Whence epithelial ovarian carcinoma?
3
Editorial Whence epithelial ovarian carcinoma? Among common malignancies, epithelial ovarian carci- noma (EOC) remains enigmatic in at least two important respects. First, the histologic region of origin for this cancer remains obscure and second, an identifiable premalignant or precursor lesion that is generally recognized by cancer pathologists is yet to be defined. This state of uncertainty is particularly problematic since the majority of these cancers are diagnosed at an advanced stage, leading directly to the high mortality to incidence ratio associated with EOC, which accounts for more deaths than all other gynecologic malignancies combined [1]. The good prognosis for patients with disease confined to the ovary suggests that early detection could lessen mortality substantially. The use of serum CA-125 measurements and radiologic technology, alone or in combination, has yet to prove effective in either the high risk or general populations [2], although the detection of diagnostic serum proteomic patterns or biomarker panels [3,4] holds promise in this context. In the genetically predisposed population, prophylactic bilateral salpingo-ophor- ectomy is a highly effective preventive measure, but is not without morbidity, side effects, and a residual risk of pelvic malignancy [5]. Development of optimal primary and secondary prevention strategies for EOC in the high-risk and general populations would, presumably, be greatly facilitated by an improved understanding of its early natural history. Theories on the histologic origin of EOC have recently undergone a dramatic transformation. Historically, the notion that the epithelial component of the ovary gives rise to the common histologic variants of EOC has gained wide accep- tance, with the major debate related to whether tumorigenesis begins in the single-cell layer of the surface epithelium or in architectural aberrations thereof. Examples of the latter include surface epithelial-lined clefts and cortical inclusion cysts, thought to result from post-ovulatory wound repair, tissue remodeling associated with pregnancy or aging, paraovarian adhesions, or simply the dynamic interaction between surface epithelium and underlying stroma [6–8]. A related literature exists as to whether these morphologic alterations of surface epithelium are more prevalent in the ovaries of women who have developed ovarian cancer or are at high genetic risk for ovarian cancer; a clear consensus does not exist in either case. Alternatively, Dubeau theorizes that ovarian carcinoma may arise in components of the secondary mullerian system, such as rete ovarii, paraovarian or paratubal cysts, endosal- pingiosis, endometriosis, or endomucinosis, located within, or adjacent to the ovary [9]. This hypothesis is supported through recognition that some fraction of clear cell and endometrioid “EOCs” arise in endometriotic implants in the ovary. In addition, the ovarian surface epithelium is actually a modified mesothelium, contiguous with and morphologically resembling the peritoneal mesothelial lining. Typical EOCs, however, are readily distinguishable from the rare primary ovarian mesothelioma [10], and instead resemble carcinomas arising in true mullerian-derived tissues such as the fallopian tube, endometrium, and endocervix [11], suggesting the requirement for a metaplastic process if EOCs do in fact arise from the ovarian mesothelium. The second question, that is whether an identifiable precursor lesion exists for EOC, is compounded by the uncertainty regarding its histologic origin, and the fact that most EOCs are of advanced stage and associated with little or no evidence of preinvasive or normal epithelium at the time of pathological diagnosis. Candidate precursor lesions include dysplasia [12], hyperplasia [13], and more subtle alterations involving cellular or nuclear atypia [14,15]. An argument for the development of EOC “de novo”, in the absence of any intermediate precursor lesion, has also been presented [16]. While tumors of low malignant potential and common benign ovarian tumors have traditionally been viewed with great skepticism as precursors for invasive EOC, this dogma is subject to challenge. Tumors of low malignant potential are now considered possible precursors for one class of EOC (see below). From a purely statistical epidemiologic perspective, it is difficult to rule out the potential role of benign ovarian tumors, in light of their prevalence, in the pathogenesis of some fraction of EOCs; molecular genetic analyses support a possible association [17]. The advent of molecular biological and genetic insights, coupled with more sophisticated laboratory technologies, have begun to allow for the study of this problem at a level beyond that of the purely morphologic, another example being the observation of loss of heterozygosity at the BRCA1 and TP53 loci in an ovarian “carcinoma in situ” lesion from a BRCA1 mutation carrier [18]. While molecular genetic coupled with morphologic analyses will continue to drive research related to these two questions as they pertain to the more traditional models of ovarian tumorigenesis, recent observations on two fronts have Available online at www.sciencedirect.com Gynecologic Oncology 109 (2008) 161 – 163 www.elsevier.com/locate/ygyno 0090-8258/$ - see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2008.03.016
Transcript of Whence epithelial ovarian carcinoma?
