Review Aging and uterine serous carcinoma

Summary. Uterine serous carcinoma (USC) is closelyassociated with advanced age in patients. The p53signature (p53S) is considered the earliest indication forthe presence of carcinogenesis of USC. Based on ourprevious studies, the presence of p53Ss have almostalways been found in elderly women and are suspectedof being responsible for the imbalance between theproliferation and apoptosis of endometrial epithelial cellswith advanced age. We have summarized the currentstate of knowledge regarding the association betweenage and cancer and propose an age-related type ofendometrial cancer instead of Type II estrogen-independent endometrial cancer.Key words: Uterus, Serous carcinoma, Aging, p53,Apoptosis

Introduction

Aging is one of the most important risk factors forthe development of neoplasia. Its status as a risk factorhas been partially attributed to the cumulative exposureto carcinogens over time and the multiple hits requiredfor the onset of neoplasia (Vogelstein et al., 2013). Apatient’s age indicates the time interval during whichdriver genes are usually mutated (Vogelstein et al.,2013). The number of somatic mutations in tumors of

self-renewing tissues is positively correlated with theage of patients at the diagnosis (Tomasetti et al., 2013).

Uterine serous carcinoma (USC) is closelyassociated with an advanced age of patients, with a meanage in the late 60s, and often arising against abackground of inactive or atrophic endometrium(Longacre and Well, 2014). These findings suggest thatUSCs have a higher number of somatic mutations thanendometrioid carcinomas of the endometrium that occurin relatively young women. However, integratedgenomic and proteomic analyses of endometrialcarcinoma showed that USC had extensive somatic copynumber alterations (SCNAs), a low mutation rate, fewDNA methylation changes, low estrogen/progesteronereceptor levels, and frequent TP53 mutations (CancerGenome Atlas Research Network et al., 2013). Theauthors suggested the ultramutated phenotype and thehypermutated type of endometrial cancers to be due tomutations in the exonuclease domain of POLE anddeficiency of mismatch repair, respectively. A highdegree of SCNAs was correlated with an unfavorableprognosis in endometrial cancer patients, while tumorswith a high mutation rate were correlated with favorableprognosis in endometrial cancer patients. Another groupreported that 9% of USCs have a very high number ofsomatic mutations, with many somatic mutations inmismatch repair and POLE genes in particular. Thesetumors had no identified SCNAs, despite the remarkablesomatic mutation burden (Zhao et al., 2013). SCNAsplay critical roles in activating oncogenes andinactivating tumor suppressors (Zack et al., 2013). TheSCNA prevalence was found to be strongly positivelyassociated with age by applying SNP microarray datafrom healthy individuals (Vattathil and Scheet, 2016).

Review

Aging and uterine serous carcinomaToru HachisugaDepartments of Obstetrics and Gynecology, University of Occupational and Environmental Health, School of Medicine, Iseigaoka, Yahatanishi-ku, Kitakyushu, Japan

Histol Histopathol (2018) 33: 1125-1133

http://www.hh.um.es

Offprint requests to: Toru Hachisuga, M.D., Departments of Obstetricsand Gynecology, University of Occupational and Enviromental Health,School of Medicine, 1-1, Iseigaoka, Yahatanishi-lu. Kitakyushu, 807-855, Japan. e-mail: [email protected]: 10.14670/HH-11-985

Histology andHistopathologyFrom Cell Biology to Tissue Engineering

The analysis of SCNA patterns in cancers showed thatSCNAs were associated with TP53 mutations accordingto The Cancer Genome Atlas Pan-cancer data (Zack etal., 2013).

