YGYNO-976574; No.

of pages: 7; 4C:
Gynecologic Oncology xxx (2016) xxx–xxx

Contents lists available at ScienceDirect

Gynecologic Oncology

journal homepage: www.elsevier.com/locate/ygyno

Historical Perspectives

Bokhman Redux: Endometrial cancer “types” in the 21st century

Adrian A. Suarez a,⁎, Ashley S. Felix b, David E. Cohn c
a
Department of Pathology, College of Medicine, The Ohio State University, United States
b
Division of Epidemiology, College of Public Health, The Ohio State University, United States
c
Department of Obstetrics and Gynecology, College of Medicine, The Ohio State University, United States

H I G H L I G H T S

• A landmark 1983 Gynecologic Oncology paper defined two types of endometrial cancer.
• Type I was associated with metabolic syndrome, low stage and low grade tumors.
• Type II was associated with high grade and clinically aggressive tumors.
• This view has contributed greatly to endometrial cancer understanding and teaching.
• Recent molecular, epidemiologic and pathologic advances challenge a dualistic view.

a r t i c l e i n f o a b s t r a c t

Article history: In 1983 Jan V. Bokhman, M.D. published a landmark paper entitled “Two Pathogenetic Types of Endometrial Car-
Received 17 October 2016 cinoma” in which an enduring dualistic view of endometrial cancer was first proposed. “Type I” cancers are
Received in revised form 1 December 2016 thought to represent estrogen driven mostly low grade endometrioid tumors strongly associated with obesity
Accepted 9 December 2016
and other components of the metabolic syndrome. “Type II” cancers represent higher grade non-endometrioid
Available online xxxx
tumors for which the latter associations are less significant. Basic tenets of this dichotomy including significant
Keywords:
prognostic differences have been abundantly confirmed by later literature. The construct has in turn contributed
Endometrial cancer a useful framework for decades of teaching and scientific advancement across disciplines. However, recent large
Endometrial carcinoma epidemiologic studies indicate a more complex web of risk factors with obesity and hormones likely playing an
Metabolic syndrome important role across the entire endometrial cancer histologic and clinical spectrum. Moreover, high quality mo-
Obesity lecular data and refinements in pathologic classification challenge any simplistic classification of endometrial
Cancer risk cancer. For example, the Cancer Genome Atlas (TCGA) recently defined four clinically distinct endometrial cancer
Risk factor types based on their overall mutational burden, specific p53, POLE and PTEN mutations, microsatellite instability
and histology. Additionally, new histologic categories with clear prognostic implications have been accepted and
it is becoming evident from an epidemiologic point of view that metabolic factors may play an important role in
endometrial cancer overall. While Bokhman's intuitive dualistic model remains relevant when working with
large registries and databases lacking granular information; most other efforts should integrate clinical, patholog-
ical and molecular specifics into more nuanced classifications.
© 2016 Elsevier Inc. All rights reserved.

1. Introduction
In the 1983 February issue of Gynecologic Oncology Jan V. Bokhman,
M.D. of the N.N. Petrov Research Institute of Oncology in Leningrad,
USSR (currently Saint Petersburg, Russia) published a landmark paper
entitled: “Two Pathogenetic Types of Endometrial Carcinoma” [1].
Bokhman described “personal observations” of 366 patients over twen-
ty years and presented the “…hypothesis that the complex of endocrine
⁎ Corresponding author at: The Ohio State University Wexner Medical Center
Department of Pathology, 410 W 10th Avenue, Columbus, OH 43210, United States.
E-mail address: Adrian.Suarez@osumc.edu (A.A. Suarez).
and metabolic disturbances arising long before the development of en-
dometrial carcinoma determines the biological peculiarities of the
tumor…”. The resulting paradigm, in particular the “Type I” versus
“Type II” endometrial cancer dichotomy profoundly influenced the liter-
ature up to this date across different disciplines.
Multiple increasingly large endometrial cancer series had appeared
in the English literature since the beginning of the 20th century. Early
interest in histologic description and potential precursor lesions includ-
ing endometrial atrophy and hyperplasia [2,3] was accompanied by the
realization that obesity, hypertension, glucose intolerance and diabetes
were highly prevalent amongst women with endometrial cancer [4–7].
This recognition paralleled the description, under various names

http://dx.doi.org/10.1016/j.ygyno.2016.12.010
0090-8258/© 2016 Elsevier Inc. All rights reserved.

