had
about the same survival as did regional stage cases as- Table 11. Survival Rates for Colorectal Cancer
signed Grade 3 or 4. Five-year relative survival rate (%)
Ovary. Approximately half of all ovarian carcino-
mas were graded. Three distinct prognostic subgroups Staee GR I GR2 GR3 GR4 Allt
were formed by histologic grading. The differences in Localized 89 86 82 69* 86
survival between Grades 1and 3 were 2 1% for localized Regional 61 59 47 43 56
stage disease, 39% for regional stage disease, and 37% Distant 7 7 5 4 6
for distant stage disease, all histologic types combined. All stages 67 59 41 30 56
Figure 3 shows the 5-year survival according to * 0.05 < SE I0.10.
grade and stage for 6591 cases of ovarian carcinoma. t All grades combined; includes ungraded cases.
 414 CANCER Supplement Ianuary 2,2995, Volume 7 5 , No. 1

Relative survival rate (%) Relative survival rate ("h)

1 00 100
Grade 1
Grade 2
80 80
Grade 3
Grade 4
60 60

40
40

20
20

"
0 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 0
Months Localized Regional Distant
Figure 1. Pancreatic adenocarcinoma: monthly relative survival rates Figure 2. Endometrial carcinoma: 5-year relative survival rates by
by grade, according to the SEER data for 1978-1986. historic stage and grade, according to the SEER data for 1978-1986.

tologic types: the 5-year survival rate, all stages com- and regional stage cases. The cases staged localized and
bined, decreased from 87% (Grade 1)to 24% (Grade 3) regional are arranged more according to histologic
for serous cystadenocarcinomas, from 83% to 35% for grade than to stage: Grade 1 tumors were associated
mucinous adenocarcinomas, and from 82% to 29% for with the best survival whether they were localized or
endometrioid carcinomas. regional, followed by Grade 2 tumors, whether they
Prostate gland. Carcinomas of the prostate were were localized or regional, then similarly, Grades 3 and
graded frequently, and 72% of the graded cases were 4. In fact, the survival rates for cases listed as regional
assigned Grade 1 or 2. Grading separated the cases in stage Grade 1 was 38% higher than those for cases as-
each stage into four distinct prognostic subsets. The signed localized stage Grade 4.
difference in survival between Grades 1 and 4 was 42% Urinary bladder. The urinary bladder was the
for both localized and regional stage disease. most frequently graded site. Histologic grading stra-
Table 13 shows the outcome for 49,471 cases
ranked according to 5-year survival. As expected, dis-
tant stage disease was associated with the poorest out-
Relative survival rate (%)
come. There was overlap, however, between localized 100
Grade 1
(3 Grade 2
Table 12.Five-Year Survival Rates for Ductal 80 Grade 3
Adenocarcinoma of the Breast
Grade 4
Stage Grade Survival (%)
60
Loca1i zed 1 96.9
Localized 2 93.0
Localized 3 86.3
40
Localized 4 86.3
Regional 1 86.3
Regional 2 77.0
20
Regional 4 60.0
Regional 3 58.9
Distant 1 33.9
0
Distant 2 23.2 Localized Regional Distant
Distant 4 16.9
Figure 3. Ovarian carcinoma: 5-year relative survival rates by historic
Distant 3 10.5 stage and grade, according to the SEER data for 1978-1986.
Histologic Grading/Cavriaga and Henson 415