In this review, I have tried to adapt the concept ofage-related cancer for ordinary Type II endometrialcancer based on the findings from recent studies on theassociation between age and cancer. Materials and methods

The contents of three previous reports, including 82postmenopausal endometria (Koi et al., 2015), 133endometrial polyps (EMPs) (Sho et al., 2016), and 225hysterectomy specimens of endometrial cancer (Nguyenet al., 2015), were reviewed. The postmenopausalwomen with a prolapsed uterus received a transdermaltreatment consisting of 17β-estradiol (E2) 0.72 mg (3cases) and E2 0.62 mg plus norethindrone acetate (P)2.70 mg (12 cases) as a matrix patch for the treatment ofsevere vaginitis before surgery for 1 to 2 months. These15 hysterectomy specimens have also been included inthis review. The details regarding the methods weredescribed in the previous studies (Koi et al., 2015;Nguyen et al., 2015; Sho et al., 2016). For theimmunohistochemical analyses, 4-μm-thick sectionswere cut from formalin-fixed paraffin-embedded tissueblocks, deparaffinized in xylene, and rehydrated throughsequential washes of alcohol and distilled water. Ki-67and p53 were detected using the ready-to-usemonoclonal antibodies against Ki-67 and p53 (clonesMIB-1 and DO-7, respectively; DAKO, Kyoto, Japan).Estrogen receptor (ER)-alpha and progesterone receptor(PR) A were detected using monoclonal antibodies(clone 6F11, diluted 1:50, and clone 16, diluted 1:50,respecttively; Novocastra, Fukuoka, Japan). The slideswere heated in an autoclave at 120°C for 5 min in 0.01M citrate buffer (pH=6.0) before immunostaining. Theslides were incubated with these antibodies for 2 hoursat room temperature. Antibody binding was visualizedusing the EnVision+ Dual link system anddiaminobenzidine as a chromogen (Dako Cytomation,

Kyoto, Japan). 3’-endlabeling of apoptotic cell DNA wasperformed using an Apop Tag in situ apoptosis detectionkit (Millipore Corporation, Tokyo, Japan) according tothe instructions of the manufacturer. The slides werecounterstained with methyl green or hematoxylin andmounted. The interpretation of the immunohistochemicalpreparations and presence of apoptotic cells was assistedwith the WinROOF image processing software program(Mitani Corp., Tokyo, Japan) (Koi et al., 2015). Thisreview was approved by the Review Board of theUniversity Hospital of Occupational and EnvironmentalHealth on Ethical Issues.Results with comments

Proliferation and apoptosis in the endometrium

Endometrium and endometrial polyps during themenstrual cycle

The immunohistochemical data of the benignendometrium using antibodies of Ki-67 and p53 and theapoptotic kit are shown in Table 1. In our previous studyof endometrial glandular cells with regular cyclicmenstruation, the labeling index (LI) for Ki-67 in theproliferative phase was significantly higher than that ofKi-67 in the secretory phase. The apoptotic activity inendometrial glandular cells increased during the latesecretory phase with a low Ki-67 index (Udo et al.,2004). Among premenopausal EMPs, the LI for Ki-67was more frequently detected during the proliferativephase than during the secretory phase and significantlypositively correlated with that for p53 (Fig. 1) (Sho etal., 2016). However, the apoptotic index showed nosignificant difference between premenopausal EMPsduring the proliferative and secretory phase and was notcorrelated with the expression of Ki-67 (Sho et al.,2016). Maia et al. (2004) said that it was impossible todiscern whether the increased expression of p53 inendometrial polyps during the proliferative phaseresulted from a direct effect of estrogen on genetranscription or as the consequence of the accumulation

1126Aging and uterine serous carcinoma

Table 1. Immunohistochemical data of the benign endometirum.

