Advertisement

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

Published:December 16, 2016DOI:https://doi.org/10.1016/j.ygyno.2016.12.010

      Highlights

      • 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.

      Abstract

      In 1983 Jan V. Bokhman, M.D. published a landmark paper entitled “Two Pathogenetic Types of Endometrial Carcinoma” in which an enduring dualistic view of endometrial cancer was first proposed. “Type I” cancers are thought to represent estrogen driven mostly low grade endometrioid tumors strongly associated with obesity and other components of the metabolic syndrome. “Type II” cancers represent higher grade non-endometrioid tumors for which the latter associations are less significant. Basic tenets of this dichotomy including significant prognostic differences have been abundantly confirmed by later literature. The construct has in turn contributed a useful framework for decades of teaching and scientific advancement across disciplines. However, recent large epidemiologic studies indicate a more complex web of risk factors with obesity and hormones likely playing an important role across the entire endometrial cancer histologic and clinical spectrum. Moreover, high quality molecular data and refinements in pathologic classification challenge any simplistic classification of endometrial cancer. For example, the Cancer Genome Atlas (TCGA) recently defined four clinically distinct endometrial cancer 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, pathological and molecular specifics into more nuanced classifications.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Gynecologic Oncology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Bokhman J.V.
        Two pathogenetic types of endometrial carcinoma.
        Gynecol. Oncol. 1983; 15: 10-17
        • Novak E.
        • Yui E.
        Relation of endometrial hyperplasia to adenocarcinoma of the uterus.
        Am. J. Obstet. Gynecol. 1936; 32: 674-698
        • Hertig A.T.
        • Sommers S.C.
        Genesis of endometrial carcinoma; study of prior biopsies.
        Cancer. 1949; 2: 946-956
        • Moss W.T.
        Common peculiarities of patients with adenocarcinoma of the endometrium with special reference to obesity, body build, diabetes and hypertension.
        Am. J. Roentgenol. Radium. Ther. 1947; 58: 203-210
        • Randall J.H.
        • Mirick D.F.
        • Wieben E.E.
        Endometrial carcinoma.
        Am. J. Obstet. Gynecol. 1951; 61: 596-602
        • Randall J.H.
        • Goddard W.B.
        A study of 531 cases on endometrial carcinoma.
        Surg. Gynecol. Obstet. 1956; 103: 221-226
        • Javert C.T.
        • Renning E.L.
        Endometrial cancer; survey of 610 cases at Woman's Hospital (1919–1960).
        Cancer. 1963; 16: 1057-1071
        • Sarafidis P.A.
        • Nilsson P.M.
        The metabolic syndrome: a glance at its history.
        J. Hypertens. 2006; 24: 621-626
        • Grodin J.M.
        • Siiteri P.K.
        • MacDonald P.C.
        Source of estrogen production in postmenopausal women.
        J. Clin. Endocrinol. Metab. 1973; 36: 207-214
        • Schindler A.E.
        • Ebert A.
        • Friedrich E.
        Conversion of androstenedione to estrone by human fat tissue.
        J. Clin. Endocrinol. Metab. 1972; 35: 627-630
        • Forney J.P.
        • Milewich L.
        • Chen G.T.
        • et al.
        Aromatization of androstenedione to estrone by human adipose tissue in vitro. Correlation with adipose tissue mass, age, and endometrial neoplasia.
        J. Clin. Endocrinol. Metab. 1981; 53: 192-199
        • Silverberg S.G.
        New aspects of endometrial carcinoma.
        Clin. Obstet. Gynecol. 1984; 11: 189-208
        • Lauchlan S.C.
        Tubal (serous) carcinoma of the endometrium.
        Arch. Pathol. Lab. Med. 1981; 105: 615-618
        • Hendrickson M.
        • Ross J.
        • Eifel P.
        • Martinez A.
        • Kempson R.
        Uterine papillary serous carcinoma: a highly malignant form of endometrial adenocarcinoma.
        Am. J. Surg. Pathol. 1982; 6: 93-108
        • Berthelsen H.G.
        • Svane H.A.
        Cancer of the endometrium and hyperestrinism; two different modes of origin of endometrial cancer.
        Dan. Med. Bull. 1956; 3: 236-239
        • Beckner M.E.
        • Mori T.
        • Silverberg S.G.
        Endometrial carcinoma: non-tumor factors in prognosis.
        Int. J. Gynecol. Pathol. 1985; 4: 131-145
        • Anderson B.