Table 3.3. Five-Year Survival Rates €or Prostate Cancer precluded the analysis of grade to outcome. No survival
Stage Grade Survival (%)
rates are reported for each stage and grade because
fewer than 25 cases were assigned to each category.
Localized 1 96.5 Soft tissue. The histologic grade of a soft tissue sar-
Regional 1 91.9
coma is an important determinant for stage assignment;
Localized 2 87.3
however, only 23% of all sarcomas were graded. Some
R’egional 2 86.4
Localized 3 66.0
histologic types, however, were graded more frequently
Regional 3 59.9 than others (Table 5).
Localized 4 54.2 For all stages combined, a survival gradient of 61%
Regional 4 49.4 was seen from Grade 1 to Grade 4. Within each stage,
Distant 1 45.7 grading identified three to four subgroups with differ-
Distant 2 38.1 ent survival rates. The 5-year survival rate for localized
Distant 4 25.3 stage Grade 1 cases was 9970, but it was 49% for the
Distant 3 21.9 same stage cases assigned Grade 4. The survival rate for
regional stage Grade 1 cases was 69%, higher than that
for localized stage Grade 4, a large difference despite a
high standard error (0.05 < standard error 5 0.10).
tified the cases of localized and regional stage disease
into four distinct subsets (Table 14). The difference be-
tween low and high grade disease was greatest for re- Discussion
gional stage disease (40%). As seen in the endometrium
and prostate, bladder carcinomas assigned regional This study provides further evidence that the less
stage Grade 1 had a better outcome than did those as- differentiated a tumor, the more likely it is to follow an
signed localized stage Grades 3 or 4. Grading revealed aggressive clinical course. For all anatomic sites studied
a subset of regionalkage cases with a 32% higher sur- in this review, the overall 5-year survival rates de-
vival rate than that expected based on stage alone (i.e., creased with advancing histologc grade. Within each
Grade 1 vs. all grades combined). stage grouping, histologic grading uncovered a survival
Brain. Although the histologic grade is required for gradient that separated the cases into three to four prog-
the assignment of TNM stage, only 42% of brain tumors riostic subgroups with different survival rates. For some
were graded. Of the 5190 graded cases, 69% were as- cancers, including those that arise in the prostate, endo-
signed Grade 3 or 4. Figure 4 shows that grading sepa- metrium, ovary, or brain, regional or distant stage cases
rated the cases into two subgroups with substantially assigned a low histologic grade had a better outcome
different outcomes: the differences in 5-year survival
between high and low grade tumors were 48% for lo-
calized stage cases and 56% for regional stage cases Relative survival rate (“7)
staged. No significant difference in survival was seen 100
between Grades 3 and 4. Grade 1
Adrenal. Only 25% of adrenal carcinomas were Grade 2
graded. The majority were high grade, and the associ- 80
Grade 3
ated 5-year survival rate was 31%, all stages and all
Grade 4
grades combined. The small number of graded cases
60

Table 14. Survival Rates €or Bladder Carcinoma 40

Five-year relative survival rate (yo)