Please cite this article as: A.A. Suarez, et al., Bokhman Redux: Endometrial cancer “types” in the 21st century, Gynecol Oncol (2016), http://
dx.doi.org/10.1016/j.ygyno.2016.12.010
2 A.A. Suarez et al. / Gynecologic Oncology xxx (2016) xxx–xxx
throughout the century, of metabolic syndrome and attendant in-
creased cardiovascular risk [8]. Additionally, significant advances in
the understanding of estrogen physiology occurred in the 1970's. Es-
trone produced by peripheral aromatization of plasma androstenedione
was identified as the principal estrogen in postmenopausal women [9].
Moreover, elegant studies reported by Schindler, Ebert and Friedrich
demonstrated that aromatization of androstenedione to estrone hap-
pened in peripheral adipose tissue and that estrone production by this
mechanism was significantly higher in women with endometrial neo-
plasia when compared to women without it [10]. Aromatase activity
was soon thereafter found to positively correlate with total body adi-
pose tissue [11]. Additionally, during the 1970's intense attention was
focused on the effect of estrogen replacement therapy on endometrial
cancer risk contributing to set the stage afresh for reconsideration of en-
dogenous hyperestrogenism and related constitutional factors [12].
2. Bokhman's pathogenetic types, tumor grade, depth of myometrial
invasion, and lymph node metastasis
Bokhman noted that 82.5% of his endometrial cancer patients were
obese, 69% had hypercholesterolemia, 60.5% had diabetes mellitus and
49% were hypertensive. Anovulatory cycles, infertility and signs of
hyperestrogenism including endometrial hyperplasia were also com-
mon amongst these women. Bokhman dubbed this group “pathogenetic
type I” and clearly documented a strong association between these clin-
ical features and endometrial cancer histologic grade. Almost 80% of
pathogenetic type I patients had lower grade (FIGO G1 or G2) tumors
while 20% had high grade (G3) tumors. On the other end of the spec-
trum were “pathogenetic type II” patients who lacked what currently
would be recognized as metabolic syndrome and whose tumors were
high grade in a remarkable 65.7% of the cases. General clinical features
and tumor characteristics of these two pathogenetic types as originally
reported are summarized in Tables 1 and 2 respectively and illustrated
in Fig. 1A–E. Not surprisingly, “deep” myometrial invasion was seen in
most (65.7%) pathogenetic type II tumors and in a minority (30.4%) of
pathogenetic type I. Additionally, Bokhman recognized that pelvic
lymph node metastases were three times more prevalent in patients
classified as having pathogenetic type II endometrial cancer compared
with pathogenetic type I (27.8% in type II versus 9.4% in type I). Impor-
tantly, having submitted his paper for publication in May of 1981,
Bokhman's histologic correlations clearly precede the modern descrip-
tions of endometrial serous carcinoma by Lauchlan [13] and
Hendrickson et al. [14]. Serous carcinoma was to be later understood
as the most common and prototypical high grade endometrial carcino-
ma. While there were tenuous suggestions to the fact even decades ear-
lier in the literature [15] and exceptions were included in the 1983
Gynecologic Oncology paper itself, the clearly stated correlations of
Table 1
General clinical features, “The signs of two main pathogenetic types of endometrial carci-
noma”.
Modified with permission from Bokhman [1].
Pathogenetic type
I II
Menstrual function History of anovulatory Normal
bleeding
Reproductive function Frequent infertility Normal
Onset of menopause Often after age 50 Often before age 50
Endometrial background Hyperplasia Atrophy
or result of previous
sampling
Obesity Present Absent
Hyperlipidemia Present Absent
Diabetes mellitus Present Absent
Hypertension Associated with Absent or not associated with
obesity and/or obesity and/or diabetes
diabetes mellitus mellitus
Please cite this article as: A.A. Suarez, et al., Bokhman Redux: Endometrial cancer “types” in the 21st century, Gynecol Oncol (2016), http://
dx.doi.org/10.1016/j.ygyno.2016.12.010
Table 2
Tumor characteristics, “Influence of pathogenetic type of the disease on tumor peculiari-
ties”.
Modified with permission from Bokhman [1].
Pathogenetic type
I II
Duration of symptoms Usually long Usually short
Myometrial invasion Frequently superficial Frequently deep
Potential for lymphovascular invasion Low High
Progesterone sensitivity High Low
Low grade (“G1 + G2”) 79.9% of cases 34.3% of cases
High grade (“G3”) 20.1% of cases 65.7% of cases
Prognosis Favorable Doubtful
the two pathogenetic types with histologic grade and stage represent
one of Bokhman's major contributions to the understanding of endome-
trial cancer. With a rare exception [16] later series confirmed these asso-
ciations. Anderson et al., Everett et al. and Münstedt et al. [17–19]
reported lower stage at presentation and lower grade tumors to be asso-
ciated with obesity in their respective studies of 492, 396 and 1180
women with endometrial cancer. The series by McCourt et al. on 473
uterine cancers showed higher body mass index to be associated with
lower stage at presentation but there was no statistically significant as-
sociation with histology or grade [20]. It should be noted however that
this series included a number of sarcomas [20]. In a study of 356 patients
with endometrial carcinoma by Pavelka et al. morbid obesity correlated
with lower grade, but not lower stage, in women with endometrioid
carcinomas [21].
3. Bokhman's pathogenetic types and survival
A second major contribution would come from Bokhman's personal
follow up of his cases throughout 20 years. Original data are presented
in Table 3. Women in the pathogenetic type I group had better 5 year
survival (85.6%) than those in the pathogenetic type II group (58.8%),
the latter suffering from “recurrences and metastases in most patients
during the first years after the treatment”. Bokhman also observed
that the ten year survival remained relatively similar to the five year
survival for pathogenetic type II (55.1%), but showed continued decline
in pathogenetic type I to 75.9% due to deaths from second malignancies
(especially breast and colon cancer), as well as to death from cardiovas-
cular disease. Ward et al. confirmed the core of these observations in an
analysis of SEER data including 33,232 deaths in women with incident
endometrial cancers from 1973 to 1988 [22]. The risk of disease specific
death from endometrial cancer was greatest up to five year after diagno-
sis with the risk of death from cardiovascular disease becoming greater
thereafter. Additionally, women with high grade tumors were more
likely to die of their endometrial cancers than women with low grade
tumors [22]. FIGO data on thousands of patients from international
data provide further evidence that unfavorable pathologic features clus-
tering in Bokhman's pathogenetic type II such as non-endometrioid his-
tology, high grade and advanced stage convey worse disease specific
survival compared to favorable pathologic features [23]. Interestingly,
the relationship between disease specific survival and obesity, a key
component of pathogenetic type I and metabolic syndrome, may be
more complicated. Despite the reported association of obesity with fa-
vorable pathologic features (briefly reviewed above) studies on disease
specific mortality have been inconsistent. Sample sizes, population dif-
ferences, time points of body mass index (BMI) measurements and in-
ability to adjust for cancer treatment may account for these
inconsistencies [24]. A recent study of 1400 incident endometrial cancer
cases within the National Institutes of Health–AARP Diet and Health
Study documented that higher pre-diagnosis BMI increased the risk of
overall and disease-specific mortality regardless of tumor grade [24].
 A.A. Suarez et al. / Gynecologic Oncology xxx (2016) xxx–xxx 3