        • Connor J.P.
        • Andrews J.I.
        • Davis C.S.
        • Buller R.E.
        • Sorosky J.I.
        • Benda J.A.
        Obesity and prognosis in endometrial cancer.
        Am. J. Obstet. Gynecol. 1996; 174: 1171-1178
        • Everett E.
        • Tamimi H.
        • Greer B.
        • et al.
        The effect of body mass index on clinical/pathologic features, surgical morbidity, and outcome in patients with endometrial cancer.
        Gynecol. Oncol. 2003; 90: 150-157
        • Münstedt K.
        • Wagner M.
        • Kullmer U.
        • Hackethal A.
        • Franke F.E.
        Influence of body mass index on prognosis in gynecological malignancies.
        Cancer Causes Control. 2008; 19: 909-916
        • McCourt C.K.
        • Mutch D.G.
        • Gibb R.K.
        • et al.
        Body mass index: relationship to clinical, pathologic and features of microsatellite instability in endometrial cancer.
        Gynecol. Oncol. 2007; 104: 535-539
        • Pavelka J.C.
        • Ben-Shachar I.
        • Fowler J.M.
        • et al.
        Morbid obesity and endometrial cancer: surgical, clinical, and pathologic outcomes in surgically managed patients.
        Gynecol. Oncol. 2004; 95: 588-592
        • Ward K.K.
        • Shah N.R.
        • Saenz C.C.
        • McHale M.T.
        • Alvarez E.A.
        • Plaxe S.C.
        Cardiovascular disease is the leading cause of death among endometrial cancer patients.
        Gynecol. Oncol. 2012; 126: 176-179
        • Creasman W.T.
        • Odicino F.
        • Maisonneuve P.
        • et al.
        Carcinoma of the corpus uteri.
        Int. J. Gynaecol. Obstet. 2003; 83: 79-118
        • Arem H.
        • Park Y.
        • Pelser C.
        • et al.
        Prediagnosis body mass index, physical activity, and mortality in endometrial cancer patients.
        J. Natl. Cancer Inst. 2013; 105: 342-349
        • Risinger J.I.
        • Berchuck A.
        • Kohler M.F.
        • Watson P.
        • Lynch H.T.
        • Boyd J.
        Genetic instability of microsatellites in endometrial carcinoma.
        Cancer Res. 1993; 53: 5100-5103
        • Duggan B.D.
        • Felix J.C.
        • Muderspach L.I.
        • Tourgeman D.
        • Zheng J.
        • Shibata D.
        Microsatellite instability in sporadic endometrial carcinoma.
        J. Natl. Cancer Inst. 1994; 86: 1216-1221
        • Caduff R.F.
        • Johnston C.M.
        • Svoboda-Newman S.M.
        • Poy E.L.
        • Merajver S.D.
        • Frank T.S.
        Clinical and pathological significance of microsatellite instability in sporadic endometrial carcinoma.
        Am. J. Pathol. 1996; 148: 1671-1678
        • Risinger J.I.
        • Hayes A.K.
        • Berchuck A.
        • Barrett J.C.
        PTEN/MMAC1 mutations in endometrial cancers.
        Cancer Res. 1997; 57: 4736-4738
        • Enomoto T.
        • Inoue M.
        • Perantoni A.O.
        • Terakawa N.
        • Tanizawa O.
        • Rice J.M.
        K-ras activation in neoplasms of the human female reproductive tract.
        Cancer Res. 1990; 50: 6139-6145
        • Mizuuchi H.
        • Nasim S.
        • Kudo R.
        • Silverberg S.G.
        • Greenhouse S.
        • Garrett C.T.
        Clinical implications of K-ras mutations in malignant epithelial tumors of the endometrium.
        Cancer Res. 1992; 52: 2777-2781
        • Tashiro H.
        • Isacson C.
        • Levine R.
        • Kurman R.J.
        • Cho K.R.
        • Hedrick L.
        p53 gene mutations are common in uterine serous carcinoma and occur early in their pathogenesis.
        Am. J. Pathol. 1997; 150: 177-185
        • Lax S.F.
        • Kendall B.
        • Tashiro H.
        • Slebos R.J.
        • Hedrick L.
        The frequency of p53, K-ras mutations, and microsatellite instability differs in uterine endometrioid and serous carcinoma: evidence of distinct molecular genetic pathways.