Staee GR1 GR2 GR3 GR4 All* 20

Localized 97 93 75 69 89
Regional 77 61 42 38 45
Distant - 12 9 5 9 0
Localized Regional
All stag,es 96 89 58 44 78
Figure 4.Brain, other specified types (Berg group 111): 5-year relative
GR: grade; -: fewer than 25 cases.
survival rates by historic stage and grade, all races, both sexes
* All erades combined: includes uneraded cases. according to the SEER data for 1978-1986.
416 CANCER Supplement January 2,2995, Volume 75, No. 1
than did cases with a less advanced stage assigned a
high grade.
Grading was most informative for cancers of the
breast, endometrium, ovary, prostate, urinary bladder,
brain, and soft tissue. In the esophagus, lung, and cer-
vix, grading appeared to be more useful in predicting
outcome for adenocarcinomas than squamous cell car-
cinomas. For ovarian carcinoma, however, the histo-
logic grade was a strong prognostic factor for all histo-
logic types studied-serous cystadenocarcinoma, mu-
cinous adenocarcinoma, and endometrioid carcinoma.
The histologic grading of breast cancer in the SEER
Program was reviewed in a recent p ~ b l i c a t i o nWhen
.~~
a modified American Joint Committee on Cancer sys-
tem was used, Stage IIA Grade 1 cases were found to
have longer survival than were high grade Stage I cases,
regardless of nodal status. Similarly, this study showed
that regional stage Grade 1 cases had the same survival
rates as did localized stage Grades 3 and 4 cases. Within
each stage grouping, histologic grading identified high
and low risk groups. Our results confirmed that histo-
logic grade is a strong predictor of outcome for invasive
ductal carcinomas of the breast. The data on lobular,
medullary, and mucinous carcinomas of the breast are
inconclusive.
Most endometrial carcinomas are low grade; this
was also the pattern seen in the present analysis. In the
endometrium, as in other sites, grading identified sub-
groups of patients with significantly less favorable out-
come than that predicted by stage of disease alone. The
histologic grade has been correlated to depth of myo-
metrial invasion and nodal involvement and currently
is reported as an adjunct to the stage of disease. In the
International Federation of Gynecology and Obstetrics
classification for endometrial carcinoma, grade is based
on architectural criteria, but nuclear grade takes prece-
dence in papillary serous, squamous cell, and clear cell
carcinoma.58*12o
In some sites, grading presented a more accurate es-
timate of outcome than stage alone. For example, the
outcome for localized and regional stage prostatic carci-
noma was strongly dependent on grade: Regional stage
cases assigned a low histologic grade were associated
with 5-year survival rates higher than those for local-
ized stage cases assigned a high grade. The predictive
value of DNA analysis and image analysis has been in-
vestigated for prostate cancer, and a relationship has
been found between ploidy status and outcome.s4Some
investigators, however, have found DNA ploidy analy-
sis and nuclear morphometry to be no more accurate in
predicting outcome for localized prostate cancer than
histologic grading using the Gleason s y ~ t e m . ~The *,~~
observation that DNA ploidy analysis does not contrib-
ute additional prognostic information beyond that pro-
vided by grading also has been reported for endometrial
carcinoma.'j4
Stage and Grade
Although the data are not shown, a relationship was
found between histologic grade and stage of disease at
diagnosis. For most cancers, the proportion of high
grade cases increased with advancing stage, whereas
the percentage of low grade cases decreased.
In general, grading is most useful for estimating
prognosis in localized stage disease. For carcinomas of
the colon, larynx, endometrium, and bladder, however,
the difference in survival between low and high grades
was greater in regional stage disease than in localized.
In distant stage ovarian carcinoma, grading identified a
subset of Grade 1cases with significantly better survival
than that which would be expected based on stage
alone; this high survival might reflect the inclusion of
tumors of low malignant potential into the group as-
signed Grade 1. Distant stage endometrial and prostate
carcinomas were also associated with a better outcome
than that expected for distant stage disease. For most
distant stage cancers, however, grading added little in-
formation about outcome, because 5-year survival rates
were so low, regardless of grade.
In this study, cases were staged as localized, re-
gional, or distant. Cases staged as localized, however,
may include cases assigned T4 in the TNM system, as in
colorectal carcinoma, for example. In the colon, T4 cases
might have an unfavorable prognosis because of tumor
penetration beyond the serosal surface, but these cases
still are considered localized in the LRD system. The 5-
year survival for localized cases therefore will be lower
in the LRD system than that for cases assigned Stage I
in the TNM staging system.lZ3Similarly, the survival for
localized cases assigned Grade 1 or 2 might be lower
than expected because of the inclusion of T4 cases. This
might partially explain the relatively small differences
in survival among Grades 1, 2, and 3 for localized colo-
rectal carcinoma, when compared with the differences
among the grades for regional cases.
Three Grades
For all anatomic sites reviewed, survival rates decreased
with advancing grade, but no significant difference in
outcome was observed between Grades 3 and 4 for car-
cinomas of the esophagus, stomach, pancreas, breast,
ovary, and brain. The use of three grades therefore is
suggested for these carcinomas, with Grade 4 reserved