Fig. 1. Complex atypical hyperplasia of the endometrium is architecturally characterized on low power microscopic examination by crowded irregular glands (A) and cytologically
characterized on high power microscopic examination by nuclear atypia (A, inset); it is an accepted precursor lesion of type I endometrial carcinomas. Low grade (FIGO
1) endometrioid adenocarcinoma morphologically reminiscent of proliferative phase endometrium (B) is the prototypical type I endometrial carcinoma. Endometrial intraepithelial
carcinoma characterized by severe epithelial atypia without invasion of the underlying stroma (C) is an accepted precursor lesion of serous carcinoma. Serous carcinoma with severe
architectural and cytological atypia (D) is the prototypical type II endometrial carcinoma. Serous carcinoma (E, upper half of the microphotograph) arising in a background atrophic
endometrium (E, lower half of the microphotograph showing cysts) conforms to Bokhman's dualistic pathogenetic classification. A case of low grade (FIGO 1) endometrioid
adenocarcinoma (F, lower half of the microphotograph) arising in a background atrophic endometrium (F, upper half of the microphotograph), does not conform to Bokhman's
dualistic pathogenetic classification. Clear cell carcinomas (G), currently considered type II by WHO, share molecular and immunophenotypical characteristics with endometrioid
carcinomas thus defying such classification. Dedifferentiated carcinomas are unaccounted for in a dualistic classification; they are clinically aggressive and combine a low grade
endometrioid component (H, left side of the microphotograph) with an undifferentiated component (H, right side of the microphotograph and inset).