        Cancer. 2000; 88: 814-824
        • Maxwell G.L.
        • Risinger J.I.
        • Gumbs C.
        • et al.
        Mutation of the PTEN tumor suppressor gene in endometrial hyperplasias.
        Cancer Res. 1998; 58: 2500-2503
        • Sherman M.E.
        • Bur M.E.
        • Kurman R.J.
        p53 in endometrial cancer and its putative precursors: evidence for diverse pathways of tumorigenesis.
        Hum. Pathol. 1995; 26: 1268-1274
        • Alvarez T.
        • Miller E.
        • Duska L.
        • Oliva E.
        Molecular profile of grade 3 endometrioid endometrial carcinoma: is it a type I or type II endometrial carcinoma?.
        Am. J. Surg. Pathol. 2012; 36: 753-761
        • Han G.
        • Sidhu D.
        • Duggan M.A.
        • et al.
        Reproducibility of histological cell type in high-grade endometrial carcinoma.
        Mod. Pathol. 2013; 26: 1594-1604
        • Mhawech-Fauceglia P.
        • Wang D.
        • Kesterson J.
        • et al.
        Gene expression profiles in stage 1 uterine serous carcinoma in comparison to grade 3 and grade 1 stage 1 endometrioid adenocarcinoma.
        PLoS One. 2011; 6: e18066
        • Ayeni T.A.
        • Bakkum-Gamez J.N.
        • Mariani A.
        • et al.
        Comparative outcomes assessment of uterine grade 3 endometrioid, serous, and clear cell carcinomas.
        Gynecol. Oncol. 2013; 129: 478-485
        • Kandoth C.
        • Schultz N.
        • Cherniack A.D.
        • et al.
        Integrated genomic characterization of endometrial carcinoma.
        Nature. 2013; 497: 67-73
        • Schultheis A.M.
        • Martelotto L.G.
        • De Filippo M.R.
        • Piscuglio S.
        • Ng C.K.
        • Hussein Y.R.
        • Reis-Filho J.S.
        • Soslow R.A.
        • Weigelt B.
        TP53 mutational spectrum in endometrioid and serous endometrial cancers.
        Int. J. Gynecol. Pathol. 2016; 35: 289-300
      1. Kurman R.J. Carcangiu M.L. Herrington C.S. Young R.H. WHO Classification of Tumors of Female Reproductive Organs. IARC, Lyon2014: 125-135
        • Silverberg S.G.
        • De Giorgi L.S.
        Clear cell carcinoma of the endometrium. Clinical, pathologic, and ultrastructural findings.
        Cancer. 1973; 31: 1127-1140
        • Bae H.S.
        • Kim H.
        • Young Kwon S.
        • Kim K.R.
        • Song J.Y.
        • Kim I.
        Should endometrial clear cell carcinoma be classified as Type II endometrial carcinoma?.
        Int. J. Gynecol. Pathol. 2015; 34: 74-84
        • Setiawan V.W.
        • Yang H.P.
        • Pike M.C.
        • et al.
        Type I and II endometrial cancers: have they different risk factors?.
        J. Clin. Oncol. 2013; 31: 2607-2618
        • Joehlin-Price A.S.
        • Perrino C.M.
        • Stephens J.
        • et al.
        Mismatch repair protein expression in 1049 endometrial carcinomas, associations with body mass index, and other clinicopathologic variables.
        Gynecol. Oncol. 2014; 133: 43-47
        • Geels Y.P.
        • Pijnenborg J.M.
        • van den Berg-van Erp S.H.
        • et al.
        Endometrioid endometrial carcinoma with atrophic endometrium and poor prognosis.
        Obstet. Gynecol. 2012; 120: 1124-1131
        • Gilks C.B.
        • Oliva E.
        • Soslow R.A.
        Poor interobserver reproducibility in the diagnosis of high-grade endometrial carcinoma.
        Am. J. Surg. Pathol. 2013; 37: 874-881
        • Soslow R.A.
        Endometrial carcinomas with ambiguous features.
        Semin. Diagn. Pathol. 2010; 27: 261-273
        • Köbel M.
        • Meng B.
        • Hoang L.N.
        • et al.
        Molecular analysis of mixed endometrial carcinomas shows clonality in most cases.
        Am. J. Surg. Pathol. 2016; 40: 166-180
        • Silva E.G.
        • Deavers M.T.
        • Bodurka D.C.
        • Malpica A.
