Ovarian Tumors of Low Malignant Potential

The article by Trimble andTrimble nicely summarizes thestate of knowledge on ovariantumors of low malignant potential(LMP) and underscores the fact thatgaps in that knowledge have led toconfusion and controversy regardingseveral issues related to these interestingneoplasms. Many of these controversiescan be characterized as debatesbetween the "lumpers" and the "splitters."The Johns Hopkins group haslong been at the forefront of researchon ovarian LMP tumors. In this review,I will attempt to place some of theauthors'comments into perspectiveand, at times, present a different pointof view.Classification, Nomenclature,and Molecular Biology
Since the original description of"semimalignant tumors" by Taylor in1929, no consensus has been reachedabout the nomenclature for ovarianLMP tumors.[1] Although we havegenerally used the term "borderline"in numerous publications, it has beenused simply because it is less cumbersomethan "tumor of low malignantpotential." However, I actually preferthe latter. I totally agree with theTrimbles that the term "borderline"sends the wrong message-that thetumor is intermediate between benignand malignant. Most of the molecularbiology studies of these tumorsstrongly suggest that they are quitedistinct from frankly malignant ovariancancers and have a very differentpathogenesis.On the other hand, I strongly disagreewith the use of the term "atypicalproliferating tumors," which hasbeen advanced by the Johns Hopkinsgroup to imply that these tumors almostalways behave in a benign fashion.This paradigm fundamentally fitsthe biology associated with stage ILMP tumors but breaks down whenone considers stage II-IV tumors. TheTrimbles suggest that peritoneal implantsassociated with ovarian LMPtumors, particularly invasive peritonealimplants, are, in fact, primaryperitoneal cancers and not somehowrelated to the primary ovarian tumor.However, this statement is speculativeand not clearly supported by molecularand genetic data. I do agree, however,that the ultimate answer to thesetypes of theories will emerge from further molecular and clonal investigations The Trimbles also briefly discussthe introduction of the term "micropapillary,"which designates a proliferativehistopathologic pattern distinctfrom the typical serous borderline pattern.The Johns Hopkins group hasproposed that so-called micropapillaryserous carcinomas be split from tumorswith the typical serous borderlinepattern,[2] but, as mentioned intheir article, this "splitting" has notbeen universally accepted by eitherthe gynecologic pathology communityor the gynecologic oncologycommunity. In fact, most prominentgynecologic pathology groups haveadvocated maintaining the micropapillarypattern as a subset of serousLMP tumors based on their clinicopathologicfindings.[3-5]Surgical Management Issues
Because of the imprecise clinicalfindings associated with ovarian LMPtumors, general obstetrician/gynecologists(rather than gynecologiconcologists) are more likely to encounterthese neoplasms while operating foran adnexal mass. Approximately 50%of serous tumors and 80% to 90% ofmucinous LMP tumors are confined toone ovary at diagnosis. Therefore, in ahigh proportion of these patients whohave not completed childbearing, fertility-sparing surgery-ovarian cystectomy,unilateral salpingo-oophorectomy,or some combination thereof-is feasible and highly desirable.After resection of the ovariantumor(s), a frozen-section examinationis recommended, whenever possible.Most expert gynecologic pathologistsshould be able to diagnoseserous ovarian LMP tumors, but mucinoustumors are more problematic.I agree with the Trimbles that manypathologists may be able to state onlythat the tumor is "at least LMP." Thediagnosis of either an ovarian LMPtumor or a frankly malignant tumor onfrozen section has implications forcomprehensive surgical staging.The issue of surgical staging is alsocontroversial, even among expert gynecologiconcologists. Because thesetumors, particularly those that arestage I, are associated with an excellentprognosis, and because no evidencesuggests that postoperativetreatment is warranted, some advocatethat surgical staging is unnecessary.However, I would submit that comprehensivesurgical staging is indicatedwhen an ovarian LMP tumor isdiagnosed, for the following reasons:(1) The information gained will furtherelucidate the biologic behavior ofthese tumors; (2) precise staging informationwill allow patients and theirfamilies to better understand theirprognosis, because the risk of recurrenceand death is higher in patientswith extraovarian spread; (3) in somecases in which frozen-section examinationsuggests the diagnosis of anovarian LMP tumor, the final diagnosiswill indicate invasive ovarian cancer.In addition, once effective therapyfor advanced-stage ovarian LMPtumors has been developed, therewill be even more compelling reasonsto justify comprehensive surgicalstaging.Postoperative Therapy, Prognosis,and Use of Biomarkers
The Trimbles are correct-no postoperativetherapy has been shown to beeffective in reducing the relapse rate orimproving survival in women with advanced-stage disease. However, essentiallyall of these studies are retrospective,and many suffer from small numbers.Approximately 30% of womenwith serous tumors have disease spreadbeyond the ovary in the form of peritonealimplants. In reported studies, approximately18% of patients withnoninvasive peritoneal implants relapse,and approximately 6% have died of tumor.[2,6-14] Among patients with invasiveperitoneal implants, approximately36% relapse, and 25% have diedof tumor.[2,6-12,14,15]Zanetta and colleagues have suggestedthat the prognosis of patientswith advanced-stage tumors may bebetter than previously reported.[14]However, longer follow-up may benecessary to demonstrate relapse ratesreflected in the prior studies, particularlythe M. D. Anderson series.[13,15]The studies from M. D. Anderson indicatethat, of all patients who relapse,approximately 75% have low-gradeserous carcinomas, and 25% have recurrentLMP tumors.[16]Several clinical or clinicopathologicfactors appear to be prognostic.These include FIGO stage, age at diagnosis,and residual disease atcompletion of primary surgery. Althoughseveral biomarkers-DNAploidy, p53 overexpression, K-ras, andso forth-have been studied in an effortto identify patients at high risk ofrelapse, none have been validated inprospective trials.The Trimbles' contention that socalledrecurrent LMP tumors representeither a primary peritoneal cancermissed at initial diagnosis or a newovarian or primary peritoneal canceris, once again, speculative. They maybe correct, but the data are thus farinconclusive. The molecular biologyof this phenomenon has not yet beenresolved. Although studies of ovarianLMP tumors and their peritoneal implantssuggest multifocality orpolyclonality rather than monoclonality,the numbers of patients inthese studies were small and the techniquesused were few.[17,18] In addition,mutational analysis of advancedstageserous LMP tumors that subsequently"recurred" suggested a secondprimary tumor rather than a true recurrence.[19] Further study is clearlyindicated.Future Directions
Future research that will allow usto bridge the gaps in our knowledgeof ovarian LMP tumors should focuson the following: (1) causative factorsin the pathogenesis of these tumors;(2) the value of comprehensive surgicalstaging; (3) elucidation of clinical,pathologic, and molecular predictiveand prognostic factors to select patientswho are at high risk of relapseand who may benefit from postoperativetherapy; (4) a search for more effectivesystemic therapies for advanced-stage tumors and for subsequentlow-grade serous carcinomas;(5) the role of microinvasion andmicropapillary pattern in prognosisand in determining optimal treatment;and (6) the clonality of the primary ovarian tumors, their peritoneal implants,and subsequent low-grade carcinomas.Such information will beginto blur the differences between the"splitters" and the "lumpers."