Number of cases ki-67 median (range) p53 median (range) apoptosis median (range) Number of p53S(%)

Postmenopausal endometriumNon-user 72 6% (0-47) 2% (0-37) 1% (0-12) 8 (11.1)E2 user 8 16% (5-43)a 0% (0-8) 5% (0-9)b 2 (25.0)E2+P user 17 3% (0-62) 0% (0-28) 0% (0-4) 1 ( 5.9)

Posmenopausal EMP 71 15% (0-76)c 3% (0-38) 1% (1-9) 9 (12.6)Premenopausal EMP

Proliferative phase 41 49% (14-81) 7% (0-32) 3% (0-11) 0 (0.0)Secretory phase 21 0% (0-15) 0% (0-6) 2% (0-8) 0 (0.0)

p53S: p53 signature, E2: 17β-estradiol, P: norethindrone acetate, EMP: endometrial polyp. aP<0.005 (E2 users versus non-users), bP=0.02 (E2 usersversus non-users), cP<0.001 (postmenopausal EMP versus non-users).

of DNA errors caused by the high rates of cell division,which in turn indirectly increased the intracellular p53 inorder to correct them or to induce apoptosis.

Endometrium and endometrial polyps inpostmenopausal women

The LI for Ki-67 was significantly positivelycorrelated with the apoptotic index in postmenopausalwomen not using hormones (Koi et al., 2015).Furthermore, the LI for p53 was significantly correlatedwith the LI for Ki-67 but not with the apoptotic index(Koi et al., 2015). Postmenopausal endometria of E2users showed significantly higher LIs for Ki-67 andapoptotic index than those of non-users (P<0.005 andP=0.02, respectively, Fig. 2), while the expression of p53did not differ significantly between postmenopausalendometria with and without E2 use (P=0.605). Thepostmenopausal endometria of E2 + P users showed nosignificant difference in the LIs for Ki-67 and p53 or inthe apoptotic index from non-hormone users (P=0.431,0.095 and 0.634, respectively). Among postmenopausalEMPs, a univariate analysis showed that the LI for Ki-67was inversely correlated with p53 and significantlycorrelated with apoptosis (Sho et al., 2016).Furthermore, a multivariate analysis showed that thesignificance of the correlation between the LI of Ki-67and apoptosis was preserved, whereas that of the inversecorrelation between the LI for Ki-67 and p53

disappeared. Postmenopausal EMPs also showed asignificantly higher LI for Ki-67 than didpostmenopausal endometria (P<0.001). A positivecorrelation between the LIs of p53 and Ki-67 was foundin postmenopausal endometria (Koi et al., 2015) but notin the postmenopausal EMPs (Sho et al., 2016). p53 signature in endometrium

In a recently proposed model of the carcinogenesisof USC, the lesion was suggested to arise predominantlyin the resting endometrium, manifesting first as p53signature (p53S) and then subsequently evolving toendometrial glandular dysplasia (EmGD), followed byserous endometrial intraepithelial carcinoma (SEIC), andfinally presenting as fully developed USC (Zheng et al.,2011). The p53S was found in the backgroundendometrium of endometrial carcinomas in 20 (10.5%)postmenopausal patients (mean age 63.0 years) exceptfor 2 premenopausal patients with Lynch syndrome inour previous study (Nguyen et al., 2015). The p53S wasmore frequently detected in non-endometrioid tumorsthan in endometrioid tumors. EIC was found to bestrongly associated with non-endometrioid tumors withthe p53S (Fig. 3). The mean age of women with p53Swas 68.7 years under a benign condition of theendometrium. Among endometrial samples, including 97postmenopausal endometria and 71 postmenopausalEMPs, p53S was associated with high proliferative


Fig. 1. The endometrial polyp in a 36-year-old woman during the proliferative phase (A). The endometrial glands showed a high proliferative activity forKi-67 (B) and moderate expression of p53 (C). The endometrial polyp in a 32-year-old woman during the secretory phase (D). The endometrial glandsshowed no expression of Ki67 (E) or p53 (F). These samples were collected via the hysteroscopy.


Fig. 2. The postmenopausal endometrium in a 79-year-old woman using estrogen (A). The endometrial glands showed high expression of Ki-67 (B)and several apoptotic bodies (arrow), (C) and weak positivity for p53 (D) and high positivity for estrogen receptor-alpha (E) and progesterone receptor(F).