        Association of low-grade endometrioid carcinoma of the uterus and ovary with undifferentiated carcinoma: a new type of dedifferentiated carcinoma?.
        Int. J. Gynecol. Pathol. 2006; 25: 52-58
        • Rauh-Hain J.A.
        • Diver E.
        • Meyer L.A.
        • et al.
        Patterns of care, associations and outcomes of chemotherapy for uterine serous carcinoma: analysis of the National Cancer Database.
        Gynecol. Oncol. 2015; 139: 77-83
        • Rauh-Hain J.A.
        • Starbuck K.D.
        • Meyer L.A.
        • et al.
        Patterns of care, predictors and outcomes of chemotherapy for uterine carcinosarcoma: a National Cancer Database analysis.
        Gynecol. Oncol. 2015; 139: 84-89
        • Liu J.
        • Westin S.N.
        Rational selection of biomarker driven therapies for gynecologic cancers: the more we know, the more we know we don't know.
        Gynecol. Oncol. 2016; 141: 65-71
        • Felix A.S.
        • Weissfeld J.L.
        • Stone R.A.
        • et al.
        Factors associated with Type I and Type II endometrial cancer.
        Cancer Causes Control. 2010; 21: 1851-1856
        • Brinton L.A.
        • Felix A.S.
        • McMeekin D.S.
        • et al.
        Etiologic heterogeneity in endometrial cancer: evidence from a Gynecologic Oncology Group trial.
        Gynecol. Oncol. 2013; 129: 277-284
        • Sherman M.E.
        • Sturgeon S.
        • Brinton L.A.
        • et al.
        Risk factors and hormone levels in patients with serous and endometrioid uterine carcinomas.
        Mod. Pathol. 1997; 10: 963-968
        • Yang H.P.
        • Wentzensen N.
        • Trabert B.
        • et al.
        Endometrial cancer risk factors by 2 main histologic subtypes: the NIH-AARP Diet and Health Study.
        Am. J. Epidemiol. 2013; 177: 142-151
        • Martínez M.E.
        • Cruz G.I.
        • Brewster A.M.
        • Bondy M.L.
        • Thompson P.A.
        What can we learn about disease etiology from case-case analyses? Lessons from breast cancer.
        Cancer Epidemiol. Biomark. Prev. 2010; 19: 2710-2714
        • Brinton L.A.
        • Trabert B.
        • Anderson G.L.
        • et al.
        Serum estrogens and estrogen metabolites and endometrial cancer risk among postmenopausal women.
        Cancer Epidemiol. Biomark. Prev. 2016; 25: 1081-1089
        • Yang H.P.
        • Cook L.S.
        • Weiderpass E.
        • et al.
        Infertility and incident endometrial cancer risk: a pooled analysis from the epidemiology of endometrial cancer consortium (E2C2).
        Br. J. Cancer. 2015; 112: 925-933
        • Trabert B.
        • Wentzensen N.
        • Felix A.S.
        • Yang H.P.
        • Sherman M.E.
        • Brinton L.A.
        Metabolic syndrome and risk of endometrial cancer in the United States: a study in the SEER-medicare linked database.
        Cancer Epidemiol. Biomark. Prev. 2015; 24: 261-267
        • Brasky T.M.
        • Moysich K.B.
        • Cohn D.E.
        • White E.
        Non-steroidal anti-inflammatory drugs and endometrial cancer risk in the VITamins And Lifestyle (VITAL) cohort.
        Gynecol. Oncol. 2013; 128: 113-119
        • Felix A.S.
        • Gaudet M.M.
        • La Vecchia C.
        • et al.
        Intrauterine devices and endometrial cancer risk: a pooled analysis of the Epidemiology of Endometrial Cancer Consortium.
        Int. J. Cancer. 2015; 136: E410-E422
        • Murali R.
        • Soslow R.A.
        • Weigelt B.
        Classification of endometrial carcinoma: more than two types.
        Lancet Oncol. 2014; 15: e268-e278
        • Talhouk A.
        • McConechy M.K.
        • Leung S.
        • et al.
        A clinically applicable molecular-based classification for endometrial cancers.
        Br. J. Cancer. 2015; 113: 299-310
        • Stelloo E.
        • Nout R.A.
        • Osse E.M.
        • et al.
        Improved risk assessment by integrating molecular and clinicopathological factors in early-stage endometrial cancer-combined analysis of the PORTEC cohorts.
        Clin. Cancer Res. 2016; 22: 4215-4224