Disclosures:

The author(s) have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1.

Taylor HC: Malignant and semimalignanttumors of the ovary. Surg Gynecol Obstet48:204-230, 1929.

2.

Seidman JD, Kurman RJ: Subclassificationof serous borderline tumors of the ovaryinto benign and malignant types: A clinicopathologicstudy of 65 advanced stage cases.Am J Surg Pathol 20:1331-1345, 1996.

3.

Eichhorn JH, Bell DA, Young RH, et al:Ovarian serous borderline tumors withmicropapillary and cribiform patterns: A studyof 40 cases and comparison with 44 cases withoutthese patterns. Am J Surg Pathol 23:397-409, 1999.

4.

Deavers MT, Tortolero-Luna G, MalpicaA, et al: Micropapillary and cribiform patternsand microinvasion in ovarian serous borderlinetumors (SBT): A study of 99 advanced stagecases. Society of Gynecologic Oncology (abstract).Gynecol Oncol 26:280, 2000.

5.

Kempson RL, Hendrickson MR: Ovarianserous borderline tumors: The citadel defended.Hum Pathol 31:525-526, 2000.

6.

Kliman L, Rome RM, Fortune DW: Lowmalignant potential tumors of the ovary: A studyof 76 cases. Obstet Gynecol 68:338-344, 1986.

7.

Manchul LA, Simm J, Levin W, et al:Borderline epithelial ovarian tumors: A reviewof 81 cases with an assessment of the impactof treatment. Int J Radiat Oncol Biol Phys22:867-874, 1992.

8.

Russell P: Borderline epithelial tumoursof the ovary: A conceptual dilemma. ClinObstet Gynaecol 11:259-277, 1984.

9.

Michael H, Roth LM: Invasive andnoninvasive implants in ovarian serous tumorsof low malignant potential. Cancer 57:1240-1247, 1986.

10.

McCaughey WT, Kirk ME, Lester W, etal: Peritoneal epithelial lesions associated withproliferative serous tumours of ovary. Histopathology8:195-208, 1984.

11.

Bell DA, Weinstock MA, Scully RE:Peritoneal implants of ovarian serous borderlinetumors: Histologic features and prognosis.Cancer 62:2212-2222, 1988.

12.

de Nictolis M, Montironi R, TommasoniS, et al: Serous borderline tumors of the ovary:A clinicopathologic, immunohistochemical,and quantitative study of 44 cases. Cancer70:152-160, 1992.

13.

Gershenson DM, Silva EG, Tortolero-Luna G, et al: Ovarian serous borderline tumorswith noninvasive peritoneal implants.Cancer 83:2157-2163, 1998.

14.

Zanetta G, Rota S, Chiari S, et al: Behaviorof borderline tumors with particular interestto persistence, recurrence, and progressionto invasive carcinoma: A prospective study.J Clin Oncol 19:2658-2664, 2001.

15.

Gershenson DM, Silva EG, Levy L, etal: Ovarian serous borderline tumors with invasiveperitoneal implants. Cancer 82:1096-1103, 1998.

16.

Crispens MA, Bodurka D, Deavers M,et al: Response and survival in patients withprogressive or recurrent serous ovarian tumorsof low malignant potential. Obstet Gynecol99:3-10, 2002.

17.

Lu KH, Bell DA, Welch WR, et al: Evidencefor the multifocal origin of bilateral andadvanced human serous borderline ovarian tumors.Cancer Res 58:2328-2330, 1998.

18.

Gu J, Roth LM, Younger C, et al: Molecularevidence for the independent origin ofextra-ovarian papillary serous tumors of lowmalignant potential. J Natl Cancer Inst93:1147-1152, 2001.

19.

Ortiz BH, Ailawadi M, Colitti C, et al:Second primary or recurrence? Comparativepatterns of p53 and K-ras mutations suggestthat serous borderline ovarian tumors and subsequentserous carcinomas are unrelated tumors.Cancer Res 61:7264-7267, 2001.