Fig. 3. An endometrial polyp with uterine serous carcinoma (USC) in a 72-year-old woman (A). The arrow indicates B. The p53 signature (p53S) andserous endometrial intraepithelial carcinoma (SEIC) associated with USC (B). The p53S showed low expression of Ki-67 (C), and high expressions ofp53 (D) and estrogen receptor-alpha (E). SEIC with high expressions of Ki-67 (C) and p53 (D), and a weak expression of estrogen receptor-alpha (E).

activity of the surrounding postmenopausal endometrialgland (P<0.001) but was not associated with the LI ofp53 or the apoptotic index (Table 2). The p53S itselfshowed a relatively low LI for Ki-67 and a low apoptoticindex compared with the surrounding endometrial glands(Fig. 4). The p53S is responsible for the imbalancebetween the proliferation and apoptosis of endometrialepithelial cells with advanced age. Tamoxifen and endometrium

Tamoxifen (TAM) is a member of a class of agentsknown as selective estrogen receptor modulators(SERMs) and is now widely used for the treatment andprevention of breast cancer. However, TAM use has beenassociated with a variety of gynecologic problems(ACOG committee opinion, 2006). EMPs and diffusecystic change are often found in TAM users. Theendometrial carcinomas of TAM users are more oftenlimited to a polyp than those of non-users (Hoogendoornet al., 2008), suggesting that the polyp-carcinomasequence plays an important role in the development ofendometrial cancer among postmenopausal breast cancerpatients treated with TAM. However, no markeddifference was observed in the incidence of the p53Sbetween postmenopausal EMPs of TAM users and non-users (Sho et al., 2016).

Gonadotropin-releasing hormone analogues (Gn-RHas) act on the hypothalamic-pituitary axis and reduceestradiol to postmenopausal levels. Our previous study

showed increased endometrial thickness (<0.5 cm ormore using transvaginal sonography) in over half ofTAM-treated postmenopausal breast cancer patients butrarely in premenopausal women with temporaryamenorrhea induced by Gn-RHa plus TAM adjuvanttherapy (Fig. 5) (Hachisuga et al., 2005). Gn-RHa plus


Fig. 4. The p53S (arrow) in the endometrium of a 67-year-old woman (A). The p53S with low expression of Ki-67 (B) and no apoptotic body (C), andpositivity for p53 (D), estrogen receptor-alpha (E) and progesterone receptor (F).

Table 2. Immunohistochemical data of the surrounding endometriumwith and without p53 signature.

Variable p53 signature p-valuepresence absence

Number of casesa 20 148Age (years) 0.783

50-59 0 1760-69 9 7270-79 9 4280-89 2 17

Ki-67 (%) 0.002median (range) 16 (4-62) 8 (0-72)

p53 (%) 0.136median (range) 3 (0-18) 1 (0-52)

Apoptosis (%) 0.224median (range) 1 (0-8) 1 (0-12)

acases including 72 postmenopausal women, 25 postmenopausalwomen with hormone use and 71 postmenopausal women withendometrial polyp

TAM adjuvant therapy induced the downregulation ofthe estradiol level, followed by a significant reduction inthe endometrial thickness (Yang et al., 2013).

Most studies have found that the relative risk ofdeveloping endometrial cancer for TAM users is two orthree times higher than that of an age-matchedpopulation (ACOG committee opinion, 2006). Thisincreased risk was limited in postmenopausal womentaking TAM. The median age at the diagnosis of TAM-related endometrial cancer was 69 years in the pooledresults from 3 countries (Jones et al., 2012). An olderage at the endometrial cancer diagnosis was associatedwith a greater risk of dying from endometrial cancer.Recent large case studies have shown a high incidence ofnon-endometrioid histological subtypes with a poorerprognosis among long-term TAM users (Hoogendoorn etal., 2008; Jones et al., 2012). The effects of TAM on theendometrium are closely related to the age of patients.Age and endometrial carcinomas