Available online at www.sciencedirect.com
Gynecologic Oncology 109 (2008) 161–163www.elsevier.com/locate/ygyno
Editorial
Whence epithelial ovarian carcinoma?
Among common malignancies, epithelial ovarian carci-noma (EOC) remains enigmatic in at least two importantrespects. First, the histologic region of origin for this cancerremains obscure and second, an identifiable premalignant orprecursor lesion that is generally recognized by cancerpathologists is yet to be defined. This state of uncertainty isparticularly problematic since the majority of these cancersare diagnosed at an advanced stage, leading directly to thehigh mortality to incidence ratio associated with EOC, whichaccounts for more deaths than all other gynecologicmalignancies combined [1]. The good prognosis for patientswith disease confined to the ovary suggests that earlydetection could lessen mortality substantially. The use ofserum CA-125 measurements and radiologic technology,alone or in combination, has yet to prove effective in eitherthe high risk or general populations [2], although thedetection of diagnostic serum proteomic patterns or biomarkerpanels [3,4] holds promise in this context. In the geneticallypredisposed population, prophylactic bilateral salpingo-ophor-ectomy is a highly effective preventive measure, but is notwithout morbidity, side effects, and a residual risk of pelvicmalignancy [5]. Development of optimal primary andsecondary prevention strategies for EOC in the high-riskand general populations would, presumably, be greatlyfacilitated by an improved understanding of its early naturalhistory.
Theories on the histologic origin of EOC have recentlyundergone a dramatic transformation. Historically, the notionthat the epithelial component of the ovary gives rise to thecommon histologic variants of EOC has gained wide accep-tance, with the major debate related to whether tumorigenesisbegins in the single-cell layer of the surface epithelium or inarchitectural aberrations thereof. Examples of the latter includesurface epithelial-lined clefts and cortical inclusion cysts,thought to result from post-ovulatory wound repair, tissueremodeling associated with pregnancy or aging, paraovarianadhesions, or simply the dynamic interaction between surfaceepithelium and underlying stroma [6–8]. A related literatureexists as to whether these morphologic alterations of surfaceepithelium are more prevalent in the ovaries of women whohave developed ovarian cancer or are at high genetic risk forovarian cancer; a clear consensus does not exist in either case.
Alternatively, Dubeau theorizes that ovarian carcinomamay arise in components of the secondary mullerian system,
0090-8258/$ - see front matter © 2008 Elsevier Inc. All rights reserved.doi:10.1016/j.ygyno.2008.03.016
such as rete ovarii, paraovarian or paratubal cysts, endosal-pingiosis, endometriosis, or endomucinosis, located within, oradjacent to the ovary [9]. This hypothesis is supportedthrough recognition that some fraction of clear cell andendometrioid “EOCs” arise in endometriotic implants in theovary. In addition, the ovarian surface epithelium is actually amodified mesothelium, contiguous with and morphologicallyresembling the peritoneal mesothelial lining. Typical EOCs,however, are readily distinguishable from the rare primaryovarian mesothelioma [10], and instead resemble carcinomasarising in true mullerian-derived tissues such as the fallopiantube, endometrium, and endocervix [11], suggesting therequirement for a metaplastic process if EOCs do in factarise from the ovarian mesothelium.
The second question, that is whether an identifiableprecursor lesion exists for EOC, is compounded by theuncertainty regarding its histologic origin, and the fact thatmost EOCs are of advanced stage and associated with little orno evidence of preinvasive or normal epithelium at the time ofpathological diagnosis. Candidate precursor lesions includedysplasia [12], hyperplasia [13], and more subtle alterationsinvolving cellular or nuclear atypia [14,15]. An argument for thedevelopment of EOC “de novo”, in the absence of anyintermediate precursor lesion, has also been presented [16].While tumors of low malignant potential and common benignovarian tumors have traditionally been viewed with greatskepticism as precursors for invasive EOC, this dogma issubject to challenge. Tumors of low malignant potential are nowconsidered possible precursors for one class of EOC (seebelow). From a purely statistical epidemiologic perspective, it isdifficult to rule out the potential role of benign ovarian tumors,in light of their prevalence, in the pathogenesis of some fractionof EOCs; molecular genetic analyses support a possibleassociation [17]. The advent of molecular biological andgenetic insights, coupled with more sophisticated laboratorytechnologies, have begun to allow for the study of this problemat a level beyond that of the purely morphologic, anotherexample being the observation of loss of heterozygosity at theBRCA1 and TP53 loci in an ovarian “carcinoma in situ” lesionfrom a BRCA1 mutation carrier [18].