4. Type I and type II endometrial cancers, a dualistic model in crisis

Table 3
Pathogenetic types and survival.
Modified with permission from Bokhman [1]. Soon after Bokhman's publication endometrial carcinoma began to
be classified as type I and type II not as the originally intended pathoge-
Pathogenetic type 5 year follow up 10 year follow up
netic types but along histological lines. This use continues in the current
n Alive (%) n Alive (%)
literature with type I frequently including all endometrioid tumors and
I 194 166 (85.6) 108 82 (75.9) type II including non-endometrioid histologies better represented by
II 102 60 (58.8) 49 27 (55.1) the prototypical serous carcinoma. Molecular studies fueled the evolv-
Total 296 226 (76.4) 157 109 (69.4)
ing concept as distinct differences were demonstrated between

Please cite this article as: A.A. Suarez, et al., Bokhman Redux: Endometrial cancer “types” in the 21st century, Gynecol Oncol (2016), http://
dx.doi.org/10.1016/j.ygyno.2016.12.010
4 A.A. Suarez et al. / Gynecologic Oncology xxx (2016) xxx–xxx
endometrioid and serous carcinomas. Microsatellite instability was
found primarily in endometrioid carcinomas [25–27] as were PTEN
[28], and K-Ras [29,30] mutations. Conversely TP53 mutations were
found in a majority of serous carcinomas and in a minority of
endometrioid tumors [31,32]. Notably, PTEN mutations were docu-
mented in endometrial hyperplasias thought to represent the precursor
lesion of endometrioid carcinomas [33] while p53 overexpression [34]
and TP53 mutations [31] were found in endometrial intraepithelial car-
cinoma thought to represent the precursor lesion of serous carcinomas.
Special considerations are in order for FIGO 3 endometrioid carcino-
mas and clear cell carcinomas in light of this dualistic model. FIGO 3
endometrioid carcinomas have been found to share phenotypic and
molecular features with serous carcinomas, including cases with p53
and p16 overexpression [35,36], commonalities on gene expression
profiles [37] and clinical behavior [38]. Moreover, in the Cancer Genome
Atlas (TCGA) molecular characterization of endometrial cancer, FIGO 3
endometrioid carcinomas segregated into each of the four molecular
groups, ranging from the clinically indolent POLE (ultramutated) cate-
gory to the ominous copy number high (serous like) [39]. Furthermore,
TCGA includes examples of FIGO 3 endometrioid carcinomas with and
without somatic TP53 mutations in the clinically favorable POLE
(ultramuted) and MSI (hypermutated) groups [Kandoth] but somatic
TP53 mutation frequency and types are similar in endometrioid and se-
rous carcinomas adjudicated to the copy number high (serous like)
TCGA group [40]. Therefore, explicit or implicit inclusion of FIGO 3
endometrioid carcinomas in a type I category where a majority of tu-
mors consist of indolent lower grade carcinomas is problematic and
may be a source of error in published and ongoing studies. It should
be noted that the current WHO classification of endometrial carcinomas
does make reference to Bokhman's pathogenetic types but restricts the
term type I to “low grade endometrioid adenocarcinoma and its vari-
ants” [41] implying that even FIGO 2 endometrioid carcinomas may
constitute a gray area. Clear cell carcinomas (Fig. 1G), whose modern
histologic description [42] might have been available to Bokhman, is
considered as a type II carcinoma in the current WHO classification
[41]. Indeed, most of these tumors display high grade histologic features
but only some pursue an aggressive clinical course. Furthermore, a siz-
able proportion of clear cell carcinomas share immunophenotypic and
molecular features with endometrioid carcinomas including microsatel-
lite instability and loss of expression of PTEN and ARID1A [43]. There-
fore, endometrial clear cell carcinoma does not comfortably fit in a
dualistic model.
From a current pathologic point of view a dualistic model of endo-
metrial cancer is further presented with multiple other challenges in-
cluding: (1) less than perfect correspondence between histology,
obesity and metabolic syndrome as clearly demonstrated in Bokhman's
original data and later larger series [44,45], (2) carcinomas arising with-
in a background of non-neoplastic endometrium that does not conform
to the model (Fig. 1F), a mismatch that may even correlate with a more
aggressive clinical course in endometrioid tumors with atrophic back-
ground [46], (3) suboptimal diagnostic reproducibility amongst expert
pathologists when it comes to high grade endometrial cancers [47],
(4) morphologically ambiguous [48], mixed [49] and dedifferentiated
[50] carcinomas (Fig. 1H).
5. Bokhman's treatment implications
While not specifically addressed in Bokhman's publication, the au-
thor does state that “In clinical practice, the attribution to the first or
second pathogenetic type of each individual patient will help to evalu-