Activation of p53 can induce several responses incells, including cell-cycle inhibition, apoptosis, geneticstability and inhibition of blood-vessel formation(Vogelstein et al., 2000). Several experimental studiesusing breast cancer cells have reported that estrogenreceptor (ER)-alpha binds to p53 and represses itstranscriptional function, resulting in the inhibition ofp53-mediated cell cycle arrest and apoptosis (Shirley etal., 2009; Konduri et al., 2010). E2 enhanced ER-alphabinding to p53 and inhibited p21 transcription. ER-alpha-positive breast cancer patients with tumorsexpressing wild-type p53 respond better to TAM therapy(Konduri et al., 2010). The inhibition of p53-mediatedtranscription by ER-alpha binding to p53 may or maynot explain the overexpression of p53 in endometriumduring the proliferative phase.

Feng et al. (2007) reported that the efficiency of thep53 pathway declines with age as a function of the lifespan of the organism. The enhanced fixation ofmutations in older individuals is suggested to beassociated with the declining fidelity of p53-mediatedapoptosis or senescence in response to stress. DeGregori(2013) said that the age-dependent accumulation ofmutations plays a relatively minor role in the increasedincidence of cancer with age. Instead, other aging-associated changes, such as alterations in tissues thatinfluence selection for oncogenic events, largely underliethe aging-associated cancer. The author suggests that thep53S is responsible for the imbalance between theproliferation and apoptosis of endometrial epithelial cellswith advanced age and the p53S is thought to be partlyassociated with precancerous lesions of USCs.

Therefore, the concept of age-related endometrialcancers is proposed instead of Type II (estrogen-independent) endometrial cancers, based on decline inthe p53 functions with age associated with thesubsequent increased number of SCNAs (Fig. 6). Oneepidemiological study showed that Type I and II

endometrial cancers share many common etiologicfactors. The etiology of type II tumors is not completelyestrogen-independent, as previously believed (Setiawanet al., 2013).

The endometrium undergoes cyclical changes inproliferation, differentiation and apoptosis in response to


Fig. 5. Transvaginal ultrasound image of a 37-year-old woman (A).Thinness of the endometrium was shown in a normal-sized-uterus. Shehad chemotherapy-induced amenorrhea with loss of serum estrogenand a high follicular-stimulating hormone value and had received TAMtherapy for two years after a breast cancer operation. Sagittal T2-weighted uterine MR image of a 72-year-old woman (B). Diffuse cysticchanges around the endometrial cavity were shown in the enlargeduterus. She had received TAM therapy for two years after breast canceroperation.

the rise and fall of ovarian estrogen and progesteronelevels. The loss of oocytes, which occurs with age, isresponsible for menopause (Pelosi et al., 2015). Thelifetime risk of cancers of many different types issuggested to be strongly correlated with the total numberof divisions of the normal self-renewing cellsmaintaining that tissue’s homeostasis (Tomasetti andVogelstein, 2015). Most cancer risk is due to randommutations arising during DNA replication in normal,noncancerous stem cells (Martincorena and Cambell,2015). The division activity of normal endometrial self-renewing cells is dramatically changed from active tostationary due to menopause, and the phenotypes ofendometrial cancers reflect these age-dependent factors.POLE is a catalytic subunit of DNA polymerase epsiloninvolved in nuclear DNA replication and repair. Tumorswith mutations in the exonuclease domain of POLE wereclassified into the ultramutated group of the endometrialcarcinoma and showed an endometrioid histologic typewith a favorable prognosis among endometrial cancerpatients (Cancer Genome Atlas Research Network et al.,2013). The POLE subtype may or may not be associatedwith a high division activity of normal endometrial self-renewing cells in the menstrual cycle, in contrast toUSC, which is associated with a declining p53 functionduring aging. USC and high-grade ovarian serous carcinoma