While molecular genetic coupled with morphologicanalyses will continue to drive research related to these twoquestions as they pertain to the more traditional models ofovarian tumorigenesis, recent observations on two fronts have
162 Editorial
prompted reconsideration of existing paradigms. The first lineof research posits that, somewhat analogous to endometrialcarcinoma, there are two types of EOC [19–21]. This modelholds that type I tumors, consisting of low-grade serouscarcinomas, mucinous, endometrioid, and clear cell carcino-mas, and malignant Brenner tumors, may arise in a stepwisefashion from tumors of low malignant potential. Type IItumors consist of high-grade serous carcinomas, carcinosar-comas, and undifferentiated carcinomas, and a putativeprecursor lesion for this type of cancer remains unidentified.Furthermore, distinct molecular genetic alterations tend tosegregate with one or the other type of EOC.
A paper in this issue of the Journal by Crum andcollaborators spotlights a more radical departure fromtraditional models of ovarian tumorigenesis in which emer-ging evidence suggests that type II (high-grade serous) EOCsare perhaps not ovarian cancers at all, but rather originate inthe fallopian tube [22, and references therein]. This hypoth-esis was perhaps first developed by Piek and colleagues, afterobserving a high incidence of dysplastic morphologic, andpreneoplastic molecular alterations in prophylacticallyremoved fallopian tubes from women with BRCA-linkedgenetic predisposition to EOC [23], followed by theirsupporting literature review on this topic [24]. Subsequently,a number of research groups have reported on the strikingprevalence of histopathologic and/or molecular geneticalterations observed in fallopian tubes from women harboringBRCA mutations who have undergone prophylactic surgery orovarian cancer surgery. The accumulated body of clinico-pathologic- and laboratory-based evidence now demandsserious consideration of this model for the pathogenesis ofat least some type II EOCs.
The paper by Folkins et al. [22] builds on previouswork from this group [25] in which strong p53 immunos-taining, termed a “p53 signature”, was identified in benigntubal mucosa from BRCA mutation carriers and fromwomen not known to be at genetic risk (controls). Notably,these p53 signatures predominated in the tubal fimbriaewere highly associated with TP53 mutations, especially inregions of tubal intraepithelial carcinoma (TIC), colocalizedwith expression of the DNA damage-response gene γ-H2AX, and most importantly, the TP53 mutations wereidentical in TIC and their associated EOCs. This workexemplifies the power of traditional morphologic analysiscombined with laser capture microdissection of selectedcells followed by genetic analysis. Using this approach, itis no longer necessary to infer the potential pathogenicrelationship between various potential precursor and malig-nant lesions; clonal relationships may be proven throughgenetic identity.
In their current work (22), Crum and colleagues use similartechniques applied to an expanded series of ovaries andfallopian tubes removed prophylactically from women withgermline BRCA mutations. The subtle novelty of this study wasthe examination of ovarian cortical inclusion cysts for thepresence of the p53 signature. Although the p53 expressionsignature (mutations were not examined) coupled with γ-H2AX
expression was frequently observed in benign appearingsalpingeal epithelium, more common in the fimbriated end,no such abnormalities were identified in the correspondingovaries. Tissues from women not known to carry BRCAmutations were not examined, however.
While compelling, these and previous data pertaining tothe “tubal model” of type II EOC pathogenesis remainsubject to the proverbial chicken or egg problem. Such adramatic paradigm shift requires clearance of the metapho-rical high bar. Several issues or questions relevant to thisburden of proof may be posed, and while to many, theanswers may seem self-evident, additional data are manda-tory. Why is the incidence of primary tubal cancersignificantly less than that of EOC? Much of the datasupporting this tubal model of EOC are derived from tissuesobtained from BRCA heterozygotes; is the tubal model morerelevant to this population? A very high proportion of thetubal abnormalities observed in this context are described as“TIC” or “carcinoma in situ”; is it possible that many ormost of these lesions would never have progressed toinvasive carcinoma, and thus would not have beendiscovered in the absence of prophylactic surgery or ovariancancer surgery? Even when coexisting with EOC harboringidentical genetic mutations, is it not possible that the EOCseeded the non-invasive tubal entity?
As these and other issues are addressed and eventuallyresolved (would not it be satisfying to explain why tuballigation lowers the risk of EOC?), the Crum group and otherscontributing to this novel hypothesis are to be commended fortheir innovative, thoughtful, and rigorous scientific contributionto the field, providing a breath of fresh air into the considerationof a biological problem that had become rather stale andseemingly intractable. The disease responsible for the majorityof gynecologic cancer deaths deserves no less.
References
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Jeff BoydCurtis & Elizabeth Anderson Cancer Institute,
Memorial University Medical Center, 4700 Waters Ave.,Savannah, GA 31404, USA
E-mail address: [email protected]: +1 912 350 1269.