ate in detail the peculiarity of the organism and choice of an accurate
course of treatment.” This forward looking statement acknowledges
the different behavior of pathogenetic type I and pathogenetic type II
endometrial cancers, and predicts that different therapies may be cho-
sen to improve the outcome in patients with type II cancers. There is
an increasing understanding of the role of adjuvant chemotherapy
Please cite this article as: A.A. Suarez, et al., Bokhman Redux: Endometrial cancer “types” in the 21st century, Gynecol Oncol (2016), http://
dx.doi.org/10.1016/j.ygyno.2016.12.010
and/or radiation therapy in women with high-grade endometrial can-
cers and non-endometrioid histologies [51,52]. Additionally, as the mo-
lecular bases of endometrial cancer have been elucidated [39],
integration of targeted therapies into the primary and adjuvant treat-
ment of endometrial cancers has been explored [53]. While technolo-
gies such as whole genome sequencing and methylation analysis had
not yet been refined when Bokhman published his paper in 1983, his
recognition of the biologic differences between pathogenetic types of
endometrial cancer predicted the development of treatment algorithms
based on subpopulations of the overall disease.
6. Epidemiologic evidence and new perspectives
Since Bokhman's formative contribution, the literature related to the
etiologic heterogeneity of endometrial cancer has expanded, with sev-
eral comprehensive epidemiological analyses investigating associations
between histologic subtypes and multiple established endometrial can-
cer risk factors. Fig. 2 summarizes five epidemiological analyses –
including two case-case [54,55], two case-control [44,56], and one co-
hort study [57] – that have evaluated age, race, reproductive character-
istics, obesity, diabetes, exogenous hormone use, and smoking history
in relation to endometrial cancer histologic subtypes. Despite different
study designs, exposure assessments, and categorization of histologic
subtype, these studies collectively affirm Bokhman's observations that
hormonal and metabolic abnormalities are more common among
endometrioid as compared with non-endometrioid subtypes. For
example, obesity is more commonly and strongly associated with
endometrioid (or type I) compared with non-endometrioid (or type
II) subtypes in studies that employ a control group. The case-case stud-
ies [54,55], which demonstrate that obesity is inversely associated with
type II or non-endometrioid subtypes when compared with type I or
endometrioid cases, are in agreement. However, the lack of a disease-
free population in these latter studies does not rule out the possibility
that odds ratios less than 1.0 could imply increased risk if compared
with non-affected controls [58]. It should be noted that, from an epide-
miologic stance, there are even greater difficulties in delineating risk
factors for tumors within the histologically heterogeneous type II rubric.
While studies have suffered from low numbers of non-endometrioid tu-
mors, incomplete collection of relevant risk factors and lack of central-
ized pathological review there is evidence of risk factor heterogeneity
amongst serous carcinomas, carcinosarcomas and clear cell carcinomas
[55].
Unlike Bokhman's original observation, this updated literature sug-
gests that non-endometrioid or type II cancers are not completely de-
void of associations with hormonal, reproductive, and metabolic
factors. For example, a recent case–control study nested within the
Women's Health Initiative Observational Study (WHI-OS) cohort of
93,676 postmenopausal women (271 incident type I cases, 42 incident
type II cases) documented stronger associations of serum unconjugated
estradiol with risks of low-grade versus high-grade tumors (OR 8.92 vs.
3.27), but the difference was not statistically significant [59]. Moreover,
parity and cigarette smoking, two factors that are consistently associat-
ed with lower endometrial cancer risk overall, are related to lower risk
of developing endometrioid and serous endometrial tumors [44,56].
Both factors are thought to decrease endometrial cancer risk by lower-
ing cumulative circulating estrogen levels relative to progesterone, im-
plying that serous endometrial cancers are not as estrogen-
independent as previously assumed. Furthermore, the potential for di-
vergent etiologies of serous, clear cell, and carcinosarcomas can now
be appreciated from this body of work. As an example, Yang et al. re-
ported that diabetes is positively associated with risk of type I and
type II endometrial tumors compared with controls [57]; however,
when the individual histologic subtypes are parsed from the type II cat-
egory as in the Epidemiology of Endometrial Cancer Consortium (E2C2)
analysis [44], a positive association for serous, but not clear cell tumors
 A.A. Suarez et al. / Gynecologic Oncology xxx (2016) xxx–xxx 5