only for undifferentiated tumors.
Histologic GradinglCarriaga and Henson
Potential Bias
In the SEER Program, grade was recorded only if spe-
cifically stated in the pathology report. Because the his-
tologic grade of a tumor sometimes can be inferred from
its histologic type, some pathologists might consider a
separate statement of grade unnecessary. This can par-
tially explain the low frequency of grading for certain
cancers, such as bronchioloalveolar carcinomas and
adrenal cortical carcinomas. For some tumors, a high
grade histologic appearance distinguishes frank carci-
noma from a benign adenoma (e.g., adrenal cortical tu-
mors). As a result, the grade distribution would be
skewed toward the higher grades.
The cases were not evenly distributed among the
four grades; instead, for the majority of cancers, Grade
3 was the most frequently assigned. A possible expla-
nation is the lumping of histologic grades into two
groups: some pathologists might only distinguish be-
tween well differentiated and poorly differentiated tu-
mors. The development of grading systems with explic-
itly stated criteria would better separate the grades.
Finally, some pathologists might assign a grade
only if' the tumor has a high grade histologic appear-
ance. To investigate this possibility, the survival for un-
graded cases can be compared with the survival rate for
all graded cases combined. The survival for ungraded
and graded cases has been compared for breast cancer:
When staged by a modified American Joint Committee
on Cancer/International Union Against Cancer system,
Stage 11,111, and IV ungraded cases were associated with
higher 5-year survival rates than the graded cases.37
This finding suggests that the graded cases might have
comprised more high grade tumors than did the un-
graded cases. In this review, ungraded cases had a
slight1.y better outcome than did graded cases for only
certain sites, including breast, cervix, and adrenal
gland-sites infrequently graded. The opposite was
seen in sites graded frequently: for cancers of the endo-
metrium, bladder, and prostate, survival rates were
higher for graded cases than for ungraded cases.
Variations in Grading Frequency
The cancers most often graded are those for which
grading is accepted widely as a predictor of outcome.
The high frequency of grading for cancers of the urinary
bladder, endometrium, and prostate reflects clinicians'
demands for the histologic grade, because grade can in-
fluence therapy in some instances. The results also sug-
gest that when detailed grading systems are widely ac-
cepted for specific sites, grading will be performed more
often, as shown by the increased frequency of grading
417
for prostatic carcinoma following the development of
Gleason's scoring system.85r86However, histologic
grade is also an important prognostic factor for invasive
ductal carcinoma of the breast, but only a small percent-
age of cases were graded. The histologic grade of soft
tissue sarcomas is an important determinant of the stage
of disease and therefore outcome, but less than 25%
were graded.
Observer Variation
Critics of histologic grading claim that observer varia-
tion diminishes its effectiveness in predicting outcome.
In the SEER Program, no common criteria for grading
were established among the many contributing pathol-
ogists; however, stage for stage, overall survival rates
decreased with advancing grade for all sites reviewed.
Therefore, in a large population of patients as recorded
in the SEER Program, interobserver variation did not
have sufficient impact to alter the relationship between
grade and outcome for more than 440,000 cases.
Benefits
The search for more sensitive predictors of outcome in
patients with cancer has been heightened in recent
years. Image analysis, flow cytometric DNA analysis,
the use of molecular markers, and other technologic
procedures are being investigated for use as objective
methods to supplement the prognostic information pro-
vided by stage of disease. Compared with these meth-
ods, histologic grading is a proven prognostic factor
with practical advantages.'7~28~4464.ss.90
Grading can be performed on exactly the same
specimen used for diagnosis without the need for addi-
tional tissue. Therefore, virtually all specimens ade-
quate for diagnosis can yield additional prognostic in-
formation, regardless of size or fixation status, with the
possible exception of very small diagnostic biopsies.
This becomes more important as submitted specimens
become smaller because of the earlier detection of tu-
mors: the amount of available tissue is often inadequate
for certain tests, especially those requiring tissue ho-
mogenates (e.g., flow cytometry). Grading is also more
efficient than other methods. Often, grading can be per-
formed on the same histologic sections used for evalua-
tion of the tumor, so the histologic grade and other mor-
phologic predictors of outcome (e.g., depth of invasion,
vascular invasion) can be reported at the very time the
final diagnosis is made. Furthermore, grading is cost-
effective and involves no new technology.
A uniform grading system with defined criteria
should be developed in a manner similar to that for can-
418 CANCER Supplement January 2,2995, Volume 75, No. 1
cer patient staging. The criteria should vary for the in-
dividual sites and should reflect the specific characteris-
tics of the different histologic types of cancer. The es-
tablishment of a uniform system of grading would
increase the frequency of grading by pathologists, sig-
nificantly reduce observer variation, and strengthen the
predictive value of histologic grade.
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