High-grade serous ovarian carcinoma wascharacterized by TP53 mutations in almost all tumors(96%). The inactivation (germline or somatic mutationor promoter methylation) of BRCA1/2 was found in

nearly half of high-grade serous ovarian carcinomas(Cancer Genome Atlas Research Network et al., 2013).Based on the evaluation of risk-reducing salpingo-oophorectomy specimens in women with BRCAmutations, the concept of a high-grade pelvic serouscarcinogenic sequence was proposed, in which thespectrum of fallopian tube (FT) epithelial transformationranges from normal epithelium through p53 S and seroustubal intraepithelial carcinoma (STIC), ultimatelypresenting as invasive carcinoma (Crum et al., 2012).STICs show high rates of cellular proliferation, p53mutations, significant cytologic atypia, and a secretoryphenotype and are commonly located in the tubalfimbria, frequently presenting in association with p53Ss(Lee et al., 2007). In nonprophylactic settings, STIC hasbeen observed in the FT in up to 60% of women withhigh-grade serous carcinoma (Crum et al., 2012), but inonly 0.8% of non-neoplastic cases in the FT (Seidman etal., 2016). These data suggest that the TP53 mutationclosely associated with the BRCA1/2 mutation in high-grade pelvic serous carcinogenic sequences. The p53Ssof the FT also showed a high rate of p53 mutations (Leeet al., 2007). However, p53S was reported to be equallyprevalent in the FTs of BRCA mutation carriers andcontrols, with no particular association with age (Mehraet al., 2011).

The most common somatic mutations in USC wereTP53, PIK3CA, FBXW7 and PPP2R1A (Cancer GenomeAtlas Research Network et al., 2013). Although theassociation between germline BRCA1/2 and thedevelopment of USC is still controversial, genomicchanges in BRCA1/2 were rare in USC (Cancer GenomeAtlas Research Network et al., 2013). Two of four p53Ss


Fig. 6. A proposed model for endometrial carcinogenesis.

in the benign endometrial polyps showed TP53mutations according to a DNA sequence analysis (Sho etal., 2016). Sixteen (42%) of the 38 samples of p53Ssshowed at least 1 TP53 mutation from 8 uteri with eitherUSC or SEIC (Zhang et al., 2009). The decline in thep53 functions with age, along with the accumulation ofgenomic alterations, including TP53 mutations, may beone reason why USCs occur in only a small portion ofolder individuals. Although the rate of point mutations intumors is similar to that of normal cells, the rate ofchromosomal changes in cancer is elevated. Cancer cellscan survive such chromosome aberrations more easilythan normal cells because they contain mutations thatincapacitate genes like TP53 (Vogelstein et al., 2013).Systematic sequencing studies of normal tissues havealso provided clues regarding the evolution from normaltissues to cancers. Half or more of the somatic mutationsin certain tumors of self-renewing tissues are estimatedto occur before the onset of neoplasia (Tomasetti et al.,2013). Martincorena and Campbell (2015) said that thestudy of established cancers has provided many cluesabout the temporal evolution of cancers, but many gapsin our understanding remain. The age-related decline inthe functions for maintaining homeostasis of humancells may be a clue to resolving the gap betweengenomic features of established cancers and normaltissues. Conclusions

We herein propose an age-related type ofendometrial cancer, instead of Type II estrogen-independent endometrial cancer, based on the currentstate of knowledge regarding the association betweenage and cancer. High-throughput DNA sequencing hasenabled the systematic sequencing of more than 10,000cancer exomes and 2,500 whole cancer genomes(Martincorena and Cambell, 2015), however, we shouldfocus more on the age-related decline in the functionsfor maintaining homeostasis in normal human cells inorder to understand the process by which normal cellstransform to invasive carcinomas.Acknowledgments. The author is grateful to Dr. Norio Wake for hiscritical review of the manuscript.

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Accepted March 22, 2018


Review Aging and uterine serous carcinoma

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