Fig. 2. Summary of epidemiologic studies evaluating established endometrial cancer risk factors by Type I/Type II or histologic subtypes.

Please cite this article as: A.A. Suarez, et al., Bokhman Redux: Endometrial cancer “types” in the 21st century, Gynecol Oncol (2016), http://
dx.doi.org/10.1016/j.ygyno.2016.12.010
6 A.A. Suarez et al. / Gynecologic Oncology xxx (2016) xxx–xxx
was noted. Taken together, data from etiologic and molecular studies
provide coherent support of distinct individual histologic subtypes.
Recent studies have begun to explore novel risk factors, including in-
fertility [60], metabolic syndrome [61], use of non-steroidal anti-
inflammatory drugs [62] and intrauterine devices [63], and how they re-
late to risk of developing endometrial cancer overall and by type. Over-
all, these studies demonstrate significant associations between the
individual risk factors with endometrial cancer risk overall and for
type I, but not type II endometrial cancer. Although conducted within
large studies, i.e. E2C2 and SEER-Medicare, small numbers of the rare
histologic subtypes represent analytic challenges.
7. Conclusions
Endometrial cancer is a complex and heterogeneous disease from
epidemiologic, clinical, pathological and molecular points of view. Any
classification or model of such an entity entails a degree of oversimplifi-
cation and implies compromises. Bokhman's work is remarkable for
having incorporated clinical and pathological information available in
the 1980s into a construct that has endured constant study including
work done on much larger case series and the advent of increasingly so-
phisticated molecular techniques. Indeed, Bokhman's intuitive and rap-
idly popular “type I” versus “type II” dualistic model has been useful in
framing decades of teaching and scientific advancement across different
disciplines. Along the way, the original pathogenetic categories have
more often than not been used in a histologic sense, a deviation that
has led to variable often vague uses. Authors and readers alike are cau-
tioned about the need to clarify the definition of these terms in work in
which they may remain relevant such as that done based on registries
and databases lacking higher level granular information. Many fields
however, would greatly benefit from more nuanced classifications
that necessarily depart from Bokhman's by integrating up to date clini-
cal, pathological and molecular data [64–66].
Conflicts of interest and source of funding
There are no conflicts of interest or funding to declare for this work.
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